GENETIC SUSCEPTIBILITY VARIANTS ASSOCIATED WITH CARDIOVASCULAR DISEASE

Abstract

The invention relates to methods of diagnosing susceptibility to cardiovascular disease, including coronary artery disease, MI, abdominal aorta aneurysm, intracranial aneurysm restenosis and peripheral arterial disease, by assessing the presence or absence of alleles of certain polymorphic markers found to be associated with cardiovascular disease. The invention further relates to kits encompassing reagents for assessing such markers, and methods for assessing the probability of response to therapeutic agents and methods using such markers.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No. 12/302,538, which is the U.S. national phase of International Application No. PCT/IS2008/000007, filed Feb. 21, 2008, which is incorporated herein by reference in its entirety, which claims priority benefit of Iceland Application No. 8613 filed Feb. 21, 2007, Iceland Application No. 8640 filed Apr. 30, 2007 and Iceland Application No. 8701 filed Dec. 21, 2007.

BACKGROUND OF THE INVENTION

Coronary Artery Disease and Myocardial Infarction

[0002] The major complications of Coronary Artery Disease, i.e. Myocardial infarction (MI) and Acute Coronary Syndrome (ACS), are the leading causes of hospital admissions in industrialized countries. Cardiovascular disease continues to be the principle cause of death in the United States, Europe and Japan. The costs of the disease are high both in terms of morbidity and mortality, as well as in terms of the financial burden on health care systems.

[0003] Myocardial infarction generally occurs when there is an abrupt decrease in coronary blood flow following a thrombotic occlusion of a coronary artery previously damaged by atherosclerosis (i.e. in subjects with coronary artery disease). In most cases, infarction occurs when an atherosclerotic plaque fissures, ruptures or ulcerates and when conditions favor thrombogenesis. In rare cases, infarction may be due to coronary artery occlusion caused by coronary emboli, congenital abnormalities, coronary spasm, and a wide variety of systemic, particularly inflammatory diseases. Medical risk factors for MI include cigarette smoking, diabetes, hypertension and serum total cholesterol levels >200 mg/dL, elevated serum LDL cholesterol, and low serum HDL cholesterol. Event rates in individuals without a prior history of cardiovascular disease are about 1%. In individuals who have had a first MI or ACS, the risk of a repeat MI within the next year is 10-14%, despite maximal medical management including angioplasty and stent placement.

[0004] Atherosclerosis can affect vascular beds in many large and medium arteries. Myocardial infarction and unstable angina (acute coronary syndrome (ACS)) stem from coronary artery atherosclerosis (Coronary Artery Disease), while ischemic stroke most frequently is a consequence of carotid or cerebral artery atherosclerosis. Limb ischemia caused by peripheral arterial occlusive disease (PAOD) may occur as a consequence of iliac, femoral and popliteal artery atherosclerosis. The atherosclerotic diseases remain common despite the wide-spread use of medications that inhibit thrombosis (aspirin) or treat medical risk factors such as elevated cholesterol levels in blood (statins), diabetes, or hypertension (diuretics and anti-hypertensives).

[0005] Atherosclerotic disease is initiated by the accumulation of lipids within the artery wall, and in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. The trapped LDL becomes oxidized and internalized by macrophages. This causes the formation of atherosclerotic lesions containing accumulations of cholesterol-engorged macrophages, referred to as "foam cells". As disease progresses, smooth muscle cells proliferate and grow into the artery wall forming a "fibrous cap" of extracellular matrix enclosing a lipid-rich, necrotic core. Present in the arterial walls of most people throughout their lifetimes, fibrous atherosclerotic plaques are relatively stable. Such fibrous lesions cause extensive remodeling of the arterial wall, outwardly displacing the external, elastic membrane, without reduction in luminal diameter or serious impact on delivery of oxygen to the heart. Accordingly, patients can develop large, fibrous atherosclerotic lesions without luminal narrowing until late in the disease process. However, the coronary arterial lumen can become gradually narrowed over time and in some cases compromise blood flow to the heart, especially under high demand states such as exercise. This can result in reversible ischemia causing chest pain relieved by rest called stable angina.

[0006] In contrast to the relative stability of fibrous atherosclerotic lesions, the culprit lesions associated with myocardial infarction and unstable angina (each of which are part of the acute coronary syndrome) are characterized by a thin fibrous cap, a large lipid core, and infiltration of inflammatory cells such as T-lymphocytes and monocyte/macrophages. Non-invasive imaging techniques have shown that most MI's occur at sites with low- or intermediate-grade stenoses, indicating that coronary artery occlusion is due most frequently to rupture of culprit lesions with consequent formation of a thrombus or blood clot and not solely due to luminal narrowing by stenosis. Plaque rupture may be due to erosion or uneven thinning of the fibrous cap, usually at the margins of the lesion where macrophages enter, accumulate, and become activated by a local inflammatory process. Thinning of the fibrous cap may result from degradation of the extracellular matrix by proteases released from activated macrophages. These changes producing plaque instability and risk of MI may be augmented by production of tissue-factor procoagulant and other factors increasing the likelihood of thrombosis.

[0007] In acute coronary syndrome, the culprit lesion showing rupture or erosion with local thrombosis typically is treated by angioplasty or by balloon dilation and placement of a stent to maintain luminal patency. Patients experiencing ACS are at high risk for a second coronary event due to the multi-vessel nature of coronary artery disease with event rates approaching 10-14% within 12 months after the first incident.

[0008] The emerging view of MI is as an inflammatory disease of the arterial vessel wall on preexisting chronic atherosclerotic lesions, sometimes triggering rupture of culprit lesions and leading to local thrombosis and subsequent myocardial infarction. The process that triggers and sustains arterial wall inflammation leading to plaque instability is unknown, however, it results in the release into the circulation of tumor necrosis factor alpha and interleukin-6. These and other cytokines or biological mediators released from the damaged vessel wall stimulate an inflammatory response in the liver causing elevation in several non-specific general inflammatory markers including C-reactive protein. Although not specific to atherosclerosis, elevated C-reactive protein (CRP) and serum amyloid A appear to predict risk for MI, perhaps as surrogates for vessel wall inflammation. Many general inflammatory markers predict risk of coronary heart disease, although these markers are not specific to atherosclerosis. For example, Stein (Stein, S., Am J Cardiol, 87 (suppl):21A-26A (2001)) discusses the use of any one of the following serum inflammatory markers as surrogates for predicting risk of coronary heart disease including C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, and matrix metalloprotease type-9. Elevation in one more of these serum inflammatory markers is not specific to coronary heart disease but also occurs with age or in association with cerebrovascular disease, peripheral vascular disease, non-insulin dependent diabetes, osteoarthritis, bacterial infection, and sepsis.

[0009] Elevated CRP or other serum inflammatory markers is also prognostic for increased risk of a second myocardial infarct in patients with a previous myocardial infarct (Retterstol, L. et al., Atheroscler., 160: 433-440 (2002)).

[0010] Although classical risk factors such as smoking, hyperlipidemia, hypertension, and diabetes are associated with many cases of coronary heart disease (CHD) and MI, many patients do not have involvement of these risk factors. In fact, many patients who exhibit one or more of these risk factors do not develop MI. Family history has long been recognized as one of the major risk factors. Although some of the familial clustering of MI reflects the genetic contribution to the other conventional risk factors, a large number of studies have suggested that there are significant genetic susceptibility factors, beyond those of the known risk factors (Friedlander Y, et al., Br. Heart J. 1985; 53:382-7, Shea S. et al., J. Am. Coll. Cardiol. 1984; 4:793-801, and Hopkins P. N., et al., Am. J. Cardiol. 1988; 62:703-7). Major genetic susceptibility factors have only been identified for the rare Mendelian forms of hyperlipidemia such as a familial hypercholesterolemia.

[0011] Genetic risk is conferred by subtle differences in genes among individuals in a population. Genes differ between individuals most frequently due to single nucleotide polymorphisms (SNP), although other variations are also important. SNP are located on average every 1000 base pairs in the human genome. Accordingly, a typical human gene containing 250,000 base pairs may contain 250 different SNP. Only a minor number of SNPs are located in exons and alter the amino acid sequence of the protein encoded by the gene. Most SNPs may have little or no effect on gene function, while others may alter transcription, splicing, translation, or stability of the mRNA encoded by the gene. Additional genetic polymorphism in the human genome is caused by insertion, deletion, translocation, or inversion of either short or long stretches of DNA. Genetic polymorphisms conferring disease risk may therefore directly alter the amino acid sequence of proteins, may increase the amount of protein produced from the gene, or may decrease the amount of protein produced by the gene.

[0012] As genetic polymorphisms conferring risk of disease are uncovered, genetic testing for such risk factors is becoming important for clinical medicine. Examples are apolipoprotein E testing to identify genetic carriers of the apoE4 polymorphism in dementia patients for the differential diagnosis of Alzheimer's disease, and of Factor V Leiden testing for predisposition to deep venous thrombosis. More importantly, in the treatment of cancer, diagnosis of genetic variants in tumor cells is used for the selection of the most appropriate treatment regime for the individual patient. In breast cancer, genetic variation in estrogen receptor expression or heregulin type 2 (Her2) receptor tyrosine kinase expression determine if anti-estrogenic drugs (tamoxifen) or anti-Her2 antibody (Herceptin) will be incorporated into the treatment plan. In chronic myeloid leukemia (CML) diagnosis of the Philadelphia chromosome genetic translocation fusing the genes encoding the Bcr and Abl receptor tyrosine kinases indicates that Gleevec (STI571), a specific inhibitor of the Bcr-Abl kinase should be used for treatment of the cancer. For CML patients with such a genetic alteration, inhibition of the Bcr-Abl kinase leads to rapid elimination of the tumor cells and remission from leukemia.

Restenosis

[0013] Coronary balloon angioplasty was introduced in the late 1970s as a less invasive method for revascularization of coronary artery disease patients than the coronary artery bypass graft (CABG) surgeries. Since then there has been a quick progress in the development of new percutaneous devices to revascularize areas with limited blood flow. However, the expanded use of angioplasty has shown that the arteries react to angioplasty by a proliferative process that limits the success of this treatment. This process is known as restenosis.

[0014] Restenosis is defined as a re-narrowing of the treated segment, which equals or exceeds 50% of the lumen in the adjacent normal segment of the artery. Depending on the patient population studied, the restenosis rates range from 30% to 44% of lesions treated by balloon dilation. This problem prompted a search for interventional techniques that minimizes the risk of restenosis. Several clinical trials have shown a significant reduction in the restenosis rates with endovascular stenting. The purpose of stenting is to maintain the arterial lumen by a scaffolding process that provides radial support. Stents, usually made of stainless steel, are placed in the artery either by a self-expanding mechanism or, using balloon expansion. However, in-stent restenosis still remains a major problem in the field of percutaneous, transluminal coronary angioplasty (PTCA), requiring patients to undergo repeated procedures and surgery. Restenosis is the result of the formation of neointima, a composition of smooth muscle-like cells in a collagen matrix. The current treatment modalities for in-stent restenosis include repeat balloon angioplasty, repeat stenting, cutting balloon angioplasty, directional coronary atherectomy, rotational coronary atherectomy, brachytherapy, and drug-eluting stents (DES). The restenosis problem can be minimised by local intravascular irradiation (intracoronary brachytherapy) and by the introduction of DES and these treatments have been shown to successfully preventing cell proliferation after stent implantation or angioplasty.

[0015] Intracoronary brachytherapy is a treatment in which sealed sources of radioactive material are used to deliver radiation at a very short distance by placing them in the artery lumen at the site of the atherosclerotic lesion. The physical benefit of brachytherapy is that doses of radiation can be delivered almost directly to the target with a very rapid falloff of dose to the surrounding normal tissue. The rationale underlining this modality is based on the ability of ionizing radiation to inhibit cell proliferation, in this case, the proliferation of smooth muscle cells that tend to form a neointima. In the near future, it would be important to be able to classify patients with respect to the risk of having in-stent restenosis. This classification can potentially be made on the basis of genetic risk factors. The outcome of the classification may determine which therapy is most appropriate and also where coronary bypass surgery has to be considered.

Aneurysms

[0016] Degenerative changes of the arterial wall may cause localized dilatation, or aneurysm, of the artery, including abdominal aorta aneurysm (AAA) and intracranial aneurysm (IA). Atherosclerotic changes of the vessel wall are found in the majority of AAA that are characterized histopathologically by chronic inflammation, destructive remodelling of elastic media and depletion of medial smooth muscle cells resulting in marked weakening of the aortic wall. In contrast, berry aneurysms of intracranial arteries are not associated with atherosclerosis. Furthermore, the histopathological features of IA are different. The typical berry aneurysms of intracranial arteries, located at arterial bifurcations, have a thin, or no, media and the internal elastic lamina is either absent or severely fragmented.

[0017] Both AAA and IA represent a degenerative process of the arteries leading to their enlargement that is usually asymptomatic with natural history culminating in either a therapeutic intervention or rupture. Rupture of IA leads to subarachnoid haemorrhage, and rupture of both IA and AAA have high morbidity and mortality. In the case of AAA the rupture risk increases with the growth rate as well as the size of the aneurysm.

[0018] Intracranial aneurysm (IA), also called cerebral aneurysm or brain aneurysm is a cerebrovascular disorder in which weakness in the wall of a cerebral artery or vein causes a localized dilation or ballooning of the blood vessel.

[0019] A common location of cerebral aneurysms is on the arteries at the base of the brain, known as the Circle of Willis. Approximately 85% of cerebral aneurysms develop in the anterior part of the Circle of Willis, and involve the internal carotid arteries and their major branches that supply the anterior and middle sections of the brain. It is believed that aneurysms may result from congenital defects, preexisting conditions such as high blood pressure and atherosclerosis, or head trauma. Cerebral aneurysms occur more commonly in adults than in children but they may occur at any age.

[0020] Cerebral aneurysms are classified both by size and shape. Small aneurysms have a diameter of less than 15 mm. Larger aneurysms include those classified as large (15 to 25 mm), giant (25 to 50 mm), and super giant (over 50 mm). Saccular aneurysms are those with a saccular outpouching and are the most common form of cerebral aneurysm. Berry aneurysms are saccular aneurysms with necks or stems resembling a berry. Fusiform aneurysms are aneurysms without stems.

[0021] A small, unchanging aneurysm will produce no symptoms. Before a larger aneurysm ruptures, the individual may experience such symptoms as a sudden and unusually severe headache, nausea, vision impairment, vomiting, and loss of consciousness, or the individual may be asymptomatic, experiencing no symptoms at all. Onset is usually sudden and without warning. Rupture of a cerebral aneurysm is dangerous and usually results in bleeding into the meninges or the brain itself, leading to a subarachnoid hemorrhage (SAH) or intracranial hematoma (ICH), either of which constitutes a stroke. Rebleeding, hydrocephalus (the excessive accumulation of cerebrospinal fluid), vasospasm (spasm, or narrowing, of the blood vessels), or multiple aneurysms may also occur. The risk of rupture from an unruptured cerebral aneurysm varies according to the size of an aneurysm, with the risk rising as the aneurysm size increases. The overall rate of aneurysm rupture is estimated at 1.3% per year. The risk of short term re-rupture increases dramatically after an aneurysm has bled, though after approximately 6 weeks the risk returns to baseline.

[0022] Emergency treatment for individuals with a ruptured cerebral aneurysm generally includes restoring deteriorating respiration and reducing intracranial pressure. Currently there are two treatment options for brain aneurysms: surgical clipping or endovascular coiling. Either surgical clipping or endovascular coiling is usually performed within the first three days to occlude the ruptured aneurysm and reduce the risk of rebleeding.

[0023] The prognosis for a patient with a ruptured cerebral aneurysm depends on the extent and location of the aneurysm, the person's age, general health, and neurological condition. Some individuals with a ruptured cerebral aneurysm die from the initial bleeding. Other individuals with cerebral aneurysm recover with little or no neurological deficit. The most significant factors in determining outcome are severity of the aneurysm and age.

[0024] Abdominal aortic aneurysm (AAA) is a localized dilatation of the abdominal aorta, that exceeds the normal diameter by more than 50%. The normal diameter of the infrarenal aorta is 2 cm. It is caused by a degenerative process of the aortic wall. The aneurysm is most commonly located infrarenally (90%), other possible locations are suprarenal and pararenal. The aneurysm can extend to include one or both of the iliac arteries. An aortic aneurysm may also occur in the thorax.

[0025] AAA is uncommon in individuals of African, African American, Asian, and Hispanic heritage. The frequency varies strongly between males and females. The peak incidence is among males around 70 years of age, the prevalence among males over 60 years totals 2-6%. The frequency is much higher in smokers than in non-smokers (8:1). Other risk factors include hypertension and male sex. In the US, the incidence of AAA is 2-4% in the adult population. Rupture of the AAA occurs in 1-3% of men aged 65 or more, the mortality being 70-95%.

[0026] The exact causes of the degenerative process remain unclear. Known risk factors include genetic factors, hemodynamic influences, atherosclerosis, and various other factors such as infection, trauma, connective tissue disorders, arteries, etc. AAAs are commonly divided according to their size and symptomatology. An aneurysm is usually considered to be present if the measured outer aortic diameter is over 3 cm (normal diameter of aorta is around 2 cm). The natural history is of increasing diameter over time, followed eventually by the development of symptoms (usually rupture). If the outer diameter exceeds 5 cm, the aneurysm is considered to be large. For aneurysms under 5 cm, the risk of rupture is low, so that the risks of surgery usually outweigh the risk of rupture. Aneurysms less than 5 cm are therefore usually kept under surveillance until such time as they become large enough to warrant repair, or develop symptoms. The vast majority of aneurysms are asymptomatic. The risk of rupture is high in a symptomatic aneurysm, which is therefore considered an indication for surgery. Possible symptoms include low back pain, flank pain, abdominal pain, groin pain or pulsating abdominal mass. The complications include rupture, peripheral embolisation, acute aortic occlusion, aortocaval or aortoduodenal fistulae. On physical examination, a palpable abdominal mass can be noted. Bruits can be present in case of renal or visceral arterial stenosis.

[0027] The main treatment options for asymptomatic AAA are immediate repair and surveillance with a view to eventual repair. Surveillance is indicated in small aneurysms, where the risk of repair exceeds the risk of rupture. As an AAA grows in diameter the risk of rupture increases. Although some controversy exists around the world, most vascular surgeons would not consider repair until the aneurysm reached a diameter of 5 cm. The threshold for repair varies slightly from individual to individual, depending on the balance of risks and benefits when considering repair versus ongoing surveillance. The size of an individual's native aorta may influence this, along with the presence of comorbidities that increase operative risk or decrease life expectancy. Currently, the main modes of repair available for an AAA are open aneurysm repair (OR), and endovascular aneurysm repair (EVAR). Open repair is indicated in young patients as an elective procedure, or in growing or large, symptomatic or ruptured aneurysms. Open repair has been the mainstay of intervention from the 1950's until recently. Endovascular repair first became practical in the 1990's and although it is now an established alternative to open repair, its role is yet to be clearly defined. It is generally indicated in older, high-risk patients or patients unfit for open repair. However, endovascular repair is feasible for only a proportion of AAA's, depending on the morphology of the aneurysm. The main advantage over open repair is that the perioperative period has less impact on the patient.

Stroke

[0028] Stroke is a group of diverse disorders encompassing several pathophysiological mechanisms. The clinical phenotype of stroke is complex but is broadly divided into: ischemic and hemorrhagic stroke. The majority of stroke events, appr 80%, is due to ischemia (cerebral infarction), that occurs when a cerebral artery becomes completely occluded and the blood supply to a part of the brain is totally or partially blocked (due to thrombosis or an embolism). Ischemic stroke is further subdivided into large artery disease (LAA) (also called large vessel disease, LVD), cardioembolic stroke and small vessel disease. Approximately 25% of ischemic stroke events are due to large-artery disease of the carotid and vertebral arteries, the two pairs of large arteries that supply the brain with blood. The most common cause of large-artery disease is atherosclerosis. Cardioembolic strokes are caused by an embolism that originates inside the heart. Embolism of cardiac origin accounts for about 1/4 of ischemic strokes. Strokes due to cardioembolism are in general severe and prone to early and long-term recurrence. Ischemic heart disease, rheumatic mitral stenosis, and prosthetic cardiac valves are major sources of cardioembolic stroke but atrial fibrillation remains the commonest cause.

[0029] There is a continued and great need to understand the genetic variants conferring risk (increased and decreased) of the cardiovascular diseases. The present invention provides genetic variants that have been shown to be associated with susceptibility to cardiovascular disease, including MI, Coronary Artery Disease (CAD), Intracranial aneurysm (IA), Abdominal Aorta Aneurysm (AAA), Peripheral Arterial Disease (PAD) and Restenosis. These variants are useful in risk management and methods for therapeutic intervention of cardiovascular diseases.

SUMMARY OF THE INVENTION

[0030] The present invention relates to methods of determining a susceptibility to cardiovascular diseases, including Coronary Artery Disease, Myocardial Infarction, Peripheral Artery Disease, Stroke, Restenosis, Intracranial Aneurysm and Abdominal Aorta Aneurysm. The invention also relates to various uses, kits, procedures and apparati useful in the determination of a susceptibility to cardiovascular disease based on evaluation of certain polymorphic markers and/or haplotypes that have been found to be associated with susceptibility to cardiovascular disease.

[0031] In one aspect, the invention relates to a method for determining a susceptibility to cardiovascular disease in a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual or in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 10, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to cardiovascular disease. The method may in one embodiment relate to determination of the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual. In another embodiment, the method relates to determination of the presence or absence of at least one allele of at least one polymorphic marker in a genotype dataset derived from the individual. The genotype dataset is derived from the individual in the sense that the information that is relates to a particular nucleic acid sample as a template relates to a single individual, for whom genetic information is derived.

[0032] In another aspect, the present invention relates to a method of determining a susceptibility to cardiovascular disease in a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from markers associated with LD Block C09 (SEQ ID NO:94), wherein determination of the presence or absence of the at least one allele is indicative of a susceptibility to cardiovascular disease. In one embodiment, the at least one polymorphic marker is selected from the markers set forth in Table 3, and markers in linkage disequilibrium therewith.

[0033] In an alternative aspect, the invention relates to a method of diagnosing a susceptibility to Cardiovascular Disease in a human individual, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, or in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the group of markers associated with LD block C09, wherein the presence of the at least one allele is indicative of a susceptibility to Cardiovascular Disease. In one embodiment, linkage disequilibrium is used as a quantitative measure of the degree to which specific markers are associated with LD Block C09.

[0034] In another aspect, the invention relates to a method of determining a susceptibility to cardiovascular disease in a human individual, comprising determining whether at least one at-risk allele in at least one polymorphic marker is present in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the markers within the LD Block C09 (SEQ ID NO:94), and markers in linkage disequilibrium therewith, and wherein determination of the presence of the at least one at-risk allele is indicative of increased susceptibility to cardiovascular disease in the individual.

[0035] The genotype dataset comprises in one embodiment information about marker identity, and the allelic status of the individual, i.e. information about the identity of the two alleles carried by the individual for the marker. The genotype dataset may comprise allelic information about one or more marker, including two or more markers, three or more markers, five or more markers, one hundred or more markers, etc. In some embodiments, the genotype dataset comprises genotype information from a whole-genome assessment of the individual including hundreds of thousands of markers, or even one million or more markers.

[0036] In one embodiment, the at least one polymorphic marker is present within the genomic segment LD Block C09, with the nucleotide sequence as set forth in SEQ ID NO:94. In another embodiment, the at least one polymorphic marker comprises at least one marker selected from rs7041637, rs2811712, rs3218018, rs3217992, rs2069426, rs2069422, rs1333034, rs1011970, rs10116277, rs1333040, rs2383207, rs1333050, D9S1814, rs10757278, rs10757274, rs1333049, D9S1870, and markers in linkage disequilibrium therewith. In another embodiment, the at least one polymorphic marker is selected from rs10757278, rs10757274, and rs10333049, and markers in linkage disequilibrium therewith. In another embodiment, the at least one polymorphic marker comprises at least one marker in strong linkage disequilibrium, as defined by numeric values for |D'| of greater than 0.8 and/or r² of greater than 0.2, with one or more markers selected from the group consisting of the markers set forth in Table 3.

[0037] In one embodiment, the method of determining a susceptibility, or diagnosing a susceptibility of, cardiovascular disease, further comprises assessing the frequency of at least one haplotype in the individual. In one such embodiment, the at least one haplotype is selected from the haplotypes that comprise at least one polymorphic marker within the genomic segment LD Block C09 (SEQ ID NO:94). In another embodiment, the at least one haplotype is selected from haplotypes that are in linkage disequilibrium with at least one marker as set forth in Table 3. In another embodiment, the at least one haplotype is selected from the haplotypes that comprise at least one polymorphic marker selected from at least one marker selected from rs7041637, rs2811712, rs3218018, rs3217992, rs2069426, rs2069422, rs1333034, rs1011970, rs10116277, rs1333040, rs2383207, rs1333050, D9S1814, rs10757278, rs10757274, rs1333049, D9S1870, and markers in linkage disequilibrium therewith.

[0038] In another aspect, the invention relates to a method of determining a susceptibility to Cardiovascular disease in a human individual, comprising determining whether at least one at-risk allele in at least one polymorphic marker is present in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Table 3, and markers in linkage disequilibrium therewith, and wherein determination of the presence of the at least one at-risk allele is indicative of increased susceptibility to Cardiovascular disease in the individual. The genotype dataset comprises in one embodiment information about marker identity, and the allelic status of the individual, i.e. information about the identity of the two alleles carried by the individual for the marker. The genotype dataset may comprise allelic information about one or more marker, including two or more markers, three or more markers, five or more markers, one hundred or more markers, etc. In some embodiments, the genotype dataset comprises genotype information from a whole-genome assessment of the individual including hundreds of thousands of markers, or even one million or more markers.

[0039] In one embodiment, the at least one polymorphic marker is present within SEQ ID NO:94, as set forth herein. In another embodiment, the at least one polymorphic marker comprises at least one marker selected from rs7041637, rs2811712, rs3218018, rs3217992, rs2069426, rs2069422, rs1333034, rs1011970, rs10116277, rs1333040, rs2383207, rs1333050, D9S1814, rs10757278, rs10757274, rs1333049, D9S1870, and markers in linkage disequilibrium therewith. In another embodiment, the at least one polymorphic marker comprises at least one marker in strong linkage disequilibrium, as defined by numeric values for |D'| of greater than 0.8 and/or r² of greater than 0.2, with one or more markers selected from the group consisting of the markers set forth in Table 3. In one preferred embodiment, the at least one polymorphic marker is selected from markers rs10757278, rs10757274, and rs1333049, and markers in linkage disequilibrium therewith. In another preferred embodiment, the at least one polymorphic marker is selected from markers rs10757278, rs10757274, and rs1333049. In yet another embodiment, the at least one polymorphic marker is selected from markers associated with LD Block C09 (SEQ ID NO:94). In one such embodiment, the at least one polymorphic marker is in linkage disequilibrium with at least one polymorphic marker within LD Block C09 (SEQ ID NO:94).

[0040] In one embodiment, the method of determining a susceptibility, or diagnosing a susceptibility of, Cardiovascular disease, further comprises assessing the frequency of at least one haplotype in the individual. In one such embodiment, the at least one haplotype is selected from the haplotypes that comprise at least one polymorphic marker as set forth in Table 10, and polymorphic markers in linkage disequilibrium therewith. In another embodiment, the at least one haplotype is selected from the haplotypes that comprise at least one polymorphic marker as set forth in Table 3, and polymorphic markers in linkage disequilibrium therewith. In another embodiment, the at least one haplotype is selected from the haplotypes that comprise at least one polymorphic marker selected from rs7041637, rs2811712, rs3218018, rs3217992, rs2069426, rs2069422, rs1333034, rs1011970, rs10116277, rs1333040, rs2383207, rs1333050, D9S1814, rs10757278, rs10757274, rs10333049, D9S1870, and markers in linkage disequilibrium therewith.

[0041] In certain embodiments of the invention, determination of the presence of at least one at-risk allele of at least one polymorphic marker in a nucleic acid sample from the individual is indicative of an increased susceptibility to the Cardiovascular disease. In one embodiment, the increased susceptibility is characterized by a relative risk (RR) or odds ratio (OR) of at least 1.15. In another embodiment, the increased susceptibility is characterized by a relative risk (RR) or odds ratio (OR) of at least 1.20. In another embodiment, the increased susceptibility is characterized by a relative risk (RR) or odds ratio (OR) of at least 1.30.

[0042] In some embodiments, the presence of rs7041637 allele A, rs2811712 allele A, rs3218018 allele A, rs3217992 allele A, rs2069426 allele C, rs2069422 allele A, rs1333034 allele A, rs1011970 allele G, rs10116277 allele T, rs1333040 allele T, rs2383207 allele G, rs1333050 allele T, D9S1814 allele 0, rs10757278 allele G, rs1333049 allele C, rs10757274 allele G, and/or D9S1870 allele X (composite allele of all alleles smaller than 2) is indicative of increased susceptibility of the Cardiovascular disease.

[0043] In particular embodiments, the presence of at least one protective allele in a nucleic acid sample from the individual is indicative of a decreased susceptibility of Cardiovascular disease. In another embodiment, the absence of at least one at-risk allele in a nucleic acid sample from the individual is indicative of a decreased susceptibility of Cardiovascular disease.

[0044] Another aspect of the invention relates to a method of assessing a susceptibility to Cardiovascular disease in a human individual, comprising screening a nucleic acid from the individual for at least one polymorphic marker or haplotype in the genomic segment with the sequence as set forth in SEQ ID NO:94, that correlates with increased occurrence of Cardiovascular disease in a human population, wherein the presence of an at-risk marker allele in the at least one polymorphism or an at-risk haplotype in the nucleic acid identifies the individual as having elevated susceptibility to the Cardiovascular disease, and wherein the absence of the at least one at-risk marker allele or at-risk haplotype in the nucleic acid identifies the individual as not having the elevated susceptibility.

[0045] In one such embodiment, the at least one polymorphic marker or haplotype comprises at least one polymorphic marker selected from the markers set forth in Table 10, and polymorphic markers in linkage disequilibrium therewith. In another embodiment, the at least one marker or haplotype comprises at least one polymorphic marker selected from the markers set forth in Table 3, and polymorphic markers in linkage disequilibrium therewith. In another embodiment, the at least one polymorphic marker or haplotype comprises at least one polymorphic marker selected from the markers rs7041637, rs2811712, rs3218018, rs3217992, rs2069426, rs2069422, rs1333034, rs1011970, rs10116277, rs1333040, rs2383207, rs1333050, D9S1814, rs10757278, rs10757274, rs10333049, D9S1870, and markers in linkage disequilibrium therewith. In certain embodiments, linkage disequilibrium is characterized by numeric values for |D'| of greater than 0.8 and/or r² of greater than 0.2.

[0046] Certain embodiments of the invention further comprise a step of screening the nucleic acid for the presence of at least one at-risk genetic variant for a Cardiovascular disease not associated with LD Block C09 (SEQ ID NO:94). Such additional genetic variants can in specific embodiments include any variant that has been identified as a susceptibility or risk variant for Cardiovascular disease.

[0047] In another aspect of the present invention, the presence of the marker or haplotype found to be associated with Cardiovascular disease, and as such useful for determining a susceptibility to Cardiovascular disease, is indicative of a different response rate of the subject to a particular treatment modality for Cardiovascular disease.

[0048] In another aspect, the invention relates to a method of identification of a marker for use in assessing susceptibility to a Cardiovascular disease in human individuals, the method comprising: [0049] identifying at least one polymorphic marker in linkage disequilibrium with at least one of the markers within LD Block C09 (SEQ ID NO:94); [0050] determining the genotype status of a sample of individuals diagnosed with, or having a susceptibility to, Cardiovascular disease; and [0051] determining the genotype status of a sample of control individuals; wherein a significant difference in frequency of at least one allele in at least one polymorphism in individuals diagnosed with, or having a susceptibility to, the Cardiovascular disease, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing susceptibility to the Cardiovascular disease.

[0052] In one embodiment, "significant" is determined by statistical means, e.g. the difference is statistically significant. In one such embodiment, statistical significance is characterized by a P-value of less than 0.05. In other embodiments, the statistical significance is characterized a P-value of less than 0.01, less than 0.001, less than 0.0001, less than 0.00001, less than 0.000001, less than 0.0000001, less than 0.0000000001, or less than 0.00000001.

[0053] In'one embodiment, the at least one polymorphic marker is in linkage disequilibrium, as characterized by numerical values of r² of greater than 0.2 and/or of greater than 0.8 with at least one marker selected from markers set forth in Table 21. In another embodiment, the at least one polymorphic marker is in linkage disequilibrium, as characterized by numerical values of r² of greater than 0.2 and/or |D'| of greater than 0.8 with at least one marker selected from markers rs10757278, rs10757274, and rs1333049.

[0054] In one embodiment, an increase in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with, or having a susceptibility to, a Cardiovascular disease, as compared with the frequency of the at least one allele in the control sample, is indicative of the at least one polymorphism being useful for assessing increased susceptibility to the Cardiovascular disease. In another embodiment, a decrease in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with, or having a susceptibility to, a Cardiovascular disease, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing decreased susceptibility to, or protection against, the Cardiovascular disease.

[0055] Another aspect of the invention relates to a method of genotyping a nucleic acid sample obtained from a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in the sample, wherein the at least one marker is selected from the markers set forth in Table 3 and Table 21, and markers in linkage disequilibrium therewith, and wherein determination of the presence or absence of the at least one allele of the at least one polymorphic marker is predictive of a susceptibility of a Cardiovascular disease.

[0056] In one embodiment, genotyping comprises amplifying a segment of a nucleic acid that comprises the at least one polymorphic marker by Polymerase Chain Reaction (PCR), using a nucleotide primer pair flanking the at least one polymorphic marker. In another embodiment, genotyping is performed using a process selected from allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5'-exonuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation analysis. In one particular embodiment, the process comprises allele-specific probe hybridization. In another embodiment, the process comprises DNA sequencing. In a preferred embodiment, the method comprises: [0057] 1) contacting copies of the nucleic acid with a detection oligonucleotide probe and an enhancer oligonucleotide probe under conditions for specific hybridization of the oligonucleotide probe with the nucleic acid; [0058] wherein [0059] a) the detection oligonucleotide probe is from 5-100 nucleotides in length and specifically hybridizes to a first segment of the nucleic acid whose nucleotide sequence is given by SEQ ID NO:94 that comprises at least one polymorphic site; [0060] b) the detection oligonucleotide probe comprises a detectable label at its 3' terminus and a quenching moiety at its 5' terminus; [0061] c) the enhancer oligonucleotide is from 5-100 nucleotides in length and is complementary to a second segment of the nucleotide sequence that is 5' relative to the oligonucleotide probe, such that the enhancer oligonucleotide is located 3' relative to the detection oligonucleotide probe when both oligonucleotides are hybridized to the nucleic acid; and [0062] d) a single base gap exists between the first segment and the second segment, such that when the oligonucleotide probe and the enhancer oligonucleotide probe are both hybridized to the nucleic acid, a single base gap exists between the oligonucleotides; [0063] 2) treating the nucleic acid with an endonuclease that will cleave the detectable label from the 3' terminus of the detection probe to release free detectable label when the detection probe is hybridized to the nucleic acid; and [0064] 3) measuring free detectable label, wherein the presence of the free detectable label indicates that the detection probe specifically hybridizes to the first segment of the nucleic acid, and indicates the sequence of the polymorphic site as the complement of the detection probe.

[0065] In a particular embodiment, the copies of the nucleic acid are provided by amplification by Polymerase Chain Reaction (PCR). In another embodiment, the susceptibility determined is increased susceptibility. In another embodiment, the susceptibility determined is decreased susceptibility.

[0066] Another aspect of the invention relates to a method of assessing an individual for probability of response to a therapeutic agent for preventing and/or ameliorating symptoms associated with a Cardiovascular disease, comprising: determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Table 21, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele of the at least one marker is indicative of a probability of a positive response to the Cardiovascular disease therapeutic agent. In one embodiment, the at least one polymorphic marker is selected from marker rs1333040, rs10116277, rs2383207 and rs10757278, and markers in linkage disequilibrium therewith. In one embodiment, the therapeutic agent is selected from beta blockers, anticoagulation agents, including heparin and/or low molecular weight heparin, antiplatelet agents, such as clopidogrel, aspirin, beta blockers, including metoprolol and carvedilol, ACE inhibitors, Statins, Aldosterone antagonists, including eplerenone, leukotriene synthesis inhibitors, the agents set forth in Agent Table I, Agent Table II, (R)-(+)-alpha-cyclopentyl-4-(2-quinolinylmethoxy)-Benzeneacetic acid, atreleuton, and 4-{(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyramide- , also known as DG-051. Other embodiments may include any one or a combination of the therapeutic agents described herein to be useful for therapeutic intervention of Cardiovascular disease.

[0067] Yet another aspect of the invention relates to a method of predicting prognosis of an individual diagnosed with, a Cardiovascular disease, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of rs1333040, rs10116277, rs2383207 and rs10757278, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele is indicative of a worse prognosis of the Cardiovascular disease in the individual. The prognosis may in certain embodiment relate to susceptibility of recurrent MI events, recurrent stroke events, or susceptibility to other complications relating to a Cardiovascular disease.

[0068] A further aspect of the invention relates to a method of monitoring progress of a treatment of an individual undergoing treatment for a Cardiovascular disease, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of rs1333040, rs10116277, rs2383207 and rs10757278, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele is indicative of the treatment outcome of the individual. The treatment may in certain embodiments be surgical treatment. In other embodiments, the treatment is by administration of a therapeutic agent, optionally including lifestyle changes or alterations in environmental exposure to risk factors for cardiovascular disease, as described further herein.

[0069] In one embodiment, the method further comprises assessing at least one biomarker in a sample from the individual. The biomarker is in certain embodiments a cardiac marker or an inflammatory marker. In one embodiment, the at least one biomarker is selected from creatin kinase, troponin, glycogen phosphorylase, C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, matrix metalloprotease type-9, serum sCD40L, leukotrienes, leukotriene metabolites, interleukin-6, tissue necrosis factor-alpha, myeloperoxidase (MPO), and N-tyrosine. In one embodiment, the leukotriene is selected from LTB4, LTC4, LTD4 and LTE4. In another embodiment, the method further comprises analyzing non-genetic information to make risk assessment, diagnosis, or prognosis of the individual. The non-genetic information is in one embodiment selected from age, gender, ethnicity, socioeconomic status, previous disease diagnosis, medical history of subject, family history of Cardiovascular disease, biochemical measurements, and clinical measurements. In a particular preferred embodiment, a further step comprising calculating overall risk is employed.

[0070] Another aspect of the invention relates to analyzing a sample comprising genomic DNA from a human individual or a genotype dataset derived from a human individual for the presence or absence of at least one at-risk allele of at least one at-risk variant for cardiovascular disease not in linkage disequilibrium with any one of the markers set forth in Table 10. Thus, the variants described herein to be associated with Cardiovascular disease may be combined with other genetic variants for Cardiovascular disease, that are not genetically related (i.e., not in linkage disequilibrium with) the markers described herein Such analysis may be undertaken in combination with any of the methods described herein. Furthermore any two markers herein, or any other combination of markers and/or haplotypes described herein to be associated with cardiovascular disease may be combined to assess an increased susceptibility to cardiovascular disease.

[0071] In some embodiments of the methods of the invention, non-genetic information is analyzed, to make risk assessment, diagnosis, or prognosis of the individual. The non-genetic information is in certain embodiments selected from age, gender, ethnicity, socioeconomic status, previous disease diagnosis, medical history of subject, family history of cardiovascular disease, biochemical measurements, and clinical measurements. Combined genetic factors and/or combinations of genetic and non-genetic factors may be analyzed by known methods, to generate a combined risk.

[0072] The invention also relates to a kit for assessing susceptibility to a Cardiovascular disease in a human individual, the kit comprising reagents for selectively detecting the presence or absence of at least one allele of at least one polymorphic marker in the genome of the individual, wherein the polymorphic marker is selected from the markers set forth in Tables 10, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to a Cardiovascular diseases.

[0073] In one embodiment, the at least one polymorphic marker is present within the genomic segment with the sequence as set forth in SEQ ID NO:94. In another embodiment, the at least one polymorphic marker is selected from the group of markers set forth in Table 21, and markers in linkage disequilibrium therewith. In another embodiment, the at least one polymorphic markers is selected from rs1333040, rs10116277, rs2383207 and rs10757278, and markers in linkage disequilibrium therewith.

[0074] In one embodiment, the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising the at least one polymorphic marker, a buffer and a detectable label. In one embodiment, the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic nucleic acid segment obtained from the subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes one polymorphic marker, and wherein the fragment is at least 30 base pairs in size. In a particular embodiment the at least one oligonucleotide is completely complementary to the genome of the individual. In another embodiment, the at least one oligonucleotide can comprise at least one mismatch to the genome of the individual. In one embodiment, the oligonucleotide is about 18 to about 50 nucleotides in length. In another embodiment, the oligonucleotide is 20-30 nucleotides in length.

[0075] In one preferred embodiment, the kit comprises:

[0076] a detection oligonucleotide probe that is from 5-100 nucleotides in length; an enhancer oligonucleotide probe that is from 5-100 nucleotides in length; and an endonuclease enzyme;

[0077] wherein the detection oligonucleotide probe specifically hybridizes to a first segment of the nucleic acid whose nucleotide sequence is given by SEQ ID NO:94 that comprises at least one polymorphic site; and wherein the detection oligonucleotide probe comprises a detectable label at its 3' terminus and a quenching moiety at its 5' terminus; wherein the enhancer oligonucleotide is from 5-100 nucleotides in length and is complementary to a second segment of the nucleotide sequence that is 5' relative to the oligonucleotide probe, such that the enhancer oligonucleotide is located 3' relative to the detection oligonucleotide probe when both oligonucleotides are hybridized to the nucleic acid; wherein a single base gap exists between the first segment and the second segment, such that when the oligonucleotide probe and the enhancer oligonucleotide probe are both hybridized to the nucleic acid, a single base gap exists between the oligonucleotides; and wherein treating the nucleic acid with the endonuclease will cleave the detectable label from the 3' terminus of the detection probe to release free detectable label when the detection probe is hybridized to the nucleic acid.

[0078] A further aspect of the invention relates to the use of an oligonucleotide probe in the manufacture of a diagnostic reagent for diagnosing and/or assessing susceptibility to Cardiovascular disease in a human individual, wherein the probe hybridizes to a segment of a nucleic acid whose nucleotide sequence is given by SEQ ID NO: 94 that comprises at least one polymorphic site, wherein the fragment is 15-500 nucleotides in length. In one embodiment, the polymorphic site is selected from the polymorphic markers rs1333040, rs10116277, rs2383207 and rs10757278, and markers in linkage disequilibrium therewith

[0079] Yet another aspect of the invention relates to a computer-readable medium on which is stored: an identifier for at least one polymorphic marker; an indicator of the frequency of at least one allele of said at least one polymorphic marker in a plurality of individuals diagnosed with a Cardiovascular disease; and an indicator of the frequency of the least one allele of said at least one polymorphic markers in a plurality of reference individuals; wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 10, and markers in linkage disequilibrium therewith. In one embodiment, the at least one polymorphic marker is selected from rs1333040, rs10116277, rs2383207 and rs10757278, and markers in linkage disequilibrium therewith.

[0080] Another aspect relates to an apparatus for determining a genetic indicator for Type 2 diabetes in a human individual, comprising: a computer readable memory; and a routine stored on the computer readable memory; wherein the routine is adapted to be executed on a processor to analyze marker and/or haplotype information for at least one human individual with respect to at least one polymorphic marker selected from the markers set forth in Table 10, and markers in linkage disequilibrium therewith, and generate an output based on the marker or haplotype information, wherein the output comprises a risk measure of the at least one marker or haplotype as a genetic indicator of a Cardiovascular disease for the human individual.

[0081] In one embodiment, the routine further comprises an indicator of the frequency of at least one allele of at least one polymorphic marker or at least one haplotype in a plurality of individuals diagnosed with a Cardiovascular disease, and an indicator of the frequency of at the least one allele of at least one polymorphic marker or at least one haplotype in a plurality of reference individuals, and wherein a risk measure is based on a comparison of the at least one marker and/or haplotype status for the human individual to the indicator of the frequency of the at least one marker and/or haplotype information for the plurality of individuals diagnosed with the Cardiovascular disease.

[0082] The present invention, as described herein, may be reduced to practice using any one, or a combination of, the polymorphic markers described herein as being useful for the determination of a susceptibility to cardiovascular disease. This includes markers that are shown herein to be associated with cardiovascular disease, but also includes markers that are in linkage disequilibrium with such variants. In one embodiment, the at least one marker is selected from the markers set forth in any of the Tables 3, 10, 21 and 26. In another embodiment, the at least one marker is selected from the markers set forth in Table 10. In another embodiment, the at least one marker is selected from the markers set forth in Table 3 and Table 21. In another embodiment, the at least one marker is selected from the markers set forth in Table 3. In another embodiment, the at least one marker is selected from the markers set forth in Table 21. In another embodiment, the at least one marker is selected from markers in linkage disequilibrium with the CDKN2A and/or CDKN2B genes. In another embodiment, the at least one marker is selected from the markers rs10811650, rs10116277, rs1333040, rs10738607, rs4977574, rs6475608, D9S1870, rs2383207, rs1333045, rs1333046, rs10757278 and rs1333048. In another embodiment, the at least one marker is selected from the markers rs1333040, rs10116277, rs2383207 and rs10757278. In another embodiment the at least one marker is rs1333040 (SEQ ID NO:59). In another embodiment, the at least one marker is rs10116277 (SEQ ID NO:56). In another embodiment, the at least one marker is rs2383207 (SEQ ID NO:82). In another embodiment, the at least one marker is rs10757278 (SEQ ID NO:88). In some embodiments, the at least one marker is further optionally selected from markers in linkage disequilibrium with any on or a combination of more than one of the above mentioned markers.

[0083] The Cardiovascular disease in the various aspects of the invention relating to methods, uses, apparatus or kits is in some embodiments an arterial disease. In one such embodiment, the arterial disease phenotype is selected from Myocardial Infarction, Acute Coronary Syndrome (ACS), Coronary Artery Disease, Stroke, Peripheral Artery Disease, Restenosis, Intracranial Aneurysm and Aorta Abdominal Aneurysm, transluminal coronary angioplasty (PTCA), and coronary artery bypass surgery (CABG). In one embodiment, the Cardiovascular disease is Myocardial Infarction. In another embodiment, the Cardiovascular disease is Myocardial Infarction or Coronary Artery Disease. In yet another embodiment, the Cardiovascular disease is Myocardial Infarction, Coronary Artery Disease, Aorta Abdominal Aneurysm or Intracranial Aneurysm. In another embodiment, the Cardiovascular Disease is Myocardial Infarction, Coronary Artery Disease, Restenosis, Aorta Abdominal Aneurysm or Intracranial Aneurysm. In one embodiment, the Stroke phenotype is Large Artery Atherosclerotic Stroke and/or Cardiogenic Stroke. The Restenosis phenotype is in one embodiment Coronary In-stent Restenosis. In certain embodiments, the In-stent Restenosis is either Restenosis following Bare Metal Stent (BMS) placement, or it is Restenosis following placement of a Drug Eluting Stent (DES).

[0084] Variants (markers and/or haplotypes comprising polymorphic markers) in linkage disequilibrium with the markers and haplotypes of the present invention are also useful for the methods and kits of the invention. The invention therefore also pertains to markers in linkage disequilibrium with the markers and haplotypes of the invention. In certain embodiments of the methods, uses, apparatus or kits of the invention, linkage disequilibrium is characterized by specific cutoff values for a quantitative measure of linkage disequilibrium. In one such embodiment, linkage disequilibrium is characterized by specific cutoff values for r². In another such embodiment, linkage disequilibrium is characterized by specific cutoff values for |D'|. In yet another embodiment, linkage disequilibrium is characterized by specific cutoff values for r² and |D'|. In one preferred embodiment, linkage disequilibrium is characterized by values for r² of greater than 0.1. In another preferred embodiment, linkage disequilibrium is characterized by values for r² of greater than 0.2. Other cutoff values for r² are also possible, including, but not limited to, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99. In another preferred embodiment, linkage disequilibrium is characterized by values for |D'| of greater than 0.5. In another preferred embodiment, linkage disequilibrium is characterized by values for |D'| of greater than 0.8. Other cutoff values for |D'| are also possible, including, but not limited to, 0.2, 0.3, 0.4, 0.6, 0.7, 0.8, 0.9, 0.95, 0.96, 0.97, 0.98 and 0.99. In certain embodiments, linkage disequilibrium is characterized by numeric cutoff values for either |D'| and r². In one such embodiment linkage disequilibrium is characterized by numeric cutoff values for either |D'| of greater than 0.8 and r² of greater than 0.2, or both.

[0085] In certain other embodiments of the methods, uses, apparatus or kits of the invention, the individual is of a specific human ancestry. In one embodiment, the ancestry is selected from black African ancestry, Caucasian ancestry and Chinese ancestry. In another embodiment, the ancestry is black African ancestry. In another embodiment, the ancestry is African American ancestry. In another embodiment, the ancestry is European ancestry. In another embodiment, the ancestry is Caucasian ancestry. The ancestry is in certain embodiment self-reported by the individual who undergoes genetic analysis or genotyping. In other embodiments, the ancestry is determined by genetic determination comprising detecting at least one allele of at least one polymorphic marker in a nucleic acid sample from the individual, wherein the presence or absence of the allele is indicative of the ancestry of the individual.

[0086] In other particular other embodiments of the methods, uses, apparatus or kits of the invention, the presence of at least one at-risk variant, i.e. an at-risk allele in at least one polymorphic marker or an at-risk haplotype, is indicative of an early onset of the Cardiovascular disease. Early onset is in some embodiments categorized as onset before age 75. In other embodiments, early onset is categorized as onset before age 70, before age 65, before age 60, before age 55, before age 50, before age 45, or before age 40. Other values for categorization of age at onset are also contemplated, including, but not limited to, all integer values of age, and such age categories are also within scope of the invention. In certain embodiments, the Cardiovascular disease is Myocardial Infarction, and the age at onset is below 50 for males and/or below 60 for females.

BRIEF DESCRIPTION OF THE DRAWINGS

[0087] The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention.

[0088] FIG. 1 shows a) Association results for 127 SNPs located in a 1 Mb interval (21.6-22.6 Mb, Build 34) on chromosome 9. Plotted is -log P, where P is the P-value adjusted for relatedness of the individual against the chromosomal location of the SNPs. b) The corresponding pair-wise correlation r² between 1004 common SNPs in the same region from the HapMap release 19 for the CEU population. c) Location of two recombination hot-spots based on the HapMap dataset (Nature 437, 1299-1320 (27 Oct. 2005)) that define the LD-block (position 21,920,147 to 21,149,982 in NCBI Build 36; SEQ ID NO:94 that includes the strongest association results. d) The pair-wise correlation structure in the region measured by D' for the same set of SNPs as used in panel b. All four panel use the same horizontal Mb scale indicated in panel a.

DETAILED DESCRIPTION OF THE INVENTION

[0089] A description of preferred embodiments of the invention follows.

DEFINITIONS

[0090] Unless otherwise indicated, nucleic acid sequences are written left to right in a 5' to 3' orientation. Numeric ranges recited within the specification are inclusive of the numbers defining the range and include each integer or any non-integer fraction within the defined range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by the ordinary person skilled in the art to which the invention pertains.

[0091] The following terms shall, in the present context, have the meaning as indicated:

[0092] A "polymorphic marker", sometime referred to as a "marker", as described herein, refers to a genomic polymorphic site. Each polymorphic marker has at least two sequence variations characteristic of particular alleles at the polymorphic site. Thus, genetic association to a polymorphic marker implies that there is association to at least one specific allele of that particular polymorphic marker. The marker can comprise any allele of any variant type found in the genome, including SNPs, microsatellites, insertions, deletions, duplications and translocations.

[0093] An "allele" refers to the nucleotide sequence of a given locus (position) on a chromosome. A polymorphic marker allele thug refers to the composition (i.e., sequence) of the marker on a chromosome. Genomic DNA from an individual contains two alleles (e.g., allele-specific sequences) for any given polymorphic marker, representative of each copy of the marker on each chromosome. Sequence codes for nucleotides used herein are: A=1, C=2, G=3, T=4. For microsatellite alleles, the CEPH sample (Centre d'Etudes du Polymorphisme Humain, genomics repository, CEPH sample 1347-02) is used as a reference, the shorter allele of each microsatellite in this sample is set as 0 and all other alleles in other samples are numbered in relation to this reference. Thus, e.g., allele 1 is 1 by longer than the shorter allele in the CEPH sample, allele 2 is 2 by longer than the shorter allele in the CEPH sample, allele 3 is 3 by longer than the lower allele in the CEPH sample, etc., and allele -1 is 1 by shorter than the shorter allele in the CEPH sample, allele -2 is 2 by shorter than the shorter allele in the CEPH sample, etc.

[0094] Sequence conucleotide ambiguity as described herein is as proposed by IUPAC-IUB. These codes are compatible with the codes used by the EMBL, GenBank, and PIR databases.

TABLE-US-00001 IUB code Meaning A Adenosine C Cytidine G Guanine T Thymidine R G or A Y T or C K G or T M A or C S G or C W A or T B C G or T D A G or T H A C or T V A C or G N A C G or T (Any base)

[0095] A nucleotide position at which more than one sequence is possible in a population (either a natural population or a synthetic population, e.g., a library of synthetic molecules) is referred to herein as a "polymorphic site".

[0096] A "Single Nucleotide Polymorphism" or "SNP" is a DNA sequence variation occurring when a single nucleotide at a specific location in the genome differs between members of a species or between paired chromosomes in an individual. Most SNP polymorphisms have two alleles. Each individual is in this instance either homozygous for one allele of the polymorphism (i.e. both chromosomal copies of the individual have the same nucleotide at the SNP location), or the individual is heterozygous (i.e. the two sister chromosomes of the individual contain different nucleotides). The SNP nomenclature as reported herein refers to the official Reference SNP (rs) ID identification tag as assigned to each unique SNP by the National Center for Biotechnological Information (NCBI).

[0097] A "variant", as described herein, refers to a segment of DNA that differs from the reference DNA. A "marker" or a "polymorphic marker", as defined herein, is a variant. Alleles that differ from the reference are referred to as "variant" alleles.

[0098] A "microsatellite" is a polymorphic marker that has multiple small repeats of bases that are 2-8 nucleotides in length (such as CA repeats) at a particular site, in which the number of repeat lengths varies in the general population. An "indel" is a common form of polymorphism comprising a small insertion or deletion that is typically only a few nucleotides long.

[0099] A "haplotype," as described herein, refers to a segment of genomic DNA that is characterized by a specific combination of alleles arranged along the segment. For diploid organisms such as humans, a haplotype comprises one member of the pair of alleles for each polymorphic marker or locus. In a certain embodiment, the haplotype can comprise two or more alleles, three or more alleles, four or more alleles, or five or more alleles. Haplotypes are described herein in the context of the marker name and the allele of the marker in that haplotype, e.g., "G rs10757278" refers to the 3 allele of marker rs7758851 being in the haplotype, and is equivalent to "rs10757278 allele G". Furthermore, allelic codes in haplotypes are as for individual markers, i.e. 1=A, 2=C, 3=G and 4=T.

[0100] The term "susceptibility", as described herein, refers to an individual (or group of individuals) being prone to developing a certain state (e.g., a certain trait, phenotype or disease), or being less able to resist a particular state than the average individual. The term encompasses both increased susceptibility and decreased susceptibility. Thus, particular alleles at polymorphic markers and/or haplotypes of the invention as described herein may be characteristic of increased susceptibility (i.e., increased risk) of cardiovascular disease, as characterized by a relative risk (RR) or odds ratio (OR) of greater than one for the particular allele or haplotype. Alternatively, the markers and/or haplotypes of the invention are characteristic of decreased susceptibility (i.e., decreased risk) of cardiovascular disease, as characterized by a relative risk of less than one.

[0101] The term "and/or" shall in the present context be understood to indicate that either or both of the items connected by it are involved. In other words, the term herein shall be taken to mean "one or the other or both".

[0102] The term "look-up table", as described herein, is a table that correlates one form of data to another form, or one or more forms of data to a predicted outcome to which the data is relevant, such as phenotype or trait. For example, a look-up table can comprise a correlation between allelic data for at least one polymorphic marker and a particular trait or phenotype, such as a particular disease diagnosis, that an individual who comprises the particular allelic data is likely to display, or is more likely to display than individuals who do not comprise the particular allelic data. Look-up tables can be multidimensional, i.e. they can contain information about multiple alleles for single markers simultaneously, or they can contain information about multiple markers, and they may also comprise other factors, such as particulars about diseases diagnoses, racial information, biomarkers, biochemical measurements, therapeutic methods or drugs, etc.

[0103] A "computer-readable medium", is an information storage medium that can be accessed by a computer using a commercially available or custom-made interface. Exemplary computer-readable media include memory (e.g., RAM, ROM, flash memory, etc.), optical storage media (e.g., CD-ROM), magnetic storage media (e.g., computer hard drives, floppy disks, etc.), punch cards, or other commercially available media. Information may be transferred between a system of interest and a medium, between computers, or between computers and the computer-readable medium for storage or access of stored information. Such transmission can be electrical, or by other available methods, such as IR links, wireless connections, etc.

[0104] A "nucleic acid sample" is a sample obtained from an individuals that contains nucleic acid. In certain embodiments, i.e. the detection of specific polymorphic markers and/or haplotypes, the nucleic acid sample comprises genomic DNA. Such a nucleic acid sample can be obtained from any source that contains genomic DNA, including as a blood sample, sample of amniotic fluid, sample of cerebrospinal fluid, or tissue sample from skin, muscle, buccal or conjunctival mucosa, placenta, gastrointestinal tract or other organs.

[0105] The term "cardiovascular disease therapeutic agent", as described herein, refers to an agent that can be used to ameliorate or prevent symptoms associated with a cardiovascular disease.

[0106] The term "coronary artery disease therapeutic agent", as described herein, refers to an agent that can be used to ameliorate or prevent symptoms associated with coronary artery disease. Such agents can for example be statins, beta blockers, calcium channel blockers, cardiac glycosides, antihypertensive agents, diuretics, agents acting on the renin-angiotensin system, and aspirin.

[0107] The term "coronary stenosis" or "coronary stenosis therapeutic method", as described herein, refers to methods that can be used to ameliorate or prevent symptoms associated with coronary artery disease. Such methods can be balloon angioplasty, stenting, cutting balloon angioplasty, percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy, rotational coronary atherectomy, brachytherapy, drug-eluting stent (DES) insertion, metal stent insertion, or coronary artery surgeries, such as Coronary Artery Bypass Surgery (CABG).

[0108] The term "cardiovascular disease-associated nucleic acid", as described herein, refers to a nucleic acid that has been found to be associated to cardiovascular disease. This includes, but is not limited to, the markers and haplotypes described herein and markers and haplotypes in strong linkage disequilibrium (LD) therewith.

[0109] The term "LD Block C09", as described herein, refers to the Linkage Disequilibrium (LD) block on Chromosome 9 between positions 21,920,147 and 22,149,982 base pairs on Chromosome 9 of NCBI (National Center for Biotechnology Information) Build 34, Build 35 and Build 36. The nucleotide sequence of the LD Block region from these Builds is set forth in SEQ ID NO:94.

[0110] The term "cardiovascular disease", as described herein, refers to the class of diseases that involve the heart or blood vessels (arteries and veins). In one embodiment, the invention pertains to arterial disease, which relate to atherosclerotic events, which are believed to have similar causes and mechanisms. Cardiovascular diseases have certain common risk factors (age, smoking, Diabetes mellitus, hypercholesterolemia, obesity, high blood pressure, stress, depression, elevated heart rate, sleep deprivation, environmental exposure).

[0111] The abbreviations "PCTA", "CABG", "MI", "PAD", "CAD", "LAA", "IA", and "AAA", as described herein, refer to the following: "PCTA" refers to Transluminal Coronary Angiopathy, "CABG" refers to Coronary Artery Bypass Surgery, "MI" refers to Myocardial Infarction, "PAD" refers to Peripheral Artery Disease, "CAD" refers to Coronary Artery Disease, "LAA Stroke" refers to Large Artery Atherosclerotic Stroke, "IA" refers to Intrachranial Aneurysm and "AAA" refers to Abdominal Aortic Aneurysm.

[0112] The term "early onset", as described herein, refers to onset of a disease that is lower than is typically observed. In the present exemplary context, the term, as applied to the MI phenotype, is defined as a MI event before the age of 50 for males and before the age of 60 for females. The term can, in alternative embodiments of the invention, be defined in alternative manner as known to the skilled person and described in further detail herein.

Association of Genetic Variants to Coronary Artery Disease

[0113] Through an association study between SNP markers on a chip containing approximately 317,000 such SNPs, the present invention has identified association of certain markers on chromosome 9 with cardiovascular diseases. The original discovery was made when an analysis of SNP data from patients diagnosed with Myocardial Infarction was made, as illustrated in Table 1 and Table 12. Several markers in a region described herein as LD block C09 were found to be strongly associated with MI, with RR values as high as 1.2. Two microsatellites within the region, D9S1814 and D9S1870, were found also to be correlated with the MI phenotype. The composite allele X of D9S1870 (a composite of all alleles shorter than 2 (alleles, -6, -4, -2 and 0, respectively), was found to associate strongly with MI (Table 1). Further investigations identified close to 90 additional markers that are strongly correlated with the five markers giving strongest association to MI (rs10116277, rs1333040, rs2383207, D9S1814 and D9S1870; see Table 3). These markers could thus serve as surrogate markers for any of these five markers and therefore be used in the methods of the present invention.

[0114] The D9S1870 marker was subsequently genotyped in a very large sample of individuals (over 70,000), including additional MI cases as well as other cardiovascular diseases, plus tenths of thousands of additional population controls. A replication study in three cohorts from the US was also performed, all containing individuals of Caucasian origin. Results of these studies for the phenotype MI revealed replication of the original finding (Table 4 and 12-14), with a combined p-value of approximately 10^-12. The corresponding population attributable risk is about 17% for this variant.

[0115] Further studies of this variant revealed a significant correlation to age at onset of MI. Arbitrarily defining early-onset MI as MI before age 50 for males and below age 60 for females revealed an increase in this early-onset group of 1.33, compared to 1.21 for all MI cases. Multiple regression of the number of copies of the composite X allele of D9S1870 and the age of onset of MI revealed a very significant decrease in age at onset for each copy of X carried by the MI individuals (Table 8). This shows that other definitions of age at onset of MI than the cutoff of 50 for males and 60 for females could also be used for detecting this trend in age at onset with carrier status for the X allele.

[0116] The present invention has also identified association between other cardiovascular diseases and variants within the LD block C09, using the X allele of D9S1870 as surrogate marker. Thus significant association was found to Peripheral Artery Disease (PAD), even after removing individuals diagnosed with MI from the PAD cohort. We also observed increased risk of Stroke as broad phenotype, as well as the Stroke subphenotype Large Vessel disease (LVD) (Table 5 and Table 29). We have also investigated association of the at-risk variants to the related disorders peripheral artery disease (PAD) and abdominal aorta aneurysm (AAA) As can be seen in Table 29, these markers are associated with these related disorders. The association is particularly compelling for AAA, wherein significant association is observed for a large number of markers in addition to these three, as shown in Table 30. These results illustrate that the markers and haplotypes of the invention are indeed reflective of disorders related to coronary artery disease, MI and in-stent restenosis, such as abdominal aorta aneurysm.

[0117] A further analysis of individuals with diagnosis of in-stent restenosis was performed (Table 9). Significant association was detected for both mild restenosis (<50%) and severe restenosis (>50%). This indicates that the present invention can be used to indicate which individuals are at increased risk of in-stent restenosis after undergoing transluminal coronary angioplasty (PTCA).

[0118] The known genes located within the LD block C09, are called CDKN2A and CDKN2B. These genes encode three proteins that are known as ARF (also known as p19^ARF and p14^ARF), p15^INK4b and p16^INK4a, all of which encode tumor suppressor proteins. p15^INK4b has its own open reading frame, but p16^INK'' and ARF have different first exons that are spliced to a common second and third exons. Despite the sharing of exons between p16^INK'' and ARF the proteins are encoded in different reading frames. Therefore, p16^INK4a and ARF are proteins that do not share homology. The products of these genes have been extensively studied and are known to play a widespread role in tumor suppression. Recent data has suggested that the ARF, p15^INK4b and p16^INK4a locus also has a role in aging of cells, i.e. the decline of replicative potential of self-renewing cells. Several groups have shown that the expression of p16^INK4a increases with aging in many tissues of rodents and humans. It has even been proposed that the expression of p16^INK4a could be used as a biomarker of physiologic, as opposed to chronologic age.

[0119] Human cancers frequently have homozygous deletions of the ARF, p15^INK4b and p16^INK4a locus with reduced expression of all three proteins, and decreased tumor suppressor activity. Knock-out studies of mice deficient for ARF, p15^INK4b or p16^INK4a have revealed that these strains are more prone to cancers than wild-type mice. Furthermore, mice with overexpression of the ARF, p15^INK4b or p16^INK4a locus show reduction in incidence of spontaneous cancers. Since cancer is the principal cause of death in mice on this background one may argue that the tumor resistance of the mice overexpressing the ARF, p15^INK4b or p16^INK4a locus would also lead to longer lifespan of these mice. However, this is not the case since these mice demonstrate a normal lifespan. This may suggest that the increased ARF, or p15^INK4b or p16^INK4a locus function and diminished tumor incidence may come at the expense of excess mortality from non-malignant causes related to aging (Cell, 127, Oct. 20, 2006), such as atherosclerotic disease.

[0120] Sequencing of the exons of CDKN2A and CDKN2B regions, including exons, exon-intron junctions and potential regulatory regions was performed using the primers as indicated in Table 12, resulting in the identification of a number of SNPs, as shown in Table 13. Three of those SNPs were not found in public databases, and the flanking sequences of those SNPs are indicated in Table 14. As it is possible that SNP markers or other polymorphisms in LD with the markers found to be associating to MI in this region of chromosome 9 show association with a higher risk, we genotyped these additional markers by sequencing, as indicated in Table 13. Several of the markers show association to MI with RR values as high as 1.7-1.8, in particular markers SG09S291 and rs2069416. These markers, and/or other markers within the CDKN2A and CDKN2B genes that are in LD with the markers of the present invention as described herein, are thus also within the scope of the invention, as those markers may represent either true disease-causing variants, or variants in strong LD with an underlying causative variant(s).

[0121] Investigation of association of the rs10757278 variant to Intrachranial Aneurysm shows significant association to this phenotype in the original Icelandic cohort, as well as replication in independent cohorts from the Netherlands and Finland (e.g., Table 32). Furthermore, the original finding of association to AAA was replicated in several cohorts from Belgium, Canada, USA, Netherlands, UK and New Zealand (Table 32). These results show that the rs10757278 marker, and markers in LD therewith, are indeed significantly associated with cardiovascular disorders, including the arterial diseases than myocardial infarction, peripheral artery disease, stroke, intracranial aneurysm and abdominal aortic aneurysm.

[0122] The original discovery of the association between variants on chromosome 9p21 and cardiovascular diseases described herein (see also Helgadottir, A., et. al., Science 316:1491-3 2007) has been replicated in several independent studies, including studies of subjects with CAD and controls. The association with CAD/MI in Caucasians has been replicated in 4,251 cases and 4,443 controls of the PROCARDIS Consortium (Hum Mol. Genet. Epub 2007 Nov. 29), in an Italian population including 416 MI cases and 308 controls (J Hum Genet. 2008; 53(2):144-50. Epub 2007 Dec. 8), in participants of the Framingham Heart Study (BMC Med. Genet. 2007 Sep. 19; 8 Suppl 1:S5), and in the Northwick Park Heart Study II (Clin Chem. Epub 2008 Feb. 4). The association of rs10757278, as well as other correlated SNPs, with CAD has also been confirmed in Asian populations from Japan and Korea with comparable odds ratios as published for Caucasians (see Arterioscler Thromb Vasc Biol. 2008 February; 28(2):360-5. Epub 2007 Nov. 29, and J Hum Genet. Epub 2008 Feb. 9). These studies, together with the data shown herein, clearly indicate that variants within the LD Block C09 region on Chromosome 9p21 are associated with cardiovascular disease in all populations.

Assessment for Markers and Haplotypes

[0123] The genomic sequence within populations is not identical when individuals are compared. Rather, the genome exhibits sequence variability between individuals at many locations in the genome. Such variations in sequence are commonly referred to as polymorphisms, and there are many such sites within each genome For example, the human genome exhibits sequence variations which occur on average every 500 base pairs. The most common sequence variant consists of base variations at a single base position in the genome, and such sequence variants, or polymorphisms, are commonly called Single Nucleotide Polymorphisms ("SNPs"). These SNPs are believed to have occurred in a single mutational event, and therefore there are usually two possible alleles possible at each SNPsite; the original allele and the mutated allele. Due to natural genetic drift and possibly also selective pressure, the original mutation has resulted in a polymorphism characterized by a particular frequency of its alleles in any given population. Many other types of sequence variants are found in the human genome, including microsatellites, insertions, deletions, inversions and copy number variations. A polymorphic microsatellite has multiple small repeats of bases (such as CA repeats, TG on the complimentary strand) at a particular site in which the number of repeat lengths varies in the general population. In general terms, each version of the sequence with respect to the polymorphic site represents a specific allele of the polymorphic site. These sequence variants can all be referred to as polymorphisms, occurring at specific polymorphic sites characteristic of the sequence variant in question. In general terms, polymorphisms can comprise any number of specific alleles. Thus in one embodiment of the invention, the polymorphism is characterized by the presence of two or more alleles in any given population. In another embodiment, the polymorphism is characterized by the presence of three or more alleles. In other embodiments, the polymorphism is characterized by four or more alleles, five or more alleles, six or more alleles, seven or more alleles, nine or more alleles, or ten or more alleles. All such polymorphisms can be utilized in the methods and kits of the present invention, and are thus within the scope of the invention.

[0124] In some instances, reference is made to different alleles at a polymorphic site without choosing a reference allele. Alternatively, a reference sequence can be referred to for a particular polymorphic site. The reference allele is sometimes referred to as the "wild-type" allele and it usually is chosen as either the first sequenced allele or as the allele from a "non-affected" individual (e.g., an individual that does not display a trait or disease phenotype).

[0125] Alleles for SNP markers as referred to herein refer to the bases A, C, G or T as they occur at the polymorphic site in the SNP assay employed. The allele codes for SNPs used herein are as follows: 1=A, 2=C, 3=G, 4=T. The person skilled in the art will however realise that by assaying or reading the opposite DNA strand, the complementary allele can in each case be measured. Thus, for a polymorphic site (polymorphic marker) containing an A/G polymorphism, the assay employed may either measure the percentage or ratio of the two bases possible, i.e. A and G. Alternatively, by designing an assay that determines the opposite strand on the DNA template, the percentage or ratio of the complementary bases T/C can be measured. Quantitatively (for example, in terms of relative risk), identical results would be obtained from measurement of either DNA strand (+ strand or - strand). Polymorphic sites (polymorphic markers) can allow for differences in sequences based on substitutions, insertions or deletions. For example, a polymorphic microsatellite has multiple small repeats of bases (such as CA repeats) at a particular site in which the number of repeat lengths varies in the general population. Each version of the sequence with respect to the polymorphic site represents a specific allele of the polymorphic site.

[0126] Typically, a reference sequence is referred to for a particular sequence. Alleles that differ from the reference are referred to as "variant" alleles. For example, the genomic DNA sequence from position 21,920,147 to position 22,149,982 base pairs on Chromosome 9 of NCBI Build 34 ("LD block C09"; SEQ ID NO:94) represents a reference sequence. A variant sequence, as used herein, refers to a sequence that differs from the reference sequence but is otherwise substantially similar. Alleles at the polymorphic genetic markers that make up the haplotypes described herein are variants. Additional variants can include changes that affect a polypeptide. Sequence differences, when compared to a reference nucleotide sequence, can include the insertion or deletion of a single nucleotide, or of more than one nucleotide, resulting in a frame shift; the change of at least one nucleotide, resulting in a change in the encoded amino acid; the change of at least one nucleotide, resulting in the generation of a premature stop codon; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of a reading frame; duplication of all or a part of a sequence; transposition; or a rearrangement of a nucleotide sequence, as described in detail herein. Such sequence changes alter the polypeptide encoded by the nucleic acid. For example, if the change in the nucleic acid sequence causes a frame shift, the frame shift can result in a change in the encoded amino acids, and/or can result in the generation of a premature stop codon, causing generation of a truncated polypeptide. Alternatively, a polymorphism associated with coronary artery disease and in-stent restenosis or a susceptibility to coronary artery disease and in-stent restenosis can be a synonymous change in one or more nucleotides (i.e., a change that does not result in a change in the amino acid sequence). Such a polymorphism can, for example, alter splice sites, affect the stability or transport of mRNA, or otherwise affect the transcription or translation of an encoded polypeptide. It can also alter DNA to increase the possibility that structural changes, such as amplifications or deletions, occur at the somatic level. The polypeptide encoded by the reference nucleotide sequence is the "reference" polypeptide with a particular reference amino acid sequence, and polypeptides encoded by variant alleles are referred to as "variant" polypeptides with variant amino acid sequences.

[0127] A haplotype refers to a segment of DNA that is characterized by a specific combination of alleles arranged along the segment. For diploid organisms such as humans, a haplotype comprises one member of the pair of alleles for each polymorphic marker or locus. In a certain embodiment, the haplotype can comprise two or more alleles, three or more alleles, four or more alleles, or five or more alleles, each allele corresponding to a specific polymorphic marker along the segment. Haplotypes can comprise a combination of various polymorphic markers, e.g., SNPs and microsatellites, having particular alleles at the polymorphic sites. The haplotypes thus comprise a combination of alleles at various genetic markers.

[0128] Detecting specific polymorphic markers and/or haplotypes can be accomplished by methods known in the art for detecting sequences at polymorphic sites. For example, standard techniques for genotyping for the presence of SNPs and/or microsatellite markers can be used, such as fluorescence-based techniques (e.g., Chen, X. et al., Genome Res. 9(5): 492-98 (1999); Kutyavin et al., Nucleic Acid Res. 34:e128 (2006)), utilizing PCR, LCR, Nested PCR and other techniques for nucleic acid amplification. Specific methodologies available for SNP genotyping include, but are not limited to, TaqMan genotyping assays and SNPlex platforms (Applied Biosystems), mass spectrometry (e.g., MassARRAY system from Sequenom), minisequencing methods, real-time PCR, Bio-Plex system (BioRad), CEQ and SNPstream systems (Beckman), Molecular Inversion Probe array technology (e.g., Affymetrix GeneChip), and BeadArray Technologies (e.g., Illumina GoldenGate and Infinium assays). By these or other methods available to the person skilled in the art, one or more alleles at polymorphic markers, including microsatellites, SNPs or other types of polymorphic markers, can be identified.

[0129] In certain methods described herein, an individual who is at an increased susceptibility (i.e., at risk) for cardiovascular disease is an individual in whom at least one specific allele at one or more polymorphic marker or haplotype conferring increased susceptibility for cardiovascular disease is identified (i.e., at-risk marker alleles or haplotypes). In one aspect, the at-risk marker or haplotype is one that confers a significant increased risk (or susceptibility) of cardiovascular disease. In one embodiment, significance associated with a marker or haplotype is measured by a relative risk. In one embodiment, significance associated with a marker or haplotype is measured by a relative risk (RR). In another embodiment, significance associated with a marker or haplotye is measured by an odds ratio (OR). In a further embodiment, the significance is measured by a percentage. In one embodiment, a significant increased risk is measured as a risk (relative risk and/or odds ratio) of at least 1.2, including but not limited to: at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, 1.8, at least 1.9, at least 2.0, at least 2.5, at least 3.0, at least 4.0, and at least 5.0. In a particular embodiment, a risk (relative risk and/or odds ratio) of at least 1.2 is significant. In another particular embodiment, a risk of at least 1.3 is significant. In yet another embodiment, a risk of at least 1.4 is significant. In a further embodiment, a relative risk of at least 1.5 is significant. In another further embodiment, a significant increase in risk is at least 1.7 is significant. However, other cutoffs are also contemplated, e.g., at least 1.15, 1.25, 1.35, and so on, and such cutoffs are also within scope of the present invention. In other embodiments, a significant increase in risk is at least about 20%, including but not limited to about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, and 500%. In one particular embodiment, a significant increase in risk is at least 20%. In other embodiments, a significant increase in risk is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% and at least 100%. Other cutoffs or ranges as deemed suitable by the person skilled in the art to characterize the invention are however also contemplated, and those are also within scope of the present invention. In certain embodiments, a significant increase in risk is characterized by a p-value, such as a p-value of less than 0.05, less than 0.01, less than 0.001, less than 0.0001, less than 0.00001, less than 0.000001, less than 0.0000001, less than 0.00000001, or less than 0.000000001.

[0130] An at-risk polymorphic marker or haplotype of the present invention is one where at least one allele of at least one marker or haplotype is more frequently present in an individual at risk for cardiovascular disease (affected), compared to the frequency of its presence in a healthy individual (control), and wherein the presence of the marker or haplotype is indicative of susceptibility to cardiovascular disease. The control group may in one embodiment be a population sample, i.e. a random sample from the general population. In another embodiment, the control group is represented by a group of individuals who are disease-free. Such disease-free control may in one embodiment be characterized by the absence of one or more specific disease-associated symptoms. In another embodiment, the disease-free control group is characterized by the absence of one or more disease-specific risk factors. Such risk factors are in one embodiment at least one environmental risk factor. Representative environmental factors are natural products, minerals or other chemicals which are known to affect, or contemplated to affect, the risk of developing the specific disease or trait. Other environmental risk factors are risk factors related to lifestyle, including but not limited to food and drink habits, geographical location of main habitat, and occupational risk factors. In another embodiment, the risk factors comprise at least one additional genetic risk factor.

[0131] As an example of a simple test for correlation would be a Fisher-exact test on a two by two table. Given a cohort of chromosomes, the two by two table is constructed out of the number of chromosomes that include both of the markers or haplotypes, one of the markers or haplotypes but not the other and neither of the markers or haplotypes. Other statistical tests of association known to the skilled person are also contemplated and are also within scope of the invention.

[0132] In other embodiments of the invention, an individual who is at a decreased susceptibility (i.e., at a decreased risk) for a disease or trait is an individual in whom at least one specific allele at one or more polymorphic marker or haplotype conferring decreased susceptibility for the disease or trait is identified. The marker alleles and/or haplotypes conferring decreased risk are also said to be protective. In one aspect, the protective marker or haplotype is one that confers a significant decreased risk (or susceptibility) of the disease or trait. In one embodiment, significant decreased risk is measured as a relative risk (or odds ratio) of less than 0.9, including but not limited to less than 0.9, less than 0.8, less than 0.7, less than 0.6, less than 0.5, less than 0.4, less than 0.3, less than 0.2 and less than 0.1. In one particular embodiment, significant decreased risk is less than 0.7. In another embodiment, significant decreased risk is less than 0.5. In yet another embodiment, significant decreased risk is less than 0.3. In another embodiment, the decrease in risk (or susceptibility) is at least 20%, including but not limited to at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% and at least 98%. In one particular embodiment, a significant decrease in risk is at least about 30%. In another embodiment, a significant decrease in risk is at least about 50%. In another embodiment, the decrease in risk is at least about 70%. Other cutoffs or ranges as deemed suitable by the person skilled in the art to characterize the invention are however also contemplated, and those are also within scope of the present invention.

[0133] The person skilled in the art will appreciate that for markers with two alleles present in the population being studied (such as SNPs), and wherein one allele is found in increased frequency in a group of individuals with a trait or disease in the population, compared with controls, the other allele of the marker will be found in decreased frequency in the group of individuals with the trait or disease, compared with controls. In such a case, one allele of the marker (the one found in increased frequency in individuals with the trait or disease) will be the at-risk allele, while the other allele will be a protective allele.

[0134] A genetic variant associated with a disease or a trait (e.g. cardiovascular disease) can be used alone to predict the risk of the disease for a given genotype. For a biallelic marker, such as a SNP, there are 3 possible genotypes: homozygote for the at risk variant, heterozygote, and non carrier of the at risk variant. Risk associated with variants at multiple loci can be used to estimate overall risk. For multiple SNP variants, there are k possible genotypes k=3ⁿ×2^p; where n is the number autosomal loci and p the number of gonosomal (sex chromosomal) loci. Overall risk assessment calculations usually assume that the relative risks of different genetic variants multiply, i.e. the overall risk (e.g., RR or OR) associated with a particular genotype combination is the product of the risk values for the genotype at each locus. If the risk presented is the relative risk for a person, or a specific genotype for a person, compared to a reference population with matched gender and ethnicity, then the combined risk--is the product of the locus specific risk values--and which also corresponds to an overall risk estimate compared with the population. If the risk for a person is based on a comparison to non-carriers of the at risk allele, then the combined risk corresponds to an estimate that compares the person with a given combination of genotypes at all loci to a group of individuals who do not carry risk variants at any of those loci. The group of non-carriers of any at risk variant has the lowest estimated risk and has a combined risk, compared with itself (i.e., non-carriers) of 1.0, but has an overall risk, compare with the population, of less than 1.0. It should be noted that the group of non-carriers can potentially be very small, especially for large number of loci, and in that case, its relevance is correspondingly small.

[0135] The multiplicative model is a parsimonious model that usually fits the data of complex traits reasonably well. Deviations from multiplicity have been rarely described in the context of common variants for common diseases, and if reported are usually only suggestive since very large sample sizes are usually required to be able to demonstrate statistical interactions between loci.

[0136] By way of an example, let us consider a total of eight variants that have been described to associate with prostate cancer (Gudmundsson, J., et al., Nat Genet. 39:631-7 (2007), Gudmundsson, J., et al., Nat Genet. 39:977-83 (2007); Yeager, M., et al, Nat Genet. 39:645-49 (2007), Amundadottir, L., et al., Nat Genet. 38:652-8 (2006); Haiman, C. A., et al., Nat Genet. 39:638-44 (2007)). Seven of these loci are on autosomes, and the remaining locus is on chromosome X. The total number of theoretical genotypic combinations is then 3⁷×2¹=4374. Some of those genotypic classes are very rare, but are still possible, and should be considered for overall risk assessment. It is likely that the multiplicative model applied in the case of multiple genetic variant will also be valid in conjugation with non-genetic risk variants assuming that the genetic variant does not clearly correlate with the "environmental" factor. In other words, genetic and non-genetic at-risk variants can be assessed under the multiplicative model to estimate combined risk, assuming that the non-genetic and genetic risk factors do not interact.

[0137] Using the same quantitative approach, the combined or overall risk associated with a plurality of variants associated with any cardiovascular disease, as described herein, may be assessed.

Linkage Disequilibrium

[0138] The natural phenomenon of recombination, which occurs on average once for each chromosomal pair during each meiotic event, represents one way in which nature provides variations in sequence (and biological function by consequence). It has been discovered that recombination does not occur randomly in the genome; rather, there are large variations in the frequency of recombination rates, resulting in small regions of high recombination frequency (also called recombination hotspots) and larger regions of low recombination frequency, which are commonly referred to as Linkage Disequilibrium (LD) blocks (Myers, S. et al., Biochem Soc Trans 34:526-530 (2006); Jeffreys, A. J., et al., Nature Genet. 29:217-222 (2001); May, C. A., et al., Nature Genet. 31:272-275 (2002)).

[0139] Linkage Disequilibrium (LD) refers to a non-random assortment of two genetic elements. For example, if a particular genetic element (e.g., "alleles" of a polymorphic marker) occurs in a population at a frequency of 0.50 (50%) and another occurs at a frequency of 0.50 (50%), then the predicted occurrence of a person's having both elements is 0.25 (25%), assuming a random distribution of the elements. However, if it is discovered that the two elements occur together at a frequency higher than 0.25, then the elements are said to be in linkage disequilibrium, since they tend to be inherited together at a higher rate than what their independent allele frequencies would predict. Roughly speaking, LD is generally correlated with the frequency of recombination events between the two elements. Allele or haplotype frequencies can be determined in a population by genotyping individuals in a population and determining the frequency of the occurrence of each allele or haplotype in the population. For populations of diploids, e.g., human populations, individuals will typically have two alleles or allelic combinations for each genetic element (e.g., a marker, haplotype or gene).

[0140] Many different measures have been proposed for assessing the strength of linkage disequilibrium (LD). Most capture the strength of association between pairs of biallelic sites. Two important pall Wise measures of LD are r² (sometimes denoted Δ²) and |D'|. Both measures range from 0 (no disequilibrium) to 1 (`complete` disequilibrium), but their interpretation is slightly different. |D'| is defined in such a way that it is equal to 1 if just two or three of the possible haplotypes are present, and it is <1 if all four possible haplotypes are present. Therefore, a value of |D'| that is <1 indicates that historical recombination may have occurred between two sites (recurrent mutation can also cause |D'| to be <1, but for single nucleotide polymorphisms (SNPs) this is usually regarded as being less likely than recombination). The measure r² represents the statistical correlation between two sites, and takes the value of 1 if only two haplotypes are present.

[0141] The r² measure is arguably the most relevant measure for association mapping, because there is a simple inverse relationship between r² and the sample size required to detect association between susceptibility loci and SNPs. These measures are defined for pairs of sites, but for some applications a determination of how strong LD is across an entire region that contains many polymorphic sites might be desirable (e.g., testing whether the strength of LD differs significantly among loci or across populations, or whether there is more or less LD in a region than predicted under a particular model). Measuring LD across a region is not straightforward, but one approach is to use the measure r, which was developed in population genetics. Roughly speaking, r measures how much recombination would be required under a particular population model to generate the LD that is seen in the data. This type of method can potentially also provide a statistically rigorous approach to the problem of determining whether LD data provide evidence for the presence of recombination hotspots. For the methods described herein, a significant r² value can be at least 0.1 such as at least 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, or at least 0.99. In one preferred embodiment, the significant r² value can be at least 0.2. Alternatively, linkage disequilibrium as described herein, refers to linkage disequilibrium characterized by values of |D'| of at least 0.2, such as 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, or at least 0.99. Thus, linkage disequilibrium represents a correlation between alleles of distinct markers. It is measured by correlation coefficient or |D'| (r² up to 1.0 and |D'| up to 1.0). In certain embodiments, linkage disequilibrium is defined in terms of values for both the r² and |D'| measures. In one such embodiment, a significant linkage disequilibrium is defined as r²>0.1 and |D'|>0.8. In another embodiment, a significant linkage disequilibrium is defined as r²>0.2 and |D'|>0.9. Other combinations and permutations of values of r² and |D'| for determining linkage disequilibrium are also contemplated, and are also within the scope of the invention. Linkage disequilibrium can be determined in a single human population, as defined herein, or it can be determined in a collection of samples comprising individuals from more than one human population. In one embodiment of the invention, LD is determined in a sample from one or more of the HapMap populations (caucasian, african, japanese, chinese), as defined (http://www.hapmap.org). In one such embodiment, LD is determined in the CEU population of the HapMap samples. In another embodiment, LD is determined in the YRI population. In yet another embodiment, LD is determined in samples from the Icelandic population.

[0142] If all polymorphisms in the genome were independent at the population level (i.e., no LD), then every single one of them would need to be investigated in association studies, to assess all the different polymorphic states. However, due to linkage disequilibrium between polymorphisms, tightly linked polymorphisms are strongly correlated, which reduces the number of polymorphisms that need to be investigated in an association study to observe a significant association. Another consequence of LD is that many polymorphisms may give an association signal due to the fact that these polymorphisms are strongly correlated.

[0143] Genomic LD maps have been generated across the genome, and such LD maps have been proposed to serve as framework for mapping disease-genes (Risch, N. & Merkiangas, K, Science 273:1516-1517 (1996); Maniatis, N., et al., Proc Natl Acad Sci USA 99:2228-2233 (2002); Reich, D E et al, Nature 411:199-204 (2001)). It is also now established that many portions of the human genome can be broken into series of discrete haplotype blocks containing a few common haplotypes; for these blocks, linkage disequilibrium data provides little evidence indicating recombination (see, e.g., Wall., J. D. and Pritchard, J. K., Nature Reviews Genetics 4:587-597 (2003); Daly, M. et al., Nature Genet. 29:229-232 (2001); Gabriel, S. B. et al., Science 296:2225-2229 (2002); Patil, N. et al., Science 294:1719-1723 (2001); Dawson, E. et al., Nature 418:544-548 (2002); Phillips, M. S. et al., Nature Genet. 33:382-387 (2003)). There are two main methods for defining these haplotype blocks: blocks can be defined as regions of DNA that have limited haplotype diversity (see, e.g., Daly, M. et al., Nature Genet. 29:229-232 (2001); Patil, N. et al., Science 294:1719-1723 (2001); Dawson, E. et al., Nature 418:544-548 (2002); Zhang, K. et al., Proc. Natl. Acad. Sci. USA 99:7335-7339 (2002)), or as regions between transition zones having extensive historical recombination, identified using linkage disequilibrium (see, e.g., Gabriel, S. B. et al., Science 296:2225-2229 (2002); Phillips, M. S. et al., Nature Genet. 33:382-387 (2003); Wang, N. et al., Am. J. Hum. Genet. 71:1227-1234 (2002); Stumpf, M. P., and Goldstein, D. B., Curr. Biol. 13:1-8 (2003)). More recently, a fine-scale map of recombination rates and corresponding hotspots across the human genome has been generated (Myers, S., et al., Science 310:321-32324 (2005); Myers, S. et al., Biochem Soc Trans 34:526530 (2006)). The map reveals the enormous variation in recombination across the genome, with recombination rates as high as 10-60 cM/Mb in hotspots, while closer to 0 in intervening regions, which thus represent regions of limited haplotype diversity and high LD. The map can therefore be used to define haplotype blocks/LD blocks as regions flanked by recombination hotspots. As used herein, the terms "haplotype block" or "LD block" includes blocks defined by any of the above described characteristics, or other alternative methods used by the person skilled in the art to define such regions. Haplotype blocks (LD blocks) can be used to map associations between phenotype and haplotype status, using single markers or haplotypes comprising a plurality of markers. The main haplotypes can be identified in each haplotype block, and then a set of "tagging" SNPs or markers (the smallest set of SNPs or markers needed to distinguish among the haplotypes) can then be identified. These tagging SNPs or markers can then be used in assessment of samples from groups of individuals, in order to identify association between phenotype and haplotype. If desired, neighboring haplotype blocks can be assessed concurrently, as there may also exist linkage disequilibrium among the haplotype blocks.

[0144] It has thus become apparent that for any given observed association to a polymorphic marker in the genome, it is likely that additional markers in the genome also show association. This is a natural consequence of the uneven distribution of LD across the genome, as observed by the large variation in recombination rates. The markers used to detect association thus in a sense represent "tags" for a genomic region (i.e., a haplotype block or LD block; e.g., the C09 LD block) that is associating with a given disease or trait, and as such are useful for use in the methods and kits of the present invention. One or more causative (functional) variants or mutations may reside within the region found to be associating to the disease or trait. Such variants may confer a higher relative risk (RR) or odds ratio (OR) than observed for the tagging markers used to detect the association. The present invention thus refers to the markers used for detecting association to the disease, as described herein, as well as markers in linkage disequilibrium with the markers. Thus, in certain embodiments of the invention, markers that are in LD with the markers and/or haplotypes of the invention, as described herein, may be used as surrogate markers. The surrogate markers have in one embodiment relative risk (RR) and/or odds ratio (OR) values smaller than for the markers or haplotypes initially found to be associating with the disease, as described herein. In other embodiments, the surrogate markers have RR or OR values greater than those initially determined for the markers initially found to be associating with the disease, as described herein. An example of such an embodiment would be a rare, or relatively rare (such as <10% allelic population frequency) variant in LD with a more common variant (>10% population frequency) initially found to be associating with the disease, such as the variants described herein. Identifying and using such markers for detecting the association discovered by the inventors as described herein can be performed by routine methods well known to the person skilled in the art, and are therefore within the scope of the present invention.

Determination of Haplotype Frequency

[0145] The frequencies of haplotypes in patient and control groups can be estimated using an expectation-maximization algorithm (Dempster A. et al., J. R. Stat. Soc. B, 39:1-38 (1977)). An implementation of this algorithm that can handle missing genotypes and uncertainty with the phase can be used. Under the null hypothesis, the patients and the controls are assumed to have identical frequencies. Using a likelihood approach, an alternative hypothesis is tested, where a candidate at-risk-haplotype, which can include the markers described herein, is allowed to have a higher frequency in patients than controls, while the ratios of the frequencies of other haplotypes are assumed to be the same in both groups. Likelihoods are maximized separately under both hypotheses and a corresponding 1-df likelihood ratio statistic is used to evaluate the statistical significance.

[0146] To look for at-risk and protective markers and haplotypes within a linkage region, for example, association of all possible combinations of genotyped markers is studied, provided those markers span a practical region. The combined patient and control groups can be randomly divided into two sets, equal in size to the original group of patients and controls. The marker and haplotype analysis is then repeated and the most significant p-value registered is determined. This randomization scheme can be repeated, for example, over 100 times to construct an empirical distribution of p-values. In a preferred embodiment, a p-value of <0.05 is indicative of an significant marker and/or haplotype association.

Haplotype Analysis

[0147] One general approach to haplotype analysis involves using likelihood-based inference applied to NEsted MOdels (Gretarsdottir S., et al., Nat. Genet. 35:131-38 (2003)). The method is implemented in the program NEMO, which allows for many polymorphic markers, SNPs and microsatellites. The method and software are specifically designed for case-control studies where the purpose is to identify haplotype groups that confer different risks. It is also a tool for studying LD structures. In NEMO, maximum likelihood estimates, likelihood ratios and p-values are calculated directly, with the aid of the EM algorithm, for the observed data treating it as a missing-data problem.

[0148] Even though likelihood ratio tests based on likelihoods computed directly for the observed data, which have captured the information loss due to uncertainty in phase and missing genotypes, can be relied on to give valid p-values, it would still be of interest to know how much information had been lost due to the information being incomplete. The information measure for haplotype analysis is described in Nicolae and Kong (Technical Report 537, Department of Statistics, University of Statistics, University of Chicago; Biometrics, 60(2):368-75 (2004)) as a natural extension of information measures defined for linkage analysis, and is implemented in NEMO.

[0149] For single marker association to a disease, the Fisher exact test can be used to calculate two-sided p-values for each individual allele. Usually, all p-values are presented unadjusted for multiple comparisons unless specifically indicated. The presented frequencies (for microsatellites, SNPs and haplotypes) are allelic frequencies as opposed to carrier frequencies. To minimize any bias due the relatedness of the patients who were recruited as families for the linkage analysis, first and second-degree relatives can be eliminated from the patient list. Furthermore, the test can be repeated for association correcting for any remaining relatedness among the patients, by extending a variance adjustment procedure described in Risch, N. & Teng, J. (Genome Res., 8:1273-1288 (1998)), DNA pooling (ibid) for sibships so that it can be applied to general familial relationships, and present both adjusted and unadjusted p-values for comparison. The differences are in general very small as expected. To assess the significance of single-marker association corrected for multiple testing we can carry out a randomization test using the same genotype data. Cohorts of patients and controls can be randomized and the association analysis redone multiple times (e.g., up to 500,000 times) and the p-value is the fraction of replications that produced a p-value for some marker allele that is lower than or equal to the p-value we observed using the original patient and control cohorts.

[0150] For both single-marker and haplotype analyses, relative risk (RR) and the population attributable risk (PAR) can be calculated assuming a multiplicative model (haplotype relative risk model) (Terwilliger, J. D. & Ott, J., Hum. Hered. 42:337-46 (1992) and Falk, C. T. & Rubinstein, P, Ann. Hum. Genet. 51 (Pt 3):227-33 (1987)), i.e., that the risks of the two alleles/haplotypes a person carries multiply. For example, if RR is the risk of A relative to a, then the risk of a person homozygote AA will be RR times that of a heterozygote Aa and RR2 times that of a homozygote aa. The multiplicative model has a nice property that simplifies analysis and computations--haplotypes are independent, i.e., in Hardy-Weinberg equilibrium, within the affected population as well as within the control population. As a consequence, haplotype counts of the affecteds and controls each have multinomial distributions, but with different haplotype frequencies under the alternative hypothesis. Specifically, for two haplotypes, hi and hj, risk(hi)/risk(hj)=(fi/pi)/(fj/pj), where f and p denote, respectively, frequencies in the affected population and in the control population. While there is some power loss if the true model is not multiplicative, the loss tends to be mild except for extreme cases. Most importantly, p-values are always valid since they are computed with respect to null hypothesis.

Linkage Disequilibrium Using NEMO

[0151] LD between pairs of markers can be calculated using the standard definition of D' and r2 (Lewontin, R., Genetics 49:49-67 (1964); Hill, W. G. & Robertson, A. Theor. Appl. Genet. 22:226-231 (1968)). Using NEMO, frequencies of the two marker allele combinations are estimated by maximum likelihood and deviation from linkage equilibrium is evaluated by a likelihood ratio test. The definitions of D' and r2 are extended to include microsatellites by averaging over the values for all possible allele combination of the two markers weighted by the marginal allele probabilities.

Risk Assessment and Diagnostics

[0152] Within any given population, there is an absolute risk of developing a disease or trait, defined as the chance of a person developing the specific disease or trait over a specified time-period. For example, a woman's lifetime absolute risk of breast cancer is one in nine. That is to say, one woman in every nine will develop breast cancer at some point in their lives. Risk is typically measured by looking at very large numbers of people, rather than at a particular individual. Risk is often presented in terms of Absolute Risk (AR) and Relative Risk (RR). Relative Risk is used to compare risks associating with two variants or the risks of two different groups of people. For example, it can be used to compare a group of people with a certain genotype with another group having a different genotype. For a disease, a relative risk of 2 means that one group has twice the chance of developing a disease as the other group. The Risk presented is usually the relative risk for a person, or a specific genotype of a person, compared to the population with matched gender and ethnicity. Risks of two individuals of the same gender and ethnicity could be compared in a simple manner. For example, if, compared to the population, the first individual has relative risk 1.5 and the second has relative risk 0.5, then the risk of the first individual compared to the second individual is 1.5/0.5=3.

[0153] As described herein, certain polymorphic markers and haplotypes comprising such markers are found to be useful for risk assessment of cardiovascular disease, e.g., arterial diseases, e.g. myocardial infarction, coronary artery disease, restenosis, peripheral artery disease, stroke, intracranial aneurysm and abdominal aortic aneurysm. Risk assessment can involve the use of the markers for diagnosing a susceptibility to the cardiovascular disease. Particular alleles of polymorphic markers are found more frequently in individuals with cardiovascular disease, than in individuals without diagnosis of cardiovascular disease. Therefore, these marker alleles have predictive value for detecting cardiovascular disease, or a susceptibility to cardiovascular disease, in an individual. Tagging markers within haplotype blocks or LD blocks comprising at-risk markers, such as the markers of the present invention, can be used as surrogates for other markers and/or haplotypes within the haplotype block or LD block. Markers with values of r² equal to 1 are perfect surrogates for the at-risk variants, i.e. genotypes for one marker perfectly predicts genotypes for the other. Markers with smaller values of r² than 1 can also be surrogates for the at-risk variant, or alternatively represent variants with relative risk values as high as or possibly even higher than the at-risk variant. The at-risk variant identified may not be the functional variant itself, but is in this instance in linkage disequilibrium with the true functional variant. The present invention encompasses the assessment of such surrogate markers for the markers as disclosed herein. Such markers are annotated, mapped and listed in public databases, as well known to the skilled person, or can alternatively be readily identified by sequencing the region or a part of the region identified by the markers of the present invention in a group of individuals, and identify polymorphisms in the resulting group of sequences. As a consequence, the person skilled in the art can readily and without undue experimentation genotype surrogate markers in linkage disequilibrium with the markers and/or haplotypes as described herein. The tagging or surrogate markers in LD with the at-risk variants detected, also have predictive value for detecting association to the cardiovascular disease, or a susceptibility to the cardiovascular disease, in an individual. These tagging or surrogate markers that are in LD with the markers of the present invention can also include other markers that distinguish among haplotypes, as these similarly have predictive value for detecting susceptibility to cardiovascular disease.

[0154] The present invention can in certain embodiments be practiced by assessing a sample comprising genomic DNA from an individual for the presence of variants described herein to be associated with cardiovascular disease. Such assessment includes steps of detecting the presence or absence of at least one allele of at least one polymorphic marker, using methods well known to the skilled person and further described herein, and based on the outcome of such assessment, determine whether the individual from whom the sample is derived is at increased or decreased risk (increased or decreased susceptibility) of cardiovascular disease. Alternatively, the invention can be practiced utilizing a dataset comprising information about the genotype status of at least one polymorphic marker described herein to be associated with cardiovascular disease (or markers in linkage disequilibrium with at least one marker shown herein to be associated with cardiovascular disease). In other words, a dataset containing information about such genetic status, for example in the form of genotype counts at a certain polymorphic marker, or a plurality of markers (e.g., an indication of the presence or absence of certain at-risk alleles), or actual genotypes for one or more markers, can be queried for the presence or absence of certain at-risk alleles at certain polymorphic markers shown by the present inventors to be associated with cardiovascular disease. A positive result for a variant (e.g., marker allele) associated with cardiovascular disease, as shown herein, is indicative of the individual from which the dataset is derived is at increased susceptibility (increased risk) of at least one cardiovascular disease (e.g., arterial diseases, e.g. myocardial infarction, coronary artery disease, restenosis, peripheral artery disease, stroke, intracranial aneurysm and abdominal aortic aneurysm).

[0155] In certain embodiments of the invention, a polymorphic marker is correlated to a cardiovascular disease by referencing genotype data for the polymorphic marker to a look-up table that comprises correlations between at least one allele of the polymorphism and the disease. In some embodiments, the table comprises a correlation for one polymorhpism. In other embodiments, the table comprises a correlation for a plurality of polymorhpisms. In both scenarios, by referencing to a look-up table that gives an indication of a correlation between a marker and cardiovascular disease, a risk for cardiovascular disease, or a susceptibility to cardiovascular disease, can be identified in the individual from whom the sample is derived. In some embodiments, the correlation is reported as a statistical measure. The statistical measure may be reported as a risk measure, such as a relative risk (RR), an absolute risk (AR) or an odds ratio (OR).

[0156] The markers and haplotypes of the invention, e.g., the markers presented in Tables 1-36 herein, e.g. the markers in Table 3, 10 and 21, may be useful for risk assessment and diagnostic purposes for cardiovascular disease (e.g., arterial diseases, e.g. myocardial infarction, coronary artery disease, restenosis, peripheral artery disease, stroke, intracranial aneurysm and abdominal aortic aneurysm), either alone or in combination. Thus, even in the cases where the increase in risk by individual markers is relatively modest, i.e. on the order of 10-30%, the association may have significant implications. Thus, relatively common variants may have significant contribution to the overall risk (Population Attributable Risk is high), or combination of markers can be used to define groups of individual who, based on the combined risk of the markers, is at significant combined risk of developing a cardiovascular disease.

Biomarkers

[0157] The cardiovascular diseases are known to have several common biomarkers, which are believed to relate to increased risk of developing cardiovascular disease. These include elevated fibrinogen, PAI-1, homocysteine, asymmetric dimethylarginine, C-reactive protein and B-type natriuretic peptide (BNP). These common biomarkers underscore the common etiology for the cardiovascular diseases. Recently, urinary peptides have been shown to be promising biomarkers for Cardiovascular disease, in particular Coronary Artery Disease (CAD) (Zimmerli, L. U., et al., Mol Cell Proteomics 7:290-8 (2008)). These have the advantage of being non-invasive, only requiring a urine sample from the individual to be assessed. In one application, a pattern of polypeptides in the urine sample is characteristic of increased risk of CAD.

[0158] Many general inflammatory markers are predictive of risk of coronary heart disease, including CAD and MI, although these markers are not specific to atherosclerosis. For example, Stein (Stein, S., Am J Cardiol, 87 (suppl):21A-26A (2001)) discusses the use of any one of the following serum inflammatory markers as surrogates for predicting risk of coronary heart disease including C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, and matrix metalloprotease type-9.

[0159] A significant association between CRP levels in serum and increased risk for coronary heart disease was found in the Women's Health Study, with the highest relative risk of 4.5 seen for those women in the highest quintile of serum CRP (Ridker, P. M. et al., New England. J. Med., 347: 1557-1565 (2001)). A similar correlation between increased serum CRP and increased risk for coronary heart disease in women has been reported (Ridker, P. M et al., New Engld. J. Med., 342:836-843 (2000); Bermudez, E. A. et. al., Arterioscler. Thromb. Vasc. Biol., 22: 1668-1673 (2002)). A similar correlation between increased serum inflammatory markers such as CRP and increased risk for coronary heart disease has been reported for men (Doggen, C. J. M. et al., J. Internal Med., 248:406-414 (2000) and Ridker, P. M. et al., New England. J. Med., 336: 973-979 (1997)). Elevated CRP or other serum inflammatory markers is also prognostic for increased risk of a second myocardial infarct in patients with a previous myocardial infarct (Retterstol, L. et al., Atheroscler., 160: 433-440 (2002)). Emerging evidence also suggests that elevated CRP is an independent risk factor for adverse clinical outcomes. See, e.g., Ridker et al., N. Engl. J. Med. 352: 1 (Jan. 6, 2005).

[0160] The end products of the leukotriene pathway are potent inflammatory lipid mediators derived from arachidonic acid. They can potentially contribute to development of atherosclerosis and destabilization of atherosclerotic plaques through lipid oxidation and/or proinflammatory effects, and LTC4, LTD4, and LTE4, are known to induce vasoconstriction. On the other hand, LTB4 is a strong proinflammatory agent. Increased production of these end products of the leukotriene pathway, could therefore serve as a risk factor for MI and atherosclerosis, whereas both inflammation and vasoconstriction/vasospasm have a well established role in the pathogenesis of MI and atherosclerosis.

[0161] In certain embodiments of the invention, the genetic risk variants for cardiovascular disease, such as MI, CAD, AAA, IA, stroke and/or PAD are assessed in combination with at least one biomarker. For example, levels of an inflammatory marker in an appropriate test sample (e.g., serum, plasma or urine) can be measured and the determination of the biomarker level in the sample, relative to a control (either a normal, disease-free control, or a random sample from the population) is made. The result of the analysis can be analyzed in combination with genetic risk conferred by the variants described herein, to determine overall risk. Representative inflammatory markers include: C-reactive protein (CRP), serum amyloid A, fibrinogen, serum sCD40L, a leukotriene (e.g., LTB4, LTC4, LTD4, LTE4), a leukotriene metabolite, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, matrix metalloprotease type-9, myeloperoxidase (MPO), and N-tyrosine. In a preferred embodiment, the marker is CRP, sCD40L or MPO. The determination of biomarkers can be made by standard methods known to the skilled person. For example, in one embodiment, production of a leukotriene metabolite is stimulated in a first test sample from the individual, using a calcium ionophore. The level of production is compared with a control level. The control level is a level that is typically found in control individual(s), such as individual who are not at risk for MI, CAD, AAA, IA, stroke or PAD; alternatively, a control level is the level that is found by comparison of disease risk in a population associated with the lowest band of measurement (e.g., below the mean or median, the lowest quartile or the lowest quintile) compared to higher bands of measurement (e.g., above the mean or median, the second, third or fourth quartile; the second, third, fourth or fifth quintile).

[0162] As described in the above, the haplotype block structure of the human genome has the effect that a large number of variants (markers and/or haplotypes) in linkage disequilibrium with the variant originally associated with a disease or trait may be used as surrogate markers for assessing association to the disease or trait. The number of such surrogate markers will depend on factors such as the historical recombination rate in the region, the mutational frequency in the region (i.e., the number of polymorphic sites or markers in the region), and the extent of LD (size of the LD block) in the region. These markers are usually located within the physical boundaries of the LD block or haplotype block in question as defined using the methods described herein, or by other methods known to the person skilled in the art. However, sometimes marker and haplotype association is found to extend beyond the physical boundaries of the haplotype block as defined. Such markers and/or haplotypes may in those cases be also used as surrogate markers and/or haplotypes for the markers and/or haplotypes physically residing within the haplotype block as defined. As a consequence, markers and haplotypes in LD (typically characterized by r² greater than 0.1, such as r² greater than 0.2, including r² greater than 0.3, also including r² greater than 0.4) with the markers and haplotypes of the present invention are also within the scope of the invention, even if they are physically located beyond the boundaries of the haplotype block as defined. This includes markers that are described herein (e.g., Tables 1-36; e.g., Tables 3, 10, and 21), but may also include other markers that are in strong LD (e.g., characterized by r² greater than 0.1 or 0.2 and/or |D'|>0.8) with one or more of the markers listed in Tables 1-35, including the markers set forth in Tables 3, 10 and 21.

[0163] For the SNP markers described herein, the opposite allele to the allele found to be in excess in patients (at-risk allele) is found in decreased frequency in cardiovascular disease. These markers and haplotypes are thus protective for cardiovascular disease, i.e. they confer a decreased risk or susceptibility of individuals carrying these markers and/or haplotypes developing cardiovascular disease.

[0164] Certain variants of the present invention, including certain haplotypes comprise, in some cases, a combination of various genetic markers, e.g., SNPs and microsatellites. Detecting haplotypes can be accomplished by methods known in the art and/or described herein for detecting sequences at polymorphic sites. Furthermore, correlation between certain haplotypes or sets of markers and disease phenotype can be verified using standard techniques. A representative example of a simple test for correlation would be a Fisher-exact test on a two by two table.

[0165] In specific embodiments, a marker allele or haplotype associated with cardiovascular disease (e.g., marker alleles as listed in Tables 3, 10 and 21) is one in which the marker allele or haplotype is more frequently present in an individual at risk for cardiovascular disease, (affected), compared to the frequency of its presence in a healthy individual (control), wherein the presence of the marker allele or haplotype is indicative of cardiovascular disease or a susceptibility to cardiovascular disease. In other embodiments, at-risk markers in linkage disequilibrium with one or more markers found to be associated with cardiovascular disease, including coronary artery disease and in-stent restenosis (e.g., markers as listed in Tables 3, 10 and 21) are tagging markers that are more frequently present in an individual at risk for cardiovascular disease (affected), compared to the frequency of their presence in a healthy individual (control), wherein the presence of the tagging markers is indicative of increased susceptibility to cardiovascular disease. In a further embodiment, at-risk markers alleles (i.e. conferring increased susceptibility) in linkage disequilibrium with one or more markers found to be associated with cardiovascular disease (e.g., marker alleles as listed in Tables 3, 10 and 21, and markers in linkage disequilibrium therewith), are markers comprising one or more allele that is more frequently present in an individual at risk for cardiovascular disease, compared to the frequency of their presence in a healthy individual (control), wherein the presence of the markers is indicative of increased susceptibility to the cardiovascular disease.

Study Population

[0166] In a general sense, the methods and kits of the invention can be utilized from samples containing nucleic acid material (DNA or RNA) from any source and from any individual. In preferred embodiments, the individual is a human individual. The individual can be an adult, child, or fetus. The nucleic acid source may be any sample comprising nucleic acid material, including biological samples, or a sample comprising nucleic acid material derived therefrom. The present invention also provides for assessing markers and/or haplotypes in individuals who are members of a target population. Such a target population is in one embodiment a population or group of individuals at risk of developing the disease, based on other genetic factors, biomarkers, biophysical parameters (e.g., weight, BMD, blood pressure), or general health and/or lifestyle parameters (e.g., history of disease or related diseases, previous diagnosis of disease, family history of disease).

[0167] The invention provides for embodiments that include individuals from specific age subgroups, such as those over the age of 40, over age of 45, or over age of 50, 55, 60, 65, 70, 75, 80, or 85. Other embodiments of the invention pertain to other age groups, such as individuals aged less than 85, such as less than age 80, less than age 75, or less than age 70, 65, 60, 55, 50, 45, 40, 35, or age 30. Other embodiments relate to individuals with age at onset of the disease in any of the age ranges described in the above. It is also contemplated that a range of ages may be relevant in certain embodiments, such as age at onset at more than age 45 but less than age 60. Other age ranges are however also contemplated, including all age ranges bracketed by the age values listed in the above. The invention furthermore relates to individuals of either gender, males or females.

[0168] The Icelandic population is a Caucasian population of Northern European ancestry. A large number of studies reporting results of genetic linkage and association in the Icelandic population have been published in the last few years. Many of those studies show replication of variants, originally identified in the Icelandic population as being associating with a particular disease, in other populations (Stacey, S. N., et al., Nat. Genet. May 27, 2007 (Epub ahead of print; Helgadottir, A., et al., Science 316:1491-93 (2007); Steinthorsdottir, V., et al., Nat. Genet. 39:770-75 (2007); Gudmundsson, J., et al., Nat. Genet. 39:631-37 (2007); Amundadottir, L. T., et al., Nat. Genet. 38:652-58 (2006); Grant, S. F., et al., Nat. Genet. 38:320-23 (2006)). Thus, genetic findings in the Icelandic population have in general been replicated in other populations, including populations from Africa and Asia.

[0169] The markers of the present invention found to be associated with cardiovascular disease are believed to show similar association in other human populations. Particular embodiments comprising individual human populations are thus also contemplated and within the scope of the invention. Such embodiments relate to human subjects that are from one or more human population including, but not limited to, Caucasian populations, European populations, American populations, Eurasian populations, Asian populations, Central/South Asian populations, East Asian populations, Middle Eastern populations, African populations, Hispanic populations, and Oceanian populations. European populations include, but are not limited to, Swedish, Norwegian, Finnish, Russian, Danish, Icelandic, Irish, Kelt, English, Scottish, Dutch, Belgian, French, German, Spanish, Portugues, Italian, Polish, Bulgarian, Slavic, Serbian, Bosnian, Chech, Greek and Turkish populations. The invention furthermore in other embodiments can be practiced in specific human populations that include Bantu, Mandenk, Yoruba, San, Mbuti Pygmy, Orcadian, Adygel, Russian, Sardinian, Tuscan, Mozabite, Bedouin, Druze, Palestinian, Balochi, Brahui, Makrani, Sindhi, Pathan, Burusho, Hazara, Uygur, Kalash, Han, Dai, Daur, Hezhen, Lahu, Miao, Oroqen, She, Tujia, Tu, Xibo, Yi, Mongolan, Naxi, Cambodian, Japanese, Yakut, Melanesian, Papuan, Karitianan, Surui, Colombian, Maya and Pima.

[0170] In one preferred embodiment, the invention relates to populations that include black African ancestry such as populations comprising persons of African descent or lineage. Black African ancestry may be determined by self reporting as African-Americans, Afro-Americans, Black Americans, being a member of the black race or being a member of the negro race. For example, African Americans or Black Americans are those persons living in North America and having origins in any of the black racial groups of Africa. In another example, self-reported persons of black African ancestry may have at least one parent of black African ancestry or at least one grandparent of black African ancestry. In another embodiment, the invention relates to individuals of Caucasian origin.

[0171] The racial contribution in individual subjects may also be determined by genetic analysis. Genetic analysis of ancestry may be carried out using unlinked microsatellite markers such as those set out in Smith et al. (Am J Hum Genet. 74, 1001-13 (2004)).

[0172] In certain embodiments, the invention relates to markers and/or haplotypes identified in specific populations, as described in the above. The person skilled in the art will appreciate that measures of linkage disequilibrium (LD) may give different results when applied to different populations. This is due to different population history of different human populations as well as differential selective pressures that may have led to differences in LD in specific genomic regions. It is also well known to the person skilled in the art that certain markers, e.g. SNP markers, have different population frequency in different populations, or are polymorphic in one population but not in another. The person skilled in the art will however apply the methods available and as thought herein to practice the present invention in any given human population. This may include assessment of polymorphic markers in the LD region of the present invention, so as to identify those markers that give strongest association within the specific population. Thus, the at-risk variants of the present invention may reside on different haplotype background and in different frequencies in various human populations. However, utilizing methods known in the art and the markers of the present invention, the invention can be practiced in any given human population.

Utility of Genetic Testing

[0173] The person skilled in the art will appreciate and understand that the variants described herein in general do not, by themselves, provide an absolute identification of individuals who will develop a particular cardiovascular disease. The variants described herein do however indicate increased and/or decreased likelihood that individuals carrying the at-risk or protective variants of the invention will develop symptoms associated with at least one cardiovascular disease (e.g., MI, CAD, IA, AAA, restenosis, stroke PAD). This information is however extremely valuable in itself, as outlined in more detail in the below, as it can be used to, for example, initiate preventive measures at an early stage, perform regular physical and/or mental exams to monitor the progress and/or appearance of symptoms, or to schedule exams at a regular interval to identify early symptoms, so as to be able to apply treatment at an early stage.

[0174] The knowledge about a genetic variant that confers a risk of developing cardiovascular disease offers the opportunity to apply a genetic test to distinguish between individuals with increased risk of developing the disease (i.e. carriers of the at-risk variant) and those with decreased risk of developing the disease (i.e. carriers of the protective variant). The core values of genetic testing, for individuals belonging to both of the above mentioned groups, are the possibilities of being able to diagnose disease, or a predisposition to disease, at an early stage and provide information to the clinician about prognosis/aggressiveness of disease in order to be able to apply the most appropriate treatment.

[0175] Individuals with a family history of cardiovascular diseases and carriers of at-risk variants may benefit from genetic testing since the knowledge of the presence of a genetic risk factor, or evidence for increased risk of being a carrier of one or more risk factors, may provide increased incentive for implementing a healthier lifestyle (e.g., lose weight, increase exercise, give up smoking, reduce stress, etc.), by avoiding or minimizing known environmental risk factors for cardiovascular diseases. Genetic testing of patients may furthermore give valuable information about the primary cause of the cardiovascular disease and can aid the clinician in selecting the best treatment options and medication for each individual.

[0176] The present invention can be thus be used for risk assessment for cardiovascular disease, including diagnosing whether an individual is at risk for developing a cardiovascular disease, such as Myocardial Infarction, Coronary Artery Disease, PAD, AAA, IA, stroke or restenosis. The polymorphic markers of the present invention can be used alone or in combination, as well as in combination with other factors, including known biomarkers, for risk assessment of an individual for cardiovascular disease. Many factors known to affect the predisposition of individual towards developing risk of developing Cardiovascular disease are known to the person skilled in the art and can be utilized in such assessment. These include, but are not limited to, age, gender, smoking status, physical activity, waist-to-hip circumference ratio, family history of Cardiovascular Disease, previously diagnosed cardiovascular disease, obesity, diagnosis of Diabetes mellitus, stress, depression, elevated heart rate, hypertriglyceridemia, low HDL cholesterol, hypertension, elevated blood pressure, cholesterol levels, HDL cholesterol, LDL cholesterol, triglycerides, apolipoprotein AI and B levels, fibrinogen, ferritin, C-reactive protein and leukotriene levels. Methods known in the art can be used for such assessment, including multivariate analyses or logistic regression, as described further herein.

Methods

[0177] Methods for risk assessment cardiovascular disease are described herein and are encompassed by the invention. The invention also encompasses methods of assessing an individual for probability of response to a therapeutic agent for a cardiovascular disease, methods for predicting the effectiveness of a therapeutic agent for cardiovascular disease, nucleic acids, polypeptides and antibodies and computer-implemented functions. Kits for assaying a sample from a subject to detect susceptibility to cardiovascular disease are also encompassed by the invention.

Diagnostic Methods

[0178] In certain embodiments, the present invention pertains to methods of diagnosing, or aiding in the diagnosis of, cardiovascular disease (e.g., MI, CAD, IA, AAA, stroke, PAD, restenosis) or a susceptibility to cardiovascular disease, by detecting particular alleles at genetic markers that appear more frequently in subjects with at least one cardiovascular disease or subjects who are susceptible to cardiovascular disease. In a particular embodiment, the invention is a method of diagnosing a susceptibility to cardiovascular disease by detecting at least one allele of at least one polymorphic marker (e.g., the markers described herein). The present invention describes methods whereby detection of particular alleles of particular markers or haplotypes is indicative of a susceptibility to cardiovascular disease. Such prognostic or predictive assays can also be used to determine prophylactic treatment of a subject prior to the onset of symptoms of the cardiovascular disease. The present invention pertains in some embodiments to methods of clinical applications of diagnosis, e.g., diagnosis performed by a medical professional. In other embodiments, the invention pertains to methods of diagnosis or determination of a susceptibility performed by a layman. Recent technological advances in genotyping technologies, including high-throughput genotyping of SNP markers, such as Molecular Inversion Probe array technology (e.g., Affymetrix GeneChip), and BeadArray Technologies (e.g., Illumina GoldenGate and Infinium assays) have made it possible for individuals to have their own genome assessed for up to one million SNPs simultaneously, at relatively little cost. The resulting genotype information, made available to the individual can be compared to information from the public literature about disease or trait risk associated with various SNPs. The diagnostic application of disease-associated alleles as described herein, can thus be performed either by the individual, through analysis of his/her genotype data, or by a health professional based on results of a clinical test. In other words, the diagnosis or assessment of a susceptibility based on genetic risk can be made by health professionals, genetic counselors or by the layman, based on information about his/her genotype and publications on various risk factors. In the present context, the term "diagnosing", "diagnose a susceptibility" and "determine a susceptibility" is meant to refer to any available diagnostic method, including those mentioned above.

[0179] In addition, in certain other embodiments, the present invention pertains to methods of diagnosing, or aiding in the diagnosis of, a decreased susceptibility to cardiovascular disease, by detecting particular genetic marker alleles or haplotypes that appear less frequently in patients diagnosed with cardiovascular disease than in individual not diagnosed with cardiovascular disease or in the general population.

[0180] As described and exemplified herein, particular marker alleles or haplotypes (e.g. the markers and haplotypes as listed in Tables 3, 10 and 21, and markers in linkage disequilibrium therewith) are associated with cardiovascular disease. In one embodiment, the marker allele or haplotype is one that confers a significant risk or susceptibility to cardiovascular disease. In another embodiment, the invention relates to a method of diagnosing a susceptibility to cardiovascular disease in a human individual, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, or in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the polymorphic markers listed in Table 3, 10 or 21, and markers in linkage disequilibrium therewith. In another embodiment, the invention pertains to methods of diagnosing a susceptibility to cardiovascular disease in a human individual, by screening for at least one marker allele or haplotype as listed in Table 21 or markers in linkage disequilibrium therewith. In another embodiment, the marker allele or haplotype is more frequently present in a subject having, or who is susceptible to, cardiovascular disease (affected), as compared to the frequency of its presence in a healthy subject (control, such as population controls). In certain embodiments, the significance of association of the at least one marker allele or haplotype is characterized by a p value <0.05. In other embodiments, the significance of association is characterized by smaller p-values, such as <0.01, <0.001, <0.0001, <0.00001, <0.000001, <0.0000001, <0.00000001 or <0.000000001.

[0181] In these embodiments, the presence of the at least one marker allele or haplotype is indicative of a susceptibility to cardiovascular disease (e.g., MI, CAD, IA, Stroke, AAA, restenosis, PAD). These diagnostic methods involve detecting the presence or absence of at least one marker allele or haplotype that is associated with cardiovascular disease. The haplotypes described herein include combinations of alleles at various genetic markers (e.g., SNPs, microsatellites). The detection of the particular genetic marker alleles that make up the particular haplotypes can be performed by a variety of methods described herein and/or known in the art. For example, genetic markers can be detected at the nucleic acid level (e.g., by direct nucleotide sequencing or by other means known to the skilled in the art) or at the amino acid level if the genetic marker affects the coding sequence of a protein encoded by a cardiovascular disease, including coronary artery disease and in-stent restenosis-associated nucleic acid (e.g., by protein sequencing or by immunoassays using antibodies that recognize such a protein). The marker alleles or haplotypes of the present invention correspond to fragments of a genomic DNA sequence associated with cardiovascular disease. Such fragments encompass the DNA sequence of the polymorphic marker or haplotype in question, but may also include DNA segments in strong LD (linkage disequilibrium) with the marker or haplotype (e.g., as determined by particular values of r² and/or |D'|).

[0182] In one embodiment, diagnosis of a susceptibility to cardiovascular disease can be accomplished using hybridization methods, including, but not limited to, Southern analysis, Northern analysis, and/or in situ hybridizations (see Current Protocols in Molecular Biology, Ausubel, F. et al., eds., John Wiley & Sons, including all supplements). The presence of a specific marker allele can be indicated by sequence-specific hybridization of a nucleic acid probe specific for the particular allele. The presence of more than one specific marker allele or a specific haplotype can be indicated by using several sequence-specific nucleic acid probes, each being specific for a particular allele. In one embodiment, a haplotype can be indicated by a single nucleic acid probe that is specific for the specific haplotype (i.e., hybridizes specifically to a DNA strand comprising the specific marker alleles characteristic of the haplotype). A sequence-specific probe can be directed to hybridize to genomic DNA, RNA, or cDNA. A "nucleic acid probe", as used herein, can be a DNA probe or an RNA probe that hybridizes to a complementary sequence. One of skill in the art would know how to design such a probe so that sequence specific hybridization will occur only if a particular allele is present in a genomic sequence from a test sample.

[0183] To determine or diagnose a susceptibility to cardiovascular disease, a hybridization sample is formed by contacting the test sample containing an cardiovascular disease-associated nucleic acid, such as a genomic DNA sample, with at least one nucleic acid probe. A non-limiting example of a probe for detecting mRNA or genomic DNA is a labeled nucleic acid probe that is capable of hybridizing to mRNA or genomic DNA sequences described herein. The nucleic acid probe can be, for example, a full-length nucleic acid molecule, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length that is sufficient to specifically hybridize under stringent conditions to appropriate mRNA or genomic DNA. For example, the nucleic acid probe can comprise all or a portion of the nucleotide sequence of LD Block C09 (SEQ ID NO:94), as described herein, optionally comprising at least one allele of a marker described herein, or at least one haplotype described herein, or the probe can be the complementary sequence of such a sequence. In a particular embodiment, the nucleic acid probe is a portion of the nucleotide sequence of LD Block C09 (SEQ ID NO:94), as described herein, optionally comprising at least one allele of a marker described herein, or at least one allele of one polymorphic marker or haplotype comprising at least one polymorphic marker described herein, or the probe can be the complementary sequence of such a sequence. Other suitable probes for use in the diagnostic assays of the invention are described herein. Hybridization can be performed by methods well known to the person skilled in the art (see, e.g., Current Protocols in Molecular Biology, Ausubel, F. et al., eds., John Wiley & Sons, including all supplements). In one embodiment, hybridization refers to specific hybridization, i.e., hybridization with no mismatches (exact hybridization). In one embodiment, the hybridization conditions for specific hybridization are high stringency.

[0184] Specific hybridization, if present, is then detected using standard methods. If specific hybridization occurs between the nucleic acid probe and the coronary artery disease and in-stent restenosis-associated nucleic acid in the test sample, then the sample contains the allele that is complementary to the nucleotide that is present in the nucleic acid probe. The process can be repeated for other markers of the present invention, or markers that make up a haplotype of the present invention, or multiple probes can be used concurrently to detect more than one marker alleles at a time. It is also possible to design a single probe containing more than one marker alleles of a particular haplotype (e.g., a probe containing alleles complementary to 2, 3, 4, 5 or all of the markers that make up a particular haplotype). Detection of the particular markers of the haplotype in the sample is indicative that the source of the sample has the particular haplotype (e.g., a haplotype) and therefore is susceptible to cardiovascular disease (e.g., MI, CAD, IA, Stroke, AAA, restenosis, PAD).

[0185] In one preferred embodiment, a method utilizing a detection oligonucleotide probe comprising a fluorescent moiety or group at its 3' terminus and a quencher at its 5' terminus, and an enhancer oligonucleotide, is employed, as described by Kutyavin et al. (Nucleic Acid Res. 34:e128 (2006)). The fluorescent moiety can be Gig Harbor Green or Yakima Yellow, or other suitable fluorescent moieties. The detection probe is designed to hybridize to a short nucleotide sequence that includes the SNP polymorphism to be detected. Preferably, the SNP is anywhere from the terminal residue to -6 residues from the 3' end of the detection probe. The enhancer is a short oligonucleotide probe which hybridizes to the DNA template 3' relative to the detection probe. The probes are designed such that a single nucleotide gap exists between the detection probe and the enhancer nucleotide probe when both are bound to the template. The gap creates a synthetic abasic site that is recognized by an endonuclease, such as Endonuclease IV. The enzyme cleaves the dye off the fully complementary detection probe, but cannot cleave a detection probe containing a mismatch. Thus, by measuring the fluorescence of the released fluorescent moiety, assessment of the presence of a particular allele defined by nucleotide sequence of the detection probe can be performed.

[0186] The detection probe can be of any suitable size, although preferably the probe is relatively short. In one embodiment, the probe is from 5-100 nucleotides in length. In another embodiment, the probe is from 10-50 nucleotides in length, and in another embodiment, the probe is from 12-30 nucleotides in length. Other lengths of the probe are possible and within scope of the skill of the average person skilled in the art.

[0187] In a preferred embodiment, the DNA template containing the SNP polymorphism is amplified by Polymerase Chain Reaction (PCR) prior to detection. In such an embodiment, the amplified DNA serves as the template for the detection probe and the enhancer probe.

[0188] Certain embodiments of the detection probe, the enhancer probe, and/or the primers used for amplification of the template by PCR include the use of modified bases, including modified A and modified G. The use of modified bases can be useful for adjusting the melting temperature of the nucleotide molecule (probe and/or primer) to the template DNA, for example for increasing the melting temperature in regions containing a low percentage of G or C bases, in which modified A with the capability of forming three hydrogen bonds to its complementary T can be used, or for decreasing the melting temperature in regions containing a high percentage of G or C bases, for example by using modified G bases that form only two hydrogen bonds to their complementary C base in a double stranded DNA molecule. In a preferred embodiment, modified bases are used in the design of the detection nucleotide probe. Any modified base known to the skilled person can be selected in these methods, and the selection of suitable bases is well within the scope of the skilled person based on the teachings herein and known bases available from commercial sources as known to the skilled person.

[0189] In another hybridization method, Northern analysis (see Current Protocols in Molecular Biology, Ausubel, F. et al., eds., John Wiley & Sons, supra) is used to identify the presence of a polymorphism associated with cardiovascular disease. For Northern analysis, a test sample of RNA is obtained from the subject by appropriate means. As described herein, specific hybridization of a nucleic acid probe to RNA from the subject is indicative of a particular allele complementary to the probe. For representative examples of use of nucleic acid probes, see, for example, U.S. Pat. Nos. 5,288,611 and 4,851,330.

[0190] Additionally, or alternatively, a peptide nucleic acid (PNA) probe can be used in addition to, or instead of, a nucleic acid probe in the hybridization methods described herein. A PNA is a DNA mimic having a peptide-like, inorganic backbone, such as N-(2-aminoethyl)glycine units, with an organic base (A, G, C, T or U) attached to the glycine nitrogen via a methylene carbonyl linker (see, for example, Nielsen, P., et al., Bioconjug. Chem. 5:3-7 (1994)). The PNA probe can be designed to specifically hybridize to a molecule in a sample suspected of containing one or more of the marker alleles or haplotypes that are associated with cardiovascular disease. Hybridization of the PNA probe is thus diagnostic for cardiovascular disease.

[0191] In one embodiment of the invention, a test sample containing genomic DNA obtained from the subject is collected and the polymerase chain reaction (PCR) is used to amplify a fragment comprising one or more markers or haplotypes of the present invention. As described herein, identification of a particular marker allele or haplotype associated with cardiovascular disease, can be accomplished using a variety of methods (e.g., sequence analysis, analysis by restriction digestion, specific hybridization, single stranded conformation polymorphism assays (SSCP), electrophoretic analysis, etc.). In another embodiment, diagnosis is accomplished by expression analysis using quantitative PCR (kinetic thermal cycling). This technique can, for example, utilize commercially available technologies, such as TaqMan® (Applied Biosystems, Foster City, Calif.). The technique can assess the presence of an alteration in the expression or composition of a polypeptide or splicing variant(s) that is encoded by a nucleic acid associated with a cardiovascular disease. Further, the expression of the variant(s) can be quantified as physically or functionally different.

[0192] In another embodiment of the methods of the invention, analysis by restriction digestion can be used to detect a particular allele if the allele results in the creation or elimination of a restriction site relative to a reference sequence. A test sample containing genomic DNA is obtained from the subject. PCR can be used to amplify particular regions that are associated with cardiovascular disease (e.g. the polymorphic markers and haplotypes of Table 3, 10 or 21, and markers in linkage disequilibrium therewith) nucleic acid in the test sample from the test subject. Restriction fragment length polymorphism (RFLP) analysis can be conducted, e.g., as described in Current Protocols in Molecular Biology, supra. The digestion pattern of the relevant DNA fragment indicates the presence or absence of the particular allele in the sample.

[0193] Sequence analysis can also be used to detect specific alleles at polymorphic sites associated with cardiovascular disease, including coronary artery disease and in-stent restenosis (e.g. the polymorphic markers and haplotypes of Table 3, 10 or 21, and markers in linkage disequilibrium therewith). Therefore, in one embodiment, determination of the presence or absence of a particular marker alleles or haplotypes comprises sequence analysis. For example, a test sample of DNA or RNA can be obtained from the test subject. PCR or other appropriate methods can be used to amplify a portion of a nucleic acid associated with cardiovascular disease, and the presence of a specific allele can then be detected directly by sequencing the polymorphic site (or multiple polymorphic sites) of the genomic DNA in the sample.

[0194] In another embodiment, arrays of oligonucleotide probes that are complementary to target nucleic acid sequence segments from a subject, can be used to identify polymorphisms in a nucleic acid associated with cardiovascular disease (e.g. the polymorphic markers of Table 3, 10, and 21, and markers in linkage disequilibrium therewith). For example, an oligonucleotide array can be used. Oligonucleotide arrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate in different known locations. These arrays can generally be produced using mechanical synthesis methods or light directed synthesis methods that incorporate a combination of photolithographic methods and solid phase oligonucleotide synthesis methods, or by other methods known to the person skilled in the art (see, e.g., Fodor, S. et al., Science, 251:767-773 (1991); Pirrung et al., U.S. Pat. No. 5,143,854 (see also published PCT Application No. WO 90/15070); and Fodor. S. et al., published PCT Application No. WO 92/10092 and U.S. Pat. No. 5,424,186, the entire teachings of each of which are incorporated by reference herein). Techniques for the synthesis of these arrays using mechanical synthesis methods are described in, e.g., U.S. Pat. No. 5,384,261; the entire teachings of which are incorporated by reference herein. In another example, linear arrays can be utilized. Additional descriptions of use of oligonucleotide arrays for detection of polymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and 5,837,832, the entire teachings of both of which are incorporated by reference herein.

[0195] Other methods of nucleic acid analysis that are available to those skilled in the art can be used to detect a particular allele at a polymorphic site associated with cardiovascular disease. Representative methods include, for example, direct manual sequencing (Church and Gilbert, Proc. Natl. Acad. Sci. USA, 81: 1991-1995 (1988); Sanger, F., et al., Proc. Natl. Acad. Sci. USA, 74:5463-5467 (1977); Beavis, et al., U.S. Pat. No. 5,288,644); automated fluorescent sequencing; single-stranded conformation polymorphism assays (SSCP); clamped denaturing gel electrophoresis (CDGE); denaturing gradient gel electrophoresis (DGGE) (Sheffield, V., et al., Proc. Natl. Acad. Sci. USA, 86:232-236 (1989)), mobility shift analysis (Orita, M., et al., Proc. Natl. Acad. Sci. USA, 86:2766-2770 (1989)), restriction enzyme analysis (Flavell, R., et al., Cell, 15:25-41 (1978); Geever, R., et al., Proc. Natl. Acad. Sci. USA, 78:5081-5085 (1981)); heteroduplex analysis; chemical mismatch cleavage (CMC) (Cotton, R., et al., Proc. Natl. Acad. Sci. USA, 85:4397-4401 (1985)); RNase protection assays (Myers, R., et al., Science, 230:1242-1246 (1985); use of polypeptides that recognize nucleotide mismatches, such as E. coli mutS protein; and allele-specific PCR.

[0196] In another embodiment of the invention, diagnosis of cardiovascular disease or a susceptibility to cardiovascular disease can be made by examining expression and/or composition of a polypeptide encoded by a nucleic acid associated with cardiovascular disease in those instances where the genetic marker(s) or haplotype(s) of the present invention result in a change in the composition or expression of the polypeptide. Thus, diagnosis of a susceptibility to cardiovascular disease can be made by examining expression and/or composition of one of these polypeptides, or another polypeptide encoded by a nucleic acid associated with cardiovascular disease, in those instances where the genetic marker or haplotype of the present invention results in a change in the composition or expression of the polypeptide. The haplotypes and markers of the present invention that show association to cardiovascular disease may play a role through their effect on one or more of these nearby genes (e.g, the CDKN2A and CDKN2B genes). Possible mechanisms affecting these genes include, e.g., effects on transcription, effects on RNA splicing, alterations in relative amounts of alternative splice forms of mRNA, effects on RNA stability, effects on transport from the nucleus to cytoplasm, and effects on the efficiency and accuracy of translation.

[0197] Thus, in another embodiment, the variants (markers or haplotypes) of the invention showing association to cardiovascular disease affect the expression of a nearby gene (e.g., CDKN2A and/or CDKN2B). It is well known that regulatory element affecting gene expression may be located far away, even as far as tenths or hundreds of kilobases away, from the promoter region of a gene. By assaying for the presence or absence of at least one allele of at least one polymorphic marker of the present invention, it is thus possible to assess the expression level of such nearby genes. It is thus contemplated that the detection of the markers or haplotypes of the present invention can be used for assessing expression for one or more of the CDKN2A and/or CDKN2B genes.

[0198] A variety of methods can be used for detecting protein expression levels, including enzyme linked immunosorbent assays (ELISA), Western blots, immunoprecipitations and immunofluorescence. A test sample from a subject is assessed for the presence of an alteration in the expression and/or an alteration in composition of the polypeptide encoded by a nucleic acid associated with cardiovascular disease. An alteration in expression of a polypeptide encoded by a nucleic acid associated with cardiovascular disease can be, for example, an alteration in the quantitative polypeptide expression (i.e., the amount of polypeptide produced). An alteration in the composition of a polypeptide encoded by a nucleic acid associated with a cardiovascular disease is an alteration in the qualitative polypeptide expression (e.g., expression of a mutant polypeptide or of a different splicing variant). In one embodiment, diagnosis of a susceptibility to cardiovascular disease is made by detecting a particular splicing variant encoded by a nucleic acid associated with cardiovascular disease, or a particular pattern of splicing variants.

[0199] Both such alterations (quantitative and qualitative) can also be present. An "alteration" in the polypeptide expression or composition (e.g., the CDKN2A and/or CDKN2B polypeptides), as used herein, refers to an alteration in expression or composition in a test sample, as compared to the expression or composition of the polypeptide in a control sample. A control sample is a sample that corresponds to the test sample (e.g., is from the same type of cells), and is from a subject who is not affected by, and/or who does not have a susceptibility to, cardiovascular disease. In one embodiment, the control sample is from a subject that does not possess a marker allele or haplotype associated with cardiovascular disease, as described herein. Similarly, the presence of one or more different splicing variants in the test sample, or the presence of significantly different amounts of different splicing variants in the test sample, as compared with the control sample, can be indicative of a susceptibility to cardiovascular disease. An alteration in the expression or composition of the polypeptide in the test sample, as compared with the control sample, can be indicative of a specific allele in the instance where the allele alters a splice site relative to the reference in the control sample. Various means of examining expression or composition of a polypeptide encoded by a nucleic acid are known to the person skilled in the art and can be used, including spectroscopy, colorimetry, electrophoresis, isoelectric focusing, and immunoassays (e.g., David et al., U.S. Pat. No. 4,376,110) such as immunoblotting (see, e.g., Current Protocols in Molecular Biology, particularly chapter 10, supra).

[0200] For example, in one embodiment, an antibody (e.g., an antibody with a detectable label) that is capable of binding to a polypeptide encoded by a nucleic acid associated with cardiovascular disease (e.g., CDKN2A and/or CDKN2B polypeptides) can be used. Antibodies can be polyclonal or monoclonal. An intact antibody, or a fragment thereof (e.g., Fv, Fab, Fab', F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a labeled secondary antibody (e.g., a fluorescently-labeled secondary antibody) and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin.

[0201] In one embodiment of this method, the level or amount of polypeptide encoded by a nucleic acid associated with cardiovascular disease in a test sample is compared with the level or amount of the polypeptide in a control sample. A level or amount of the polypeptide in the test sample that is higher or lower than the level or amount of the polypeptide in the control sample, such that the difference is statistically significant, is indicative of an alteration in the expression of the polypeptide encoded by the nucleic acid, and is diagnostic for a particular allele or haplotype responsible for causing the difference in expression. Alternatively, the composition of the polypeptide in a test sample is compared with the composition of the polypeptide in a control sample. In another embodiment, both the level or amount and the composition of the polypeptide can be assessed in the test sample and in the control sample.

[0202] In another embodiment, the diagnosis of a susceptibility to cardiovascular disease is made by detecting at least one marker or haplotypes of the present invention (e.g., associated alleles of the markers listed in Table 3, 10 and/or 21, and markers in linkage disequilibrium therewith), in combination with an additional protein-based, RNA-based or DNA-based assay.

Kits

[0203] Kits useful in the methods of the invention comprise components useful in any of the methods described herein, including for example, primers for nucleic acid amplification, hybridization probes, restriction enzymes (e.g., for RFLP analysis), allele-specific oligonucleotides, antibodies that bind to an altered polypeptide encoded by a nucleic acid associated with cardiovascular disease (e.g., MI, CAD, IA, Stroke, AAA, restenosis, PAD) (e.g., antibodies that bind to a polypeptide encoded by LD Block C09 (SEQ ID NO:94), or the CDKN2A and/or CDKN2B genes or fragments thereof, e.g., a genomic segment comprising at least one polymorphic marker and/or haplotype of the present invention) or to a non-altered (native) polypeptide encoded by a nucleic acid associated with a cardiovascular disease, means for amplification of a nucleic acid associated with a cardiovascular disease, means for analyzing the nucleic acid sequence of a nucleic acid associated with a cardiovascular disease, means for analyzing the amino acid sequence of a polypeptide encoded by a nucleic acid associated with a cardiovascular disease, etc. The kits can for example include necessary buffers, nucleic acid primers for amplifying nucleic acids of the invention (e.g., a nucleic acid segment comprising one or more of the polymorphic markers as described herein), and reagents for allele-specific detection of the fragments amplified using such primers and necessary enzymes (e.g., DNA polymerase). Additionally, kits can provide reagents for assays to be used in combination with the methods of the present invention, e.g., reagents for use with other diagnostic assays as described herein.

[0204] In one embodiment, the invention pertains to a kit for assaying a sample from a subject to detect cardiovascular disease or a susceptibility to cardiovascular disease, wherein the kit comprises reagents necessary for selectively detecting at least one allele of at least one polymorphism of the present invention in the genome of the individual. In a particular embodiment, the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising at least one polymorphism of the present invention. In another embodiment, the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic segment obtained from a subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes one polymorphism, wherein the polymorphism is selected from the group consisting of the polymorphisms as listed in any of the Tables 3, 10 and 21, and polymorphic markers in linkage disequilibrium therewith. In yet another embodiment the fragment is at least 20 base pairs in size. Such oligonucleotides or nucleic acids (e.g., oligonucleotide primers) can be designed using portions of the nucleic acids flanking polymorphisms (e.g., SNPs or microsatellites) that are indicative of a cardiovascular disease. In another embodiment, the kit comprises one or more labeled nucleic acids capable of detecting one or more specific polymorphic markers or haplotypes associated with cardiovascular disease, and reagents for detection of the label. Suitable labels include, e.g., a radioisotope, a fluorescent label, an enzyme label, an enzyme co-factor label, a magnetic label, a spin label, an epitope label.

[0205] In particular embodiments, the polymorphic marker or haplotype to be detected by the reagents of the kit comprises one or more markers, two or more markers, three or more markers, four or more markers or five or more markers selected from the group consisting of the markers in Table 3, 10 and 21, and markers in linkage disequilibrium therewith. In another embodiment, the marker or haplotype to be detected comprises the markers listed in Table 3, 10 or 21. In another embodiment, the marker or haplotype to be detected comprises at least one marker from the group of markers in strong linkage disequilibrium, as defined by values of r² greater than 0.2, to at least one of the group of markers consisting of rs10757278, rs10116277, rs1333040, D9S1814, D9S1870 and rs2383207. In yet another embodiment, the marker or haplotype to be detected comprises at least one marker selected from the group of markers consisting of rs10757278, rs7041637, rs2811712, rs3218018, rs3217992, rs2069426, rs2069422, rs1333034, rs1011970, rs10116277, rs1333040, rs2383207, rs1333050, D9S1814, and D9S1870.

[0206] In one preferred embodiment, the kit for detecting the markers of the invention comprises a detection oligonucleotide probe, that hybridizes to a segment of template DNA containing a SNP polymorphisms to be detected, an enhancer oligonucleotide probe and an endonuclease. As explained in the above, the detection oligonucleotide probe comprises a fluorescent moiety or group at its 3' terminus and a quencher at its 5' terminus, and an enhancer oligonucleotide, is employed, as described by Kutyavin et al. (Nucleic Acid Res. 34:e128 (2006)). The fluorescent moiety can be Gig Harbor Green or Yakima Yellow, or other suitable fluorescent moieties. The detection probe is designed to hybridize to a short nucleotide sequence that includes the SNP polymorphism to be detected. Preferably, the SNP is anywhere from the terminal residue to -6 residues from the 3' end of the detection probe. The enhancer is a short oligonucleotide probe which hybridizes to the DNA template 3' relative to the detection probe. The probes are designed such that a single nucleotide gap exists between the detection probe and the enhancer nucleotide probe when both are bound to the template. The gap creates a synthetic abasic site that is recognized by an endonuclease, such as Endonuclease IV. The enzyme cleaves the dye off the fully complementary detection probe, but cannot cleave a detection probe containing a mismatch. Thus, by measuring the fluorescence of the released fluorescent moiety, assessment of the presence of a particular allele defined by nucleotide sequence of the detection probe can be performed.

[0207] The detection probe can be of any suitable size, although preferably the probe is relatively short. In one embodiment, the probe is from 5-100 nucleotides in length. In another embodiment, the probe is from 10-50 nucleotides in length, and in another embodiment, the probe is from 12-30 nucleotides in length. Other lengths of the probe are possible and within scope of the skill of the average person skilled in the art.

[0208] In a preferred embodiment, the DNA template containing the SNP polymorphism is amplified by Polymerase Chain Reaction (PCR) prior to detection, and primers for such amplification are included in the reagent kit. In such an embodiment, the amplified DNA serves as the template for the detection probe and the enhancer probe.

[0209] Certain embodiments of the detection probe, the enhancer probe, and/or the primers used for amplification of the template by PCR include the use of modified bases, including modified A and modified G. The use of modified bases can be useful for adjusting the melting temperature of the nucleotide molecule (probe and/or primer) to the template DNA, for example for increasing the melting temperature in regions containing a low percentage of G or C bases, in which modified A with the capability of forming three hydrogen bonds to its complementary T can be used, or for decreasing the melting temperature in regions containing a high percentage of G or C bases, for example by using modified G bases that form only two hydrogen bonds to their complementary C base in a double stranded DNA molecule. In a preferred embodiment, modified bases are used in the design of the detection nucleotide probe. Any modified base known to the skilled person can be selected in these methods, and the selection of suitable bases is well within the scope of the skilled person based on the teachings herein and known bases available from commercial sources as known to the skilled person.

[0210] In one such embodiment, the presence of the marker or haplotype is indicative of a susceptibility (increased susceptibility or decreased susceptibility) to Cardiovascular disease. In another embodiment, the presence of the marker or haplotype is indicative of response to a therapeutic agent for a Cardiovascular disease. In another embodiment, the presence of the marker or haplotype is indicative of prognosis of a Cardiovascular disease. In yet another embodiment, the presence of the marker or haplotype is indicative of progress of treatment of a cardiovascular disease. Such treatment may include intervention by surgery, medication or by other means (e.g., lifestyle changes).

[0211] In a further aspect of the present invention, a pharmaceutical pack (kit) is provided, the pack comprising a therapeutic agent and a set of instructions for administration of the therapeutic agent to humans diagnostically tested for one or more variants of the present invention, as disclosed herein. The therapeutic agent can be a small molecule drug, an antibody, a peptide, an antisense or RNAi molecule, or other therapeutic molecules. In one embodiment, an individual identified as a carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent. In one such embodiment, an individual identified as a homozygous carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent. In another embodiment, an individual identified as a non-carrier of at least one variant of the present invention is instructed to take a prescribed dose of the therapeutic agent.

[0212] In certain embodiments, the kit further comprises a set of instructions for using the reagents comprising the kit.

Therapeutic Agents

[0213] Variants of the present invention (e.g., the markers and/or haplotypes of the invention as described herein, e.g., the markers listed in Table 3, 10 and 21) can be used to identify novel therapeutic targets for cardiovascular disease. For example, genes containing, or in linkage disequilibrium with, variants (markers and/or haplotypes) associated with cardiovascular disease, or their products (e.g., the CDKN2A and CDKN2B genes and their gene products), as well as genes or their products that are directly or indirectly regulated by or interact with these genes or their products, can be targeted for the development of therapeutic agents to treat cardiovascular disease, or prevent or delay onset of symptoms associated with cardiovascular disease. Therapeutic agents may comprise one or more of, for example, small non-protein and non-nucleic acid molecules, proteins, peptides, protein fragments, nucleic acids (DNA, RNA), PNA (peptide nucleic acids), or their derivatives or mimetics which can modulate the function and/or levels of the target genes or their gene products.

[0214] The nucleic acids and/or variants of the invention, or nucleic acids comprising their complementary sequence, may be used as antisense constructs to control gene expression in cells, tissues or organs. The methodology associated with antisense techniques is well known to the skilled artisan, and is described and reviewed in AntisenseDrug Technology: Principles, Strategies, and Applications, Crooke, ed., Marcel Dekker Inc., New York (2001). In general, antisense nucleic acid molecules are designed to be complementary to a region of mRNA expressed by a gene, so that the antisense molecule hybridizes to the mRNA, thus blocking translation of the mRNA into protein. Several classes of antisense oligonucleotide are known to those skilled in the art, including cleavers and blockers. The former bind to target RNA sites, activate intracellular nucleases (e.g., RnaseH or Rnase L), that cleave the target RNA. Blockers bind to target RNA, inhibit protein translation by steric hindrance of the ribosomes. Examples of blockers include nucleic acids, morpholino compounds, locked nucleic acids and methylphosphonates (Thompson, Drug Discovery Today, 7:912-917 (2002)). Antisense oligonucleotides are useful directly as therapeutic agents, and are also useful for determining and validating gene function, for example by gene knock-out or gene knock-down experiments. Antisense technology is further described in Layery et al., Curr. Opin. Drug Discov. Devel. 6:561-569 (2003), Stephens et al., Curr. Opin. Mol. Ther. 5:118-122 (2003), Kurreck, Eur. J. Biochem. 270:1628-44 (2003), Dias et al., Mol. Cancer. Ter. 1:347-55 (2002), Chen, Methods Mol. Med. 75:621-636 (2003), Wang et al., Curr. Cancer Drug Targets 1:177-96 (2001), and Bennett, Antisense Nucleic Acid Drug. Dev. 12:215-24 (2002)

[0215] The variants described herein can be used for the selection and design of antisense reagents that are specific for particular variants. Using information about the variants described herein, antisense oligonucleotides or other antisense molecules that specifically target mRNA molecules that contain one or more variants of the invention can be designed. In this manner, expression of mRNA molecules that contain one or more variant of the present invention (markers and/or haplotypes) can be inhibited or blocked. In one embodiment, the antisense molecules are designed to specifically bind a particular allelic form (i.e., one or several variants (alleles and/or haplotypes)) of the target nucleic acid, thereby inhibiting translation of a product originating from this specific allele or haplotype, but which do not bind other or alternate variants at the specific polymorphic sites of the target nucleic acid molecule.

[0216] As antisense molecules can be used to inactivate mRNA so as to inhibit gene expression, and thus protein expression, the molecules can be used to treat a disease or disorder, such as a cardiovascular disease. The methodology can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Such mRNA regions include, for example, protein-coding regions, in particular protein-coding regions corresponding to catalytic activity, substrate and/or ligand binding sites, or other functional domains of a protein.

[0217] The phenomenon of RNA interference (RNAi) has been actively studied for the last decade, since its original discovery in C. elegans (Fire et al., Nature 391:806-11 (1998)), and in recent years its potential use in treatment of human disease has been actively pursued (reviewed in Kim & Rossi, Nature Rev. Genet. 8:173-204 (2007)). RNA interference (RNAi), also called gene silencing, is based on using double-stranded RNA molecules (dsRNA) to turn off specific genes. In the cell, cytoplasmic double-stranded RNA molecules (dsRNA) are processed by cellular complexes into small interfering RNA (siRNA). The siRNA guide the targeting of a protein-RNA complex to specific sites on a target mRNA, leading to cleavage of the mRNA (Thompson, Drug Discovery Today, 7:912-917 (2002)). The siRNA molecules are typically about 20, 21, 22 or 23 nucleotides in length. Thus, one aspect of the invention relates to isolated nucleic acid molecules, and the use of those molecules for RNA interference, i.e. as small interfering RNA molecules (siRNA). In one embodiment, the isolated nucleic acid molecules are 18-26 nucleotides in length, preferably 19-25 nucleotides in length, more preferably 20-24 nucleotides in length, and more preferably 21, 22 or 23 nucleotides in length.

[0218] Another pathway for RNAi-mediated gene silencing originates in endogenously encoded primary microRNA (pri-miRNA) transcripts, which are processed in the cell to generate precursor miRNA (pre-miRNA). These miRNA molecules are exported from the nucleus to the cytoplasm, where they undergo processing to generate mature miRNA molecules (miRNA), which direct translational inhibition by recognizing target sites in the 3' untranslated regions of mRNAs, and subsequent mRNA degradation by processing P-bodies (reviewed in Kim & Rossi, Nature Rev. Genet. 8:173-204 (2007)).

[0219] Clinical applications of RNAi include the incorporation of synthetic siRNA duplexes, which preferably are approximately 20-23 nucleotides in size, and preferably have 3' overlaps of 2 nucleotides. Knockdown of gene expression is established by sequence-specific design for the target mRNA. Several commercial sites for optimal design and synthesis of such molecules are known to those skilled in the art.

[0220] Other applications provide longer siRNA molecules (typically 25-30 nucleotides in length, preferably about 27 nucleotides), as well as small hairpin RNAs (shRNAs; typically about 29 nucleotides in length). The latter are naturally expressed, as described in Amarzguioui et al. (FEBS Lett. 579:5974-81 (2005)). Chemically synthetic siRNAs and shRNAs are substrates for in vivo processing, and in some cases provide more potent gene-silencing than shorter designs (Kim et al., Nature Biotechnol. 23:222-226 (2005); Siolas et al., Nature Biotechnol. 23:227-231 (2005)). In general siRNAs provide for transient silencing of gene expression, because their intracellular concentration is diluted by subsequent cell divisions. By contrast, expressed shRNAs mediate long-term, stable knockdown of target transcripts, for as long as transcription of the shRNA takes place (Marques et al., Nature Biotechnol. 23:559-565 (2006); Brummelkamp et al., Science 296: 550-553 (2002)).

[0221] Since RNAi molecules, including siRNA, miRNA and shRNA, act in a sequence-dependent manner, the variants of the present invention (e.g., the markers and haplotypes set forth in Tables 3, 10 and 21) can be used to design RNAi reagents that recognize specific nucleic acid molecules comprising specific alleles and/or haplotypes (e.g., the alleles and/or haplotypes of the present invention), while not recognizing nucleic acid molecules comprising other alleles or haplotypes. These RNAi reagents can thus recognize and destroy the target nucleic acid molecules. As with antisense reagents, RNAi reagents can be useful as therapeutic agents (i.e., for turning off disease-associated genes or disease-associated gene variants), but may also be useful for characterizing and validating gene function (e.g., by gene knock-out or gene knock-down experiments).

[0222] Delivery of RNAi may be performed by a range of methodologies known to those skilled in the art. Methods utilizing non-viral delivery include cholesterol, stable nucleic acid-lipid particle (SNALP), heavy-chain antibody fragment (Fab), aptamers and nanoparticles. Viral delivery methods include use of lentivirus, adenovirus and adeno-associated virus. The siRNA molecules are in some embodiments chemically modified to increase their stability. This can include modifications at the 2' position of the ribose, including 2'-O-methylpurines and 2'-fluoropyrimidines, which provide resistance to Rnase activity. Other chemical modifications are possible and known to those skilled in the art.

[0223] The following references provide a further summary of RNAi, and possibilities for targeting specific genes using RNAi: Kim & Rossi, Nat. Rev. Genet. 8:173-184 (2007), Chen & Rajewsky, Nat. Rev. Genet. 8: 93-103 (2007), Reynolds, et al., Nat. Biotechnol. 22:326-330 (2004), Chi et al., Proc. Natl. Acad. Sci. USA 100:6343-6346 (2003), Vickers et al., J. Biol. Chem. 278:7108-7118 (2003), Agami, Curr. Opin. Chem. Biol. 6:829-834 (2002), Layery, et al., Curr. Opin. Drug Discov. Devel. 6:561-569 (2003), Shi, Trends Genet. 19:9-12 (2003), Shuey et al., Drug Discov. Today 7:1040-46 (2002), McManus et al., Nat. Rev. Genet. 3:737-747 (2002), Xia et al., Nat. Biotechnol. 20:1006-10 (2002), Plasterk et al., curr. Opin. Genet. Dev. 10:562-7 (2000), Bosher et al., Nat. Cell Biol. 2:E31-6 (2000), and Hunter, Curr. Biol. 9:R440-442 (1999).

[0224] A genetic defect leading to increased predisposition or risk for development of a cardiovascular disease, or a defect causing the disease, may be corrected permanently by administering to a subject carrying the defect a nucleic acid fragment that incorporates a repair sequence that supplies the normal/wild-type nucleotide(s) at the site of the genetic defect. Such site-specific repair sequence may concompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The administration of the repair sequence may be performed by an appropriate vehicle, such as a complex with polyethelenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus vector, or other pharmaceutical compositions suitable for promoting intracellular uptake of the administered nucleic acid. The genetic defect may then be overcome, since the chimeric oligonucleotides induce the incorporation of the normal sequence into the genome of the subject, leading to expression of the normal/wild-type gene product. The replacement is propagated, thus rendering a permanent repair and alleviation of the symptoms associated with the disease or condition.

[0225] The present invention provides methods for identifying compounds or agents that can be used to treat cardiovascular disease. Thus, the variants of the invention are useful as targets for the identification and/or development of therapeutic agents. In certain embodiments, such methods include assaying the ability of an agent or compound to modulate the activity and/or expression of a nucleic acid that includes at least one of the variants (markers and/or haplotypes) of the present invention, or the encoded product of the nucleic acid (e.g, one or both of the CDKN2A and CDKN2B genes). This in turn can be used to identify agents or compounds that inhibit or alter the undesired activity or expression of the encoded nucleic acid product. Assays for performing such experiments can be performed in cell-based systems or in cell-free systems, as known to the skilled person. Cell-based systems include cells naturally expressing the nucleic acid molecules of interest, or recombinant cells that have been genetically modified so as to express a certain desired nucleic acid molecule.

[0226] Variant gene expression in a patient can be assessed by expression of a variant-containing nucleic acid sequence (for example, a gene containing at least one variant of the present invention, which can be transcribed into RNA containing the at least one variant, and in turn translated into protein), or by altered expression of a normal/wild-type nucleic acid sequence due to variants affecting the level or pattern of expression of the normal transcripts, for example variants in the regulatory or control region of the gene. Assays for gene expression include direct nucleic acid assays (mRNA), assays for expressed protein levels, or assays of collateral compounds involved in a pathway, for example a signal pathway. Furthermore, the expression of genes that are up- or down-regulated in response to the signal pathway can also be assayed. One embodiment includes operably linking a reporter gene, such as luciferase, to the regulatory region of the gene(s) of interest.

[0227] Modulators of gene expression can in one embodiment be identified when a cell is contacted with a candidate compound or agent, and the expression of mRNA is determined. The expression level of mRNA in the presence of the candidate compound or agent is compared to the expression level in the absence of the compound or agent. Based on this comparison, candidate compounds or agents for treating cardiovascular disease can be identified as those modulating the gene expression of the variant gene. When expression of mRNA or the encoded protein is statistically significantly greater in the presence of the candidate compound or agent than in its absence, then the candidate compound or agent is identified as a stimulator or up-regulator of expression of the nucleic acid. When nucleic acid expression or protein level is statistically significantly less in the presence of the candidate compound or agent than in its absence, then the candidate compound is identified as an inhibitor or down-regulator of the nucleic acid expression.

[0228] The invention further provides methods of treatment using a compound identified through drug (compound and/or agent) screening as a gene modulator (i.e. stimulator and/or inhibitor of gene expression).

Methods of Assessing Probability of Response to Therapeutic Agents and Methods, Methods of Monitoring Treatment Progress and Methods for Treating Cardiovascular Disease

[0229] As is known in the art, individuals can have differential responses to a particular therapy (e.g., a therapeutic agent or therapeutic method). Pharmacogenomics addresses the issue of how genetic variations (e.g., the variants (markers and/or haplotypes) of the present invention) affect drug response, due to altered drug disposition and/or abnormal or altered action of the drug. Thus, the basis of the differential response may be genetically determined in part. Clinical outcomes due to genetic variations affecting drug response may result in toxicity of the drug in certain individuals (e.g., carriers or non-carriers of the genetic variants of the present invention), or therapeutic failure of the drug. Therefore, the variants of the present invention may determine the manner in which a therapeutic agent and/or method acts on the body, or the way in which the body metabolizes the therapeutic agent.

[0230] Accordingly, in one embodiment, the presence of a particular allele of a polymorphic marker, or the presence of a haplotype as described herein is indicative of a different response rate to a particular treatment modality for a cardiovascular disease. This means that a patient diagnosed with cardiovascular disease, or at risk for a cardiovascular disease, and carrying a certain allele at a polymorphic or haplotype of the present invention (e.g., the at-risk alleles and/or haplotypes of the invention) would respond better to, or worse to, a specific therapeutic, drug and/or other therapy used to treat the cardiovascular disease. Therefore, the presence or absence of the marker allele or haplotype could aid in deciding what treatment should be used for a the patient. For example, for a newly diagnosed patient, the presence of a marker or haplotype of the present invention may be assessed (e.g., through testing DNA derived from a blood sample or other sample containing genomic DNA, as described herein). If the patient is positive for a marker allele or haplotype at (that is, at least one specific allele of the marker, or haplotype, is present), then the physician recommends one particular therapy (e.g., one particular therapeutic agent or a combination of therapeutic agents), while if the patient is negative for the at least one allele of a marker, or a haplotype, then a different course of therapy may be recommended (which may include recommending that no immediate therapy, other than serial monitoring for progression of the disease, be performed). Thus, the patient's carrier status could be used to help determine whether a particular treatment modality should be administered. The value lies within the possibilities of being able to diagnose the disease at an early stage and provide information to the clinician about prognosis/aggressiveness of the disease in order to be able to apply the most appropriate treatment.

[0231] As one example, the application of a genetic test for restenosis can identify subjects who are at high risk of developing restenosis after coronary stent procedure. While it is know that some treatment methods for coronary artery disease, such as introducing drug-eluting stents and brachytherapy, are associated with decreased risk of in-stent restenosis, the use of these methods are restricted because of number of reasons, including economical reasons. Identification of individuals within the group of those undergoing coronary stent procedure who are carriers of genetic risk variants for in-stent restenosis will allow targeting of those individuals that would benefit most from therapy associated with decreased risk of in-stent restenosis.

[0232] The present invention also relates to methods of monitoring effectiveness of a treatment for a cardiovascular disease, including coronary artery disease, MI, stroke, PAD, IA, AAA and restenosis. This can be done based on the genotype and/or haplotype status of the markers and haplotypes of the present invention, or by monitoring expression of genes that are associated with the variants (markers and haplotypes) of the present invention (e.g., CDKN2A and CDKN2B). The risk gene mRNA or the encoded polypeptide can be measured in a tissue sample (e.g., a peripheral blood sample, or a biopsy sample). Expression levels and/or mRNA levels can thus be determined before and during treatment to monitor its effectiveness. Alternatively, or concomitantly, the genotype and/or haplotype status of at least one risk variant for cardiovascular disease as presented herein is determined before and during treatment to monitor its effectiveness.

[0233] The treatment modules of a cardiovascular disease to which the invention pertains includes, but is not limited to, methods of treatment for myocardial infarction or susceptibility to myocardial infarction; methods of phophylaxis therapy for myocardial infarction; methods of treatment for transient ischemic attack or stroke, or susceptibility to stroke; methods of treatment for claudication, PAD or susceptibility to PAD; methods of treatment for acute coronary syndrome (e.g., unstable angina, non-ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI)); methods for reducing risk of MI, stroke or PAD; methods for decreasing risk of a second myocardial infarction or stroke; methods of treatment for atherosclerosis, such as for patients requiring treatment (e.g., angioplasty, stents, revascularization procedure) to restore blood flow in arteries (e.g., coronary, carotid, and/or femoral arteries); methods of treatment for asymptomatic ankle/brachial index of less than 0.9; and/or methods for decreasing leukotriene synthesis (e.g., for treatment of myocardial infarction, stroke or PAD), methods for treatment of abdominal aorta aneurysm, methods for treatment of intracranial aneurysm.

[0234] Treatment of coronary artery disease and MI may be categorized as (i) preventive treatment and (ii) disease management. The main goal of the latter is to minimize damage to the heart and prevent further complications. The first line of disease management typically includes one or more of administration of oxygen, aspirin, glyceryl nitrate (nitroglycerin) and analgesia, such as morphine or related drugs. Once diagnosis of MI is made, additional therapy may include beta blockers, anticoagulation agents, including heparin and/or low molecular weight heparin, and possibly also antiplatelet agents, such as clopidogrel. Secondary prevention, i.e. the management of risk of a recurrent MI, typically includes one or more of the following: Antiplatelet drug therapy, including aspirin and/or clopidogrel, beta blocker therapy, including metoprolol and carvedilol, ACE inhibitor therapy, Statin therapy, Aldosterone antagonist therapy, including eplerenone. Further, non-therapeutic administration of food supplements such as omega-3 fatty acids may be benefitional.

[0235] New preventive therapy for cardiovascular disease, including CAD, MI and stroke, includes agents that act on the formation and/or rupture of plaques, and also includes phosphodiesterase inhibitors. Such therapeutic agents are useful in the methods of the invention, as described herein. This includes, but is not limited to, agents that target the leukotriene synthesis pathway. The leukotriene synthesis inhibitor can be any agent that inhibits or antagonizes a member of the leukotriene synthesis pathway (e.g., FLAP, 5-LO, LTC4S, LTA4H, and LTB4DH). For example, the leukotriene synthesis inhibitor can be an agent that inhibits or antagonizes FLAP polypeptide activity (e.g., a FLAP inhibitor) and/or FLAP nucleic acid expression (e.g., a FLAP nucleic acid antagonist). In another embodiment, the leukotriene synthesis inhibitor is an agent that inhibits or antagonizes polypeptide activity and/or nucleic acid expression of another member of the leukotriene biosynthetic pathway (e.g., LTC4S, LTA4H) or that increases breakdown of leukotrienes (e.g., LTB4DH). In preferred embodiments, the agent alters activity and/or nucleic acid expression of FLAP, LTA4H or of 5-LO. Preferred agents include those set forth in the Agent Table I herein. In another embodiment, preferred agents can be: 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-alpha,alpha-dimeth- yl-5-(2-quinolinylmethoxy)-1H-Indole-2-propanoic acid otherwise known as MK-0591, (R)-(+)-alpha-cyclopentyl-4-(2-quinolinylmethoxy)-Benzeneacetic acid, otherwise known as BAY-x-1005, 3-(3-(1,1-dimethylethylthio-5-(quinoline-2-ylmethoxy)-1-(4-chloromethylph- enypindole-2-yl)-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid otherwise known as A-81834; or can be zileuton, atreleuton, 6-((3-fluoro-5-(tetrahydro-4-methoxy-2H-pyran-4yl)phenoxy)methyl)-1-methy- l-2(1H)-quinlolinone otherwise known as ZD-2138, 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-alpha,alpha-dimeth- yl-5-(2-quinolinylmethoxy)-1H-Indole-2-propanoic acid otherwise known as MK-886, 4-(3-(4-(2-Methyl-imidazol-1-yl)-phenylsulfanyl)-phenyl)-tetrahyd- ro-pyran-4-carboxylic acid amide otherwise known as CJ-13610. Additional agents include those described in Penning et al., Med. Chem. 2002 45(16):3482-90, Penning, Curr Pharm Des. 2001, 7(3):163-79 and Penning et al., J Med. Chem. 2000 43(4):721-35. In another embodiment, the agent alters metabolism or activity of a leukotriene (e.g., LTA4, LTB4, LTC4, LTD4, LTE4, Cys LT1, Cys LT2), such as leukotriene antagonists or antibodies to leukotrienes, as well as agents which alter activity of a leukotriene receptor (e.g., BLT1, BLT2, CysLTR1, and CysLTR2).

[0236] In other preferred embodiments, the agent alters activity and/or nucleic acid expression of LTA4H. Preferred agents include those set forth in the Agent Table II; but also include the following agents: 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpieridine; 1-[2-[4-(4-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine; 3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propionic acid; methyl 3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propionate; 3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propionic acid; methyl-3-[methyl[3-[4-(3-theinylmethyl)phenoxy]propyl]amino]propionate; 3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propionic acid; 3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propionic acid; N-[3-[[3-[4-(phenylmethyl)phenoxy]propyl]methylamino]propionyl]benzenesul- fonamide; 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-(1H-tetrazol-5-y- l)piperidine; 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-(1H-tetrazol-5-yl)piperidine. In another embodiment, preferred agents can be: ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate, otherwise known as SC-56938; [4-[5-(3-Phenyl-propyl)thiophen-2-yl]butoxy]acetic acid, otherwise known as RP64966; (R)--S-[[4-(dimethylamino)phenyl]methyl]-N-(3-mercapto-2-methyl-1-oxoprop- yl-L-cycteine, otherwise known as SA6541. In one preferred embodiment, the therapeutic agent is 4-{(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]pyrrolidin-1-yl}-butyramide, also known as DG-051.

[0237] The agents for treating or preventing a cardiovascular disease can be administered alone, or in combination with a statin. Statins include, but are not limited to, the agents rovuvastatin, fluvastatin, atorvastatin, lovastatin (also known as mevolin), simvastatin, pravastatin, pitavastatin, mevastatin, cerevastatin, ML-236A, ML-236B, MBV-530A and MB-530B.

[0238] All agents listed in the above and in Agent Table I and Agent Table II also include their optically pure enantiomers, salts, chemical derivatives, and analogues.

TABLE-US-00002 AGENT TABLE I Date Patent Issued/ Product_Name Application (Code) Structure Chemical Name Patent Ref Published MOA Abbott atreleuton (ABT-761) ##STR00001## (R)-(+)-N-[3[5-[(4- fluorophenyl)methyl]-2thienyl]- 1methyl-2-propynyl]- N-hydroxurea U.S. Pat. No. 5,288,751, U.S. Pat. No. 5,288,743, U.S. Pat. No. 5,616,596 2/22/94 04/01/97 5-LPO inhibitor Abbott A-81834 ##STR00002## 3-(3-(1,1-dimethylethylthio-5- (quinoline-2-ylmethoxy)-1-(4- chloromethylphenyl)indole-2-yl)- 2,2-dimethylpropionaldehyde oxime-0-2-acetic acid WO9203132, U.S. Pat. No. 5,459,150 3/5/1992, 10/17/95 FLAP inhibitor Abbott A-86886 ##STR00003## 3-(3-(1,1-dimethylethylthio-5- (pyridin-2-ylmethoxy)-1-(4- chloromethylphenyl)indole-2-yl)- 2,2-dimethylpropionaldehyde oxime-0-2-acetic acid WO9203132, U.S. Pat. No. 5,459,150 3/5/1992, 10/17/95 5-LPO inhibitor Abbott A-93178 ##STR00004## FLAP inhibitor AstraZeneca ##STR00005## EP 623614 9/11/94 5-LPO inhibitor AstraZeneca ZD-2138 ##STR00006## 6-((3-fluoro-5- (tetrahydro-4-methoxy-2H- pyran-4yl)phenoxy)methyl) 1-methyl-2(1H)- quinlolinone (alternatively NH can be N-methyl) EP 466452 5-LPO inhibitor Bayer BAY-X-1005 ##STR00007## (R)-(+)-alpha-cyclopentyl 4-(2-quinolinylmethoxy)- Benzeneacetic acid U.S. Pat. No. 4,970,215 EP 344519, DE 19880531 FLAP inhibitor Merck MK-0591 ##STR00008## 1-((4- chlorophenyl)methyl)-3- ((1,1-dimethylethyl)thio) alpha, alpha-dimethyl-5- (2-quinolinylmethoxy)-1H- Indole-2-propanoic acid EP 419049, US 19890822 FLAP inhibitor Merck MK-866 (3[3-)4-chlorobenzyl)-3-t-butyl- thio-5-isopropylindol-2yl]2,2- dimethyl-proanoic acid 5-LPO inhibitor Merck MK-886 ##STR00009## 1-((4-chlorophenyl)methyl)-3- ((1,1dimethylethyl)thio)- alpha, alpha-dimethyl-5-(2- quinolinylmethoxy)-1H- Indole-2-propanoic acid EP 419049, US 19890822 5-LPO inhibitor Pfizer CJ-13610 4-(3-(4-(2-Methyl- imidazol-1-yl)- phenylsulfanyl)-phenyl)- tetrahydro-pyran-4- carboxylic acid amide 5-LPO inhibitor

TABLE-US-00003 AGENT TABLE II Target Compound ID Chemical Name Patent/Reference LTA4H SC-57461A 3-[methyl[3-[4- Penning, T. D. et. al. Bioorg Med. Chem. Inhibitor (phenylmethyl)phenoxy]- Letters (2003), 13, 1137-1139. propyl]amino]propionic acid ibid, (2002), 12, 3383-3386 LTA4H SC-56938 Ethyl-1-[2-[4- Penning, T. D. et. al. Bioorg Med. Chem. Inhibitor (phenylmethyl)phenoxy]ethyl]-4- Letters (2003), 13, 1137-1139. piperidine-carboxylate ibid, (2002), 12, 3383-3386. US 6506876A1 LTA4H RP 64966 [4-[5-(3-Phenyl-propyl)thiophen- WO9627585 Inhibitor 2-yl]butoxy]acetic acid LTA4H SA 6541 (R)-S-[[4- WO9809943 Inhibitor (dimethylamino)phenyl]methyl]- N-(3-mercapto-2methyl-1- oxopropyl-L-cycteine LTA4H SA-9499/SA- (R)-3-(4-Dimethylamino- Inhibitor 6541 benzylsulfanyl)-2-((R)-3- mercapto-2-methyl- propionylamino)-propionic acid LTB4 Receptor Amelubant/ Carbamic acid,((4-((3-((4-(1-(4- U.S. Pat. No. 6,576,669 Antagonist BIIL-284 hydroxyphenyl)-1- methylethyl)phenoxy)methyl)phenyl)methoxy)phenyl)iminomethyl)- ethyl ester LTB4 Receptor BIRZ-227 5-Chloro-2-[3-(4-methoxy- Journal of Organic Chemistry 1998, Antagonist phenyl)-2-pyridin-2-yl- 63: 2 (326-330). pyrrolidin-1-yl]-benzooxazole LTB4 Receptor CP 195543 2-[(3S,4R)-3,4-dihydro-4- Process: WO 98/11085 1998, priority US Antagonist hydroxy-3-(phenylmethyl)-2H-1- 60/26372 1996; J. Pharamacology and Expert. benzopyran-7-yl]-4- Therapy, 1998, 285: 946-54 (trifluoromethyl)benzoic acid LTB4 Receptor Ebselen 2-Phenyl-benzo[d]isoselenazol-3-one Journal of Cerebral Blood Flow and Antagonist Metabolism 1995, July 2-6 (S162); Drugs of the Future 1995, 20: 10 (1057) LTB4 Receptor LTB 019; 4-[5-(4-Carbamimidoyl- ACS Meeting 1994, 207th: San Diego (MEDI Antagonist CGS-25019C phenoxy)-pentyloxy]-N,N- 003); International Congress of the diisopropyl-3-methoxy- Inflammation Research Association 1994, benzamide maleate 7th: White Haven (Abs W23) LTB4 Receptor LY 210073 5-(2-Carboxy-ethyl)-6-[6-(4- J Med Chem 1993 36 (12) 1726-1734 Antagonist methoxy-phenyl)-hex-5- enyloxy]-9-oxo-9H-xanthene-2- carboxylic acid LTB4 Receptor LY 213024 5-(3-carboxybenzoyl)-2- J Med Chem 1993 36 (12) 1726-1734 Antagonist (decyloxy)benzenepropanoic acid LTB4 Receptor LY 255283 1-[5-ethyl-2-hydroxy-4-[[6- EP 276064 B 1990, priority US 2479 1987 Antagonist methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone LTB4 Receptor LY 264086 7-carboxy-3-(decyloxy)-9-oxo- U.S. Pat. No. 4,996,230 1991, priority Antagonist 9H-xanthene-4-propanoic acid US 481413 1990 LTB4 Receptor LY 292728 7-carboxy-3-[3-[(5-ethyl-4'- EP 743064 A 1996, priority US 443179 1995 Antagonist fluoro-2-hydroxy[1,1'-biphenyl]- 4-yl)oxy]propoxy]-9-oxo-9H- xanthene-4-propanoic acid disodium salt LTB4 Receptor LY-293111 Benzoic acid,2-(3-(3-((5-ethyl-4'- Proceedings of the American Society for Antagonist (VML-295) fluoro-2-hydroxy(1,1'-biphenyl)- Clinical Oncology 2002, 21: 1 (Abs 343) [LY- 4-yl)oxy)propoxy)-2-propylphenoxy)- 293111 for Cancer] SCRIP World Pharmaceutical News 1997, 2272 (13) [for VML-295] LTB4 Receptor ONO 4057; (E)-2-(4-carboxybutoxy)-6-[[6- EP 405116 A 1991 Antagonist LB 457 (4-methoxyphenyl)-5- hexenyl]oxy]benzenepropanoic acid LTB4 Receptor PF 10042 1-[5-hydroxy-5-[8-(1-hydroxy-2- EP 422329 B 1995, priority US 409630 1989 Antagonist phenylethyl)-2-dibenzofuranyl]- 1-oxo pentyl]pyrrolidine LTB4 Receptor RG-14893 8-Benzyloxy-4-[(methyl- SCRIP World Pharmaceutical News Antagonist phenethyl-carbamoyl)-methyl]- 1996, 2168 (20) naphthalene-2-carboxylic acid LTB4 Receptor SB-201993 3-{6-(2-Carboxy-vinyl)-5-[8-(4- WO-09500487 Antagonist methoxy-phenyl)-octyloxy]-pyridin-2- ylmethylsulfanylmethyl}-benzoic acid LTB4 Receptor SC-52798 7-[3-(2-Cyclopropylmethyl-3- Bioorganic and Medicinal Chemistry Letters Antagonist methoxy-4-thiazol-4-yl- 1994, 4: 6 (811-816); Journal of Medicinal phenoxy)-propoxy]-8-propyl- Chemistry 1995, 38: 6 (858-868) chroman-2-carboxylic acid LTB4 Receptor SC-53228 3-{7-[3-(2-Cyclopropylmethyl-3- International Congress of the Inflammation Antagonist methoxy-4-methylcarbamoyl- Research Association 1994, 7th: White Haven phenoxy)-propoxy]-8-propyl- (Abs W5) chroman-2-yl}-propionic acid LTB4 Receptor WAY 121006 3-fluoro-4'-(2-quinolinylmethoxy)-[1,1'- Drugs under Experimental and Clinical Antagonist biphenyl]-4-acetic acid research 1991, 17: 8 (381-387) LTB4 Receptor ZD-2138 3-Amino-3-(4-methoxy- International Symposium on Medicinal Antagonist tetrahydro-pyran-4-yl)-acrylic Chemistry 1994, 13th: Paris (P 197) acid 1-methyl-2-oxo-1,2- dihydro-quinolin-6-ylmethyl ester

[0239] Alternatively, biological networks or metabolic pathways related to the markers and haplotypes of the present invention can be monitored by determining mRNA and/or polypeptide levels. This can be done for example, by monitoring expression levels or polypeptides for several genes belonging to the network and/or pathway, in samples taken before and during treatment. Alternatively, metabolites belonging to the biological network or metabolic pathway can be determined before and during treatment. Effectiveness of the treatment is determined by comparing observed changes in expression levels/metabolite levels during treatment to corresponding data from healthy subjects.

[0240] In a further aspect, the markers of the present invention can be used to increase power and effectiveness of clinical trials. Thus, individuals who are carriers of the at-risk variants of the present invention may be more likely to respond to a particular treatment modality. In one embodiment, individuals who carry at-risk variants for gene(s) in a pathway and/or metabolic network for which a particular treatment (e.g., small molecule drug, e.g. the small molecule drugs as listed in the above, e.g., the drugs listed in Agent Table I and Agent Table II) is targeting, are more likely to be responders to the treatment. In another embodiment, individuals who carry at-risk variants for a gene, which expression and/or function is altered by the at-risk variant, are more likely to be responders to a treatment modality targeting that gene, its expression or its gene product.

[0241] In a further aspect, the markers and haplotypes of the present invention can be used for targeting the selection of pharmaceutical agents for specific individuals. Personalized selection of treatment modalities, lifestyle changes (e.g., change in diet, exercise, weight loss program, smoking abstinence, less stressful lifestyle, etc.) or combination of the two, can be realized by the utilization of the at-risk variants of the present invention. Thus, the knowledge of an individual's status for particular markers of the present invention, can be useful for selection of treatment options that target genes or gene products affected by the at-risk variants of the invention. Certain combinations of variants may be suitable for one selection of treatment options, while other gene variant combinations may target other treatment options. Such combination of variant may include one variant, two variants, three variants, or four or more variants, as needed to determine with clinically reliable accuracy the selection of treatment module.

[0242] In addition to the diagnostic and therapeutic uses of the variants of the present invention, the variants (markers and haplotypes) can also be useful markers for human identification, and as such be useful in forensics, paternity testing and in biometrics. The specific use of SNPs for forensic purposes is reviewed by Gill (Int. J. Legal Med. 114:204-10 (2001)). Genetic variations in genomic DNA between individuals can be used as genetic markers to identify individuals and to associate a biological sample with an individual. Genetic markers, including SNPs and microsatellites, can be useful to distinguish individuals. The more markers that are analyzed, the lower the probability that the allelic combination of the markers in any given individual is the same as in an unrelated individual (assuming that the markers are unrelated, i.e. that the markers are in perfect linkage equilibrium). Thus, the variants used for these purposes are preferably unrelated, i.e. they are inherited independently. Thus, preferred markers can be selected from available markers, such as the markers of the present invention, and the selected markers may comprise markers from different regions in the human genome, including markers on different chromosomes.

[0243] In certain applications, the SNPs useful for forensic testing are from degenerate codon positions (i.e., the third position in certain codons such that the variation of the SNP does not affect the amino acid encoded by the codon). In other applications, such for applications for predicting phenotypic characteristics including race, ancestry or physical characteristics, it may be more useful and desirable to utilize SNPs that affect the amino acid sequence of the encoded protein. In other such embodiments, the variant (SNP or other polymorphic marker) affects the expression level of a nearby gene, thus leading to altered protein expression.

Computer-Implemented Aspects

[0244] The present invention also relates to computer-implemented applications of the polymorphic markers and haplotypes described herein to be associated with cardiovascular disease. Such applications can be useful for storing, manipulating or otherwise analyzing genotype data that is useful in the methods of the invention. One example pertains to storing genotype information derived from an individual on readable media, so as to be able to provide the genotype information to a third party (e.g., the individual), or for deriving information from the genotype data, e.g., by comparing the genotype data to information about genetic risk factors contributing to increased susceptibility to cardiovascular disease, and reporting results based on such comparison.

[0245] One such aspect relates to computer-readable media. In general terms, such medium has capabilities of storing (i) identifier information for at least one polymorphic marker or a haplotye; (ii) an indicator of the frequency of at least one allele of said at least one marker, or the frequency of a haplotype, in individuals with cardiovascular disease (e.g., MI; CAD, IA, AAA, stroke, restenosis, PAD); and an indicator of the frequency of at least one allele of said at least one marker, or the frequency of a haplotype, in a reference population. The reference population can be a disease-free population of individuals. Alternatively, the reference population is a random sample from the general population, and is thus representative of the population at large. The frequency indicator may be a calculated frequency, a count of alleles and/or haplotype copies, or normalized or otherwise manipulated values of the actual frequencies that are suitable for the particular medium.

[0246] Additional information about the individual can be stored on the medium, such as ancestry information, information about sex, physical attributes or characteristics (including height and weight), biochemical measurements (such as blood pressure, blood lipid levels, lipid levels, such as cholesterol levels), biomarkers relevant for cardiovascular disease, as described further herein, or other useful information that is desirable to store or manipulate in the context of the genotype status of a particular individual.

[0247] The invention furthermore relates to an apparatus that is suitable for determination or manipulation of genetic data useful for determining a susceptibility to cardiovascular disease in a human individual. Such an apparatus can include a computer-readable memory, a routine for manipulating data stored on the computer-readable memory, and a routine for generating an output that includes a measure of the genetic data. Such measure can include values such as allelic or haplotype frequencies, genotype counts, sex, age, phenotype information, values for odds ratio (OR) or relative risk (RR), population attributable risk (PAR), or other useful information that is either a direct statistic of the original genotype data or based on calculations based on the genetic data.

[0248] The markers and haplotypes shown herein to be associated with increased susceptibility (e.g., increased risk) of cardiovascular disease, are in certain embodiments useful for interpretation and/or analysis of genotype data. Thus in certain embodiments, an identification of an at-risk allele for a cardiovascular disease, as shown herein, or an allele at a polymorphic marker in LD with any one of the markers shown herein to be associated with cardiovascular disease, is indicative of the individual from whom the genotype data originates is at increased risk of cardiovascular disease. In one such embodiment, genotype data is generated for at least one polymorphic marker shown herein to be associated with cardiovascular disease, or a marker in linkage disequilibrium therewith. The genotype data is subsequently made available to the individual from whom the data originates, for example via a user interface accessible over the internet, together with an interpretation of the genotype data, e.g., in the form of a risk measure (such as an absolute risk (AR), risk ratio (RR) or odds ration (OR)) for the cardiovascular disease. In another embodiment, at-risk markers identified in a genotype dataset derived from an individual are assessed and results from the assessment of the risk conferred by the presence of such at-risk varians in the dataset are made available to the individual, for example via a secure web interface, or by other communication means. The results of such risk assessment can be reported in numeric form (e.g., by risk values, such as absolute risk, relative risk, and/or an odds ratio, or by a percentage increase in risk compared with a reference), by graphical means, or by other means suitable to illustrate the risk to the individual from whom the genotype data is derived. In particular embodiments, the results of risk assessment is made available to a third party, e.g., a physician, other healthcare worker or genetic counselor.

Markers Useful in Various Aspects of the Invention

[0249] The above-described applications can all be practiced with the markers and haplotypes of the invention that have in more detail been described with respect to methods of assessing susceptibility to cardiovascular disease and described in detail herein. Thus, these applications can in general be reduced to practice using any of the markers listed in Tables 1-35, and markers in linkage disequilibrium therewith. In some embodiments, the marker is selected from the markers set forth in Tables 3, 10 or 21, and markers in linkage disequilibrium therewith. In one embodiment, the markers or haplotypes are present within the genomic segment whose sequence is set forth in SEQ ID NO:94. In another embodiment, the markers and haplotypes comprise at least one marker selected from rs7041637, rs2811712, rs3218018, rs3217992, rs2069426, rs2069422, rs1333034, rs1011970, rs10116277, rs1333040, rs2383207, rs1333050, D9S1814, rs10757278, rs10757274, rs10333049, D9S1870, optionally including markers in linkage disequilibrium therewith. In one specific embodiment, linkage disequilibrium is defined by numerical values for r² of greater than 0.2. In another embodiment, the marker or haplotype comprises at least one marker selected from rs7041637 allele A, rs2811712 allele A, rs3218018 allele A, rs3217992 allele A, rs2069426 allele C, rs2069422 allele A, rs1333034 allele A, rs1011970 allele G, rs10116277 allele T, rs1333040 allele T, rs2383207 allele G, rs1333050 allele T, D9S1814 allele 0, rs10757278 allele G, rs1333049 allele C, rs10757274 allele G, and/or D9S1870 allele X (composite allele of all alleles smaller than 2), wherein the indicated allele is indicative of increased susceptibility of the Cardiovascular disease.

Nucleic Acids and Polypeptides

[0250] The nucleic acids and polypeptides described herein can be used in methods and kits of the present invention. An "isolated" nucleic acid molecule, as used herein, is one that is separated from nucleic acids that normally flank the gene or nucleotide sequence (as in genomic sequences) and/or has been completely or partially purified from other transcribed sequences (e.g., as in an RNA library). For example, an isolated nucleic acid of the invention can be substantially isolated with respect to the complex cellular milieu in which it naturally occurs, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. In some instances, the isolated material will form part of a composition (for example, a crude extract containing other substances), buffer system or reagent mix. In other circumstances, the material can be purified to essential homogeneity, for example as determined by polyacrylamide gel electrophoresis (PAGE) or column chromatography (e.g., HPLC). An isolated nucleic acid molecule of the invention can comprise at least about 50%, at least about 80% or at least about 90% (on a molar basis) of all macromolecular species present. With regard to genomic DNA, the term "isolated" also can refer to nucleic acid molecules that are separated from the chromosome with which the genomic DNA is naturally associated. For example, the isolated nucleic acid molecule can contain less than about 250 kb, 200 kb, 150 kb, 100 kb, 75 kb, 50 kb, 25 kb, 10 kb, 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of the nucleotides that flank the nucleic acid molecule in the genomic DNA of the cell from which the nucleic acid molecule is derived.

[0251] The nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated. Thus, recombinant DNA contained in a vector is included in the definition of "isolated" as used herein. Also, isolated nucleic acid molecules include recombinant DNA molecules in heterologous host cells or heterologous organisms, as well as partially or substantially purified DNA molecules in solution. "Isolated" nucleic acid molecules also encompass in vivo and in vitro RNA transcripts of the DNA molecules of the present invention. An isolated nucleic acid molecule or nucleotide sequence can include a nucleic acid molecule or nucleotide sequence that is synthesized chemically or by recombinant means. Such isolated nucleotide sequences are useful, for example, in the manufacture of the encoded polypeptide, as probes for isolating homologous sequences (e.g., from other mammalian species), for gene mapping (e.g., by in situ hybridization with chromosomes), or for detecting expression of the gene in tissue (e.g., human tissue), such as by Northern blot analysis or other hybridization techniques.

[0252] The invention also pertains to nucleic acid molecules that hybridize under high stringency hybridization conditions, such as for selective hybridization, to a nucleotide sequence described herein (e.g., nucleic acid molecules that specifically hybridize to a nucleotide sequence containing a polymorphic site associated with a haplotype described herein). In one embodiment, the invention includes variants that hybridize under high stringency hybridization and wash conditions (e.g., for selective hybridization) to a nucleotide sequence that comprises the nucleotide sequence of LD Block C09 (SEQ ID NO:94) or a fragment thereof (or a nucleotide sequence comprising the complement of the nucleotide sequence of LD Block C09 as set forth in SEQ ID NO:94), wherein the nucleotide sequence comprises at least one at-risk allele of at least one polymorphic marker, or at least one haplotype, as described herein.

[0253] The percent identity of two nucleotide or amino acid sequences can be determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first sequence). The nucleotides or amino acids at corresponding positions are then compared, and the percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=# of identical positions/total # of positions×100). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, of the length of the reference sequence. The actual comparison of the two sequences can be accomplished by well-known methods, for example, using a mathematical algorithm. A non-limiting example of such a mathematical algorithm is described in Karlin, S, and Altschul, S., Proc. Natl. Acad. Sci. USA, 90:5873-5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0), as described in Altschul, S. et al., Nucleic Acids Res., 25:3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., NBLAST) can be used. See the website on the world wide web at ncbi.nlm.nih.gov. In one embodiment, parameters for sequence comparison can be set at score=100, wordlength=12, or can be varied (e.g., W=5 or W=20). Other examples include the algorithm of Myers and Miller, CABIOS (1989), ADVANCE and ADAM as described in Torellis, A. and Robotti, C., Comput. Appl. Biosci. 10:3-5 (1994); and FASTA described in Pearson, W. and Lipman, D., Proc. Natl. Acad. Sci. USA, 85:2444-48 (1988). In another embodiment, the percent identity between two amino acid sequences can be accomplished using the GAP program in the GCG software package (Accelrys, Cambridge, UK).

[0254] The present invention also provides isolated nucleic acid molecules that contain a fragment or portion that hybridizes under highly stringent conditions to a nucleic acid that comprises, or consists of, the nucleotide sequence of LD Block C09 (SEQ ID NO:94), or a nucleotide sequence comprising, or consisting of, the complement of the nucleotide sequence of LD Block C09 (SEQ ID NO:94), wherein the nucleotide sequence comprises at least one polymorphic allele contained in the markers and haplotypes described herein. The nucleic acid fragments of the invention are at least about 15, at least about 18, 20, 23 or 25 nucleotides, and can be 30, 40, 50, 100, 200, 500, 1000, 10,000 or more nucleotides in length.

[0255] The nucleic acid fragments of the invention are used as probes or primers in assays such as those described herein. "Probes" or "primers" are oligonucleotides that hybridize in a base-specific manner to a complementary strand of a nucleic acid molecule. In addition to DNA and RNA, such probes and primers include polypeptide nucleic acids (PNA), as described in Nielsen, P. et al., Science 254:1497-1500 (1991). A probe or primer comprises a region of nucleotide sequence that hybridizes to at least about 15, typically about 20-25, and in certain embodiments about 40, 50 or 75, consecutive nucleotides of a nucleic acid molecule comprising a contiguous nucleotide sequence from LD Block C09 and comprising at least one allele of at least one polymorphic marker or at least one haplotype described herein, or the complement thereof. In particular embodiments, a probe or primer can comprise 100 or fewer nucleotides; for example, in certain embodiments from 6 to 50 nucleotides, or, for example, from 12 to 30 nucleotides. In other embodiments, the probe or primer is at least 70% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to the contiguous nucleotide sequence or to the complement of the contiguous nucleotide sequence. In another embodiment, the probe or primer is capable of selectively hybridizing to the contiguous nucleotide sequence or to the complement of the contiguous nucleotide sequence. Often, the probe or primer further comprises a label, e.g., a radioisotope, a fluorescent label, an enzyme label, an enzyme co-factor label, a magnetic label, a spin label, an epitope label.

[0256] The nucleic acid molecules of the invention, such as those described above, can be identified and isolated using standard molecular biology techniques and the sequence information provided by the nucleotide sequence of LD Block C09 (SEQ ID NO:94). See generally PCR Technology: Principles and Applications for DNA Amplification (ed. H. A. Erlich, Freeman Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications (Eds. Innis, et al., Academic Pres), San Diego, Calif., 1990); Mattila, P. et al., Nucleic Acids Res., 19:4967-4973 (1991); Eckert, K. and Kunkel, T., PCR Methods and Applications, 1:17-24 (1991); PCR (eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. No. 4,683,202, the entire teachings of each of which are incorporated herein by reference.

[0257] In general, the isolated nucleic acid sequences of the invention can be used as molecular weight markers on Southern gels, and as chromosome markers that are labeled to map related gene positions. The nucleic acid sequences can also be used to compare with endogenous DNA sequences in patients to identify a susceptibility to a cardiovascular disease, and as probes, such as to hybridize and discover related DNA sequences or to subtract out known sequences from a sample (e.g., subtractive hybridization). The nucleic acid sequences can further be used to derive primers for genetic fingerprinting, to raise anti-polypeptide antibodies using immunization techniques, and/or as an antigen to raise anti-DNA antibodies or elicit immune responses.

[0258] Two polypeptides, as described herein (or a region of the polypeptides) are substantially homologous or identical when the amino acid sequences are at least about 45-55%. In other embodiments, two polypeptides (or a region of the polypeptides) are substantially homologous or identical when they are at least about 70-75%, at least about 80-85%, at least about 90%, at least about 95% homologous or identical, or are identical. A substantially homologous amino acid sequence, according to the present invention, will be encoded by a nucleic acid molecule comprising the nucleotide sequence of LD Block C09 (SEQ ID NO:94) or a portion thereof, and further comprising at least one polymorphism as shown in Table 3, 10 or 21, wherein the encoding nucleic acid will hybridize to the nucleotide sequence of LD Block C09 (SEQ ID NO:94), under stringent conditions as more particularly described herein. In on embodiment, the polypeptide comprises all or a portion of the amino acid sequence of CDKN2A and/or CDKN2B.

Antibodies

[0259] Polyclonal antibodies and/or monoclonal antibodies that specifically bind one form of the gene product but not to the other form of the gene product are also provided. Antibodies are also provided which bind a portion of either the variant or the reference gene product that contains the polymorphic site or sites. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain antigen-binding sites that specifically bind an antigen. A molecule that specifically binds to a polypeptide of the invention is a molecule that binds to that polypeptide or a fragment thereof, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the polypeptide. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab')₂ fragments which can be generated by treating the antibody with an enzyme such as pepsin. The invention provides polyclonal and monoclonal antibodies that bind to a polypeptide of the invention. The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope of a polypeptide of the invention. A monoclonal antibody composition thus typically displays a single binding affinity for a particular polypeptide of the invention with which it immunoreacts.

[0260] Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a desired immunogen, e.g., polypeptide of the invention or a fragment thereof. The antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide. If desired, the antibody molecules directed against the polypeptide can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A chromatography to obtain the IgG fraction. At an appropriate time after immunization, e.g., when the antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein, Nature 256:495-497 (1975), the human B cell hybridoma technique (Kozbor et al., Immunol. Today 4: 72 (1983)), the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, 1985, Inc., pp. 77-96) or trioma techniques. The technology for producing hybridomas is well known (see generally Current Protocols in Immunology (1994) Coligan et al., (eds.) John Wiley & Sons, Inc., New York, N.Y.). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with an immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds a polypeptide of the invention.

[0261] Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating a monoclonal antibody to a polypeptide of the invention (see, e.g., Current Protocols in Immunology, supra; Galfre et al., Nature 266:55052 (1977); R. H. Kenneth, in Monoclonal Antibodies: A New Dimension in Biological Analyses, Plenum Publishing Corp., New York, N.Y. (1980); and Lerner, Yale J. Biol. Med. 54:387-402 (1981)). Moreover, the ordinarily skilled worker will appreciate that there are many variations of such methods that also would be useful.

[0262] Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody to a polypeptide of the invention can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide to thereby isolate immunoglobulin library members that bind the polypeptide. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP® Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Pat. No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al., Bio/Technology 9: 1370-1372 (1991); Hay et al., Hum. Antibod. Hybridomas 3:81-85 (1992); Huse et al., Science 246: 1275-1281 (1989); and Griffiths et al., EMBO J. 12:725-734 (1993).

[0263] Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art.

[0264] In general, antibodies of the invention (e.g., a monoclonal antibody) can be used to isolate a polypeptide of the invention by standard techniques, such as affinity chromatography or immunoprecipitation. A polypeptide-specific antibody can facilitate the purification of natural polypeptide from cells and of recombinantly produced polypeptide expressed in host cells. Moreover, an antibody specific for a polypeptide of the invention can be used to detect the polypeptide (e.g., in a cellular lysate, cell supernatant, or tissue sample) in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. The antibody can be coupled to a detectable substance to facilitate its detection. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹31I, ³⁵S or ³H.

[0265] Antibodies may also be useful in pharmacogenomic analysis. In such embodiments, antibodies against variant proteins encoded by nucleic acids according to the invention, such as variant proteins that are encoded by nucleic acids that contain at least one polymorphic marker of the invention, can be used to identify individuals that require modified treatment modalities.

[0266] Antibodies can furthermore be useful for assessing expression of variant proteins in disease states, such as in active stages of a cardiovascular disease, or in an individual with a predisposition to a disease related to the function of the protein, in particular a cardiovascular disease. Examples are provided by biomarker (e.g., cardiac markers), as described further herein. Antibodies specific for a variant protein of the present invention that is encoded by a nucleic acid that comprises at least one polymorphic marker or haplotype as described herein (e.g., CDKN2A and/or CDKN2B) can be used to screen for the presence of the variant protein, for example to screen for a predisposition to cardiovascular disease as indicated by the presence of the variant protein.

[0267] Antibodies can be used in other methods. Thus, antibodies are useful as diagnostic tools for evaluating proteins, such as variant proteins of the invention, in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic or other protease digest, or for use in other physical assays known to those skilled in the art. Antibodies may also be used in tissue typing. In one such embodiment, a specific variant protein has been correlated with expression in a specific tissue type, and antibodies specific for the variant protein can then be used to identify the specific tissue type.

[0268] Subcellular localization of proteins, including variant proteins, can also be determined using antibodies, and can be applied to assess aberrant subcellular localization of the protein in cells in various tissues. Such use can be applied in genetic testing, but also in monitoring a particular treatment modality. In the case where treatment is aimed at correcting the expression level or presence of the variant protein or aberrant tissue distribution or developmental expression of the variant protein, antibodies specific for the variant protein or fragments thereof can be used to monitor therapeutic efficacy.

[0269] Antibodies are further useful for inhibiting variant protein function (e.g., CDKN2A and/or CDKN2B), for example by blocking the binding of a variant protein to a binding molecule or partner. Such uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be for example be used to block or competitively inhibit binding, thereby modulating (i.e., agonizing or antagonizing) the activity of the protein. Antibodies can be prepared against specific protein fragments containing sites required for specific function or against an intact protein that is associated with a cell or cell membrane. For administration in vivo, an antibody may be linked with an additional therapeutic payload, such as radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent, including bacterial toxins (diphtheria or plant toxins, such as ricin). The in vivo half-life of an antibody or a fragment thereof may be increased by pegylation through conjugation to polyethylene glycol.

[0270] The present invention further relates to kits for using antibodies in the methods described herein. This includes, but is not limited to, kits for detecting the presence of a variant protein in a test sample. One preferred embodiment comprises antibodies such as a labelled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample, means for determining the amount or the presence and/or absence of variant protein in the sample, and means for comparing the amount of variant protein in the sample with a standard, as well as instructions for use of the kit.

[0271] The present invention will now be exemplified by the following non-limiting examples.

Exemplification

[0272] The following contains description of the identification of susceptibility factors found to be associated with coronary artery disease and in-stent restenosis through single-point analysis of SNP markers and microsatellite markers.

Methods

[0273] The study was approved by the Data Protection Commission of Iceland and the National Bioethics Committee.

Icelandic Coronary Artery Disease and in-Stent Restenosis Cohort

[0274] The association between markers in LD block C09 to coronary artery disease was originally discovered as an association between the markers and myocardial infarction, which is the most feared complication of coronary artery disease (subphenotype of coronary artery disease).

[0275] Over the last eight years individuals who have suffered an MI we have been recruited through cardiovascular disease (CVD) genetic programs at deCODE. Currently blood samples have been collected from 2525 MI patients. The individuals who had suffered an MI were identified from a registry of over 10,000 individuals who: a) had an MI before the age of 75 in Iceland in the years 1981 to 2002 and satisfy the MONICA criteria (J Clin Epidemiol 41, 105-14 (1988)); b) participated in a large prospective epidemiology study (1) done by the Icelandic Heart Association (INA) over the past 30 years and had MI prior to 1981; c) had MI discharge diagnosis from the major hospitals in Reykjavik in the years 2003 and 2004. MI diagnoses of all individuals in the registry follow strict diagnostic rules based on signs, symptoms, electrocardiograms, cardiac enzymes and necropsy findings (2). The patients were contacted through collaborating physicians in the CVD genetic programs at deCODE. Most of the participants in the study visited the IHA and had their blood drawn, although participants who lived outside the Reykjavik area visited their local health care center.

[0276] Additional subjects with coronary artery disease, but are without known history of myocardial infarction, are identified from a list of those who have undergone coronary stent procedure in the major hospitals in Reykjavik in the years 1993 and 2003.

[0277] For over 700 subjects on this list, information on in-stent restenosis is available, including subjects with variable degree of restenosis (0-100% in-stent restenosis). A confirmed proband with restenosis is a subject who has 50% in-stent stenosis or more as determined by coronary angiography read by an intervention cardio/radiologist.

[0278] The controls used for the study were recruited as a part of various genetic programs at deCODE. The medical history for the controls were unknown unless if the control subjects also had participated in any of the CVD genetic programs (i.e. MI, stroke, peripheral vascular disease, type II diabetes, obesity, familial combined hyperlipidemia, coronary restenosis, and hypertension genetic programs). Individuals with known MI, stroke, peripheral vascular or coronary artery disease were excluded as controls.

Subjects from the United States Cohort from Philadelphia

[0279] The study participants from Philadelphia were enrolled at the University of Pennsylvania Medical Center through the PENN CATH study program which studies the association of biochemical and genetic factors to coronary artery disease (CAD) in subjects undergoing cardiac catheterization. A total of 3850 subjects have participated. For the purpose of the current study we selected from the PENN CATH study individuals diagnosed with one of the following coronary artery disease: MI based on criteria for acute MI in terms of elevations of cardiac enzymes and electrocardiographic changes, or a self-reported history of MI, history of coronary artery bypass surgery (CABG) or percutaneous, transluminal coronary angioplasty (PTCA). To use as controls we selected individuals who were without significant luminal stenosis on coronary angiography (luminal stenosis less than 50%). Ethnicity information was self-reported.

[0280] The University of Pennsylvania Institutional Review Board approved the study and all subjects provided written informed consent.

Cohort from Cleveland

[0281] The study participants were enrolled at the Cleveland Clinic Heart Center through the Genebank program, which is a registry of data in conjunction with biological samples for individuals undergoing coronary catheterization. The diagnostic criteria for MI were based on at least two of the following: prolonged chest pain, ECG patterns consistent with acute MI or significant elevation of cardiac enzymes. Subjects from the Genebank registry who were without significant luminal stenosis (<50% stenosis), as assessed with coronary angiography, and were without previous history of CAD, were selected as controls for the current study.

[0282] This study was approved by the Cleveland Clinic Foundation Institutional Review Board on Human Subjects and all subjects gave written informed consent.

Cohort from Atlanta

[0283] The study participants were enrolled at the Emory University Hospital, the Emory Clinic and Grady Memorial Hospitals through its Emory Genebank study and Clinical Registry in Neurology (CRIN). The Emory Genebank studies the association of biochemical and genetic factors with CAD in subjects undergoing cardiac catheterization. For the purpose of the current study those subjects who had a self-reported history of MI, CABG, or PTCA, were selected and used as a patient group. Control subjects were selected from a group of individuals with non-vascular neurological diseases (mainly Parkinson's and Alzheimer's diseases) recruited from CRIN, their spouses, unrelated friends and community volunteers. These subjects were matched for age, and ethnicity to the patient population. Controls were excluded if they had a known history of MI or coronary artery disease. All subjects provided written informed consent. Information on ethnicity was self-reported.

Genotyping

[0284] A genome-wide scan of 1570 Icelandic individuals diagnosed with myocardial infarction (MI) and 7088 population controls was performed using Infinium HumanHap300 SNP chips from Illumina for assaying approximately 317,000 single nucleotide polymorphisms (SNPs) on a single chip (Illumina, San Diego, Calif., USA). SNP genotyping for replication in other case-control cohorts was carried using the Centaurus platform (Nanogen).

Statistical Methods for Association Analysis

[0285] To test individual markers for association to disease phenotypes such as coronary artery disease or myocardial infarction, we use a likelihood ratio test to calculate a two-sided P-value for each allele of the markes. We calculate relative risk (RR) and population attributable risk (PAR) assuming a multiplicative model (C. T. Falk, P. Rubinstein, Ann Hum Genet. 51 (Pt 3), 227 (1987); J. D. Terwilliger, J. Ott, Hum Hered 42, 337 (1992)). To elucidate the linkage disequilibrium between markers in the region we used the CEPH Caucasian HapMap data. We calculated LD between pairs of SNPs using the standard definition of D' (R. C. Lewontin, Genetics 50, 757 (1964)) and for the correlation coefficient r² (W. G. Hill, A. Robertson, Genetics 60, 615 (Nov., 1968). For the Icelandic cohort, to take into account that some of the individuals are related to each other, we obtained the null statistic of the test statistic either by simulating genotypes through the Icelandic genealogy or from the test statistic for all the 300,000 tested for association in the initial genome-wide association scan (citation). Model-free estimates of the genotype relative risk are generated as follows: RR of genotype G₁ compared to genotype G₀ was estimated by [n(G₁)/n(G₀)]/[m(G₁)/m(G₀)] where n and m denote genotype counts in patients and controls respectively. Results from different cohorts were combined using a Mantel-Hanezel model (citation) where cohorts are allowed to have different population frequencies for the alleles/genotypes but assume to have common relative risks.

[0286] We use multiple regression to test for association between markers and quantitative traits, such as ago of onset of MI in the cases, where the number of copies of the at-risk variant carried by an individual is taken as explanatory variable and the quantitative trait as the response variable. The association is adjusted for age and gender, where appropriate, by including corresponding terms in the regression analysis as explanatory variables.

Correction for Relatedness of the Subjects and Genomic Control

[0287] Some of the individuals in both the Icelandic patient and control groups are related to each other, causing the chi-square test statistic to have a mean >1 and median >0.675 (Devlin, B & Roeder, K., Biometrics 55, 997 (1999)). We estimated the inflation factor for the genome-wide association by calculating the average of the 305,953 chi-square statistics, which was a method of genomic control (Devlin, B & Roeder, K., Biometrics 55, 997 (1999)) to adjust for both relatedness and potential population stratification. The inflation factor was estimated as 1.129 and the results presented from the genome-wide association are based on adjusting the chi-square statistics by dividing each of them by 1.129. For the Icelandic replication cohort and the combined Icelandic replication and discovery cohort, we used a previously described procedure where we simulated genotypes through the genealogy of 708,683 Icelanders to estimate the adjustment factor (S9). The corresponding adjustment factors were 1.092 and 1.029, respectively.

PCR Screening of cDNA Libraries

[0288] cDNA libraries were constructed from whole blood (pool of 90 individuals), EBV-transformed human lymphoblastoid cells (pool of 90 individuals), human cardiac myocyte cells (Sciencell, Cat. no. 6200), human aortic smooth muscle cells (Sciencell, Cat. no. 6110), human cardiac fibroblast ventricular cells (Sciencell Cat. no. 6310) and human primary umbilical vein endothelial cells (HUVEC) (pool of 4 individuals). Total RNA was isolated using the RNeasy RNA isolation kit (Qiagen, Cat. no. 75144), the RNeasy RNA isolation from whole blood kit (Qiagen, Cat. no. 52304) or the mirVana RNA isolation kit, using the total RNA isolation procedure (Ambion Inc. Cat. no. 1560) according to manufacturer's recommendations. cDNA libraries were prepared at deCODE using the High Capacity cDNA Archive Kit with random primers (Applied Biosystems PN 4322171). In addition to the libraries above, two commercial cDNA libraries from whole heart (Clontech-639304) and aorta (Clontech-639325) were screened.

[0289] PCR screening was carried out using the Advantage2® Polymerase mix (Clontech cat. no. 639202) according to manufacturer's instructions with primers from Operon Biotechnologies. The PCR reactions were carried out in 10 μl volume at a final concentration of 3.5 μM of forward and reverse primers, 2 mM dNTP, 1× Advantage 2 PCR buffer, 0.2 μl of Advantage enzyme and 0.5 μl of cDNA library. (See Table 23). Expression was detected for all of the ESTs in several of the libraries tested (Table 24). None of the ESTs have an open reading frame larger than 77 bp. Many of them overlap with a recently reported antisense non-coding RNA whose expression has been shown to cocluster with p14/ARF (Pasmant, E., et al., Cancer Res 67, 3963 (2007)).

Sequencing of CDKN2A and CDKN2B

[0290] PCR amplifications and sequencing reactions were set up on Zymark SciClone ALH300 robotic workstations and amplified on MJR Tetrads. PCR products were verified for correct length by agarose gel electrophoresis and purified using AMPure (Agencourt Bioscience). Purified products were sequenced using an ABI PRISM Fluorescent Dye Terminator system, repurified using CleanSEQ (Agencourt), and resolved on Applied Biosystems 3730 capillary sequencers. SNP calling from primary sequence data was carried out using deCODE Genetics Sequence Miner software. All CDKN2A and CDKN2B variants identified by the automated systems were confirmed by manual inspection of primary signal traces. Samples from 96 early onset MI patients were sequenced using primers indicated in Table 25 and a list of the SNPs identified is provided in Table 26.

Surveying for Candidate Regulatory Variants in the Candidate Region

[0291] The University of California Santa Cruz genome browser (genome.ucsc.edu) was used to extract positions of SNPs and conserved TF binding sites for a 600 kb surrounding the MI region (hg release 17, chromosome 9, bases 21800000 to 22400000). The two tables were cross referenced with Python scripts and SNPs that resided in binding sites were interrogated for LD with rs1333040 in the CEU sample of Hapmap (release 22). The analyses were implemented for release 18 of the human genome, and the results converted to hg 17 coordinates.

[0292] This bioinformatic analysis of 600 kb surrounding the MI region yielded 16 SNPs which coincide with conserved binding sites for transcription factors (Table 27). Lack of LD to SNPs tagging the MI haplotype enabled exclusion of a half of the 16 SNPs from this candidate list. The remaining polymorphisms could impact gene function by altering conserved TF binding sites. In parallel we looked for correlation between SNPs located in conserved blocks (based on Multiz alignments available through the UCSC genome browser, release hg 18) and the MI haplotype tagging SNPs. While about half of the 74 SNPs are represented in HapMap, we found none that were highly correlated with the MI haplotype (data not shown). In sum, these analyses do not identify particular SNPs as putative regulatory variants on the MI haplotypes. Note of caution, the analysis will only detect a proportion of the functional candidates in the region because; i) the MI haplotypes have not been sequenced fully, ii) several candidate SNPs are not typed in Hapmap, hence it is unknown whether they sit on the risk conferring haplotypes. In addition, it is a realistic possibility that polymorphisms in less conserved regions are the functional MI variants.

Example 1

Genome-Wide Association Study

[0293] We successfully genotyped 1570 Icelandic myocardial infarction patients and 7088 population control individuals without known history of coronary artery disease (Cohort A) using the Illumina 330K chip. We performed a genome-wide scan for association to MI, testing individually each of the 309,091 SNPs that was successfully genotyped. Three markers (rs10116277, rs1333040, rs2383207), all located in a single LD block (denoted herein as LD block C09) on chromosome 9p show strong association to MI (see FIG. 1 and Table 1a). All three markers are strongly correlated (Table 2) and the population frequency of the at-risk variants range from 42% to 49%, and the corresponding relative risk is approximately 1.2. The risk alleles of the same three markers also showed a significant correlation to lower age at onset within the MI patient--individuals carrying the at-risk variant are at significant risk of developing MI at a younger age than individuals who are non-carriers of the at-risk allele (Table 8a).

[0294] The LD-block LD block C09 containing the three associated marker is flanked and defined by two recombination hot-spots--one at approximately 21,920,000 bp in Build 34, the other approximately 22,150,000 bp on chromosome 9 (Nature 437, 1299-1320 (27 Oct. 2005))). Investigating other genetic markers in LD block C09, we identified two micro-satellite markers, D9S1870 and D9S1814, that are strongly correlated with the at-risk alleles of the markers rs10116277, rs1333040, and rs2383207. Table 1b shows the association of each of the alleles of the microsatellite markers to MI in the same cohort of MI patients and controls that was used in the genome-wide association scan. For marker D9S1814 the associated allele was allele 0, however for D9S1870 multiple alleles (alleles -4, -2 and 0) showed increased risk of MI. By investigating the correlation between the different alleles of D9S1870 to the at-risk alleles of the markers rs10116277, rs1333040 and rs2383207, observed that by pooling together all alleles of D9S1870 shorter than 2 (alleles -6, -4, -2 and 0 respectively), the composite allele, denoted X, was strongly correlated to the original at-risk alleles of the SNP (Table 2). Composite allele X of D9S1870 and allele 0 of D9S1814 show similar association to MI as the at-risk alleles of rs10116277, rs1333040 and rs2383207 (Table 1c) and all five at-risk alleles are highly correlated (Table 2).

[0295] Further investigation of all SNPs in the HapMap v9 CEU dataset that are located in the chromosomal region defined by LD block C09 identified further 88 markers that are strongly correlated with the at-risk allele of at least one of the five markers rs10116277, rs1333040, rs2383207, D9S1814 and D9S1870 (Table 3) and hence those markers could also be used as surrogate markers to tag the observed association to MI in LD block C09.

[0296] We genotyped the micro-satellite marker D9S1870 in a large cohort of over 70,000 Icelanders that included, among others, 668 additional MI cases and 58,643 additional controls without known history of coronary artery disease (Cohort B). In addition we typed the microsatellite D9S1870 in three replication cohorts from US including; 549 MI patients and 606 controls from Cleveland; 580 MI cases and 404 controls from UPenn; and 400 MI cases and 477 controls from Emory. All individuals in the US cohorts are of Caucasian origin. We tested the composite allele X for association to MI in all four cohorts (Table 4a and b), and all but one (Cleveland) showed significant association. Combining the results from the four replication cohorts (Table 4c) yielded a combined P-value=2.65×10^-8. Combined with the original Icelandic cohort used in the genome-wide association (Cohort A) the P-value is 1.44×10^-12 and, assuming a multiplicative model, each allele X confers an estimated relative risk (RR) of 1.214 [95% CI:1.151-1.281] per copy carried, compare with the risk for non-carriers. The corresponding combined population attributable risk (PAR) is 17.1%.

[0297] If we investigate separately the risk conferred for individuals heterozygous for the risk allele X and individuals homozygous for X, relative to individuals that do not carry X (Table 7a), the estimated genotype relative risk (GRR) for heterozygous individuals is 1.204 [CI:1.094-1.324] and for homozygous individuals GRR is 1.507 [CI:1.360-1.670]. This is consistent with the multiplicative model, i.e an additive contribution of the allele X to the risk of MI.

[0298] We further investigated the correlation of the risk allele X to age of onset of MI in all four cohorts. Restricting the analysis to early-onset MI cases, defined as a MI event before the age of 50 for males and before the age of 60 for females, the relative risk for the cohorts combined increases to 1.331 [CI:1.223-1.449; P=3.96×10^-11; PAR=24.7%] compared to 1.214 for all MI cases (Table 6c). Correspondingly the genotype relative risk increases to 1.314 [CI:1.105-1.562] and 1.790 [CI:1.517-2.113] for heterozygous and homozygous carriers of allele X respectively (Table 7b). Alternatively, we tested using multiple regression the correlation between the number of copies of X carried by individuals in the MI case group and the age of onset of MI (Table 8b). Combining results from all four cohorts, we observed that the mean age of onset decreased by 0.95 year [SE=0.25] for each copy of X carried by the MI individuals (P=0.000099).

[0299] Among individuals typed for the marker D9S1870 in the Icelandic and the Emory cohort are individuals that have undergone percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft surgery (CABG), both indicative of severe coronary artery disease (CAD). We tested if those individuals also had an increased frequency of the risk allele X compared to controls, speculating that the variant might predispose individuals to a more general coronary artery disease than just MI (Table 5a and c). In both cohorts we observed similarly increased risk for PTCA and CABG as for MI, if not stronger, that was very significant in the Icelandic cohort, although for the Emory cohort only the association to PTCA was significant. It should be noted, however, that the number of individuals with PTCA and CABG in the Emory cohort is small. This association remained in the Icelandic cohort even after removing known MI cases from the PTCA and CABG groups (Table 5b).

[0300] In addition, in the Icelandic cohort we investigated the association to other diseases related to coronary artery disease, such as peripheral artery disease (PAD) and stroke phenotypes such as infarct or transient ischemic attack (TIA). For 1661 PAD cases we observed a very significant association, P=5.36×10^-5 and RR=1.154 [CI:1.074-1.239] (Table 5a)--this association remained significant after removing MI cases from the PAD cohort in the analysis although the effect was somewhat weaker (Table 5b). For 1678 individuals with infarct or TIA we did not observe significant association to X, however, for individuals diagnosed with large vessel diseases (LVD)--the stroke sub-phenotype that is most closely related to coronary artery disease--we observed an increased risk, RR=1.120 or 1.172 if we include or exclude MI cases respectively (Table 5a and b). There are however only 197 individuals in the Icelandic cohort diagnosed with LVD and this association in not statistically significant.

[0301] We investigated the frequency of the risk variant X of marker D9S1870 in a group of 454 Icelandic individuals for which we had information on in-stent restenosis and that are genotyped for the variant. The cohort was divided into individuals with severe in-stent restenosis (50% or greater) and individuals with mild in-stent restenosis (less than 50%). As all those individuals have undergone PTCA, and hence have coronary artery disease, both groups have significantly higher frequency of the variant X than is observed in controls (Table 9a). However, the frequency in the group of individuals with severe restenosis is higher than in the group with mild restenosis, RR=1.067 [CI:0.827-1.376], and although this difference is not significant (Table 9b), this suggests that the variant could be indicative of the severity of in-stent restenosis in coronary artery disease patients that have undergone PT

Example 2

A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction

[0302] Coronary artery disease (CAD), including acute myocardial infarction (MD, is the leading cause of death worldwide (Thom, T., et al., Circularion 113:e85 (2006)). Identification of the underlying genetic architecture of heart disease may provide improved risk assessment and better measures for prevention and treatment.

[0303] To this end we conducted a genome-wide association study on Icelandic patients with MI, using the Illumina Hap300 chip. After quality filtering, 305,953 SNPs were tested for association to MI in a sample of 1607 cases, with age at onset before 70 in males and 75 in females, and 6728 controls without a history of CAD (Helgadottir, A., et al., Science 316:1491 (2007)). The results were adjusted for relatedness between individuals and potential population stratification using a method of genomic control (3). Although none of the SNPs were significant after adjusting for the number of tests performed more signals bordering on significance were observed than expected by chance. Hence, we further explored the SNPs that were closest to genome wide significance.

[0304] The strongest association to MI was observed with three correlated SNPs, rs1333040, rs2383207 and rs10116277, each with odds ratio (OR) around 1.22 for the risk allele and P of approximately 1×10^-6 (Table 15). All three SNPs are located within the linkage disequilibrium (LD) block on chromosome 9p21 denoted herein as LD block C09 (FIG. 1). Apart from these three SNPs, eleven other SNPs in the same LD block showed nominally significant association to MI. The associations to these SNPs tended to become weaker after accounting for the association to the three SNPs mentioned above (Table 15). After adjustment, a few remained nominally significant (P<0.05), but none had a P<0.01.

[0305] To replicate the observed associations we genotyped the three SNPs, rs1333040, rs2383207 and rs10116277, in an additional 665 Icelandic MI cases and 3533 controls and in three case-control sample sets of European descent from three cities from the United States: Philadelphia, Atlanta, and Durham (2). For consistency we used the same age at onset criteria in the association analysis as for the discovery group. The association to MI was replicated with significance in all four groups (Table 16). When the replication sets were combined using a Mantel-Haenszel model (Mantel, N. & Haenszel, J. Natl. Cancer Inst. 22:719 (1959)), all three SNPs showed highly significant association to MI (P<1×10^-8), with ORs comparable to those observed in the Icelandic discovery samples. When all groups were combined, rs2383207 showed the most significant association (P=2.0×10^-16), with an OR of 1.25 (95% CI 1.18-1.31) for the risk allele G. It is noted that rs2383207 and rs10116277 are highly correlated (r²=0.90) and their effects could not be reliably distinguished from each other in these data. The SNP rs1333040 is also substantially correlated with rs2383207 and rs10116277 (r²=0.57 and 0.67 respectively). In an attempt to refine this association signal, we identified the SNPs that are substantially correlated with rs2383207 (r²>0.5) based on the Hapmap CEU data and are not part of the Illumina Hap300 chip. Among the 36 such SNPs, we selected eight to be genotyped. Each of the 36 SNPs was either one of the eight or it had a very good surrogate among them (r²>0.90) (Table 21). With data from all case-control groups combined, allele G of the refinement SNP rs10757278 showed the strongest association to the disease (OR=1.28, P=1.2×10^-20; Tables 12 and 16). Furthermore, while rs2383207 was no longer significant after adjusting for rs10757278 (P=0.25), rs10757278 remained significant with adjustment for rs2383207 (P=2.0×10^-5). Among the SNPs in this region that showed very significant association to the disease when tested individually, none was significant after adjustment for rs10757278 with the exception of the refinement SNP rs13330406, which was marginally significant (P=0.044) with adjustment (Table 22). Henceforth, for simplicity of presentation, we focus on the most significant SNP rs10757278 in the main text but additional results for other SNPs in the region are provided Tables 16 to 20.

[0306] To investigate the mode of inheritance in more detail, we computed genotype specific ORs for rs10757278. With results from all groups combined, relative to non-carriers, the ORs for heterozygous and homozygous carriers of the risk allele G were 1.26 and 1.64, respectively (Table 13). Assuming a frequency of 45.3% for the allele, the average of the frequencies in Iceland and the US, the corresponding PAR is 21%.

[0307] Because the impact of genetic factors on CAD has been shown to be greater at early ages (5) we investigated the correlation of allele G of rs10757278 to age at onset of MI. Note that in this analysis we used all cases with a known age at onset including those who had onset after the age of 70 or 75 for males and females, respectively. This added a total of 973 cases to the study groups compared to what was used in the case-control analyses. Regressing the age at onset on the number of risk alleles showed that, for each copy of the risk allele, the age at onset of MI was on average reduced by approximately one year (P=2.9×10^-7) (Table 18). Alternatively, restricting the case-control analysis to early onset MI, defined as an MI before the age of 50 for males and before the age of 60 for females, the allelic OR for rs10757278 G in all groups combined increased to 1.42 (95% CI 1.31-1.53) (Table 19). Relative to non-carriers, genotype specific OR for early onset MI is 1.49 and 2.02 for heterozygous and homozygous carriers of the risk allele, respectively (Table 13).

[0308] Having established that allele G of rs10757278 is associated to MI, we explored its impact on the broader phenotype of CAD (Table 14). To eliminate bias that could have arisen from the selection of the most significant variants in the initial genome-wide study, the cases and controls from the Icelandic discovery group (Iceland A) were not included here. We do note that if the latter were included, there would be little change to the estimated effects, but the results would become more significant due to the larger sample sizes. Also, the group from Durham did not have CAD cases without MI. As expected, rs10757278 was associated with high significance to CAD (OR=1.29, P=3.6×10^-14 for the groups combined). After removal of MI cases from the analyses, the associations remained significant for the groups from Iceland and Atlanta, but not in the Philadelphia group. Combining results from the three groups gave an OR of 1.24 (P=0.000011).

[0309] The variants on chromosome 9q21 associated to MI are located in an LD block that contains the CDKN2A and CDKN2B genes. The proteins encoded by these genes, called p16^INK4a, ARF and p15^INK4b have a critical role in regulating cell proliferation, cell aging/senescence, and apoptosis in many cell types (Kim, W. Y. & Sharpless, N. E. Cell 127:265 (2006)). These are all important features of atherogenesis, the underlying cause of MI and CAD (Lusis, A. J. Nature 407:233 (2000); Minamino, T. & Komuro, I. Circ Res 100:15 (2007)). Sequencing of 93 early onset MI patients across exons, exon-intron junctions, and regulatory regions of CDKN2A and CDKN2B did not reveal obvious candidates for functional variants or other variants that could account for the observed association to rs10757278 (Tables 25 and 26). In addition to CDKN2A and CDKN2B genes, the LD block contains two exons of the mRNA transcript AF109294, a hypothetical methylthioadenosine phosphorylase fusion protein mRNA and several ESTs that are expressed in various tissues (Helgadottir, A., et al., Science 316:1491 (2007)). The functional relevance of the variants of this genomic region to MI/CAD remains to be elucidated.

[0310] In summary, we have shown that a common genetic variant located in the vicinity of the tumor suppressor genes CDKN2A and CDKN2B on chromosome 9p21 associate to MI. This is the first common variant discovered to consistently confer substantial risk (OR>1.20) of MI in multiple case-control groups of European descent. Due to its high frequency, the population attributable risk of the variant is approximately 21% for MI in general and approximately 31% for early onset cases, which is substantial from a public health point of view. However, as the relative risks are not extremely high, it explains only a small fraction of the familial clustering of the disease and would not generate large linkage scores. Hence, others susceptibility variants remain to be identified and some could be located in candidate regions identified by genome-wide linkage scans (Zintzaras, E. & Kitsios, G., J Hum Genet. 51:1015 (2006); Wang Q., et al., Am J Hum Genet. 74:262 (2004); Samani, N. J., et al., Am J Hum Genet. 77:1011 (2005)). There is evidence supporting that the variant identified here could increase the risk of CAD in general in addition to their impact on MI, an observation that warrants further investigation. The mechanism whereby the genetic variants exert their effects in the pathogenesis of MI remains to be elucidated.

Example 3

[0311] Genotyping of Polymorphic Markers Identified Through Sequencing

[0312] Sequencing of the exons of CDKN2A and CDKN2B genes, the exon-intron junctions and potential regulatory regions using the primers as indicated in Table 25 resulted in the identification of a number of SNPs, as shown in Table 26. Flanking sequences for three of those SNPs that were not found in public databases are indicated in Table 31. As it is possible that SNP markers or other polymorphisms in LD with the markers found to be associating to MI in this region of chromosome 9 show association with a higher risk, we genotyped these additional markers by sequencing, as indicated in Table 28. Several of the markers show association to MI with RR values as high as 1.7-1.8, in particular markers SG09S291 and rs2069416.

Example 4

[0313] Association to Related Cardiovascular Disorders

[0314] We have investigated association of the at-risk variants of the invention to the related disorders peripheral artery disease (PAD), abdominal aorta aneurysm (AAA) and large vessel disease stroke (LVD) for three of the markers giving signal on Chromosome 9 as presented herein. As can be seen in Table 29, these markers are associated with these related disorders. The association is particularly compelling for AAA, wherein significant association is observed for a large number of markers in addition to these three, as shown in Table 30. These results illustrate that the markers and haplotypes of the invention are indeed reflective of disorders related to coronary artery disease, MI and in-stent restenosis, such as abdominal aorta aneurysm.

Example 5

Further Refinement of Association to the Arterial Phenotypes AAA, IA and Stroke

[0315] To investigate the effect of rs10757278 on other cardiovascular diseases in more detail, we further explored the association to abdominal aortic aneurysm (AAA) and Stroke, and also investigated the arterial disorder intrachranial aneurysm (IA).

Methods

Study Populations

Coronary Artery Disease Groups

[0316] The coronary artery disease groups from Iceland and the United States were as described above (see also Helgadottir, A., et. al., Science 316:1491-3 (2007))

Icelandic Controls

[0317] The 14278 Icelandic controls used in the association study were selected among individuals who have participated in various GWA studies and were recruited as part of genetic programs at deCODE. The medical histories of the controls were unknown unless they had also participated in one or more of the CVD genetic programs (i.e. MI, stroke, PAD, T2D, obesity, familial combined hyperlipidemia, coronary restenosis, and hypertension). Individuals with known MI, stroke, PAD or CAD, or with T2D were excluded as controls. Of the 14259 controls 9202 overlap with those used in our previous GWA study in MI (Helgadottir, A., et. al., Science 316:1491-3 (2007)). The controls included 5615 males and 8644 females and their mean age was 55.2 (SD 21.7). The breakdown of the control group into the various genetic programs was approximately (with the frequency of the two variants, rs10757278 allele G and rs10811661 allele T in parenthesis): Schizophrenia 500 (0.428/0.825), Prostate cancer 900 (0.447/0.815), Breast Cancer 1300 (0.433/0.817), Colon Cancer 700 (0.413/0.817), Addiction 2600 (0.444/0.814), Anxiety 900 (0.442/0.824), Infectious diseases 1200 (0.434/0.821), Population Controls 700 (0.427/0.830), Microarray expression studies 400 (0.445/0.817), Longevity 1100 (0.450/0.819), Migraine 1100 (0.446/0.818), Restless Leg Syndrome 400 (0.439/0.812), Alzheimer disease 350 (0.457/0.822), Asthma 1300 (0.419/0.819), Dyslexia 600 (0.438/0.830). No significant differences in frequencies were observed between the disease groups for either of the two variants (P=0.52 and P=0.99 for rs10757278 and rs10811661, respectively).

Stroke Groups

[0318] Icelandic stroke patients were recruited from a registry of over 4000 individuals which includes individuals diagnosed with ischemic stroke or TIA at the major hospital in Reykjavik, the Landspitali University Hospital, during the years 1993 to 2002. Stroke patients have been enrolled over the past nine years through the cardiovascular disease (CVD) genetics program at deCODE. Swedish patients with ischemic stroke or TIA attending the stroke unit or the stroke outpatient clinic at Karolinska University Hospital, Huddinge unit in Stockholm, Sweden were recruited from 1996 to 2002 as part of an ongoing genetic epidemiology study, the South Stockholm Ischemic Stroke Study (SSISS). All patients from Iceland and Sweden had clinically relevant investigations performed, including brain imaging with computed tomography (CT) or/and magnetic resonance imaging (MRI) as well as ancillary diagnostic investigations including duplex ultrasonography of the carotid and vertebral arteries, echocardiography, Holter monitoring, MR-angiography, CT-angiography and standardized blood tests. Patients were classified into ischemic subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification by a physician reviewing original imaging and data (Adams, H. P. Jr., et al., Stroke 24:35-41 (1993)). Patients classified with cardioembolic stroke and documented atrial fibrillation were excluded from the analysis. The Swedish controls used in this study are population-based controls recruited from the same region in central Sweden as the patients, representing the general population in this area. The individuals were either blood donors (recruited in 2001) or healthy volunteers (collected in 1990-1994) recruited by the Clinical Chemistry Department at the Karolinska University Hospital to represent a normal reference population. These stroke studies from Iceland and Sweden were approved by relevant Institutional Review Boards or ethics committees and all participants provided written informed consent.

Intracranial Aneurysm Groups

[0319] Icelandic IA patients were identified through an inpatient database from 1994-2006 at the Landspitali University Hospital, which is the only hospital with a neurosurgical service in the country. All patients in the years 1996-2006 with the ICD10 diagnosis 160.0-7 (aneurysmal subarachnoid hemorrhage), 167.1 (ruptured cerebral aneurysm) and 169.0 (sequele of subarachnoid haemorrhage) were enrolled, as well as patients with the ICD9 diagnosis 430 (subarachnoid hemorrhage from ruptured cerebral aneurysm) in the years 1994-1996. This totaled 367 IA patients. All patients had clinically relevant investigations performed, including CT scan of the head and or conventional cerebral angiogram, CT-angiogram or MRi angiogram. DNA samples were available for 170 of the 367 patients.

[0320] Dutch patients with ruptured (91.5%) or unruptured (8.5%) IA admitted to the University Medical Center Utrecht were used for the study. Ruptured intracranial aneurysms were defined by symptoms suggestive of subarachnoidal hemorrage (SAH) combined with subarachnoid blood on CT and a proven aneurysm at angiography (conventional angiogram, CT- or MR-angiogram) and unruptured intracranial aneurysms were identified by CT or MR angiography or conventional angiography. Multiple intracranial aneurysms were found in 20.5% of cases. Mean age at time of SAH was 49.5 years (range 10-84) and 66.1% of the patients were females. The controls were healthy Dutch blood bank donors of European origin.

[0321] Finnish IA patients admitted for treatment of intracranial aneurysm at either the University Hospital of Kuopio, or University Hospital of Helsinki, in Finland, were used for the study. This study group and the Finnish controls used have been described previously (Weinsheimer, S. et al., Stroke 38:2670-6 (2007)).

[0322] The Icelandic, Dutch and Finnish IA studies were approved by relevant Institutional Review Boards or ethics committees and all participants provided written informed consent.

Peripheral Arterial Disease Groups

[0323] Icelandic patients with PAD were recruited from a registry of individuals diagnosed with PAD at the major hospital in Reykjavik, the Landspitali University Hospital, during the years 1983 to 2006. The PAD diagnosis was confirmed by vascular imaging or segmental pressure measurements. PAD patients have been enrolled over the past nine years as part of the CVD genetics program at deCODE.

[0324] Italian patients and controls were recruited among subjects consecutively admitted to the Department of Internal Medicine and Angiology of the A. Gemelli University Hospital of Rome, from 2000 to 2001. Inclusion criteria for the PAD group were European descent and presence of PAD. Diagnosis of PAD was performed in accordance with established criteria (J Vasc Surg 4:80-94 (1986)). All patients had an ankle/arm pressure index lower than 0.8 and were at Fontaine's stage II, with intermittent claudication and no rest pain or trophic lesions. Inclusion criteria for the control group were European descent, absence of PAD and CAD and no relationship with cases. Additional, exclusion criteria from the study were tumours, chronic inflammatory diseases, and autoimmune diseases (Flex, A., et al., Eur J Vasc Endovasc Surg 24: 264-8 (2002)).

[0325] Swedish PAD patients and controls were recruited at the Department of Vascular Diseases at Malmo University Hospital, a single referral centre for all patients with critical limb ischemia in the three southernmost health-care districts in Sweden (723,750 inhabitants in 2001). The diagnosis of critical limb ischemia was made in accordance with TransAtlantic Inter-Society Consensus scientific criteria of ulceration, gangrene, or rest pain caused by PAD proven by ankle pressure (<50 to 70 mm Hg), reduced toe pressure (<30 to 50 mm Hg), or reduced transcutaneous oxygen tension (Dormandy, J. A. & Rutherford, R. B. J Vasc Surg 31:S1-S296 (2000)). Diagnosis was confirmed by an experienced vascular surgery consultant and toe pressure measurements in patients with arteries in the affected leg that were noncompressible and the ankle pressure was >50 to 70 mm Hg. The control group consisted of healthy individuals included in a health screening programme for a preventive medicine project. None of those had symptomatic PAD (Barani, J., et al., J Vasc Surg 42:75-80 (2005)).

[0326] New Zealand PAD patients were recruited from the Otago-Southland region of the country, the vast majority (>97%) being of Anglo-European ancestry as reported previously (Jones G. T., et al., Clin Chem 53:679-85 (2007)). PAD was confirmed by an ankle brachial index<0.7, pulse volume recordings and angiography/ultrasound imaging. The control group consisted of elderly individuals with no previous history of vascular disease from the same geographical region. Controls were asymptomatic for PAD and had ankle brachial indexes >1. An abdominal ultrasound scan excluded concurrent AAA from both the PAD and control groups.

[0327] The Icelandic, Italian, Swedish, and New Zealand PAD studies were approved by relevant Institutional Review Boards or ethics committees and all participants provided written informed consent.

Abdominal Aortic Aneurysm Groups

[0328] Icelandic patients with AAA were recruited from a registry of individuals who were admitted either for emergency repair of symptomatic or ruptured AAA or for an elective surgery to the Landspitali, University Hospital, in Reykjavik, Iceland in the years 1980-2005. Subjects with AAA were enrolled over the last nine years as part of the CVD genetics program at deCODE. In some of the analyses AAA cases that overlapped with a comprehensive list of CAD patients (Helgadottir, A., et. al., Science 316:1491-3 (2007)) diagnosed in Iceland in the years 1981-2006 were excluded. Of the 397 (288 males and 109 females, mean age 75.3 (SD 8.7)) AAA cases, 208 overlapped with the CAD patients. Of the 189 (131 males and 58 females, mean age 75.5 (SD 9.3)) remaining CAD, information was not available for 138 cases and 51 individuals reported in a questionnaire as not having been diagnosed with CAD.

[0329] UK patients with AAA referred to vascular surgeons at 93 UK hospitals were entered into UK Small Aneurysm Trial. For the purpose of the current study those randomised to surveillance in the UK Small Aneurysm Trial with AAA diameter 4.0-5.5 cm were selected as a patient group, although some patients had been monitored before their aneurysm reached the 4.0 cm threshold for the trial. Mean AAA diameter at baseline was 4.5 cm (3.2-5.5 cm) (Eriksson, P., et al., Br J Surg 92:1372-6 (2005)). Information on the occurrence of CAD was available for 97% (466 out of 479) of AAA cases. History of CAD was regarded as positive if the subject was under treatment for angina, had a previous MI, coronary artery bypass graft surgery or angioplasty or if ECG coding had any indications of ischeamia, as judged by two independent expert observers. Among those with this information, the frequency of CAD amongst the AAA subjects was 52%. Controls were of European descent, recruited from England.

[0330] Belgian and Canadian patients with AAA who were admitted either for emergency repair of ruptured AAA or for an elective surgery to the University Hospital of Liege in Belgium and to Dalhousie University Hospital in Halifax Canada, respectively, were used for this study. Details of these case-control sets have been previously reported (Ogata, T., et al., J Vasc Surg 41:1036-42 (2005)). All patients were of European descent and had a diameter of infrarenal aorta >3 cm. Thirty-five patients were diagnosed with AAA using ultrasonography and did not undergo surgery because of old age or because the aneurysm was relatively small. Approximately 40% of AAA patients had a family history of AAA. For Belgian AAA patients, information on CAD history was ascertained for those who underwent surgery through interviews as well as from medical files. In addition, all patients underwent cardiologic explorations such as transthoracic echography, stress tests and coronary angiography if CAD was suspected. CAD information for this study was available for 45% (79 out of 176) of AAA cases from Belgium. Among those with this information, the frequency of CAD amongst the AAA subjects was 29%. Control samples (51% males) of European descent were obtained from spouses of AAA patients or from individuals admitted to the same hospitals for reasons other than AAA.

[0331] Patients admitted to the University Hospital of Pittsburgh for either elective or emergency surgery for AAA were selected for the study (St Jean, P. L., et al., Ann Hum Genet. 59:17-24 (1995)). History of CAD was self-reported and was available for 86% (87 out of 101). Among those with this information, the frequency of CAD amongst the AAA subjects was 48%. Controls were selected from participants of the PENN CATH study program at the University of Pennsylvania Medical Center Philadelphia. The control group represents individuals who were without significant luminal stenosis on coronary angiography (luminal stenosis less than 50%) and did not have a history of MI. These are the same controls as were used in the association analysis for the CAD samples from Pennsylvania (Helgadottir, A., et. al., Science 316:1491-3 (2007)).

[0332] New Zealand patients with AAA were recruited from the Otago-Southland region of the country, the vast majority (>97%) being of Anglo-European ancestry as reported previously (Jones, G. T., et al., Clin Chem 53:679-85 (2007)). Approximately 80% of patients had undergone surgical AAA repair (typically AAA's >50 mm in diameter). Controls were the same vascular disease free individuals as described for comparison with the New Zealand PAD group. CAD information was available for 98% (575 out of 588) of the AAA patients. Of those with information the frequency of CAD was 40%.

[0333] AAA sample set from the Netherlands was recruited from 8 centres in the country, mostly when patients visited their vascular surgeon or in rare cases during hospital admission. The controls were healthy Dutch blood donors of European origin. Information on other CVD was self-reported and available for 69% (330 out of 480). Treatment for angina pectoris, previous MI, coronary bypass surgery or stent insert was considered as CAD. Of the 330 with information, 96 had CAD (29%).

[0334] These AAA studies from Iceland, UK, Belgium, Canada, Pennsylvania, The Netherlands and New Zealand were approved by relevant Institutional Review Boards or ethics committees and all participants provided written informed consent.

Snp Genotyping.

[0335] SNP genotyping for all samples was carried out at deCODE genetics in Reykjavik, Iceland. Individual SNP genotyping was carried out with the Centaurus (Nanogen) platform (Kutyavin, I. V., et al., Nucleic Acids Res 34:e128 (2006)). The quality of each Centaurus SNP assay was evaluated by genotyping each assay in the CEU and/or YRI HapMap samples and comparing the results to the HapMap data. The key markers rs10757278 and rs10811661 were re-genotyped on more than 10% of samples and a mismatch was observed in less than 0.5% of samples. For some of the samples we had previously genotyped the SNPs rs1333040, rs2383207, and rs10116277 either with the Illumina 317K Bead chip or with the Centaurus method. These SNPs are highly correlated with rs10757278 (r²=0.57, 0.87, and 0.90, respectively, in the HapMap CEU dataset) and were used to impute the genotypes for rs10757278 where they were missing. In addition, for a large number of the Icelandic samples the SNP rs2383208, which is present on the Illumina 317K Bead chip, was previously genotyped. This SNP is a perfect surrogate for the SNP rs10811661 (r²=1 in the HapMap CEU dataset) and was used to impute genotypes for rs10811661.

[0336] The SNPs did not deviate from Hardy Weinberg Equilibrium in any of study cohorts used for the analyses.

Association Analysis

[0337] We used a standard likelihood ratio statistics, implemented in the NEMO software (to calculate two-sided P values and odds ratio (OR) for each individual allele, assuming a multiplicative model for risk, i.e., that the risk of the two alleles a person carries multiply. Allelic frequencies, rather than carrier frequencies are presented for the markers, and, for the Icelandic study groups, P values are given after adjustment for the relatedness of the subjects by simulating genotypes through the genealogy of 708,683 Icelanders as previously described (Stefansson, H., et al., Nat Genet. 37:129-37 (2005)). When estimating genotype specific OR (Table 34) genotype frequencies in the population were estimated assuming HWE. Heterogeneity tests were performed assuming that the estimates of OR for various groups have log-normal distributions. A likelihood ratio chi-square test was used with associated degrees of freedom equal to the number of groups compared minus one.

[0338] In general, allele/haplotype frequencies are estimated by maximum likelihood and tests of differences between cases and controls are performed using a generalized likelihood ratio test. This method is particularly useful in situations where there are some missing genotypes for the marker of interest and genotypes of another marker, which is in strong LD with the marker of interest, are used to provide some partial information. To handle uncertainties with phase and missing genotypes, maximum likelihood estimates, likelihood ratios and P values are computed directly for the observed data, and hence the loss of information due to uncertainty in phase and missing genotypes is automatically captured by the likelihood ratios.

[0339] The correlation of rs10757278 allele G and rs10811661 allele TT to both age and sex was tested in the Icelandic control population. Neither of the alleles demonstrated significant association to these covariates. In addition, no significant difference was detected in the frequency of the variants between males and females within the AAA cases (data not shown). Furthermore, including age and sex as covariates in the association analysis of rs10757278 allele G to AAA in the Icelandic samples had negligible impact on the results. Thus, for simplicity, the association analysis is presented without adjustment for age and sex.

[0340] The possibility that the association results observed for rs10757278 allele G to AAA was influenced by population stratification was addressed for the UK AAA cases and controls by typing 13 SNPs identified by the WTCCC as showing strong evidence for geographic differentiation in the WTCCC samples (Nature 447:661-78 (2007)). Only one of those SNPs showed nominally significant difference between the UK AAA cases and controls (P=0.017), which is not significant if we adjust for having tested 13 SNPs. If we adjust for this SNP in the case-control analysis, the association of rs10757278 allele G to AAA in the UK case-control group is not affected (P=0.0052 and OR=1.36 instead of P=0.0063 and OR=1.35). In the Icelandic case-control analysis we have adjusted for the relatedness of the study individuals. This adjustment has been shown to agree very well with the adjustment based on genomic control, which would include adjustment for any population stratification, in recent publications of genome-wide association studies in the Icelandic population (Steinthorsdottir, V., et al., Nat Genet. 39:770-5 (2007); Gudmundsson, J. et al., Nat Genet. 39:631-7 (2007)). Most importantly, the very similar allelic odds ratios obtained from the five AAA data sets makes it highly unlikely that population stratification has any substantial impact on the estimates of the effect.

[0341] Results from multiple case-control groups were combined using a Mantel-Haenszel model in which the groups were allowed to have different population frequencies for alleles, haplotypes and genotypes but were assumed to have common relative risks (Mantel, N. & Haenszel, W. J Natl Cancer Inst 22: 719-48 (1959)).

Results

[0342] The results shown in Table 32 shows results from the Icelandic IA cohort, replication cohorts, and a combined analysis for the cohorts. When data from the multiple case-control groups studied were combined separately for IA, AAA, PAD and LAA/cardiogenic stroke, rs10757278 allele G showed significant association to all of the four phenotypes. However, the estimated effect size differed substantially and was strongest for AAA (combined analysis, OR=1.31, P=1.2×10^-12) and IA (combined analysis, OR=1.29, P=2.5×10^-6). In addition to the high overall statistical significance, it is also important to note that the estimated risk conferred by rs10757278 allele G to IA and AAA was very similar across the three IA sample sets from Iceland (OR=1.36), Finland (OR=1.33), and the Netherlands (OR=1.24) (P_het, the P-value for the test of heterogeneity=0.75), and the seven AAA sample sets from Iceland (OR=1.37), Belgium (OR=1.21), Canada (OR=1.29), Pennsylvania US (OR=1.39), United Kingdom (UK) (OR=1.35), Netherlands (OR=1.31), and New Zealand (OR=1.25), (P_het=0.98). The effect of rs10757278 allele G on IA and AAA is comparable to that previously reported for CAD (Helgadottir, A., et al. Science 316:1491-3 (2007)) (Table 32).

[0343] Because of high co-morbidity between AAA and CAD, we explored the nature of the effect of the variant on the two conditions, by repeating the association analysis for AAA after removing cases with evidence of CAD. As shown in Table 33, the effect of rs 10757278 allele G on AAA without evidence of CAD was only slightly smaller than that for the whole sample sets, or OR=1.3 for the Icelandic, 1.31 for UK, 1.19 for Pennsylvania, 1.20 for Belgian, 1.25 for The Netherlands, and 1.18 for the New Zealand sample sets. For the six different groups with available CAD information, after removing known CAD cases the combined OR was 1.25 and P=3.0×10^-6, indicating that the association to AAA is not simply a consequence of the association between rs10757278 allele G and CAD. To our knowledge there is no evidence in the literature suggesting co-segregation of IA and CAD. Furthermore, the gender ratio in IA is also different from that for the atherosclerotic diseases such as CAD; IA is more frequent in females than in males, and the peak incidence is also at a younger age than for CAD (Schievink, W. I., N Engl J Med 336:28-40 (1997)). The effect of rs10757278 allele G on IA is thus not mediated through CAD.

[0344] When genotype-specific effects were studied based on data from all seven AAA and the three IA sample sets the ORs for heterozygous and homozygous carriers of the risk allele G were estimated to be 1.36 and 1.74, respectively for AAA and 1.38 and 1.72, respectively, for IA (Table 34). Assuming a population frequency of 47.5% for the G allele, the corresponding population attributable risk is about 26% for both AAA and IA. It is noted that rs10757278 allele G is the first common sequence variant described that affects the risk of IA or AAA.

[0345] The prevalence of AAA (defined as >3 cm aortic diameter) has been reported to be 4.3% and 1.0% in men and women over 50 years of age, respectively (Lederle, F. A., et al, J Vasc Surg 34:122-6 (2001); Lederle, F. A., et al. Arch Intern Med 160:1425-30 (2000)), and 2-5% of the general population have IA (Brisman, J. L, et al., N Engl J Med 355:928-39 (2006)). Both AAA and IA represent a degenerative process of the arteries leading to their enlargement that is usually asymptomatic with natural history culminating in either a therapeutic intervention or rupture. Rupture of IA leads to subarachnoid haemorrhage, and rupture of both IA and AAA have high morbidity and mortality (Brisman, J. L, et al., N Engl J Med 355:928-39 (2006); Thompson, R. w. Cardiovasc Surg 10: 389-94 (2002)). In the case of AAA the rupture risk increases with the growth rate as well as the size of the aneurysm. While patients from the UK study group included only those with small asymptomatic aneurysms (aortas <5.5 cm diameter), the other study groups included mainly patients undergoing aneurysm repair and are therefore likely to be biased towards larger and symptomatic aneurysms (aortas >5.5 cm diameter). Despite recruitment differences the ORs were similar, suggesting that the variant does not confer direct risk of the growth of aortic aneurysms. This concept was further investigated in the sample set from UK, where the subjects with small asymptomatic AAA had been followed with sequential aortic aneurysm size measurements (Eriksson, P. et al., Br J Surg 92:1372-6 (2005)). As shown in Table 35, there is no evidence of an association between rs10757278 allele G and either aneurysm growth or rupture. Rather there is some indication that allele G is correlated with slow growth. The difference in average growth rates between the homozygous GG group and the heterozygous AG group is -0.46 mm/year and is nominally significant (P=0.05), an observation that warrants further investigation. If confirmed, this inverse association would echo previous findings where slower aneurysm growth rates were observed in patients with low ankle/brachial pressure index, a marker of generalised atherosclerosis (Brady A. R., et al., Circulation 110:16-21 (2004)). These data suggest that the sequence variant leads to increased susceptibility of developing aneurysm rather than increasing the risk of rapid aneurysm progression.

[0346] The effect of rs10757278 allele G on the risk of PAD and LAA/cardiogenic stroke appeared to be weaker than that for AAA, IA and CAD (Table 32). In the Icelandic samples there was no difference in the frequency of rs10757278 allele G between the AAA and IA cases, however the frequency was lower in both the PAD and LAA/cardiogenic stroke cases than in the combined group of AAA and IA cases (P=0.012 and P=0.052, respectively). Furthermore, after excluding PAD and LAA/cardiogenic stroke subjects with known CAD from the analysis the effect was reduced even further, particularly for PAD (Table 33).

[0347] We tested the association of several variants in the LD block C09 region with MI in African American samples. As shown by the results presented in Table 36, the effect in African Americans is comparable in magnitude, as measured by Relative Risk, to the effect in Caucasian samples. The lack of nominal statistical significance of the association (p-value less than 0.05) in the African American samples for many of the markers is due to the relatively small samples size. Most importantly, the association observed in African Americans, together with reported association in Asian samples originating from Japan and Korea with comparable risk to that determined for Caucasians (see Arterioscler Thromb Vasc Biol. 2008 February; 28(2):360-5. Epub 2007 Nov. 29, and J Hum Genet. Epub 2008 Feb. 9) shows that the genetic effects originally discovered in Caucasian samples from Iceland manifests itself in other human populations. The effect therefore has implications for cardiovascular disease in all major human populations.

[0348] These data demonstrate that rs10757278 allele G has less effect on the atherosclerotic diseases, PAD and LAA/cardiogenic stroke, than on CAD. In contrast, the effect on the two aneurysmal diseases, AAA with weaker association to atherosclerosis and IA with no such relationship, was comparable to that on CAD, suggesting that the variant plays a role in a pathophysiological component common to these arterial phenotypes. This may involve abnormal vascular remodelling and/or repair which has been identified as a key in the pathogenesis CAD, AAA and IA (Chatzidisis, Y. S. et al., J Am Coll Cardiol 49:2379-93 (2007); Hashimoto, T. et al., Neurol Res 8:372-80 (2006); Moore, J. E., Jr., et al, Atherosclerosis 110:225-40 (2006)). The sequence variant rs10757278 allele G on chromosome 9p21, and/or variants in linkage disequilibrium with rs10757278, may thus function as a genetic determinant of the tissue response to unfavourable conditions that prevail in the lower abdominal aorta, in the circle of Willis where lAs occur, and in those regions of the coronary tree that are prone to develop unstable, rupture prone atherosclerotic plaques.

Tables

TABLE-US-00004 [0349] TABLE 1 a) Results for the 12 SNPs in LD block C09 that showed nominally significant association to myocardial infarction in the Icelandic discovery cohort (Cohort A) of 1570 MI cases and 7088 controls. Shown is the frequency of the risk allele in cases and controls, the corresponding relative risk (RR), the unadjusted P-value and the P-value after adjusting for the relatedness of cases and controls. Also included are results for a test of association to MI for the same SNPs conditioned on the association of the SNP rs1333040. b) Association to MI for the different alleles of the micro-satellites D9S1814 and D9S1870 in Cohort A. c) Association to MI of the at-risk allele 0 for D9S1814 and of the composite at-risk allele X of D9S1870 in Cohort A. The composite allele X includes alleles -6, -4, -2 and 0 of D9S1870. Conditioned on Frequency rs1333040 SNP Allele Position Cases Controls RR P P* RR** P** r2*** a) rs7041637 A 21951866 0.251 0.232 1.104 0.031 0.044 1.003 0.96 0.12 rs2811712 A 21988035 0.890 0.874 1.171 0.010 0.016 1.146 0.040 0.05 rs3218018 A 21988139 0.894 0.878 1.174 0.010 0.016 1.149 0.038 0.03 rs3217992 A 21993223 0.376 0.344 1.149 0.00071 0.0015 1.015 0.80 0.28 rs2069426 C 21996273 0.895 0.880 1.159 0.019 0.028 1.134 0.063 0.02 rs2069422 A 21998026 0.891 0.874 1.174 0.0092 0.015 1.149 0.037 0.05 rs1333034 A 22034122 0.890 0.874 1.168 0.012 0.018 1.143 0.043 0.05 rs1011970 G 22052134 0.801 0.772 1.189 0.00034 0.00081 1.114 0.050 0.13 rs10116277 T 22071397 0.463 0.419 1.195 7.05 × 10^-6 2.63 × 10^-5 1.054 0.52 0.67 rs1333040 T 22073404 0.538 0.491 1.209 1.56 × 10^-6 6.98 × 10^-6 NA NA NA rs2383207 G 22105959 0.502 0.456 1.204 2.64 × 10^-6 1.11 × 10^-5 1.102 0.15 0.57 rs1333050 T 22115913 0.694 0.672 1.107 0.017 0.025 1.005 0.92 0.27 b) D9S1814 -2 22078225 0.019 0.019 1.049 0.79 0.81 -- -- -- D9S1814 0 22078225 0.500 0.451 1.217 1.35 × 10^-6 6.17 × 10^-6 -- -- -- D9S1814 2 22078225 0.359 0.385 0.895 0.015 0.023 -- -- -- D9S1814 4 22078225 0.112 0.149 0.720 4.00 × 10^-6 1.60 × 10^-5 -- -- -- D9S1870 -6 22093010 0.019 0.020 0.961 0.79 0.81 -- -- -- D9S1870 -4 22093010 0.039 0.029 1.352 0.0090 0.015 -- -- -- D9S1870 -2 22093010 0.376 0.339 1.177 0.00011 0.00031 -- -- -- D9S1870 0 22093010 0.044 0.043 1.038 0.72 0.74 -- -- -- D9S1870 2 22093010 0.072 0.074 0.974 0.74 0.76 -- -- -- D9S1870 4 22093010 0.166 0.200 0.797 2.96 × 10^-5 9.31 × 10^-5 -- -- -- D9S1870 6 22093010 0.104 0.114 0.905 0.14 0.17 -- -- -- D9S1870 8 22093010 0.079 0.080 0.989 0.89 0.89 -- -- -- D9S1870 10 22093010 0.072 0.077 0.931 0.37 0.40 -- -- -- D9S1870 12 22093010 0.021 0.018 1.152 0.34 0.37 -- -- -- c) D9S1814 0 22078225 0.500 0.451 1.217 1.35 × 10^-6 6.17 × 10^-6 1.118 0.099 0.53 D9S1870 X 22093010 0.486 0.438 1.211 2.52 × 10^-6 1.07 × 10^-5 1.113 0.081 0.55 *P-value adjuste for relatedness of cases and controls. **P-value adjusted for relatedness and conditioned on the association to rs133304, and the corresponding relative risk. ***Pair-wise correlation r2 between the SNP and the at-risk variant rs1333040

TABLE-US-00005 TABLE 2 Pair-wise correlation among the 5 markers, 3 SNPs and 2 micro-satellites, that show strongest association to myocardial infarction in LD block C09, based on the HapMap v19 CEU dataset. In the upper right corner are shown values for the correlation coefficient r², while in the lower left corner are values for D'. r² Marker rs10116277 rs1333040 D9S1814 D9S1870 rs2383207 D' rs10116277 -- 0.667 0.806 0.839 0.905 rs1333040 1.000 -- 0.528 0.550 0.569 D9S1814 0.964 0.829 -- 0.651 0.743 D9S1870 1.000 1.000 0.954 -- 0.779 rs2383207 1.000 0.879 0.893 1.000 --

TABLE-US-00006 TABLE 3 List of all SNPs (from HapMap v19 CEU dataset) in LD block C09 that are correlated, with correlation coefficient r² ≧ 0.2, with at least one of the five markers (rs10116277, rs1333040, D9S1814, D9S1870 or rs2383207). For each SNP shown the table includes the position (in Build 34 and in SEQ ID NO: 94) and the correlation coefficient r² to each of the five at-risk markers. SNP Position^a Position^b D9S1814 D9S1870 rs1333040 rs2383207 rs10116277 rs7041637 21951866 31720 0.18 0.12 0.20 0.21 0.15 rs3218020 21987872 67726 0.46 0.33 0.37 0.55 0.41 rs3217992 21993223 73077 0.43 0.28 0.34 0.53 0.38 rs1063192 21993367 73221 0.22 0.09 0.27 0.28 0.16 rs2069418 21999698 79552 0.19 0.06 0.25 0.25 0.14 rs2069416 22000004 79858 0.41 0.24 0.32 0.50 0.36 rs573687 22001642 81496 0.23 0.07 0.28 0.20 0.17 rs545226 22002422 82276 0.31 0.18 0.24 0.40 0.27 rs10811640 22003411 83265 0.21 0.09 0.29 0.29 0.19 rs10811641 22004137 83991 0.41 0.27 0.33 0.50 0.36 rs2106120 22007101 86955 0.23 0.10 0.31 0.32 0.21 rs2106119 22007550 87404 0.23 0.10 0.31 0.32 0.21 rs643319 22007836 87690 0.22 0.09 0.29 0.32 0.20 rs7044859 22008781 88635 0.23 0.10 0.31 0.32 0.21 rs523096 22009129 88983 0.17 0.05 0.22 0.23 0.12 rs10757264 22009732 89586 0.21 0.09 0.29 0.30 0.19 rs10965212 22013795 93649 0.29 0.14 0.38 0.40 0.27 rs1292137 22014023 93877 0.24 0.09 0.31 0.34 0.21 rs1292136 22014351 94205 0.30 0.16 0.37 0.41 0.28 rs10811644 22015067 94921 0.25 0.11 0.33 0.34 0.22 rs7035484 22015240 95094 0.24 0.10 0.32 0.33 0.22 rs10738604 22015493 95347 0.49 0.35 0.41 0.60 0.44 rs615552 22016077 95931 0.17 0.06 0.21 0.20 0.10 rs543830 22016639 96493 0.23 0.08 0.28 0.31 0.17 rs1591136 22016834 96688 0.29 0.14 0.38 0.40 0.27 rs7049105 22018801 98655 0.29 0.14 0.38 0.40 0.27 rs679038 22019080 98934 0.23 0.08 0.28 0.31 0.17 rs10965215 22019445 99299 0.27 0.13 0.35 0.38 0.25 rs564398 22019547 99401 0.21 0.07 0.26 0.29 0.15 rs7865618 22021005 100859 0.24 0.10 0.29 0.31 0.18 rs10115049 22022119 101973 0.29 0.14 0.38 0.40 0.27 rs634537 22022152 102006 0.24 0.08 0.29 0.33 0.20 rs2157719 22023366 103220 0.26 0.11 0.32 0.33 0.19 rs2151280 22024719 104573 0.27 0.15 0.36 0.38 0.25 rs1008878 22026112 105966 0.24 0.12 0.30 0.32 0.18 rs1556515 22026367 106221 0.26 0.13 0.32 0.35 0.20 rs1333037 22030765 110619 0.28 0.12 0.34 0.36 0.21 rs1360590 22031443 111297 0.31 0.15 0.40 0.43 0.29 rs1412829 22033926 113780 0.23 0.08 0.28 0.31 0.17 rs1360589 22035317 115171 0.30 0.12 0.36 0.40 0.23 rs7028570 22038683 118537 0.31 0.14 0.40 0.43 0.29 rs944801 22041670 121524 0.30 0.12 0.36 0.40 0.23 rs10965219 22043687 123541 0.30 0.13 0.40 0.48 0.27 rs7030641 22044040 123894 0.30 0.12 0.36 0.40 0.23 rs10120688 22046499 126353 0.38 0.18 0.47 0.51 0.35 rs2184061 22051562 131416 0.50 0.24 0.59 0.44 0.40 rs1537378 22051614 131468 0.50 0.24 0.59 0.44 0.40 rs8181050 22054391 134245 0.47 0.22 0.55 0.40 0.38 rs8181047 22054465 134319 0.33 0.49 0.38 0.28 0.21 rs10811647 22055002 134856 0.70 0.49 0.59 0.83 0.62 rs1333039 22055657 135511 0.47 0.22 0.55 0.40 0.38 rs10965224 22057276 137130 0.45 0.21 0.53 0.40 0.35 rs10811650 22057593 137447 0.70 0.49 0.59 0.83 0.63 rs10811651 22057830 137684 0.48 0.23 0.56 0.41 0.39 rs4977756 22058652 138506 0.47 0.22 0.55 0.40 0.38 rs10757269 22062264 142118 0.94 0.66 0.80 0.78 0.84 rs9632884 22062301 142155 0.93 0.65 0.80 0.78 0.84 rs1412832 22067543 147397 0.32 0.48 0.37 0.28 0.22 rs10116277 22071397 151251 -- 0.67 0.81 0.84 0.90 rs10965227 22071796 151650 0.28 0.02 0.13 0.18 0.31 rs6475606 22071850 151704 1.00 0.67 0.81 0.84 0.90 rs1333040 22073404 153258 0.67 -- 0.53 0.55 0.57 rs1537370 22074310 154164 1.00 0.67 0.81 0.84 0.90 rs7857345 22077473 157327 0.36 0.55 0.43 0.32 0.26 rs10738607 22078094 157948 1.00 0.69 0.81 0.84 0.90 rs10757272 22078260 158114 1.00 0.67 0.81 0.84 0.90 rs4977574 22088574 168428 1.00 0.67 0.81 0.84 0.90 rs2891168 22088619 168473 1.00 0.67 0.81 0.84 0.90 rs1537371 22089568 169422 1.00 0.67 0.81 0.84 0.90 rs1556516 22090176 170030 1.00 0.67 0.81 0.84 0.90 rs6475608 22091702 171556 0.36 0.54 0.42 0.31 0.25 rs7859727 22092165 172019 1.00 0.66 0.80 0.84 0.90 rs1537373 22093341 173195 1.00 0.67 0.81 0.84 0.90 rs1333042 22093813 173667 0.97 0.63 0.81 0.81 0.94 rs7859362 22095927 175781 0.90 0.57 0.74 0.78 1.00 rs1333043 22096731 176585 0.94 0.60 0.74 0.81 0.97 rs1412834 22100131 179985 0.90 0.57 0.74 0.78 1.00 rs7341786 22102241 182095 0.88 0.54 0.71 0.75 0.97 rs10511701 22102599 182453 0.88 0.54 0.71 0.75 0.97 rs10733376 22104469 184323 0.90 0.57 0.74 0.78 1.00 rs10738609 22104495 184349 0.90 0.57 0.74 0.78 1.00 rs2383206 22105026 184880 0.90 0.57 0.74 0.78 1.00 rs944797 22105286 185140 0.90 0.57 0.74 0.78 1.00 rs1004638 22105589 185443 0.90 0.57 0.74 0.78 1.00 rs2383207 22105959 185813 0.90 0.57 0.74 0.78 -- rs1537374 22106046 185900 0.90 0.57 0.74 0.78 1.00 rs1537375 22106071 185925 0.90 0.57 0.74 0.78 1.00 rs1333045 22109195 189049 0.69 0.37 0.52 0.60 0.65 rs10738610 22113766 193620 0.94 0.60 0.77 0.78 0.97 rs1333046 22114123 193977 0.94 0.60 0.77 0.78 0.97 rs10757278 22114477 194331 0.90 0.57 0.74 0.75 0.87 rs1333047 22114504 194358 0.90 0.59 0.72 0.74 0.88 rs4977575 22114744 194598 0.90 0.59 0.72 0.74 0.88 rs1333048 22115347 195201 0.97 0.63 0.77 0.81 0.94 rs1333049 22115503 195357 0.90 0.59 0.72 0.74 0.88 rs1333050 22115913 195767 0.17 0.27 0.06 0.15 0.20 ^aPosition with respect to NCBI Build 34, Build 35 or Build 36 ^bPosition with respect to SEQ ID NO: 94 (LD Block C09)

TABLE-US-00007 TABLE 4 a) Association of the composite at-risk allele X of the micro-satellite D9S1870 to myocardial infarction (MI) in a replication cohort (Cohort B) of 668 Icelandic MI cases and 58,543 controls and in the combined Icelandic cohort (Cohort A + B). Included in the table is the number of cases n and controls m, the allele frequency in cases and controls, the corresponding P value adjusted for relatedness of the study individuals, the relative risk (RR) with 95% confidence interval (CI), and the population attributed risk (PAR). Known CAD or CVD cases have been excluded from the control cohort. b) Association of allele X to MI in three distinct US replication cohorts. All cases and controls in those three cohorts are of Caucasian origin. c) Combined association results, using a Mantel-Haenzel model, for the composite at-risk allele X in all replication cohorts combined, and in all cohorts combined, respectively. Frequency Cohort (n/m) Cases Controls P* RR CI PAR a) Iceland Cohort B (668/58643) 0.501 0.441 1.39 × 10^-5 1.274 [1.142, 1.420] 0.203 Cohort A + B (2238/65731) 0.491 0.441 8.91 × 10^-10 1.221 [1.145, 1.301] 0.169 b) US replication cohorts Cleveland (549/606) 0.501 0.478 0.27 1.097 [0.932, 1.292] 0.087 UPenn (580/404) 0.539 0.483 0.014 1.252 [1.046, 1.499] 0.205 Emory (400/477) 0.548 0.482 0.0064 1.299 [1.076, 1.569] 0.236 c) Combined** Replication cohorts (2197/60130) 2.65 × 10^-8 1.231 [1.144, 1.324] 0.183 All cohorts (3767/67218) 1.44 × 10^-12 1.214 [1.151, 1.281] 0.171 *P-values for the Icelandic cohorts are adjusted for relatedness using simulations (see methods) **Mantel-Haenzel model was used to combine the results from the different cohorts.

TABLE-US-00008 TABLE 5 a) Association of the composite at-risk allele X of D9S1870 in Icelandic cases with various cardiovascular disease phenotypes. Included in the table are association results for individuals who have undergone PTCA or CABG, for the combined MI and CAD (PTCA and CABG) cohort, individuals with PAD or that have had infarct or TIA, and stroke patients diagnosed with LVD. In all tests the same set of 65,731 Icelandic controls without known CAD complications is used. b) Association of allele X in Iceland to the same coronary artery disease phenotypes as in a) after excluding all known cases of MI from the list of cases. C) Association of allele X to PTCA, CABG and a combined phenotype MI and other CAD, in the Emory cohort. Frequency Phenotype (n) Cases Controls RR CI P P* PAR a) Iceland PTCA (1791) 0.489 0.441 1.211 [1.129, 1.298] 2.69E-08 8.60E-08 0.163 CABG (642) 0.514 0.441 1.338 [1.189, 1.506] 3.38E-07 1.31E-06 0.243 MI + other CAD (3513) 0.488 0.441 1.209 [1.148, 1.273] 2.57E-14 6.24E-13 0.162 PAD(1661) 0.477 0.441 1.154 [1.074, 1.239] 5.36E-05 8.58E-05 0.123 Stroke, Infarct + TIA 0.448 0.441 1.027 [0.958, 1.102] 0.45 0.45 0.023 (1678) Stroke, LVD (197) 0.469 0.441 1.120 [0.915, 1.370] 0.27 0.27 0.098 b) Iceland, excl. MI cases PTCA (941) 0.483 0.441 1.183 [1.077, 1.300] 0.00033 0.00045 0.144 CABG (221) 0.501 0.441 1.270 [1.044, 1.545] 0.013 0.017 0.202 PAD(1322) 0.464 0.441 1.096 [1.012, 1.186] 0.021 0.025 0.079 Stroke, Infarct + TIA 0.450 0.441 1.037 [0.960, 1.119] 0.35 0.36 0.032 (1390) Stroke, LVD (153) 0.480 0.441 1.172 [0.934, 1.470] 0.17 0.17 0.136 c) Emory PTCA (141) 0.567 0.482 1.408 [1.079, 1.839] 0.012 NA 0.302 CABG (112) 0.549 0.482 1.308 [0.977, 1.751] 0.071 NA 0.242 MI + other CAD (476) 0.551 0.482 1.320 [1.103, 1.581] 0.0025 NA 0.250 *P-value adjusted for relatedness using simulations.

TABLE-US-00009 TABLE 6 Association of the composite at-risk allele X of D9S1870 to early-onset MI or CAD a) in Iceland, b) in the three US replication cohorts, c) in all early-onset MI cohorts combined. Early-onset MI is defined as a MI event before the age 50 for males and before the age of 60 for females. Frequency Phenotype (n) Cases Controls RR CI P P* PAR a) Iceland Early onset MI (646/65731) 0.514 0.441 1.339 [1.193, 1.503] 3.63E-07 7.51E-07 0.243 Early onset CAD 0.532 0.441 1.439 [1.227, 1.687] 6.12E-06 7.40E-06 0.298 (320/65731) Early onset MI + CAD 0.511 0.441 1.325 [1.200, 1.464] 9.87E-09 2.70E-08 0.235 (877/65731) b) US cohorts Emory EO MI (222/477) 0.559 0.482 1.359 [1.084, 1.703] 0.0078 NA 0.273 Cleveland EO MI (183/606) 0.514 0.478 1.155 [0.914, 1.459] 0.2281 NA 0.133 Upenn EO MI (275/490) 0.569 0.473 1.469 [1.191, 1.811] 0.00033 NA 0.330 c) All cohorts combined Early onset MI -- -- 1.331 [1.223, 1.449] 3.96E-11 NA 0.247 (1326/67304) *P-value adjusted for relatedness using simulations.

TABLE-US-00010 TABLE 7 Model-free estimates of the genotype relative risks (GRR) of the composite allele X of D9S1870. Included is the risk for heterozygous carriers (0X) and homozygous carriers (XX) compared with risk for non-carriers (00) and the corresponding 95% confidence intervals (CI). Results are shown for a) all MI cases versus controls and b) for early-onset MI cases versus controls for the whole Icelandic cohort, the three US replication cohorts and for all the cohorts combined sing a Mantel-Haenzel model. Genotype relative risk (GRR) Phenotype (n/m) OX CI XX CI a) All MI cases Iceland (2238/65731) 1.173 [1.060, 1.298] 1.507 [1.338, 1.697] Cleveland (549/606) 1.077 [0.804, 1.443] 1.204 [0.860, 1.686] UPenn (679/490) 1.443 [1.074, 1.938] 1.728 [1.228, 2.431] Emory (400/477) 1.213 [0.836, 1.760] 1.669 [1.144, 2.435] Combined 1.204 [1.094, 1.324] 1.507 [1.360, 1.670] (3866/67304) b) Early onset MI cases Iceland (641/65731) 1.191 [0.982, 1.444] 1.803 [1.453, 2.237] Cleveland (183/606) 1.432 [0.932, 2.201] 1.867 [1.176, 2.964] UPenn (275/490) 1.692 [1.134, 2.524] 2.237 [1.440, 3.476] Emory (222/477) 1.069 [0.567, 2.017] 1.328 [0.827, 2.133] Combined 1.314 [1.105, 1.562] 1.790 [1.517, 2.113] (1321/67304)

TABLE-US-00011 TABLE 8 a) Association of the risk alleles of the markers rs10116277, rs1333040 and rs2383207 to age of onset of MI in the Icelandic Cohort A. The analysis is done using multiple regression where age of onset of MI is taken as the response variable and the number of copies of X is used as explanatory variable. The analysis is adjusted for gender by include sex of the individuals as an explanatory variable. Included in the table is the effect size, the standard error of the mean (SE) and the corresponding P-value. b) Association of the composite at-risk allele X of D9S1870 to age-of-onset of MI in the combined Icelandic MI patient cohort, and for the three US replication cohorts. Results for the four cohorts are combined weighting the contribution from each cohort proportional to the inverse of the standard error. In all tests only cases with known age-of-onset are included. Cohort/Marker (n) Effect SE P a) SNPs in Iceland A rs10116277 (1293) -0.94 0.32 0.0039 rs1333040 (1293) -1.01 0.32 0.0018 rs2383207 (1293) -0.79 0.32 0.015 b) D9S1870 allele X Iceland (2127) -0.93 0.29 0.0016 Cleveland (424) -0.47 0.79 0.55 UPenn (646) -1.19 0.69 0.083 Emory (403) -1.38 0.87 0.11 Combined (3600) -0.95 0.25 0.000099

TABLE-US-00012 TABLE 9 a) Association of the composite risk allele X of D9S1870 to either mild (<50%) or severe (≧50%) in-stent restenosis in coronary artery disease patients that have undergone PTCA compared to controls without known history of CAD. b) Comparision of the frequency of the risk variant X in patients with severe in-stent restenosis to patients with mild in-stent restenosis. Frequency Phenotype (n, m) Cases Controls RR CI P a) Restenosis patients vs controls Mild restenosis, 0.492 0.441 1.228 [1.050, 1.436] 0.010 <50% (323/65731) Severe restenosis 0.509 0.441 1.313 [1.071, 1.608] 0.0086 (≧50% (193/65731) b) Severe vs mild 0.509 0.492 1.067 [0.827, 1.376] 0.62 restenosis (193/323)

TABLE-US-00013 TABLE 10 A. SNP markers within LD Block C09 (Between 21,920,147 and 22,149,982 on C09; NCBI Build 34, Build 35 and Build 36 (SEQ ID NO: 94)). Marker Type of Location(NCBI Build Orientation Location (SEQ ID NO: 1) rs7864029 C/G 21920147 + 1 rs2518714 A/C 21920303 + 157 rs10965187 A/G 21920505 + 359 rs2811715 G/T 21920571 + 425 rs2518715 C/T 21920700 + 554 rs12002708 A/C 21920762 + 616 rs10811639 A/G 21920803 + 657 rs11998828 C/T 21920812 + 666 rs7868374 A/G 21921609 + 1463 rs4977570 G/T 21921642 + 1496 rs7390564 G/T 21921642 + 1496 rs7869004 G/T 21921896 + 1750 rs974679 A/G 21922245 + 2099 rs2891010 A/G 21922261 + 2115 rs12003714 A/G 21922366 + 2220 rs28756321 C/G 21923029 + 2883 rs12000395 A/G 21923096 + 2950 rs2188126 C/G 21923125 + 2979 rs12003027 C/T 21924442 + 4296 rs7023582 A/C 21924684 + 4538 rs28613732 A/G 21925807 + 5661 rs10965188 C/G 21925874 + 5728 rs12552975 C/T 21926059 + 5913 rs7875199 C/T 21926381 + 6235 rs12236992 A/C 21927299 + 7153 rs7021848 C/T 21927351 + 7205 rs7036999 A/G 21927875 + 7729 rs12345808 A/G 21928367 + 8221 rs35148759 C/T 21929306 + 9160 rs7872310 A/G 21929387 + 9241 rs2811716 C/T 21930017 + 9871 rs10965189 A/C 21930588 + 10442 rs4308829 C/T 21931196 + 11050 rs10965190 A/G 21931385 + 11239 rs10965191 A/G 21932535 + 12389 rs12345373 A/G 21933199 + 13053 rs4977750 A/C 21934317 + 14171 rs10965193 A/G 21934544 + 14398 rs4246843 C/T 21934627 + 14481 rs4382559 A/G 21934818 + 14672 rs4360371 A/C 21935562 + 15416 rs16938595 A/T 21935605 + 15459 rs10965194 A/G 21936214 + 16068 rs2811717 C/T 21936322 + 16176 rs6475598 C/T 21936322 + 16176 rs2811718 A/T 21936891 + 16745 rs10965196 C/G 21937472 + 17326 rs2811719 C/G 21937472 + 17326 rs2811720 C/G 21937957 + 17811 rs6475599 C/G 21937957 + 17811 rs11521166 C/T 21938376 + 18230 rs2518718 A/T 21938489 + 18343 rs10965197 C/T 21938666 + 18520 rs2106117 G/T 21939527 + 19381 rs2106118 A/T 21939528 + 19382 rs2427852 A/T 21940432 + 20286 rs2157716 C/T 21940446 + 20300 rs2263145 C/T 21940452 + 20306 rs2427853 C/T 21940472 + 20326 rs2382894 C/G 21940523 + 20377 rs2427854 A/T 21940721 + 20575 rs7047211 A/T 21940722 + 20576 rs11532909 A/T 21940723 + 20577 rs13297154 A/T 21940725 + 20579 rs13298455 A/T 21940741 + 20595 rs2891092 A/G 21940782 + 20636 rs6415737 A/G 21940782 + 20636 rs4503179 A/G 21940879 + 20733 rs12349081 A/C 21941902 + 21756 rs2518722 C/T 21942926 + 22780 rs10757260 A/G 21943137 + 22991 rs28369665 C/T 21944487 + 24341 rs10965199 C/T 21944653 + 24507 rs10757261 A/G 21944953 + 24807 rs12335859 A/G 21945460 + 25314 rs12335941 A/G 21945669 + 25523 rs2027938 A/G 21946078 + 25932 rs9657608 C/T 21946230 + 26084 rs2518716 A/G 21946470 + 26324 rs2027939 A/G 21946492 + 26346 rs7869996 C/T 21946914 + 26768 rs10965200 C/G 21948142 + 27996 rs717326 A/G 21948524 - 28378 rs35116241 A/C 21949093 + 28947 rs2518717 C/T 21949751 + 29605 rs3948753 A/G 21949860 + 29714 rs2106115 C/T 21949900 + 29754 rs10965201 C/G 21949950 + 29804 rs2106116 C/T 21949966 + 29820 rs10965202 A/G 21951180 + 31034 rs1985742 A/T 21951227 + 31081 rs7041637 A/C 21951866 + 31720 rs2263146 C/T 21953048 + 32902 rs35732310 A/C 21953841 + 33695 rs4518744 A/C 21954015 + 33869 rs2188127 C/G 21955232 + 35086 rs3731257 C/T 21956221 - 36075 rs3731256 C/T 21956617 - 36471 rs11793581 G/T 21957446 + 37300 rs28695347 A/C 21957706 + 37560 rs3731255 C/G 21957855 - 37709 rs3731253 C/G 21957952 - 37806 rs3088440 A/G 21958159 + 38013 rs11515 C/G 21958199 - 38053 rs34011899 A/C 21958712 + 38566 rs2255962 A/G 21959827 + 39681 rs2518719 A/G 21960427 + 40281 rs3731249 A/G 21960916 - 40770 rs6413464 G/T 21960979 - 40833 rs34170727 C/T 21960988 - 40842 rs6413463 A/T 21960989 - 40843 rs35741010 A/G 21961054 - 40908 rs34886500 C/T 21961063 - 40917 rs4987127 A/G 21961085 - 40939 rs11552822 G/T 21961108 - 40962 rs34968276 A/C 21961109 - 40963 rs11552823 C/T 21961116 - 40970 rs3731247 C/T 21961352 - 41206 rs12377672 C/T 21961418 + 41272 rs3731246 C/G 21961989 - 41843 rs3731245 A/G 21962445 - 42299 rs3731244 A/G 21962813 - 42667

rs3731243 A/G 21963050 - 42904 rs2811708 G/T 21963422 + 43276 rs3731241 A/G 21963767 - 43621 rs13288666 C/T 21963857 + 43711 rs3731240 A/G 21964131 - 43985 rs3731239 C/T 21964218 - 44072 rs3814960 A/C/G/T 21965017 + 44871 rs3731238 A/G 21965561 - 45415 rs3731237 A/G 21965728 - 45582 rs3731236 C/T 21966976 - 46830 rs3731235 G/T 21967450 - 47304 rs12350633 C/G 21967553 + 47407 rs3731234 A/C 21967579 - 47433 rs3731233 A/T 21968358 - 48212 rs3731232 C/G 21968443 - 48297 rs2518720 C/T 21968979 + 48833 rs3731230 C/T 21969163 - 49017 rs2518721 A/G 21969204 + 49058 rs3731229 A/C 21969497 - 49351 rs3731228 A/G 21969602 - 49456 rs2811709 A/G 21970151 + 50005 rs3731227 C/T 21970744 - 50598 rs3731226 C/T 21970792 - 50646 rs13297747 C/G 21970941 + 50795 rs36170221 C/G 21970941 + 50795 rs36153543 C/T 21970944 + 50798 rs7874405 C/T 21970944 + 50798 rs13302595 C/T 21971034 + 50888 rs13301751 A/G 21971039 + 50893 rs13302611 C/T 21971068 + 50922 rs13302761 C/T 21971100 + 50954 rs13302792 C/T 21971168 + 51022 rs3731225 A/G 21971351 - 51205 rs3731224 C/T 21971411 - 51265 rs4074785 A/G 21971583 + 51437 rs3731223 A/G 21973834 - 53688 rs3731222 A/G 21973914 - 53768 rs3731221 A/G 21974010 - 53864 rs3731220 A/G 21974019 - 53873 rs3731219 A/G 21974086 - 53940 rs3731218 C/T 21974331 - 54185 rs3731217 G/T 21974661 - 54515 rs3731216 G/T 21975576 - 55430 rs3731215 C/T 21975771 - 55625 rs3731214 A/G 21975968 - 55822 rs3731213 A/G 21976218 - 56072 rs3731212 C/T 21976271 - 56125 rs3731211 A/T 21976847 - 56701 rs3731210 A/G 21976859 - 56713 rs3731208 C/T 21977155 - 57009 rs3731207 C/T 21977353 - 57207 rs12376353 C/G 21977433 + 57287 rs3731206 A/G 21977472 - 57326 rs3731205 A/G 21977522 - 57376 rs3731204 A/G 21977584 - 57438 rs10757262 A/T 21977874 + 57728 rs3731202 A/G 21978800 - 58654 rs3731201 A/G 21978896 - 58750 rs3731199 A/G 21979330 - 59184 rs3731198 A/G 21979477 - 59331 rs7036656 C/T 21980457 + 60311 rs7867492 C/T 21981016 + 60870 rs3731197 A/G 21981371 - 61225 rs3731196 A/G 21981652 - 61506 rs3731195 C/T 21981695 - 61549 rs3731194 C/G 21981752 - 61606 rs2811710 C/T 21981923 + 61777 rs3731192 G/T 21982274 - 62128 rs3731191 C/T 21983048 - 62902 rs2811711 C/T 21983964 + 63818 rs3731190 C/T 21984282 - 64136 rs2518723 A/G 21985882 - 65736 rs7860185 C/T 21986986 + 66840 rs3218024 A/G 21987437 - 67291 rs3218023 C/T 21987597 - 67451 rs3218022 A/G 21987723 - 67577 rs3218021 G/T 21987752 - 67606 rs3218020 C/T 21987872 - 67726 rs3218019 A/G 21987904 - 67758 rs2811712 A/G 21988035 + 67889 rs3218018 A/C 21988139 - 67993 rs3218016 A/G 21988273 - 68127 rs3218015 C/G 21988392 - 68246 rs3218013 C/T 21988556 - 68410 rs3218012 C/T 21988660 - 68514 rs3218011 A/G 21988676 - 68530 rs3218010 A/G 21988733 - 68587 rs3218009 C/G 21988757 - 68611 rs10965208 A/G 21988965 + 68819 rs2811713 A/G 21989328 + 69182 rs2811714 C/T 21989334 + 69188 rs3218007 A/G 21989800 - 69654 rs3218006 G/T 21989980 - 69834 rs3218005 A/G 21990247 - 70101 rs3218004 C/G 21990687 - 70541 rs3218003 C/G 21990770 - 70624 rs3218002 C/T 21990841 - 70695 rs3218001 C/G 21990959 - 70813 rs3218000 C/T 21991078 - 70932 rs3217999 C/T 21991572 - 71426 rs3217998 A/C 21991667 - 71521 rs3217997 A/G 21992316 - 72170 rs3217996 C/T 21992322 - 72176 rs3217994 A/G 21992864 - 72718 rs3217993 C/T 21993169 - 73023 rs3217992 A/G 21993223 - 73077 rs1063192 C/T 21993367 - 73221 rs3217990 A/C 21993521 - 73375 rs3217989 A/G 21993790 - 73644 rs3217988 A/G 21994082 - 73936 rs2285329 C/T 21994153 - 74007 rs10965209 A/G 21994669 + 74523 rs3217987 C/T 21995061 - 74915 rs11792943 A/G 21995123 + 74977 rs11792944 G/T 21995127 + 74981 rs3217986 A/C 21995330 - 75184 rs3217985 C/T 21995453 - 75307 rs3217984 C/G 21995493 - 75347 rs3217983 C/T 21995623 - 75477 rs3217982 C/T 21995647 - 75501 rs3217981 A/G 21996269 - 76123 rs2069426 A/C 21996273 - 76127 rs974336 A/G 21996348 - 76202 rs3217980 C/T 21996607 - 76461 rs2069425 C/T 21996793 - 76647

rs2285328 C/T 21996966 - 76820 rs2285327 A/G 21997048 - 76902 rs3217979 A/G 21997187 - 77041 rs3217978 G/T 21997330 - 77184 rs2069423 C/T 21997771 - 77625 rs2069422 A/C 21998026 - 77880 rs2069421 A/G 21998313 - 78167 rs3217976 A/C 21998439 - 78293 rs2069420 A/T 21998504 - 78358 rs2069419 A/C/T 21999337 - 79191 rs2069418 C/G 21999698 - 79552 rs3217974 A/C 21999908 - 79762 rs3217973 C/T 21999960 - 79814 rs2069416 A/C/T 22000004 - 79858 rs495490 C/T 22000412 - 80266 rs3808845 A/G 22000575 + 80429 rs3808846 A/G 22000946 + 80800 rs575427 C/T 22001477 - 81331 rs573687 C/T 22001642 - 81496 rs13298881 C/T 22002051 + 81905 rs16935753 A/G 22002229 + 82083 rs16935754 C/T 22002236 + 82090 rs545226 C/T 22002422 - 82276 rs7032979 C/T 22002457 + 82311 rs10811640 G/T 22003411 + 83265 rs10757263 C/T 22003805 + 83659 rs10811641 C/G 22004137 + 83991 rs7042051 C/T 22004758 + 84612 rs7027610 C/T 22004872 + 84726 rs7045307 C/T 22005057 + 84911 rs1101330 G/T 22005465 - 85319 rs13295358 A/C 22005465 + 85319 rs1101329 A/G 22005997 - 85851 rs1633381 A/G 22005997 - 85851 rs10217269 C/T 22006173 + 86027 rs10217281 A/G 22006617 + 86471 rs10965211 C/T 22006891 + 86745 rs28451206 C/G 22006921 + 86775 rs2157718 G/T 22007025 - 86879 rs2106120 A/C 22007101 - 86955 rs16905562 A/T 22007425 + 87279 rs2106119 C/T 22007550 - 87404 rs643319 G/T 22007836 - 87690 rs575237 C/T 22008108 - 87962 rs642323 C/T 22008121 - 87975 rs7044859 A/T 22008781 + 88635 rs523096 C/T 22009129 - 88983 rs518394 C/G 22009673 - 89527 rs10757264 A/G 22009732 + 89586 rs490005 C/T 22010493 - 90347 rs7858261 C/T 22010757 + 90611 rs34623146 A/G 22010822 + 90676 rs597816 A/G 22011172 - 91026 rs7048912 A/G 22011425 + 91279 rs568447 C/T 22011615 - 91469 rs567453 C/G 22011737 - 91591 rs7018665 A/G 22011819 + 91673 rs11515247 C/T 22012269 + 92123 rs581876 A/G 22012376 - 92230 rs7039304 A/T 22012786 + 92640 rs11789770 C/G 22012982 + 92836 rs10965212 A/T 22013795 + 93649 rs1292137 A/T 22014023 - 93877 rs504318 A/T 22014023 - 93877 rs1292136 A/G 22014351 - 94205 rs496892 A/G 22014351 - 94205 rs647188 A/C 22014965 - 94819 rs10811643 A/G 22014966 + 94820 rs10811644 A/T 22015067 + 94921 rs7035484 C/G 22015240 + 95094 rs10738604 A/G 22015493 + 95347 rs11791383 C/G 22015814 + 95668 rs615552 A/G 22016077 - 95931 rs1591137 C/T 22016483 - 96337 rs613312 C/T 22016594 - 96448 rs543830 A/T 22016639 - 96493 rs1591136 C/G 22016834 - 96688 rs10965214 A/T 22017274 + 97128 rs599452 C/T 22017402 - 97256 rs598664 A/G 22017551 - 97405 rs7049105 A/G 22018801 + 98655 rs679038 C/T 22019080 - 98934 rs10965215 A/G 22019445 + 99299 rs564398 A/G 22019547 - 99401 rs4977753 C/T 22020027 + 99881 rs662463 C/T 22020438 - 100292 rs7865618 A/G 22021005 + 100859 rs649436 C/T 22021085 - 100939 rs10115049 A/G 22022119 + 101973 rs634537 A/C 22022152 - 102006 rs2157719 A/G 22023366 - 103220 rs1759417 A/G 22023389 - 103243 rs1633383 A/G 22023532 - 103386 rs2151280 C/T 22024719 - 104573 rs1008878 G/T 22026112 + 105966 rs7029531 C/G 22026170 + 106024 rs1556515 A/G 22026367 - 106221 rs35975148 A/T 22027071 + 106925 rs17694478 C/G 22027171 + 107025 rs12376000 C/T 22029426 + 109280 rs1333037 A/G 22030765 - 110619 rs7028469 G/T 22031342 + 111196 rs1360590 A/G 22031443 - 111297 rs17694493 C/G 22031998 + 111852 rs12352425 A/G 22032086 + 111940 rs12686542 A/C 22032227 + 112081 rs10965216 C/T 22032879 + 112733 rs1412830 A/G 22033612 - 113466 rs1333036 A/G 22033819 - 113673 rs1412829 C/T 22033926 - 113780 rs1333035 C/T 22034059 - 113913 rs1333034 A/G 22034122 - 113976 rs10965217 A/T 22034317 + 114171 rs13290048 C/T 22034804 + 114658 rs28419335 A/G 22035035 + 114889 rs28621545 G/T 22035037 + 114891 rs1360589 A/G 22035317 - 115171 rs12338105 C/G 22035344 + 115198 rs1333033 A/G 22035653 - 115507 rs17834131 A/G 22036168 + 116022 rs12340618 A/G 22037050 + 116904 rs7851706 C/T 22037437 + 117291 rs12683931 A/G 22037916 + 117770 rs10120806 C/T 22037945 + 117799 rs7027950 C/T 22038391 + 118245 rs7028268 A/G 22038414 + 118268

rs7028570 A/G 22038683 + 118537 rs10757265 C/T 22038859 + 118713 rs10738605 C/G 22039130 + 118984 rs10757266 C/T 22039555 + 119409 rs10811645 A/G 22039656 + 119510 rs2151279 C/T 22039845 - 119699 rs6475603 A/G 22040612 + 120466 rs944799 A/G 22040613 + 120467 rs944800 A/G 22040898 + 120752 rs17694555 A/G 22041295 + 121149 rs944801 C/G 22041670 + 121524 rs6475604 C/T 22042734 + 122588 rs10757267 C/G 22042810 + 122664 rs4433231 G/T 22043244 + 123098 rs11790231 A/G 22043591 + 123445 rs7854869 A/C 22043651 + 123505 rs10965219 A/G 22043687 + 123541 rs7027048 A/G 22043709 + 123563 rs17756311 A/G 22043895 + 123749 rs7030641 C/T 22044040 + 123894 rs17694572 A/G 22044356 + 124210 rs7874604 C/T 22044690 + 124544 rs2383204 A/G 22045048 + 124902 rs7036489 A/G 22045992 + 125846 rs7039467 A/G 22046213 + 126067 rs7866660 A/T 22046233 + 126087 rs10965220 A/G 22046279 + 126133 rs7853090 C/T 22046295 + 126149 rs7866783 A/G 22046359 + 126213 rs10120688 A/G 22046499 + 126353 rs13292618 A/G 22047339 + 127193 rs10121501 C/G 22047390 + 127244 rs13299593 C/T 22048918 + 128772 rs7021816 A/C 22049277 + 129131 rs10757268 C/T 22049905 + 129759 rs2095144 C/T 22050136 - 129990 rs2383205 A/G 22050935 + 130789 rs2184061 G/T 22051562 - 131416 rs1537378 C/T 22051614 - 131468 rs4977754 A/C 22052012 + 131866 rs1011970 G/T 22052134 + 131988 rs10965221 G/T 22052999 + 132853 rs8181050 A/G 22054391 + 134245 rs8181047 A/G 22054465 + 134319 rs10811647 C/G 22055002 + 134856 rs1333038 A/G 22055572 + 135426 rs4144664 C/T 22055656 + 135510 rs1333039 C/G 22055657 + 135511 rs4977755 A/T 22056363 + 136217 rs28557075 A/G 22056572 + 136426 rs10965223 A/G 22057004 + 136858 rs10965224 A/T 22057276 + 137130 rs10811648 C/T 22057542 + 137396 rs10811649 C/T 22057554 + 137408 rs10811650 A/G 22057593 + 137447 rs10811651 A/G 22057830 + 137684 rs16905597 A/G 22058074 + 137928 rs1412831 A/G 22058646 + 138500 rs4977756 A/G 22058652 + 138506 rs16905599 A/G 22059144 + 138998 rs34871414 A/C 22059537 + 139391 rs7042970 A/G 22059580 + 139434 rs4451405 C/T 22061750 + 141604 rs4645630 A/G 22061751 + 141605 rs12555547 C/G 22062040 + 141894 rs10757269 A/G 22062264 + 142118 rs9632884 C/G 22062301 + 142155 rs9632885 A/G 22062638 + 142492 rs10757270 A/G 22062719 + 142573 rs17761197 C/T 22062730 + 142584 rs10965226 G/T 22063170 + 143024 rs16923583 A/T 22063334 + 143188 rs1855185 G/T 22063996 + 143850 rs7855162 C/T 22064793 + 144647 rs1831733 C/T 22066071 + 145925 rs1831734 C/T 22066208 + 146062 rs10757271 A/G 22066795 + 146649 rs10811652 A/C 22067085 + 146939 rs1412832 C/T 22067543 + 147397 rs7855660 C/T 22068305 + 148159 rs6475605 C/G 22069020 + 148874 rs16905613 A/G 22070363 + 150217 rs7858034 A/T 22070791 + 150645 rs12347950 A/G 22071128 + 150982 rs1412833 A/G 22071346 + 151200 rs10116277 G/T 22071397 + 151251 rs10965227 A/G 22071796 + 151650 rs6475606 C/T 22071850 + 151704 rs1547704 A/G 22072340 + 152194 rs1547705 A/C 22072375 + 152229 rs10965228 A/G 22072380 + 152234 rs7853953 A/C 22073017 + 152871 rs1333040 C/T 22073404 + 153258 rs1537370 C/T 22074310 + 154164 rs10122192 G/T 22074633 + 154487 rs1970112 C/T 22075598 + 155452 rs10120722 A/C 22076840 + 156694 rs16905635 C/T 22076883 + 156737 rs7857345 C/T 22077473 + 157327 rs10738606 A/T 22078090 + 157944 rs10738607 A/G 22078094 + 157948 rs10757272 C/T 22078260 + 158114 rs16905640 A/G 22078556 + 158410 rs13300638 G/T 22078937 + 158791 rs13284693 A/T 22079014 + 158868 rs12235973 A/T 22079193 + 159047 rs10757273 A/C 22080301 + 160155 rs10965230 C/T 22080416 + 160270 rs9644859 A/G 22080521 + 160375 rs7019916 C/T 22080683 + 160537 rs7020031 C/T 22080753 + 160607 rs7034707 C/T 22080811 + 160665 rs34597771 C/T 22081731 + 161585 rs34555767 G/T 22081924 + 161778 rs7866503 G/T 22081924 + 161778 rs7869527 A/G 22082097 + 161951 rs2210538 A/G 22082257 + 162111 rs7870178 A/G 22082551 + 162405 rs34184423 A/G 22082924 + 162778 rs34168773 A/T 22083299 + 163153 rs9722878 G/T 22083462 + 163316 rs7848875 A/G 22084281 + 164135 rs35537809 A/G 22084330 + 164184 rs4977757 A/G 22084330 + 164184 rs7388840 A/G 22084330 + 164184

rs10738608 A/C 22084796 + 164650 rs35869261 A/T 22085567 + 165421 rs35062160 G/T 22085730 + 165584 rs2891167 C/T 22085851 + 165705 rs10757274 A/G 22086055 + 165909 rs16905644 C/T 22087022 + 166876 rs6475607 A/G 22087693 + 167547 rs7037832 A/G 22088038 + 167892 rs1333041 C/G 22088374 + 168228 rs4977574 A/G 22088574 + 168428 rs2891168 A/G 22088619 + 168473 rs10965231 A/G 22088674 + 168528 rs11787814 A/G 22088683 + 168537 rs1537371 A/C 22089568 + 169422 rs7856476 A/T 22089940 + 169794 rs1556516 C/G 22090176 + 170030 rs12238050 A/C 22090726 + 170580 rs10965232 C/T 22091120 + 170974 rs13292938 G/T 22091259 + 171113 rs7028026 A/G 22091435 + 171289 rs6475608 C/T 22091702 + 171556 rs10125231 A/G 22092128 + 171982 rs7859727 C/T 22092165 + 172019 rs1537372 G/T 22093183 + 173037 rs10965233 A/G 22093314 + 173168 rs1537373 G/T 22093341 + 173195 rs7022719 C/T 22093748 + 173602 rs1333042 A/G 22093813 + 173667 rs4336695 C/G 22094450 + 174304 rs7872591 A/C 22095595 + 175449 rs7859362 C/T 22095927 + 175781 rs10757275 A/G 22096225 + 176079 rs6475609 A/G 22096271 + 176125 rs1333043 A/T 22096731 + 176585 rs7855190 C/T 22098069 + 177923 rs10217720 A/G 22098942 + 178796 rs10217426 C/G 22099387 + 179241 rs1412834 C/T 22100131 + 179985 rs17761319 G/T 22100478 + 180332 rs16905648 A/G 22101973 + 181827 rs7341786 A/C 22102241 + 182095 rs7341791 A/G 22102427 + 182281 rs10511701 C/T 22102599 + 182453 rs17834367 C/T 22102606 + 182460 rs7032115 A/G 22102943 + 182797 rs13301964 C/G 22103324 + 183178 rs16905652 A/T 22103924 + 183778 rs10733376 C/G 22104469 + 184323 rs10738609 A/G 22104495 + 184349 rs2383206 A/G 22105026 + 184880 rs10965234 G/T 22105078 + 184932 rs10965235 A/C 22105105 + 184959 rs4990722 G/T 22105217 + 185071 rs944796 C/G 22105285 + 185139 rs944797 C/T 22105286 + 185140 rs1004638 A/T 22105589 - 185443 rs10965236 C/G 22105633 + 185487 rs2383207 A/G 22105959 + 185813 rs1537374 A/G 22106046 + 185900 rs1537375 C/T 22106071 + 185925 rs1537376 C/T 22106220 + 186074 rs7851006 A/G 22107669 + 187523 rs17834457 C/T 22108026 + 187880 rs17761446 G/T 22108102 + 187956 rs7854631 A/C 22108378 + 188232 rs4977758 A/T 22108481 + 188335 rs4977759 C/T 22108885 + 188739 rs1333044 A/G 22109128 + 188982 rs1333045 C/T 22109195 + 189049 rs12685422 A/C 22111167 + 191021 rs10217586 A/T 22111349 + 191203 rs7860589 C/T 22111353 + 191207 rs7020671 A/T 22112193 + 192047 rs10965237 A/C 22112530 + 192384 rs13285121 A/T 22112912 + 192766 rs7869069 G/T 22113590 + 193444 rs10738610 A/C 22113766 + 193620 rs7854016 A/C 22113967 + 193821 rs1333046 A/T 22114123 + 193977 rs7857118 A/T 22114140 + 193994 rs17761458 A/G 22114368 + 194222 rs10757277 A/G 22114450 + 194304 rs10811656 C/T 22114472 + 194326 rs10757278 A/G 22114477 + 194331 rs1333047 A/T 22114504 + 194358 rs10757279 A/G 22114630 + 194484 rs4977575 C/G 22114744 + 194598 rs1333048 A/C 22115347 + 195201 rs1333049 C/G 22115503 + 195357 rs1333050 C/T 22115913 + 195767 rs12345199 A/G 22116454 + 196308 rs12336106 A/G 22116885 + 196739 rs10757281 C/T 22117613 + 197467 rs10811657 A/G 22117641 + 197495 rs17834529 C/G 22117777 + 197631 rs1889086 C/T 22117879 - 197733 rs10965238 A/G 22117883 + 197737 rs10965239 A/G 22117965 + 197819 rs12379111 C/G 22118180 + 198034 rs10811658 A/G 22118600 + 198454 rs12347779 C/G 22118709 + 198563 rs10965240 C/T 22119164 + 199018 rs7020996 C/T 22119579 + 199433 rs10965241 C/G 22119594 + 199448 rs10965243 A/G 22120065 + 199919 rs10965244 A/T 22120389 + 200243 rs10965245 A/G 22120515 + 200369 rs2891169 A/G 22121825 + 201679 rs4977576 A/C 22121861 + 201715 rs2383208 A/G 22122076 + 201930 rs10965246 C/T 22122698 + 202552 rs10965247 A/G 22122729 + 202583 rs10965248 C/T 22122878 + 202732 rs10965249 C/T 22123131 + 202985 rs7045889 A/G 22123251 + 203105 rs10965250 A/G 22123284 + 203138 rs10217762 C/T 22123645 + 203499 rs10811659 C/T 22123716 + 203570 rs12686509 A/T 22123767 + 203621 rs10757282 C/T 22123984 + 203838 rs10965251 A/G 22124029 + 203883 rs10811660 A/G 22124068 + 203922 rs10811661 C/T 22124094 + 203948 rs10757283 C/T 22124172 + 204026 rs10811662 A/G 22124253 + 204107 rs7019437 C/G 22124302 + 204156

rs7019472 C/T 22124395 + 204249 rs7019778 A/C 22124651 + 204505 rs13287212 G/T 22125071 + 204925 rs10965252 A/G 22125919 + 205773 rs12555274 C/G 22126440 + 206294 rs1333051 A/T 22126489 + 206343 rs10965253 G/T 22126687 + 206541 rs7018475 G/T 22127685 + 207539 rs9969854 G/T 22127710 + 207564 rs11791416 A/G 22128105 + 207959 rs10757284 C/G 22128458 + 208312 rs4977761 C/T 22128762 + 208616 rs35660019 A/G 22128865 + 208719 rs10811663 A/G 22129220 + 209074 rs10965254 A/G 22129485 + 209339 rs10965255 C/T 22130019 + 209873 rs2065501 A/C 22130224 + 210078 rs2065503 A/T 22130336 + 210190 rs7866021 C/T 22130339 + 210193 rs7866410 G/T 22130627 + 210481 rs12340450 A/T 22130678 + 210532 rs7854629 A/G 22131034 + 210888 rs7026735 C/T 22131269 + 211123 rs2065504 G/T 22131552 + 211406 rs2065505 A/G 22131790 + 211644 rs4977577 C/T 22131875 + 211729 rs6475610 C/T 22131894 + 211748 rs12376511 C/T 22132756 + 212610 rs10811664 A/G 22132907 + 212761 rs7859532 A/C 22132956 + 212810 rs7862936 A/G 22133133 + 212987 rs7849199 A/T 22133293 + 213147 rs7849302 C/T 22133377 + 213231 rs10757287 A/T 22133570 + 213424 rs2151285 A/T 22134255 - 214109 rs2151284 C/G 22134276 - 214130 rs2151283 G/T 22134305 - 214159 rs2151282 A/G 22134316 - 214170 rs7867100 A/G 22134460 + 214314 rs7853656 G/T 22134530 + 214384 rs2065500 A/G 22135694 + 215548 rs7030345 A/T 22135739 + 215593 rs13298423 A/C 22136196 + 216050 rs13298664 C/T 22136202 + 216056 rs10811665 C/T 22136604 + 216458 rs7022662 C/G 22137715 + 217569 rs13286296 A/T 22137761 + 217615 rs13285137 A/C 22137863 + 217717 rs28752115 A/G 22137944 + 217798 rs12341394 C/T 22138055 + 217909 rs28539212 A/G 22138269 + 218123 rs4614078 C/G 22140034 + 219888 rs7856219 C/T 22140261 + 220115 rs7043398 A/C 22140707 + 220561 rs12337417 C/T 22140792 + 220646 rs12115577 A/T 22140863 + 220717 rs10811666 A/T 22140867 + 220721 rs13293520 C/T 22140897 + 220751 rs7873930 C/T 22141050 + 220904 rs6475611 A/G 22141139 + 220993 rs7047414 A/C 22141412 + 221266 rs10965256 A/G 22141465 + 221319 rs10965257 C/T 22141528 + 221382 rs7849231 C/T 22142401 + 222255 rs4097833 C/G 22142520 - 222374 rs6475612 A/G 22142580 + 222434 rs6475613 G/T 22142643 + 222497 rs7021554 C/T 22142884 + 222738 rs6475614 C/T 22143265 + 223119 rs7853123 A/G 22143360 + 223214 rs10965258 A/G 22143663 + 223517 rs7853621 A/T 22143714 + 223568 rs7045424 C/T 22144009 + 223863 rs6475615 A/G 22144408 + 224262 rs12001831 G/T 22144411 + 224265 rs13295528 A/T 22144432 + 224286 rs7046009 C/T 22144458 + 224312 rs10965259 C/T 22144489 + 224343 rs10965260 A/T 22144539 + 224393 rs10965261 C/T 22144585 + 224439 rs10965262 C/T 22144592 + 224446 rs7030057 C/T 22144628 + 224482 rs10965263 C/G 22144648 + 224502 rs10965264 C/G 22144655 + 224509 rs7046289 C/T 22144664 + 224518 rs7029976 A/T 22144682 + 224536 rs10965265 G/T 22144683 + 224537 rs7046298 C/T 22144684 + 224538 rs7030278 C/G 22144691 + 224545 rs12343752 A/G 22145075 + 224929 rs7033903 A/G 22145090 + 224944 rs944802 A/G 22145709 - 225563 rs1930590 C/T 22146785 - 226639 rs7028213 G/T 22147360 + 227214 rs7856172 C/T 22147489 + 227343 rs7042842 A/G 22147512 + 227366 rs7856274 G/T 22147532 + 227386 rs7869966 C/G 22147546 + 227400 rs7869852 A/T 22147555 + 227409 rs7870203 C/G 22147567 + 227421 rs7870099 C/T 22147624 + 227478 rs7856433 C/T 22147671 + 227525 rs7856749 G/T 22147902 + 227756 rs1333052 A/C 22147908 + 227762 rs12238587 A/T 22148168 + 228022 rs10738611 A/G 22148598 + 228452 rs10122243 C/T 22148924 + 228778 rs10757288 C/T 22149416 + 229270 rs10811667 A/C 22149982 + 229836 B. Microsatellite markers within LD Block on C09 (between 21,920,147 and 22,149,982; NCBI Build 34/35/36) (Forward primers: SEQ ID NOs: 187-192; Reverse primers: SEQ ID NOs: 193-198, respectively). Start End Marker position position strand Forward primer Reverse Primer DG9S762 21977346 21977478 + TTATTACGAGCCTGGTCTGGA CTGTTCGTGCAGGATGAATG DG9S761 21980412 21980677 + CCCATCTAAGGGTAGAGAAGC AAGCAAGATTCCAAACAGTAAACA DG9S760 21994905 21995264 + AGCAATCTAGGCGTTTGCAC TGCTGGCCTTTGCTCTTACT DG9S746 22034929 22035109 + TGCTAAATGATCTATTTCCACCAT CCTTTGCATAGGGAGACCAC D9S1814 22078225 22078501 + CTTCGATTGCTGGGATTATG GGGCCTGTGAACCTACTGAC D9S1870 22093010 22093220 - TGGGTATGGTTTTCTGG TTGAGGCAGGTCAAATAA

TABLE-US-00014 TABLE 11 Amplimers for surrogate SNPs for rs10116277, rs1333040, and/or rs2383207 in the CEU population, as listed in Table 3. rs7041637 (SEQ ID NO: 1) TTTCGCAATGCTTATTTTCAATTTCTTCAGAAATGCCTTAAAGATATTAATGGAGGTAACAACT TAATCTCAAATAGTAATCCATAGACAGAATATGTAA[A/C]AGCAATGTTCTCTGATCTGTTCTTTGGCTT CTATTCCCTAGAGAAATAGTTCTCTAAGACCAAACAGTCTATAGATAGAATTGTAGCAACAGTCAATTA T rs3218020 (SEQ ID NO: 2) GTGGAGAGAAAATGATTATACTTTGAGCTATATGGCTCCAATAAACAAAGATAGATCCCTCAA TTTAAATTTGATCCTCAGAAAACTGAGGGTCAGAGAA[C/T]CCCTCAGGCATGACGGGATAATGTGAC AGTTAATTTGGTATGTCAACTTGGCTAGGCTGTGGTACCCAGTGTTTGAGTCAAACACCAGTCTAAATA TTGC rs3217992 (SEQ ID NO: 3) AGTACTATATTACACTGTTTTTTTTGTTTGTTTTGTTAGTTTTTTTTATTTAAAGCAAACCTCAAA CATTATTGGGTATCAATTACCACCTGGTTGTATT[A/G]AAATAGTAACTTATCAATGCCATGTAAAAATT AATTCCATTTTCGAAGCCACCTGGCAGACAGGTTTAGCTGTTTCATCAGCAGCCTAATATATACTGTT rs1063192 (SEQ ID NO: 4) CATTATACTGGGTCATGAAAAATTATCCCTTGAAATAGATATGAAACATGTTACTTCATTTCTG GTTTAAATAACTTGTGGAATCTTTCCTAATGACAAC[C/T]TGATATTAAGGGAAACTAAAGAAAATGTTA TTGTGGATCCCACAGTACTATATTACACTGTTTTTTTTGTTTGTTTTGTTATTTTTTTTATTTAAAGCA rs2069418 (SEQ ID NO: 5) TGATACAAGTTATGAAACTTGTGAAGCCCAAGTACTGCCTGGGGATGAATTTAACTTGTATGA CAGGTGCAGAGCTGTCGCTTTCAGACATCTTAAGAAA[C/G]ACGGAGTTATTTTGAATGACTTTCTCTC GGTCACAAGGGAGCCACCAACGTCTCCACAGTGAAACCAACTGGCTGGCTGAAGGAACAGAAATCCT CTGCT rs2069416 (SEQ ID NO: 6) AAATAAAAATAAGATACCTGACAAAGTGGGTTTAAATAGGTAAGAGTGCAAACAAAGATTTAC TGTACAAATATGATGAAACTGGGATCTCAGATTCTTA[A/C/T]AGTATAATTTTTTTTTGTCTTATGTGTG CCAGGTTGCCACTCTCAATCTCGAACTAGTTTTTTTCTCTTTTAAGGGTTGTATCCATAATGCAAAAATG GA rs573687 (SEQ ID NO: 7) GTCCAAGACAAATGTGCTATTGTATTACATGTGAAATGTCATCTTTGAAGTCTGGTAAGGGTG TGCTGTGAGGTGAGCCATCTGGAAAACACAGTGTAGA[C/T]TGAAAAATAATTATAAGCCAGTTTATTA CTTTTTTCCAGTTAAGCCTACCATGACAGCTGCTAAAAAAAACACTATGTAGTATAAAGGGTAAAAAGA CTC rs545226 (SEQ ID NO: 8) GGGGTGCAGGTTGTTGGTGTGGCCACACTTCTTCTTGCGGCAATTGACAGCATAGGGGTGCA GGAGAGCATAGCGCTTATGGCAGATCATCTTGTTTCAG[C/T]TGTATTTCTAGGTGAGCTGGAAGAGT GAAGGCTCAATAATGCCACCTCGCAGGTGCAGCACCAGGTGCGGGGTGGGCTGTTTCTGGACGTTGT AGTCTGA rs10811640 (SEQ ID NO: 9) TCTTAATTTTTACACATTTTACTTTTCATTTCTTTTTAAACTGTTATTAATAATTTATTCATTTGAA TAAGGATTAAAATAAGGCTAGGATATTGAAATT[G/T]GTTGAAATTGCTACAGTCTCTTGTATCTCTCTC TCTCTCTTTTTTTTCTTATAAGGGACAGGTTTCATTCACCTTGTCGACCAGGCTGGAGTGCAATACT rs10811641 (SEQ ID NO: 10) TGTGATTCTAGCAGCCATGGATAATTATTTCATAGATTATTATTTTCTTGGGGATGGCAAAATG GTGATATTCTAATTTTACTATTCCTTCATTTACTAG[C/G]TGGAATGTCTTTTTAAATTATTTATTTATTTA TTTATTATTTGAGACAGAGTCTTGCACTGTCACCCAGGCTGGAGTGCAGTGGTGTGATCATAGCTCAC rs2106120 (SEQ ID NO: 11) TGCGCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACTGCGCCTCGCCAACT TCCTTATTTTAAATGCCATTTCCCACTAAAAATAAAAC[A/C]AGTAATTCTTTGAAAAAAAGTTAATATTA TGTATAGGACTGGAAGTATATAAGATAAAACTGGAATATATTGTCATACCAGAAATCAAAGATTTTGTC AA rs2106119 (SEQ ID NO: 12) ATTACTGATGTGACAAGGTACACAAGCCAATGTTGACATAATGTTTTCAAAATGGGGTGTCTG CTGTAACTGAACTAAATATAATAACTTTATTCAAGAA[C/T]GAGTTTCAATGATAGGACAAAACTTGATA AAATGAATAAATAAATAATTATATGCCAGAGTTCAGTAAACCCTGTGTGTACACCTGAAAAAGCTCAAA CT rs643319 (SEQ ID NO: 13) GAACAGAGCAGAAGAGAGTCTGGATACACAAATTTCACAATTATTGGCTCCCATCAACATATC TAACTCAAGCATAAAGTTGTTTCAGCAGTAGTTTAAG[G/T]TTGGTTACTAATGCAACACCTCTTTGCAT GCAATGGCCCATTAAATTATCTTCAACTTTAAAAGGTTCCTTTGTTTTTAAATGCTTATAATGAACAAAT A rs7044859 (SEQ ID NO: 14) TATGTGATGTAAAGAGCGCCAACATGTTTATATCCTCCTATTTCAATCTACTTTTACTTCATCTA CATTTTTAGCAATAATGTGAACATGAAATCTTGAA[A/T]AATTAGCTATCTGTAATATATTTACTCATCC ACTCAAAATATTGAGCCCCCCCAATAAATATCATACACTATATTCTAGGTACAGGTGATAAACAATTCA rs10757264 (SEQ ID NO: 15) CCAGTGAAAGTTAGAGAGAGGGGTCTAGAGCTCAGGGAGGAGTGTGTATCCCTAATTTAGAC TAATTTGCATTAACAGCTGTAGTAATGCAATTTTCTCT[A/G]TACTGAAATGCAGACATTTGAGTATAGA AAATTAGCAGACATTTGAATATAGAAGAAAGATTTACTTTCCTTCAGAAAAAGAATAGTAGAGTATAAA GAA rs10965212 (SEQ ID NO: 16) TCGTGCCACTGCACTCCAGCCTGGGTGAGTTGAGAGTCCGTATCAAAAGCAAACCTACACATT TTTGTGGCCTGTTTTTAGCTCTATCAAGTCAGTTACA[A/T]TCTTCTGTATTCTAGCTTTTTTATCTGTAA GCTCCTGCAATGCTTTATTAGAATTTTTAGTTCTTTGCATTTTGTTACAACATACTCCTATAACTCTGC rs1292137 (SEQ ID NO: 17) TAAAAGAAAAAATAATCCAAATGTCAGCAACCTCAAAGATTGAAGGTAGATGAGCCCACAAAG ATAAGAAATAATCAGCACAAGAACACTGAAAACTCAA[A/T]AATCAAGAGTACCTTCTTTCCTCCAAAG GACCACATCACCTCTCTGGCAAGCGTTCAGTACCAGGCTGAGGCTGAGATGGCTGAAATGATAGAAG CAGAA rs10811644 (SEQ ID NO: 18) CAAGACCACTCTGCAGATATCAAGTCTGAAAATTCCCCTAGGGCCAAAGTCTATTATGGGAGC AAGTTGAGCCTAGAGGGATCGCCATCCCTGTCCATGC[A/T]CTGCTGTAGACACTCCTGCACTAAACC CTCTGGGCTCCACATCAGCTGGCTTGCTGCTCTACCACTTTGCTTGTCTCTTGGGGGCTCCACCCCAG AGAGA rs7035484 (SEQ ID NO: 19) GTCTCTTGGGGGCTCCACCCCAGAGAGATGTGGGTCAGCAATCATTCAGTTCAATCAGCCCA GGATGGAGAGTCTGTGCTATGGGCCCAAGCCAGGGGCT[C/G]TCTGTCTGGTGACGAGCAGCTGGG GGGTGGGGTGGGACCTGTGGGAGATGGACTGGCCTCCTCTCCTTGAGTCAACTGCTGCTTATTGGAG GTGTGGATG rs10738604 (SEQ ID NO: 20) CCATTGCAGAGGTAGTGGCAGAGAGGCTTTCAGTTGTCCGTGGCGGCTCTGTCCAGGGAGTT GCTGAGTTGCTATTGGCTTGATATCTCTGGTGGGGTGT[A/G]GCTAGAGGTCCAGGCCTGGAGGACC TGCTCGTTGAAGAGATGTGGGAATGGGCACCCACATAACAGTCTGTTCACTTTTCCATAGGGCTGCTG TAGTATG rs615552 (SEQ ID NO: 21) GGGGAGCTTAAGCAGGGGTGGAAGGGGAACCCCAGCACAGAACAGCTGCCCGACAAAAATG TGGCCACACTGTTTTTTTTTTTTTTTAGCAGGTCCCCA[A/G]TCCCGTTCCTCATCACTGGGTAGAGT CTCCCATCTGGGGTCCCCGGCTACCCCAACTGGTGTTCTCTGACTGAGAGAGGTTTCAGACTTCCATG GGACCT rs543830 (SEQ ID NO: 22) TGGGCAAAAGTAGCTGCGACTTTGGCAAAGCTGGAGGTTAGACCCCCAAACATACCCCAGGA GGTTAGACTCCCATACATACCCCAGAAAAGAGGCTGAA[A/T]CCAGCGAGATCAGCAGAGAAGGTCTA CAGGCCCCACTTCCACAGCGCCTCACAGGATAAGACCCACTGGCTTGGAATTCCAGCTAGCCACCAGT AGCAAC rs1591136 (SEQ ID NO: 23) AAGTGGTAAGTGAATGCGCAACTCTGGGAATCCACACTGCTCTCACAGATCTTTGCAAACCTC AGATCAGGAGATCCCCTTGTGAACTCACTCCATTAGG[C/G]CCTTCACACACAGCCACGTGGAGTCTC AGCAGAGCAGCCACTCAGGCATGCATGGAGACCCAAGAGCTTTAGCTACTCCAGCTTTCTGGGTGTCT GGGCA rs7049105 (SEQ ID NO: 24) CTTAACAGCAAAGTATCAGATTCATTTATAAAACAATGTGACTGATCTTTATGTATGGTTTGTG AAACATTTATGCAGTGTCACTTCAGAAAACTCTGCC[A/G]TTATAGATTTGAATTGATTAAGGATATCC ACTCCTTTCCTTGGCATGATACAAATAAATTACTAAAGTATAATTGTAACAATGATAAATATAAGTGACA A rs679038 (SEQ ID NO: 25) CACCCTTGGGGAAGGGGATCAAAATATAGTGATTTTCTAATTCTAAGATTCGTTCTGTGTATA TTAGCTGCTATTCTTCTAGAAAGAAGACTTTCACCA[C/T]CGTCCCTTGGATTTTTTTTTTTAATTTTTGT ATGGTTTAAATTGCATCATCATTCTTTTTGATGTCCAAATTGTCCCAAATTAAGCCAGTTAGAGAAACA rs10965215 (SEQ ID NO: 26) TAATGGGATTCCTGATGGAATGTTTAGTCTGAATCTAATCACATAGAGACTTGTCTGACAAATC CAGATTTTTTGGATGTTTTGCAGGACTATTTGCCAC[A/G]ACATTTCAAAGGATTCCAAGAGAGAATAT TGGTGTCCATGCTGTGATGATTCCTCAGCTCCTCTCATCTGATCTCCGTCCTGGCCCCCATGACTTTCT TT rs564398 (SEQ ID NO: 27) CTCTTCTTTTATCACACAGACCTGAAAGATGATGGTTTCCCAAACAGCACTTACAGCAATAGGT GTGGGCCTCAGTGGCACATACCACACCCTAACTACC[A/G]CAAAGAAAGTCATGGGGGCCAGGACGG AGATCAGATGAGAGGAGCTGAGGAATCATCACAGCATGGACACCAATATTCTCTCTTGGAATCCTTTG AAATG rs10115049 (SEQ ID NO: 28) CAAATCTTTCCCTAAGGGAGATTTCAGATGAGGCCCCCAGCCTTGGTAGACACCTTGATTGCA GTCTTGTGAGAGATTGTGAAGCAGAGCTATTCTCAGA[A/G]TTCATGGGTGTTTTAAGCTATGAGGTTT TTTTTGGGGGGAGAATGGTCATTTGTGATTCAGCTATACATAAGTCTACAAAAGTCATTCCAGAAGTGA TTC rs634537 (SEQ ID NO: 29) TGGGGCTCACAACCACATGATTCTACCTCCACTGAATCACTTCTGGAATGACTTTTGTAGACTT ATGTATAGCTGAATCACAAATGACCATTCTCCCCCC[A/C]AAAAAAACCTCATAGCTTAAAACACCCAT GAATTCTGAGAATAGCTCTGCTTCACAATCTCTCACAAGACTGCAATCAAGGTGTCTACCAAGGCTGG GGG rs2157719 (SEQ ID NO: 30) TTTTTATAGTGTGACTCATTTACATATGCATGTGTATGTTTAGGTGCTATTATTAAATTTTGCTG GCATATAGTGAGGAAATTGTGATTCAAATTCGTCC[A/G]TATGTACTCCTCCCCCACCATCTGCTCTGC CCCTCCATTTACCAGAAGGCTAGCTTTAGCTACTTGTGCATGTAAAACAGAAGCAAGCAACACTGTGA AA rs2151280 (SEQ ID NO: 31) GAACATAGATACTCCTTCATTCATGTATTGTCTATGGGTGAGTCTTTATTACAACAGCAGAGAT GAGTAGTTGTGACAGAAACTCGATGGCCCTCAAAAG[C/T]GAAACAAGCTACTATCAGGACCTCTATA GAAAAAGTTTGCCAACCTCTACACTGTAGTATGCCTTAAGGATTTTTAGAAGATTGAGTATGATAAACA CTT rs1008878 (SEQ ID NO: 32) GAAGGGATGATCAGTCCTTCCCTCCTCTATTTTCTTGAGCCCCGTTTTTCACCTTTCTTTTTCTC TCTCCTTTCTTATCATGAAGAATAAAGACAAATGA[G/T]AACAGATCTACCTTAGGCTGATACAGGGCA GGGAATCCATTTAATAATAAAACGTGGGTCAAAATTCATTTTCTCCTTTTGAATTGAAATTATATTGTG rs1556515 (SEQ ID NO: 33) ATTTGATGCAACTTACACACTGTTGTTATACCTCTAGAATTAAAATGACAATTTTTTAAATAATT TTGGGGGGCCTAGATTTGCTATTTAACCTATCAAA[A/G]AATTGTGTCTTACAGTATTATTCAAATGTA GTGTGTAAAGACTTATACTATTGGTCCTAAGCACTACTGGTTGTTTTAGGCTTTTTCTCTTTCTCTGTAG rs1333037 (SEQ ID NO: 34) ACATTTATATAATTAAGATGCTAACACTGACTGACAGAAATGTCAGTAAGATGAAATCAGACT GCATGGGAGTTTTATGTTACATTAATTTGTAAATTGT[A/G]TATCTCTGTATTCATGTGAGTGTGGCTAT CATGATGTTAGACATCCAGCTACAAAGGAGGCATTCGTGCACACACACAGTCTCCAATCTTCTGTTTAC CT rs1360590 (SEQ ID NO: 35) TAGACAAAGTTTAATGTTCCCTTTTATATGTTTTCCTGGTAAACAAAAATTGTCTCAGGGTTATT ATGCATATATGATATTGTCAAGAAACTTTCTGGGT[A/G]CTGTGGGGCAAAGTCTTCTCCATAAATAAG CTAGGGTTGATTGGAGTTTTCACTTTGAAAAATATCGCACAGGAGGATCTCAACAGCTAGACAATTTCC A rs1412829 (SEQ ID NO: 36) AAATTAAATGACATACGTAAAGTCCTCAATAAATAATAGCTCTTATTACCATTGCTATGGTTAC TATCACTATTTCTGTATTTTCTTTTGCCATTCCTCA[C/T]GCTTGAATATGAATCTCATGGGTAGAGTTT CCCAAAGCATGATATGTGTAGTACTACTAAAGGCAAGATTTTGGGTGCATACAGACAAAAAAATAATTT A rs1360589 (SEQ ID NO: 37) AAACCAGAGGAGTAAAATTCTACTTTCACCAGTAATTAGCAGTGTGGAGTTGAGTAAATAAAC CTCTCTAAGTCTCAGTTTCTACATCTACTAAATCTAA[A/G]CAAATTCAAAACAGTGATTATTTCATTAG ATTAGATATTTTGATTAGTCTTAAATGTCTAATATATAATAAACACTCAACAGGTAGTAGCTATTCTATG T rs7028570 (SEQ ID NO: 38) TCATTTCTTCTTTTAAGGTCTTAATTTCTTGTTTTTCGAGTTTCATGGGAGATATCCAGTCACCA ATCCAATCCATATCGGGGAAAAGTACAACAAATGA[A/G]TGAAATTTGTAACCAACCTTGGATGATGG AATAAGACATTTGGGAGAACACAGGAGAAGTGGGGAGGTTAAGGAGGGATAGCTCTGTGAAAATTTT GCAT rs944801 (SEQ ID NO: 39) AACTAATTCTCCAAATTTGCAATTTGGCAGCATCCTACTGGGACTCTAGAAGGCTGATAAATC ATGGAGAGTAGGTATTCATATAGGAACTATGAAAGCT[C/G]TATGTAGTAAACACTACTTAAGAAGGC CTTACATTTCATAAAAAGTTGGAGATTTTTGTGGAGACTCATAAAATGCATCCTTTATATCAGTGAAGTT TTT rs10965219 (SEQ ID NO: 40) ACTCGTAGCCAGAGCTACCTTCCAGATGACTTCTTTCTACCACTTTCTTTCTTCCCAGTGTAAG AGAATGCAAGTATATGCTGATGTTTGGAGCAAGAAC[A/G]TTCAAAAATTTTCTTATTAACATAACTTCT AATGGAAATACAGTATACTACTATGGTGCATACAAAGAAGAAATAGCAACATATATTTGTTTTAGACCT G rs7030641 (SEQ ID NO: 41) ATAAGCAGCCTTAAATTAAAAAAAAAAAAGTTAACTCATAACTAACTGTGTGACCTGGGATAA GTTACTGACCCTCTTTAGGGCTTAGGGTCCTAATCTG[C/T]AAAACGGAAATTATAATAATAACCTTAG CTAGCATTTCTTGTGCACATACTATAAGCTGGTGATAAACAATTTATACACACTATCTCATTTAATCCTC AC rs10120688 (SEQ ID NO: 42) TCCAATGCAAAAGAATAATAGGAGCAAAAGCACAGTGGTGAGAAATTGGAGGGGAACTGTGA AAATTGCCACATAGATTAGAGGCAGGAAAATAAAGGAC[A/G]GCTAAGTTTATATAGTGAACAGTGAG CCGCATGGACACAGGTGACTGTTTTCTCCTTTTTGAACCCCTGCTTACTCCAGAGTCACCACCTCTCCT GGCTT rs2184061 (SEQ ID NO: 43)

TATTCTGAGTATTAATTCCTGTTTCCAAATAGATTACTCTTTTAAACATAGCACTACTACTTACC TAATGAAATTTAGTTGCTATTAATGGATGAATTTT[G/T]TATCTAACAGGCTTGATTTTGATTATGCATT TTAAATGTCAGTCAGACACATATTAATAATGATCCATGTTTGTAGCTAATAGGCCCAATATATACTTT rs1537378 (SEQ ID NO: 44) GTAAGGGCTGGGACAAATAAACACAAGTAATTTTCAAATATATTAATAATAATATTCTGAGTAT TAATTCCTGTTTCCAAATAGATTACTCTTTTAAACA[C/T]AGCACTACTACTTACCTAATGAAATTTAGTT GCTATTAATGGATGAATTTTGTATCTAACAGGCTTGATTTTGATTATGCATTTTAAATGTCAGTCAGAC rs8181050 (SEQ ID NO: 45) TGGTGGTCCTAAAGTGGCATTAAGGAGCCAATAAATTGTCATTCCTACCTTAGCTCTGTGTCA GATGAAATACACAGCATAGTGTGGGGAGAAAATGTTG[A/G]GCTTATTGGGGATGGGGTCTTTCACAT AAAGGAAGAAGGTTTCAGAAGGCATAGTGGTATGAAAAGAGGAGAAACCAAAGGGAGGAAGGTCAAT AAAGGG rs8181047 (SEQ ID NO: 46) CAGCATAGTGTGGGGAGAAAATGTTGGGCTTATTGGGGATGGGGTCTTTCACATAAAGGAAG AAGGTTTCAGAAGGCATAGTGGTATGAAAAGAGGAGAA[A/G]CCAAAGGGAGGAAGGTCAATAAAGG GTTAAGAACGAGGGGAGGCAAATTGACTTTCTTTCAGCATATGAGGATTATAGGAATGGAAACCTTAA TTGGAAT rs10811647 (SEQ ID NO: 47) GAGGATTTAATGCAATTGTTTGTGGGAAAGCACTTTAACAACTCTAAATTACGATATATATGCT AGGTTTTATTGTTACCCACACCTTTGATGTATTTCT[C/G]TTTGTACTCTTCACTGTATCTGTAACACATT CCCTAGGATAATTAGGGCTACCCTTTAACAAAGCCAAGATTCTATTTATAGTGGTAAGCTGGCACCTGG rs1333039 (SEQ ID NO: 48) CTTCTGCTATTGAACGAACTTTTTGTTAAGGTAGCTCCCAAGCAGGTTCAGTAGCTTTGTTCTA TTATCACTTTTCTACTGACAGTGATTTTTTTCCTTT[C/G]AAGGCCTGGGACATGGAGACTGCTTTTCTG CAGAAACCACATCCCTTGGAGTAATGAGCTACACCTACCTCAATTATTCAGTGCAGTACAACACTCCAG G rs10965224 (SEQ ID NO: 49) ACATTGTGCACATGTACCCTAGAACTTAAAGTATAATAATAAACAAAAAAAACCACTGCACAAT CTCTAGTATTCAGATGGAGACTAAGCATGATTTTTC[A/T]TATAAAAGAGCAGATCAGAATGTTGTATC TTTTATTCAGAAGACTGGAGTTAATCACTGTTATCTTTAGTACTTAGTGCTGCCAAGGCTGTGTGTTCA CA rs10811650 (SEQ ID NO: 50) ACAGAGTGCTTATTTAAAGAAAAATAAAAAGAACACACACACACACGCACGCACACACACACG CACGCACACACACACACATGTAGCTACATGTCTAGGA[A/G]GGATGTGGAGAGCTGAAATATGAAGG CAAAATAAAACATCTTTTTCAAAGTATACAGCCTACAGTGGTTAGCACAGAGCTGGCCACATAGCAGG GGTTTC rs10811651 (SEQ ID NO: 51) CAATAATGTAGAAGCAAAGAGCCTAAAGTGTTTTCATAAATCTTAAGTGGTAGCTTTATGTTCC AGTTCAGCAAAACACAAATTTGAAGGCAATCTGTAC[A/G]TTAGGGTTCAGGTGAAGAAGGCAAAGGA ATCAATGAAATTGTAAAAGCTTTCCAAATTTGCCTTTTCTCTTAAGATTGTCTTTCTCTCATTCTCTTCTC C rs4977756 (SEQ ID NO: 52) TTTCTGTAGCAGAAGTGTAAGGGTGTTACTCGTAGGAGGCCTCTATTGAACTCTTTTCCAGTG ACGTAGTGTGTGGTCTTTAAGTGGCTTTGCAATGATA[A/G]TAAGATCAGCATTGCATTACTGAATGAG CTCCTTTAGTAAACGTGGATATGTGCTTTCTGAATCTATTTGTTTGTTTTTCCCAAGTCATAAACAGTGA AT rs10757269 (SEQ ID NO: 53) CCATTTAGAGTACTTGCCTCTGAGGGAAATAAAAATTTGCTAGCAATTTTCTCTAAATGACATT ATCATAGGCACTTAATTCCTTGATAGGTTCTTTTAG[A/G]TAATTTTTTTATAATGAAGCAATTAATTTG ATTCACGAAAGTAAGTTTCTAGTTTATATAAAGACCAGATCTGGCCTATTTCTTAGCTTGTCTACATTTG rs9632884 (SEQ ID NO: 54) TGCTAGCAATTTTCTCTAAATGACATTATCATAGGCACTTAATTCCTTGATAGGTTCTTTTAGAT AATTTTTTTATAATGAAGCAATTAATTTGATTCAC[C/G]AAAGTAAGTTTCTAGTTTATATAAAGACCAG ATCTGGCCTATTTCTTAGCTTGTCTACATTTGAGTAGTTCCATTGCTGGAAAATGACCCTGGAGCTTTT rs1412832 (SEQ ID NO: 55) AAGTTGCTCTCAACATACTTAAAGTTTTCCAATAACTGAATTAAATATCAGTTTATCAGTTTAAT ATAAACAATTAGGGTAAATGAAAATAAAATTTCAG[C/T]TCTTTGGTTCCATTAGCCATGGTTCAGGAG CAGAATAGTCACCTGAGGCTAGTGACAACGCTTTTGGATCACAGGAAAGAAGAAAAAAAATCAAAATA AT rs10116277 (SEQ ID NO: 56) TTATAACTAATGAGGCAATGTGTCTTGAGTATTTTGAATTAACTCTCTAGAATCGATTCTTGGG GAGGTTATTTACTTTGAAGTGATGGACAGAGTGTAG[G/T]AGATTTATGAGTGAACTCTTGTCTGATTT GGAAATATAGAGTTGTTTAGGCTAGGTATTACCAACCCAAAGTTGACACTTGAGTCACCTAAGTTCTTC TC rs10965227 (SEQ ID NO: 57) TATTAGTTGTGTAATCTTGAAAAAATCTCTGACACTTTTCCCTCTGACTCAGTTTCCCCATCTG GCACCCAATCTTTTACAGTGTTATGAAAAATAGGGA[A/G]AATGTAGAAAGGAAGAACATGGCACCCA ATCCTTAATGGACACTCAGTGAAAGCTGGCTATCATCATCATTTTTGGGGTTGTTGTGTTCTACAAATG TAT rs6475606 (SEQ ID NO: 58) TCCCCATCTGGCACCCAATCTTTTACAGTGTTATGAAAAATAGGGAAAATGTAGAAAGGAAGA ACATGGCACCCAATCCTTAATGGACACTCAGTGAAAG[C/T]TGGCTATCATCATCATTTTTGGGGTTGT TGTGTTCTACAAATGTATTTTCCCAGGAGTTTTTTTTACTCTGTCTCCTCTTTCCTTCATATACCCCCAGC C rs1333040 (SEQ ID NO: 59) TGGGAAGGATGAATTAATGGGATGGAGTGCAGGGGATGCAGAGTGCCCACTTATGGAATGA TTTCATTCAAGAGAGACAGGAGGGTCAGAGGTAAGAATG[C/T]TACCGCTGGGACAGAGAGGAAGGT ACAGATATGAGATATGGTAAGAAGGTATACTACAACAGTGGCTCCCAAATCTCAATGAGTAGCCAGTT CTCATGGA rs1537370 (SEQ ID NO: 60) TTTGAGCCCAAGTCTCTTTCTGACTCTAGGCTTAGAGCTTTAGGGCTATTTCACAAAAGGGCT GTTCCTAGGTCAGGCATGACAACTTCTATATTACCTT[C/T]GTAAAAGAAGCAATATAATCTACCACTAT TAAATTTTGCAGGTTAATTTTATATTATGTTTAAATACAGAAAACTTTATTTAAAACTCAGTTGAATTTCT rs7857345 (SEQ ID NO: 61) GAAACTGGATCCCTGATGACATTGAACCATTGACTGAATCTACCCTGGAACCATCAGGAAATA ATCCTTAGTTTTTTAAAGATGCTTTTTTAGTTGTGTTTT[C/T]TATTACAAGTACCTGAAAGCATCCTAACTA ATCAATGCTAAATGCATCTCTCACAGTTTATGCTTATTTTTCAGAAATGCCTAGTGGAAATTTCTATTGC rs10738607 (SEQ ID NO: 62) TCCTTCCACTGACTGAGACTATTTCCTTGCCACAATCAGAAGAACTAAAAGAAAGGAGGATAT CTGTTAATATATGAATTTATCTAAATGTCATGCAGTG[A/G]CTTCTAAAATCATCTGGTGTGCTCTGTTT CCCCTTGGAGGTGACTTAGGCCTGGCATCCCAAACAATACATACTGGAGTGAAGCTCCAGGAAACCCT GAG rs10757272 (SEQ ID NO: 63) ATACATACTGGAGTGAAGCTCCAGGAAACCCTGAGGAGAAGAGAAGGGCTTAAAGAGCAATC AGCCTTCGATTGCTGGGATTATGAAAGGTCGTAAGAAG[C/T]GAATGTTGCAATGTTTTATTATACTTG ATATTGAAGCAAGGACAAGTAATAATTTATTATTCTCTCCATGTCAGTGGTATTTACCTTTTTGGAATCA TGT rs4977574 (SEQ ID NO: 64) ATAAAAATAAAATAAAATAAAAAATGAAAAACAAAGTCCACTTGTAACCACATGTCAGTAGCAT GTTTGCTTTCAGGGTACATCAAATGCATTCTATAGC[A/G]CAGGATGTTCCAGTCACTCTAACAAAAGA TGTCCTGTTTGGAACACCAACTCTGTATCAGTTACTTCAGACACTTTCTCTCATTGAGTCCCTTCAGCAA G rs2891168 (SEQ ID NO: 65) AACCACATGTCAGTAGCATGTTTGCTTTCAGGGTACATCAAATGCATTCTATAGCACAGGATG TTCCAGTCACTCTAACAAAAGATGTCCTGTTTGGAAC[A/G]CCAACTCTGTATCAGTTACTTCAGACAC TTTCTCTCATTGAGTCCCTTCAGCAAGCCCTTTTAGGTTTATGTTCTTAGATGAGGAAACCAAGTCTTA GAA rs1537371 (SEQ ID NO: 66) ATATTTTCTTGTTTTTAGATGCACATATACGTACTTTTTTAGCTGGTCATTTCTTTCTGAAATTG GAATGAATCTTACAATCAATGGCATGTTATAATTT[A/C]ATTGGCAGCATTATTTGTCTCTTAAGGGCCC CCAAATAATAGTGTGTCACATAACTGATAGCATCTCAAATTAGATGAAATACAGTAGTCCAGGCAAGAA rs1556516 (SEQ ID NO: 67) GTTATGGGATAAAGGCGATAGTATTTTATTGACTATATTTTATTCTTTTAATTATTCCTCTAATT TCTTAAAACAACTTTATTGAGGTATAACTTCCACG[C/G]TATAATTTCACCCATTTTAAGTGCATGAATT CAGTGATTTTTAGTAGAGTCATTGAGTAGTGTAACCATTCCTACAATGGTTATAGCACATTTTTATCAT rs6475608 (SEQ ID NO: 68) TGTTTTCTTTTATTTTTCCTTCTAAAATAATCACACGTTTCATTGCAACCCTAACCCTCTTCAAC ACACACACACACACACACACACACACACACACACA[C/T]GGCTTCTAGATTCTACATGTACAAGAGTGC AAATCAAACTACCATAGAAAAACTAAGAAGAGAGGCCTAGAAGCAAGAGGCTGATACACTATCTCAGG CT rs7859727 (SEQ ID NO: 69) AACCAACACTTAAAATGCAGGGAATTTAAGATAAAAATTTGATAAAAATGGGAAGATTTGGCC GTATTGGGCTCATGGTAACTGAGATGCATCTGAATGA[C/T]AGGCATTCCTTTGAATTGCACATTTGCT CTTGTTTTTACTATAGGCCACTCTCACTTTCTGTTTTTTTCCCCGGCTTTGAAACGATCAGTTTTAGTAC TG rs1537373 (SEQ ID NO: 70) ATGACTGGGCAATTATGTCATTATCACCACTGATATATAGCTGGAAGAGTTTAGTGTTGCCCT GCTAAGATCTGGATTTTCTTTTCTGGAGCTTGGCTAT[G/T]GGGGCATTGAGAAGTCCAGCCAGGAGG TTGGTCAGAGGCTAACCCAAAAAGCTTTGCTTAACTCTGGGCTACAGCTGGGGGTTGCCAGAGAGAA GTGCCT rs1333042 (SEQ ID NO: 71) AATTTATTTGAGTAGACAGCCAACCCCCTGTATTGTACTCCTTTAAAAAATATTTTAGGCTTTTT AAATGCTGAGGCAAGGGGACATACCAAACACTAAC[A/G]GGCACATTGGGGTTTTCTGGCTATTGAAA TAAAAATGTCCTTACATAACACTGATGTACTGGAATAGCACTGCGTTCCAGTGACGGTTATTGCAACTC AG rc7R59162 (SEQ ID NO: 72) GGAGCATGATGTGCTTTGATTTCAACTATGGGCTTTATTACTTACTAACTGGGTTACTTTGGTT AAGTTGTTTGACTCTTGTTTTTTGAGATGGAGTCAG[C/T]CTGGGAGACTCCAGCTCTGTCGCCCAGG CCGGAGTGCAATGGCACGATCTTGGCTCACTGCAACCTCTGCCTCCCGGATACAAGCGATTCTCATGC CTTA rs1333043 (SEQ ID NO: 73) CTGGCACAAAGTAGGCACTTCATATATAAAAGCTGTGATTATTGATGAACCAGTAGTGAGGTA CATAACTGGGGAAGGAGAAGGGGCCAGTTTGTGGGAA[A/T]GCTTTTTTAGTTATTAATAGTAAGGTG GTAAAATAATAATAGTAATAATAACCAAAAGTTACTGAAAACTAAATACAGTGCTAAACTCTTTAAAAGG AGT rs1412834 (SEQ ID NO: 74) CTTCTTTAGCTGTAAATAAGTAATTGTATGAGGTGATGGTTAAGGTGATTTACTAATTTTACAA TTCTATTATTTTATGAATAGACCCTAGTTAGGATAG[C/T]TTGAAATAGATACTTAATCCACTATTATTCT CTCTTCTAAGATATAGTTACTAGTTGATCATACTTTTCCTTAAAGGCTGAACTGAATTCTCTGATATCA rs7341786 (SEQ ID NO: 75) GAAACATACTGGTTAATGGAATTCCAGAAAGGACTGAACAATCAAACCATTTTGAAGGACAGC ATAGAGCTGGACTCTAGAACAGCCAAAACAAGGGGTT[A/C]AACCACTGCGAGGGATCTCTCTCCAAC TCTTGCTCAGGCTTTTCTCCCTGGCTTGACTTTCTTCTCTTTCACTGTAGATTGGCTTCTCTCACATGGC AAG rs10511701 (SEQ ID NO: 76) TATTATGTGTGGCTGACTATATAAAAACATGGATATTTTCTTGGAATCACTTGGTTTGACTGGG AGAAGACCATTCTCAAAACAAAGGAAGTGCAATTTA[C/T]AGAAGGTAGTAGAATAGGCAGATAAAAC AATAATTCTTCACTATATTGCTCAAATAATCCCCATGACATTTTTAGTATATTATAAAGAGAGTTCTAAA GT rs10733376 (SEQ ID NO: 77) GAGAAAGATGTTAAGATGAAATTAGATGTGCAAGAGATTCGCCGAGGTAAACCTTGTGGGAG AAAATGGAGAGGTACATAGAGGAGCCTGGGCAGACTGT[C/G]TGGCTACTATGTAAGACTCATCCCC ATGAAGGAGAAAGGAGAGGAAGGCAAAGAAGAAAAACCTTAAGATTTCAATTCTAAGAACGTTTTGAC AAAGCTG rs10738609 (SEQ ID NO: 78) TGTGCAAGAGATTCGCCGAGGTAAACCTTGTGGGAGAAAATGGAGAGGTACATAGAGGAGC CTGGGCAGACTGTGTGGCTACTATGTAAGACTCATCCCC[A/G]TGAAGGAGAAAGGAGAGGAAGGCA AAGAAGAAAAACCTTAAGATTTCAATTCTAAGAACGTTTTGACAAAGCTGATTAGGAGTATTTAAGGCA AAGCTGC rs2383206 (SEQ ID NO: 79) AAATACTTTAACTCATGGCCCGATGATTTTCAGTTAACCAAATTCTCCCTTACTATCCTGGTTG CCCCTTCTGTCTTTTCCTTAGAAATGTTATTGTAGT[A/G]TTTGCAAGATGGCCTGAATCCTGAACCCC CCATCTTCAATGAGCACCAAATGGTAATTATAGATTCCCAGCTGTAGAGCTATGTCAGACAAAGGAAAC TT rs944797 (SEQ ID NO: 80) CTCTTCCTTGGTGGCTTAAAGTTAGGCTGAAGAAGATTTACATTATGTTGTGCATGACCTCTTT AGTTTGGTTCTACTTATACTTTCAAGGAGGGAAGAC[C/T]GGGGAAGGTGTCCCTTAGTGAGCATATT TTGTACAAATGAAAACAGGGTACTAACACTTATGCCAGGACGCATGCATAAACTAGGATGGTTCTGAG AAAA rs1004638 (SEQ ID NO: 81) AGAACCTTAATGGGAGCACAGGTCCCACCCACCCCTTGCTACCCCATGTACTTGTTCCCATCT TCACCCAAGAGAGGAAACACTCTGGAACTAGGGCAGC[A/T]TAAGTGAAGCAGAGTGAAAAGGAATG TGAAGTTTTGAGAAGAAAGAAAAGGCTAAAGTGTCTATCTTTCCACATTGCTTTTTTCAGGTTTCTCTTC GGAA rs2383207 (SEQ ID NO: 82) GATGAAAAATTCATATTCATCTGAATTTTATAAGTGAATCATGAGAACTCAAAGATACTTAGCC CTTGGGACCATTTTTTACTCCTGTTCGGATCCCTTC[A/G]GCTAAGCATGATTATTTACTATTTTCAGCT ATTAGTTATGTCTTGTTGAAAAAGTATGAAAAGAGCTGCCCAATAAATTAGAGTGTATGCTCAACATTC T rs1537374 (SEQ ID NO: 83) TTCGGATCCCTTCAGCTAAGCATGATTATTTACTATTTTCAGCTATTAGTTATGTCTTGTTGAAA AAGTATGAAAAGAGCTGCCCAATAAATTAGAGTGT[A/G]TGCTCAACATTCTCTTAGCTTCTTTATCTCT TTCCAAAATTGGATCAAATGACATTGGACATGATCAACTTCTTACTGTTTTGACAAACATCTGAGGATA rs1537375 (SEQ ID NO: 84) TTATTTACTATTTTCAGCTATTAGTTATGTCTTGTTGAAAAAGTATGAAAAGAGCTGCCCAATA AATTAGAGTGTATGCTCAACATTCTCTTAGCTTCTT[C/T]ATCTCTTTCCAAAATTGGATCAAATGACAT TGGACATGATCAACTTCTTACTGTTTTGACAAACATCTGAGGATACTTTTATAATTGATAATTTGGACTA rs1333045 (SEQ ID NO: 85) TTTTGTGCCTCAGTTTCCTCATTCAATATGGGTGTAATAACTGTGCCTGTCTTGTAGGATTATT GTGAGGCCCAAGTGCAATAATATATAGTACACTGTG[C/T]CTGGCATCTAGTAAGCATTCATTAAGATG ACATGAAGATAACACAGATATATCTTAACATGTAATTATGATTTTGCTTATTCAAGGCCAAGCATTCCAA T rs10738610 (SEQ ID NO: 86) GAAGAAGAAGACAGTCAGAGAGAAGTGAGGGCTTACTTTTCATGTTTAAAGTCTGTTATGTGG TAAAGGGATTAGATTTATCTGTGTTGTTCCAGGGGAC[A/C]GAAATAGGACAAATGGATGCAAATAGA GTGAGGAAGATTTAAAACAAATGGAGAAGACATTCTAAAATCAACTACAATGAGCGTAAACAATGACA ACGGA

rs1333046 (SEQ ID NO: 87) TCATATGCATAGACAAATACACCAAACTGATGAATATTTGCCTTGTATAATCTTTTTGTAGTTTT TTTATGAACATATATTACTCAAACAATTTAGAACA[A/T]TTGGCAATATATATATATTTCATTTATAAAAG GTTAGGAAGATTAATTACACTTTCTGAGGTCGCAACTAAAAGCCAAGATTTTAATCCATTTCTATTTG rs10757278 (SEQ ID NO: 88) AGTGTCACTGGAAAGTGACAAAGAGGACAGTTAAGTTAGTTGGAACTGAACTGAGGCCAGAC AGGGCTGTGGGACAAGTCAGGGTGTGGTCATTCCGGTA[A/G]GCAGCGATGCAGAATCAAGACAGA GTAGTTTCTCCTTCTCTCTCTCTCTTTAATTGTAACGCCTTTTATAACAAACAAATATTATGCTTATTTCT GTCTT rs1333047 (SEQ ID NO: 89) CAGTTAAGTTAGTTGGAACTGAACTGAGGCCAGACAGGGCTGTGGGACAAGTCAGGGTGTG GTCATTCCGGTAAGCAGCGATGCAGAATCAAGACAGAGT[A/T]GTTTCTCCTTCTCTCTCTCTCTTTAA TTGTAACGCCTTTTATAACAAACAAATATTATGCTTATTTCTGTCTTTAAATTTTTTGTAGTAATTTCTCA TCA rs4977575 (SEQ ID NO: 90) TTTTCTAGTTGAGCTATCATTCATATTTATTATGTGGAACTAGAGGTAGTCCTGGCTACTTGGG AACAGCGTGGAGTCTAGCCATGTCAGGGCCAGAAGT[C/G]GTCTCAGCTAAGTTAGAATGTGATACCA TTGTTTACACAAGTGTGGCCTGCCTTCAAGATAGGGTGAGGTGTTTTATGACCACAGGCTTTATGAGTT ATA rs1333048 (SEQ ID NO: 91) TGACTCTGAAGATCATACCCGAAGTAGAGCTGCAAAGATATTTGGAATATTGGTAATATCCAA TAAAGAATGACCTTCATGCTATTTTGAGGAGATGTTT[A/C]AATGTCGAATTATTGAAATATTTATAAAA TACAAATAAACTAACTCTGCTTCATATTCCAACTTGTGTATGACACTTCTTAGGCTATCATTTCATTCCA A rs1333049 (SEQ ID NO: 92) TTCCAACTTGTGTATGACACTTCTTAGGCTATCATTTCATTCCAAATTTATGGTCACTACCCTAC TGTCATTCCTCATACTAACCATATGATCAACAGTT[C/G]AAAAGCAGCCACTCGCAGAGGTAAGCAAG ATATATGGTAAATACTGTGTTGACAAAAGTATGCAGAAGCAGTCACATTTATACAGTAGTGAAGGAAAT GT rs1333050 (SEQ ID NO: 93) AATTACAGTATATCTAAAAAAAGAATAATATATAACAACTGAAAAAATAAAATAGTTGATATAA GCAGATATTCCAAGATCTGCCAGACATATTGTTAAA[C/T]GAAAAATCTAGATACAAAATTGTTTATAGT TCTCTTTCATACTATAGCCAAAGAAAATTCAGAAAAAACTACTTACAGTTGATCCTTGAATAATGCAGCA

TABLE-US-00015 TABLE 12 Association results for the MI phenotype for rs2383207 (G) and rs10757278 (G), in 9p21 in Iceland and the US. Results are shown for the initial Icelandic discovery MI case-control group (Iceland A), an independent Icelandic replication group (Iceland B) and for the three US replication groups of Caucasian origin. Also included are the results for the MI case-control groups combined. Study population (n/m)^a Frequency Variant (allele) Controls Cases OR (95% CI) P Iceland A (1607/6728) rs2383207 (G) 0.455 0.506 1.22 (1.13-1.33) 1.4 × 10^-6 rs10757278 (G) 0.434 0.489 1.25 (1.15-1.36) 1.5 × 10^-7 Iceland B (665/3533) rs2383207 (G) 0.462 0.525 1.29 (1.15-1.45) 0.000026 rs10757278 (G) 0.436 0.503 1.31 (1.16-1.47) 0.000014 Atlanta (596/1284) rs2383207 (G) 0.541 0.593 1.23 (1.07-1.42) 0.0030 rs10757278 (G) 0.484 0.551 1.31 (1.14-1.50) 0.00015 Philadelphia (582/504) rs2383207 (G) 0.524 0.602 1.37 (1.16-1.63) 0.00026 rs10757278 (G) 0.470 0.550 1.38 (1.17-1.64) 0.00019 Durham (1137/718) rs2383207 (G) 0.513 0.559 1.20 (1.05-1.37) 0.0060 rs10757278 (G) 0.460 0.521 1.28 (1.12-1.46) 0.00027 Combined Iceland^b (2274/10260) rs2383207 (G) 0.458 0.511 1.24 (1.16-1.33) 3.3 × 10^-10 rs10757278 (G) 0.435 0.493 1.26 (1.18-1.35) 5.3 × 10^-12 US groups^c (2315/2508) rs2383207 (G) 0.526 0.585 1.25 (1.15-1.36) 1.1 × 10^-7 rs10757278 (G) 0.471 0.541 1.31 (1.21-1.43) 1.5 × 10^-10 Replication groups^d (2980/6041) rs2383207 (G) 0.494 0.555 1.27 (1.18-1.36) 1.4 × 10^-11 rs10757278 (G) 0.454 0.522 1.31 (1.22-1.40) 1.0 × 10^-14 All groups^b,d (4589/12768) rs2383207 (G) 0.492 0.548 1.25 (1.18-1.31) 2.0 × 10^-16 rs10757278 (G) 0.453 0.517 1.28 (1.22-1.35) 1.2 × 10^{-20 a}Number of MI cases (n) and controls (m). ^bWhen combining the Icelandic cohorts they are analysed together and the results adjusted for relatedness in the combined group. ^cFor the combined groups OR and P value are calculated using a Mantel-Haenszel model and the frequency in cases and controls is a simple average over the frequency in the individual groups. ^dWhen combining Icelandic and US groups, the frequency in cases and controls is the average over the two populations.

TABLE-US-00016 TABLE 13 Genotype specific odds ratio for the risk allele of rs10757278. Shown is the risk for heterozygous carriers (0X) and homozygous carriers (XX) compared to the risk for non-carriers (00), together with 95% confidence intervals (CI), and the population attributable risk (PAR). The lower part of the table includes the corresponding values when the analysis is restricted to early-onset MI cases. Study population (n/m)^a Genotype specific Odds Ratio^b Variant (allele) 00 0X (95% CI) XX (95% CI) PAR^b Iceland^c (2272/10261) rs10757278 (G) 1 1.25 (1.12-1.39) 1.58 (1.38-1.81) 0.19 US groups (2315/2508) rs10757278 (G) 1 1.28 (1.14-1.45) 1.72 (1.45-2.03) 0.23 All groups (4587/12769) rs10757278 (G) 1 1.26 (1.16-1.36) 1.64 (1.47-1.82) 0.21 Early onset MI (<50 for males; <60 for females) Iceland^c (621/10261) rs10757278 (G) 1 1.38 (1.13-1.69) 1.94 (1.53-2.46) 0.27 US groups (1080/2508) rs10757278 (G) 1 1.56 (1.32-1.85) 2.08 (1.69-2.58) 0.34 All groups (1701/12769) rs10757278 (G) 1 1.49 (1.31-1.69) 2.02 (1.72-2.36) 0.31 ^aNumber of MI cases (n) and control (m). ^bGenotype specific odds ratio for heterozygous (0X) and homozygous carrier (XX) compared to non-carriers (00). ^cPopulation attributable risk (PAR). ^dFor the Icelandic groups, P values and OR were adjusted for relatedness using simulations.

TABLE-US-00017 TABLE 14 Association of the G allele of rs10757278 to coronary artery disease (CAD). The association results are shown for CAD, both including and excluding known MI cases. Results are shown for the Icelandic case-control group (excluding the discovery group), for two of the US groups, and for the groups combined. Study population (n1/n2/m)^a All CAD cases Excluding MI cases Variant (allele) Cont. frq Case. frq OR (95% CI) P Case. frq OR (95% CI) P Iceland^b (1563/773/3533) rs10757278 (G) 0.439 0.496 1.26 (1.15-1.37) 1.9 × 10^-7 0.490 1.22 (1.09-1.37) 0.00050 Atlanta (724/128/1284) rs10757278 (G) 0.484 0.552 1.31 (1.15-1.50) 0.000036 0.557 1.34 (1.04-1.73) 0.026 Philadelphia (709/126/504) rs10757278 (G) 0.470 0.547 1.36 (1.16-1.60) 0.00019 0.528 1.26 (0.96-1.66) 0.10 Combined US groups^c (1433/254/1788) rs10757278 (G) 0.477 0.550 1.33 (1.20-1.47) 2.7 × 10^-8 0.542 1.30 (1.08-1.57) 0.0059 All groups^c (2996/1027/5321) rs10757278 (G) 0.458 0.523 1.29 (1.21-1.38) 3.6 × 10^-14 0.525 1.24 (1.13-1.37) 0.000011 ^aNumber of all cases (n₁), cases excluding MI patients (n₂), and controls (m). ^bIndividuals used in the initial discovery group have been excluded both from cases and controls. ^cFor the combined groups, the allelic frequency in cases and controls is a simple average over the individual groups or, when combining Icelandic and US groups, the average over the two populations.

TABLE-US-00018 TABLE 15 Association to MI on 9p21 Shown are all SNPs in the region 21.92 to 22.12 (NCBI build 34) on 9p21 that show nominally significant association to MI in the genome-wide association study. Results are shown for 1607 MI cases and 6728 controls from the Icelandic discovery cohort. Also included are the corresponding results if the association test is done adjusting for the observed association to the three SNPs, rs1333040, rs10116277 and rs2383207 (indicated in bold). Frequency SNP Allele Position Controls MI cases OR P^a OR^b P^b rs10757260 A 21943137 0.606 0.627 1.09 0.041 1.10 0.037 rs7041637 A 21951866 0.233 0.253 1.12 0.021 0.99 0.91 rs2811712 A 21988035 0.875 0.893 1.19 0.0076 1.16 0.022 rs3218018 A 21988139 0.879 0.896 1.20 0.0074 1.17 0.021 rs3217992 A 21993223 0.344 0.378 1.16 0.00055 0.98 0.75 rs2069426 C 21996273 0.881 0.897 1.18 0.0146 1.15 0.038 rs2069422 A 21998026 0.875 0.894 1.20 0.0059 1.17 0.018 rs2151280 T 22024719 0.464 0.486 1.09 0.038 0.96 0.43 rs1333034 A 22034122 0.875 0.893 1.19 0.0073 1.17 0.021 rs1011970 G 22052134 0.772 0.806 1.22 9.2 × 10^-5 1.14 0.020 rs10116277 T 22071397 0.418 0.468 1.22 1.9 × 10^-6 na na rs1333040 T 22073404 0.490 0.542 1.23 6.1 × 10^-7 na na rs2383207 G 22105959 0.455 0.506 1.22 1.4 × 10^-6 na na rs1333050 T 22115913 0.671 0.693 1.11 0.020 0.97 0.61 ^aP value adjusted using genomic controls. ^bP value and OR adjusted for the observed association to rs1333040, rs2383207 and rs10116277.

TABLE-US-00019 TABLE 16 Association to MI. Shown is the association for the risk alleles of the three SNPs from the genome-wide study, rs1333040, rs2383207 and rs10116277, and the most significant refinement SNP, rs10757278, to MI in the combined Icelandic case-control group and in the three US case-controls groups. Study population (n/m)^a Controls Cases Variant (allele) AA/Aa/aa Frq. AA/Aa/aa Frq OR (95% CI) P Iceland A (1607/6728) rs1333040 (T) 1770/3315/1636 0.490 342/783/478 0.542 1.23 (1.14-1.34) 6.1 × 10^-7 rs2383207 (G) 2022/3280/1418 0.455 389/811/408 0.506 1.22 (1.13-1.33) 1.4 × 10^-6 rs10116277 (T) 2305/3212/1208 0.418 454/805/350 0.468 1.22 (1.13-1.33) 1.9 × 10^-6 rs10757278 (G) 592/869/318 0.434 413/770/376 0.489 1.25 (1.15-1.36) 1.5 × 10^-7 Iceland B (665/3533) rs1333040 (T) 893/1750/889 0.499 135/312/188 0.541 1.18 (1.05-1.33) 0.0065 rs2383207 (G) 1016/1770/746 0.462 146/319/171 0.525 1.29 (1.15-1.45) 0.000026 rs10116277 (T) 1160/1770/602 0.421 178/317/148 0.480 1.27 (1.12-1.43) 0.00010 rs10757278 (G) 224/366/128 0.436 160/329/161 0.503 1.31 (1.16-1.47) 0.000014 Atlanta (596/1284) rs1333040 (T) 190/588/369 0.573 63/253/230 0.648 1.37 (1.19-1.58) 0.000016 rs2383207 (G) 273/603/381 0.541 100/270/206 0.593 1.23 (1.07-1.42) 0.0030 rs10116277 (T) 296/571/310 0.503 114/273/190 0.565 1.28 (1.12-1.47) 0.00041 rs10757278 (G) 341/618/287 0.484 119/291/175 0.551 1.31 (1.14-1.50) 0.00015 Philadelphia (582/504) rs1333040 (T) 80/225/172 0.585 55/263/232 0.661 1.38 (1.16-1.65) 0.00031 rs2383207 (G) 105/250/127 0.524 86/274/197 0.602 1.37 (1.16-1.63) 0.00026 rs10116277 (T) 120/222/125 0.505 86/262/178 0.587 1.39 (1.18-1.65) 0.00013 rs10757278 (G) 137/254/103 0.470 116/281/169 0.550 1.38 (1.17-1.64) 0.00019 Durham (1137/718) rs1333040 (T) 101/364/230 0.588 159/520/427 0.618 1.14 (0.99-1.30) 0.067 rs2383207 (G) 156/377/176 0.513 230/535/353 0.559 1.20 (1.05-1.37) 0.0060 rs10116277 (T) 166/366/174 0.504 256/526/334 0.534 1.13 (0.99-1.29) 0.076 rs10757278 (G) 189/370/134 0.460 261/545/304 0.521 1.28 (1.12-1.46) 0.00027 Combined Iceland^b (2274/10260) rs1333040 (T) 2663/5065/2525 0.493 477/1095/666 0.542 1.21 (1.14-1.30) 1.6 × 10^-8 rs2383207 (G) 3038/5050/2164 0.458 535/1130/579 0.511 1.24 (1.16-1.33) 3.3 × 10^-10 rs10116277 (T) 3465/4982/1810 0.419 632/1122/498 0.471 1.23 (1.15-1.32) 1.1 × 10^-9 rs10757278 (G) 816/1235/446 0.435 573/1099/537 0.493 1.26 (1.18-1.35) 5.3 × 10^-12 US groups^c (2315/2508) rs1333040 (T) 0.582 0.642 1.27 (1.17-1.39) 3.6 × 10^-8 rs2383207 (G) 0.526 0.585 1.25 (1.15-1.36) 1.1 × 10^-7 rs10116277 (T) 0.504 0.562 1.24 (1.14-1.35) 3.1 × 10^-7 rs10757278 (G) 0.471 0.541 1.31 (1.21-1.43) 1.5 × 10^-10 Replication groups^d (2980/6041) rs1333040 (T) 0.541 0.592 1.24 (1.16-1.33) 1.3 × 10^-9 rs2383207 (G) 0.494 0.555 1.27 (1.18-1.36) 1.4 × 10^-11 rs10116277 (T) 0.463 0.521 1.25 (1.17-1.34) 1.3 × 10^-10 rs10757278 (G) 0.454 0.522 1.31 (1.22-1.40) 1.0 × 10^-14 All groups^b,d (4589/12768) rs1333040 (T) 0.538 0.592 1.24 (1.17-1.30) 4.1 × 10^-15 rs2383207 (G) 0.492 0.548 1.25 (1.18-1.31) 2.0 × 10^-16 rs10116277 (T) 0.492 0.548 1.24 (1.17-1.30) 1.8 × 10^-15 rs10757278 (G) 0.453 0.517 1.28 (1.22-1.35) 1.2 × 10^{-20 a}Number of MI cases (n) and controls (m). ^bWhen combining the Icelandic cohorts they are analysed together and the results adjusted for relatedness in the combined group. ^cFor the combined groups OR and P value are calculated using a Mantel-Haenszel model and the frequency in cases and controls is a simple average over the frequency in the individual groups. ^dWhen combining Icelandic and US groups, the frequency in cases and controls is the average over the two populations.

TABLE-US-00020 TABLE 17 Genotype specific odds ratio. The upper part shows the genotype specific odds ratios for the risk alleles of the three SNPs from the genome-wide study, rs1333040, rs2383207 and rs10116277, and the most significant refinement SNP, rs10757278, for all MI cases. Shown is the risk for heterozygous carriers (0X) and homozygous carriers (XX) compared to the risk for non-carriers (00), together with 95% confidence intervals (CI). Also included is the population attributed risk (PAR). The lower part of the table includes the corresponding values when the analysis is restricted to early-onset MI cases. Study population (n/m)^a Genotype specific Odds Ratio^b Variant (allele) 00 0X (95% CI) XX (95% CI) PAR^c Iceland^d (2272/10261) rs1333040 (T) 1 1.18 (1.05-1.32) 1.46 (1.28-1.68) 0.17 rs2383207 (G) 1 1.26 (1.13-1.40) 1.53 (1.34-1.76) 0.19 rs10116277 (T) 1 1.23 (1.11-1.37) 1.52 (1.32-1.74) 0.17 rs10757278 (G) 1 1.25 (1.12-1.39) 1.58 (1.38-1.81) 0.19 US groups (2315/2508) rs1333040 (T) 1 1.34 (1.16-1.55) 1.65 (1.38-1.97) 0.28 rs2383207 (G) 1 1.18 (1.04-1.34) 1.54 (1.30-1.82) 0.19 rs10116277 (T) 1 1.16 (1.03-1.31) 1.52 (1.29-1.79) 0.17 rs10757278 (G) 1 1.28 (1.14-1.45) 1.72 (1.45-2.03) 0.23 All groups (4587/12768) rs1333040 (T) 1 1.24 (1.14-1.35) 1.52 (1.37-1.69) 0.22 rs2383207 (G) 1 1.22 (1.13-1.32) 1.54 (1.39-1.71) 0.20 rs10116277 (T) 1 1.20 (1.11-1.30) 1.53 (1.38-1.69) 0.18 rs10757278 (G) 1 1.26 (1.16-1.36) 1.64 (1.47-1.82) 0.21 Early onset MI (<50 for males; <60 for females) Iceland^d (621/10261) rs1333040 (T) 1 1.28 (1.01-1.63) 1.94 (1.50-2.50) 0.27 rs2383207 (G) 1 1.30 (1.04-1.62) 1.80 (1.40-2.32) 0.24 rs10116277 (T) 1 1.32 (1.06-1.63) 1.86 (1.44-2.40) 0.24 rs10757278 (G) 1 1.38 (1.13-1.69) 1.94 (1.53-2.46) 0.27 US groups (1080/2508) rs1333040 (T) 1 1.58 (1.29-1.94) 2.00 (1.58-2.53) 0.38 rs2383207 (G) 1 1.40 (1.16-1.67) 1.88 (1.52-2.33) 0.31 rs10116277 (T) 1 1.50 (1.26-1.79) 1.90 (1.53-2.35) 0.32 rs10757278 (G) 1 1.56 (1.32-1.85) 2.08 (1.69-2.58) 0.34 All groups (1701/12769) rs1333040 (T) 1 1.46 (1.25-1.70) 1.95 (1.65-2.32) 0.34 rs2383207 (G) 1 1.36 (1.18-1.56) 1.84 (1.56-2.17) 0.28 rs10116277 (T) 1 1.43 (1.25-1.64) 1.87 (1.58-2.20) 0.29 rs10757278 (G) 1 1.49 (1.31-1.69) 2.02 (1.72-2.36) 0.31 ^aNumber of MI cases (n) and control (m). ^bGenotype specific odds ratio for heterozygous (0X) and homozygous carrierr (XX) compared to non-carriers (00). ^cPopulation attibuted risk (PAR). ^dFor the Icelandic groups, P values and OR were adjusted for relatedness using simulations.

TABLE-US-00021 TABLE 18 Association to age at onset of MI. Shown is the association of the risk alleles of the three SNPs from the genome-wide study, rs1333040, rs2383207 and rs10116277, and the most significant refinement SNP, rs10757278, to age at onset of MI. The results are based on regressing the sex adjusted age at onset on the number of risk alleles an individual carries. The combined analysis is done by including a cohort indicator as a explanatory variable in the regression. All MI cases with known age at onset, including late-onset MI, from the four study groups are included in the analysis; this adds 973 MI cases to the study groups compared to the case-controls analysis. Study population (n/m)^a Effect (s.e.m.) P Iceland (2896/750) rs1333040 (T) -1.20 (0.31) 0.00012 rs2383207 (G) -1.04 (0.31) 0.00080 rs10116277 (T) -1.05 (0.31) 0.00069 rs10757278 (G) -1.08 (0.31) 0.00042 Atlanta (611/40) rs1333040 (T) -1.36 (0.69) 0.050 rs2383207 (G) -1.16 (0.65) 0.075 rs10116277 (T) -1.47 (0.64) 0.023 rs10757278 (G) -1.35 (0.65) 0.038 Philadelphia (555/82) rs1333040 (T) -0.85 (0.79) 0.28 rs2383207 (G) -1.01 (0.76) 0.19 rs10116277 (T) -1.01 (0.76) 0.18 rs10757278 (G) -1.25 (0.74) 0.092 Durham (1213/101) rs1333040 (T) -0.89 (0.48) 0.19 rs2383207 (G) -1.11 (0.46) 0.017 rs10116277 (T) -1.14 (0.46) 0.013 rs10757278 (G) -1.19 (0.46) 0.0098 Combined US groups (2379/223) rs1333040 (T) -0.97 (0.36) 0.0014 rs2383207 (G) -1.09 (0.34) 0.0014 rs10116277 (T) -1.19 (0.34) 0.00039 rs10757278 (G) -1.26 (0.34) 0.00019 All groups (5275/793) rs1333040 (T) -1.10 (0.23) 2.7 × 10^-6 rs2383207 (G) -1.06 (0.23) 3.5 × 10^-6 rs10116277 (T) -1.12 (0.23) 9.2 × 10^-7 rs10757278 (G) -1.16 (0.23) 2.9 × 10^{-7 a}n is the number of MI cases used in the regression and m is the number of MI cases used that were not included in the case-control analysis.

TABLE-US-00022 TABLE 19 Association to early-onset MI. Shown is the association of the risk alleles of the three SNPs from the genome-wide study, rs1333040, rs2383207 and rs10116277, and the most significant refinement SNP, rs10757278, to early-onset MI in the combined Icelandic case-control group and in the three US case-controls groups. Early-onset MI is defined as a MI event before the age of 50 for males and before the age of 60 for females. Study population (n/m)^a Controls Cases Variant (allele) AA/Aa/aa Frq. AA/Aa/aa Frq OR (95% CI) P Iceland^b (621/10261) rs1333040 (T) 2663/5065/2525 0.493 114/293/210 0.576 1.40 (1.24-1.57) 1.9 × 10^-8 rs2383207 (G) 3038/5050/2164 0.458 133/310/176 0.533 1.35 (1.20-1.52) 3.4 × 10^-7 rs10116277 (T) 3465/4982/1810 0.419 156/308/153 0.496 1.36 (1.21-1.53) 1.9 × 10^-7 rs10757278 (G) 816/1235/446 0.435 142/299/166 0.518 1.40 (1.24-1.57) 3.5 × 10^-8 Atlanta (305/1284) rs1333040 (T) 190/588/369 0.573 27/131/121 0.659 1.44 (1.20-1.74) 0.00011 rs2383207 (G) 273/603/381 0.541 45/145/105 0.600 1.27 (1.06-1.52) 0.0082 rs10116277 (T) 296/571/310 0.504 47/150/97 0.584 1.38 (1.16-1.65) 0.00035 rs10757278 (G) 341/618/287 0.484 53/161/86 0.558 1.35 (1.13-1.61) 0.00099 Philadelphia (211/504) rs1333040 (T) 80/225/172 0.585 17/102/83 0.661 1.38 (1.09-1.75) 0.0075 rs2383207 (G) 105/250/127 0.524 30/95/75 0.618 1.47 (1.17-1.85) 0.0011 rs10116277 (T) 120/222/125 0.505 27/97/66 0.593 1.42 (1.13-1.79) 0.0026 rs10757278 (G) 137/254/103 0.470 39/103/63 0.561 1.44 (1.15-1.81) 0.0017 Durham (564/720) rs1333040 (T) 101/364/230 0.588 64/249/234 0.651 1.31 (1.11-1.54) 0.0012 rs2383207 (G) 156/377/176 0.513 91/271/192 0.596 1.40 (1.20-1.64) 0.000026 rs10116277 (T) 166/366/174 0.504 97/278/178 0.572 1.31 (1.12-1.53) 0.00070 rs10757278 (G) 189/370/134 0.459 105/278/168 0.559 1.49 (1.28-1.75) 5.0 × 10^-7 Combined US groups^c (1080/2508) rs1333040 (T) 0.582 0.657 1.37 (1.23-1.52) 1.6 × 10^-8 rs2383207 (G) 0.526 0.605 1.37 (1.23-1.52) 4.8 × 10^-9 rs10116277 (T) 0.504 0.583 1.36 (1.22-1.51) 9.5 × 10^-9 rs10757278 (G) 0.471 0.559 1.43 (1.29-1.59) 1.7 × 10^-11 All groups^c (1701/12769) rs1333040 (T) 0.538 0.617 1.38 (1.28-1.50) 1.6 × 10^-15 rs2383207 (G) 0.492 0.569 1.36 (1.26-1.47) 8.2 × 10^-15 rs10116277 (T) 0.462 0.540 1.36 (1.26-1.47) 9.2 × 10^-15 rs10757278 (G) 0.453 0.539 1.42 (1.31-1.53) 3.3 × 10^{-18 a}Number of MI cases (n) and controls (m). ^bFor the Icelandic group the P value and CI are adjusted for relatedness using simulations. ^cFor the combined groups, the frequency in cases and controls is a simple average over the frequency in the individual group or, when combining Icelandic and US groups, the average over the two populations.

TABLE-US-00023 TABLE 20 Association to coronary artery disease. Association of the risk alleles of the three SNPs from the genome-wide study, rs1333040, rs2383207 and rs10116277, and the most significant refinement SNP, rs10757278, to coronary artery disease (CAD) in an Icelandic group of CAD patients and in groups of CAD patients from two of the US study groups. The study group from Durham does not include any CAD patients in addition to the MI patients and was excluded from this part of the analysis. Also included are the corresponding results if all known MI cases are excluded from the CAD patient group. Study population (n₁/n₂/m)^a Controls All CAD cases Excluding MI cases Variant (allele) AA/Aa/aa Frq. AA/Aa/aa Frq. OR (95% CI) P AA/Aa/aa Frq. OR (95% CI) P Iceland^b (1563/773/3533) rs1333040 (T) 893/1750/889 0.499 308/697/413 0.533 1.15 (1.05-1.25) 0.0020 152/328/192 0.527 1.12 (1.00-1.25) 0.057 rs2383207 (G) 1016/1770/746 0.462 353/732/387 0.513 1.23 (1.13-1.34) 2.2 × 10^-6 186/353/185 0.500 1.17 (1.04-1.31) 0.0067 rs10116277 (T) 1160/1770/602 0.421 409/707/333 0.474 1.24 (1.14-1.35) 9.5 × 10^-7 204/333/158 0.468 1.21 (1.08-1.35) 0.0010 rs10757278 (G) 224/366/128 0.439 393/745/376 0.496 1.26 (1.15-1.37) 1.9 × 10^-7 203/365/188 0.490 1.22 (1.09-1.37) 0.00050 Atlanta (724/128/1284) rs1333040 (T) 190/588/369 0.572 75/310/281 0.649 1.38 (1.21-1.58) 2.4 × 10^-6 12/57/51 0.655 1.42 (1.09-1.86) 0.010 rs2383207 (G) 273/603/381 0.541 117/335/249 0.595 1.25 (1.09-1.42) 0.00093 17/65/43 0.606 1.30 (1.00-1.69) 0.046 rs10116277 (T) 296/571/310 0.503 130/341/228 0.571 1.31 (1.15-1.50) 0.000038 16/68/38 0.598 1.47 (1.13-1.90) 0.0039 rs10757278 (G) 341/618/287 0.484 139/362/207 0.552 1.31 (1.15-1.50) 0.000036 20/71/32 0.557 1.34 (1.04-1.73) 0.026 Philadelphia (709/126/504) rs1333040 (T) 80/225/172 0.585 59/273/235 0.648 1.31 (1.11-1.55) 0.00170 24/49/47 0.588 1.02 (0.76-1.35) 0.92 rs2383207 (G) 105/250/127 0.524 89/285/200 0.600 1.36 (1.15-1.60) 0.00023 25/52/46 0.587 1.29 (0.98-1.71) 0.072 rs10116277 (T) 120/222/125 0.504 90/274/180 0.582 1.37 (1.16-1.61) 0.00017 26/52/43 0.556 1.23 (0.93-1.62) 0.14 rs10757278 (G) 137/254/103 0.470 146/339/208 0.547 1.36 (1.16-1.60) 0.00019 30/57/38 0.528 1.26 (0.96-1.66) 0.10 Combined US groups^c (1433/254/1788) rs1333040 (T) 0.579 0.649 1.35 (1.22-1.50) 1.9 × 10^-8 0.621 1.23 (1.01-1.51) 0.044 rs2383207 (G) 0.533 0.598 1.29 (1.17-1.43) 9.8 × 10^-7 0.597 1.30 (1.08-1.57) 0.0068 rs10116277 (T) 0.504 0.577 1.34 (1.21-1.48) 2.1 × 10^-8 0.577 1.35 (1.12-1.63) 0.0018 rs10757278 (G) 0.477 0.550 1.33 (1.20-1.47) 2.7 × 10^-8 0.542 1.30 (1.08-1.57) 0.0059 All groups^c (2996/1027// 5321) rs1333040 (T) 0.539 0.591 1.22 (1.14-1.31) 3.2 × 10^-9 0.590 1.14 (1.04-1.26) 0.0082 rs2383207 (G) 0.497 0.555 1.25 (1.17-1.34) 1.3 × 10^-11 0.565 1.20 (1.09-1.32) 0.00019 rs10116277 (T) 0.462 0.525 1.28 (1.20-1.37) 1.7 × 10^-13 0.541 1.25 (1.13-1.37) 7.8 × 10^-6 rs10757278 (G) 0.458 0.523 1.29 (1.21-1.38) 3.6 × 10^-14 0.525 1.24 (1.13-1.37) 0.000011 ^aNumber of all cases (n₁), cases excluding MI patients (n₂), and controls (m). ^bIndividuals used in the initial discovery group have been excluded both from cases and controls. ^cFor the combined groups, the allelic frequency in cases and controls is a simple average over the individual groups or, when combining Icelandic and US groups, the average over the two populations.

TABLE-US-00024 TABLE 21 Markers correlated with the at-risk signal. All SNPs in the LD-block (based on the HapMap v19 CEU dataset) that are correlated, with r² ≧ 0.5, to at least one of the three SNPs, rs1333040, rs10116277 and rs2383207, together with the correlation coefficients D' and r². Additional markers selected for typing on both the Icelandic and all the US case/control groups are indicated in bold italic. rs1333040 rs10116277 rs2383207 SNP Position^a Position^b Frq D' r² D' r² D' r² rs10811647 22055002 134856 0.449 0.95 0.49 0.92 0.70 0.92 0.62 22057593 137447 0.450 0.95 0.49 0.93 0.70 0.92 0.63 rs9632884 22062301 142155 0.521 0.96 0.65 1 0.93 0.93 0.84 rs10116277 22071397 151251 0.500 1 0.67 1 1 1 0.90 rs6475606 22071850 151704 0.500 1 0.67 1 1 1 0.90 rs1333040 22073404 153258 0.600 1 1 1 0.67 0.88 0.57 rs1537370 22074310 154164 0.500 1 0.67 1 1 1 0.90 rs7857345 22077473 157327 0.733 1 0.55 1 0.36 0.81 0.26 22078094 157948 0.504 1 0.69 1 1 1 0.90 rs10757272 22078260 158114 0.500 1 0.67 1 1 1 0.90 22088574 168428 0.500 1 0.67 1 1 1 0.90 rs2891168 22088619 168473 0.500 1 0.67 1 1 1 0.90 rs1537371 22089568 169422 0.500 1 0.67 1 1 1 0.90 rs1556516 22090176 170030 0.500 1 0.67 1 1 1 0.90 22091702 171556 0.737 1 0.54 1 0.36 0.8 0.25 rs7859727 22092165 172019 0.496 1 0.66 1 1 1 0.90 rs1537373 22093341 173195 0.500 1 0.67 1 1 1 0.90 rs1333042 22093813 173667 0.508 0.96 0.63 1 0.97 1 0.94 rs7859362 22095927 175781 0.525 0.88 0.57 1 0.90 1 1 rs1333043 22096731 176585 0.517 0.92 0.60 1 0.94 1 0.97 rs1412834 22100131 179985 0.525 0.88 0.57 1 0.90 1 1 rs7341786 22102241 182095 0.533 0.84 0.54 1 0.88 1 0.97 rs10511701 22102599 182453 0.533 0.84 0.54 1 0.88 1 0.97 rs10733376 22104469 184323 0.525 0.88 0.57 1 0.90 1 1 rs10738609 22104495 184349 0.525 0.88 0.57 1 0.90 1 1 rs2383206 22105026 184880 0.525 0.88 0.57 1 0.90 1 1 rs944797 22105286 185140 0.525 0.88 0.57 1 0.90 1 1 rs1004638 22105589 185443 0.525 0.88 0.57 1 0.90 1 1 rs2383207 22105959 185813 0.525 0.88 0.57 1 0.90 1 1 rs1537374 22106046 185900 0.525 0.88 0.57 1 0.90 1 1 rs1537375 22106071 185925 0.525 0.88 0.57 1 0.90 1 1 22109195 189049 0.548 0.68 0.37 0.92 0.69 0.85 0.65 rs10738610 22113766 193620 0.517 0.92 0.60 1 0.94 1 0.97 22114123 193977 0.517 0.92 0.60 1 0.94 1 0.97 22114477 194331 0.491 0.95 0.57 0.96 0.90 1 0.87 rs1333047 22114504 194358 0.492 0.96 0.59 0.97 0.90 1 0.88 rs4977575 22114744 194598 0.492 0.96 0.59 0.97 0.90 1 0.88 22115347 195201 0.508 0.96 0.63 1 0.97 1 0.94 rs1333049 22115503 195357 0.492 0.96 0.59 0.97 0.90 1 0.88 ^aBase-pair location in NCBI Build 34, Build 35 and Build 36. ^bPosition in SEQ ID NO: 94 (LD Block C09)

TABLE-US-00025 TABLE 22a Association to MI for additional markers typed in the LD block C09. Association to MI of the three SNPs from the genome-wide association study and of the 10 highly correlated refinement markers. The association is calculated for the combined Icelandic and US case-control groups with OR and P-values combined using a Mantel-Haenszel model. Also included are the corresponding adjusted P values for each marker when the association is tested conditional on the observed association of each of the other markers. Frequency^b Unadjusted Adjusted P values SNP Allele Position^a Controls Cases OR P rs10811650 rs10116277 rs1333040 rs10738607 rs10811650 G 22057593 0.398 0.449 1.21 3.0 × 10^-12 na 0.79 0.10 0.43 rs10116277 T 22071397 0.461 0.516 1.24 1.8 × 10^-15 1.2 × 10^-4 na 0.011 0.47 rs1333040 T 22073404 0.537 0.592 1.24 4.1 × 10^-15 6.6 × 10^-5 0.040 na 0.18 rs10738607 G 22078094 0.463 0.525 1.27 2.1 × 10^-19 6.2 × 10^-9 2.5 × 10^-5 4.2 × 10^-6 na rs4977574 G 22088574 0.465 0.525 1.27 1.1 × 10^-18 1.6 × 10^-8 1.8 × 10^-4 1.7 × 10^-5 0.43 rs6475608 C 22091702 0.700 0.737 1.18 6.3 × 10^-8 0.058 0.52 0.84 0.71 rs2383207 G 22105959 0.492 0.548 1.25 2.0 × 10^-16 9.2 × 10^-6 0.017 3.8 × 10^-4 0.42 rs1333045 C 22109195 0.508 0.563 1.24 6.3 × 10^-15 3.4 × 10^-5 0.024 4.1 × 10^-4 0.92 rs1333046 A 22114123 0.468 0.526 1.25 2.5 × 10^-17 6.2 × 10^-7 0.0036 1.5 × 10^-4 0.20 rs10757278 G 22114477 0.453 0.517 1.28 1.2 × 10^-20 .sup. 4.8 × 10^-10 2.7 × 10^-6 4.8 × 10^-7 0.039 rs1333048 C 22115347 0.472 0.532 1.26 6.0 × 10^-18 1.6 × 10^-7 9.5 × 10^-4 4.6 × 10^-5 0.39 Adjusted P values SNP rs4977574 rs6475608 rs2383207 rs1333045 rs1333046 rs10757278 rs1333048 rs10811650 0.47 1.6 × 10^-6 0.47 0.063 1.00 0.51 0.86 rs10116277 0.83 3.0 × 10^-9 0.20 0.0046 0.38 0.67 0.65 rs1333040 0.11 1.6 × 10^-8 0.011 2.3 × 10^-4 0.027 0.15 0.050 rs10738607 0.056 7.1 × 10^-13 2.8 × 10^-4 8.0 × 10^-6 0.0015 0.61 0.0079 rs4977574 na 2.7 × 10^-12 0.0021 7.3 × 10^-5 0.033 0.61 0.076 rs6475608 0.72 na 0.70 0.83 0.93 0.73 0.93 rs2383207 0.73 3.2 × 10^-10 na 0.0020 0.56 0.25 0.78 rs1333045 0.85 1.2 × 10^-8 0.15 na 0.50 0.17 0.62 rs1333046 0.68 5.0 × 10^-11 0.038 5.0 × 10^-4 na 0.044 0.74 rs10757278 0.0041 5.0 × 10^-14 2.0 × 10^-5 2.6 × 10^-7 2.4 × 10^-5 na 1.1 × 10^-4 rs1333048 0.94 1.2 × 10^-11 0.017 2.4 × 10^-4 0.24 0.10 na ^aBase-pair location in NCBI Build 34. ^bThe frequency in cases and controls is a simple average over the frequency in Iceland and in US.

TABLE-US-00026 TABLE 22b Genotype count for additional markers typed in the LD block C09. Genotype counts in cases and controls for the eight additional refinement SNPs typed in the LD block C09 and for the three SNPs from the genome-wide study, rs1333040, rs2383207 and rs10116277. Genotype counts are shown for the combined Icelandic case-control group (Iceland A + B) and for the three US replication cohorts. For each SNP counts are shown for the risk allele a and the wild type allele A. Risk Iceland A + B Philadelphia Atlanta Durham Al- Controls Cases Controls Cases Controls Cases Controls Cases SNP lele Position^a AA/aA/aa AA/aA/aa AA/aA/aa AA/aA/aa AA/aA/aa AA/aA/aa AA/aA/aa AA/aA/aa rs10811650 G 22057593 819/1015/ 652/878/336 143/193/74 107/239/119 293/394/147 165/271/133 202/380/112 344/527/222 279 rs10116277 T 22071397 3465/4982/ 632/1122/498 120/222/125 86/262/178 296/571/310 114/273/190 166/366/174 256/526/334 1810 rs1333040 T 22073404 2663/5065/ 477/1095/666 80/225/172 55/263/232 190/588/369 63/253/230 101/364/230 159/520/427 2525 rs10738607 G 22078094 1502/2326/ 558/1099/547 131/244/116 105/278/173 332/603/312 114/283/186 187/373/137 261/552/312 933 rs4977574 G 22088574 1507/2335/ 554/1105/556 130/246/119 103/286/180 332/597/325 115/274/188 187/383/144 267/549/316 964 rs6475608 C 22091702 235/980/ 170/870/1059 36/200/250 26/199/342 101/476/616 24/210/330 58/276/353 67/415/588 1135 rs2383207 G 22105959 3038/5050/ 535/1130/579 105/250/127 86/274/197 273/603/381 100/270/206 156/377/176 230/535/353 2164 rs1333045 C 22109195 610/1264/ 433/1102/655 115/262/114 95/289/180 286/605/347 93/290/200 159/378/169 218/548/345 638 rs1333046 A 22114123 1519/2266/ 583/1078/554 123/244/120 102/274/181 315/586/330 114/273/191 182/378/154 251/539/323 959 rs10757278 G 22114477 816/1235/ 573/1099/537 137/254/103 116/281/169 341/618/287 119/291/175 189/370/134 261/545/304 446 rs1333048 C 22115347 1372/2202/ 473/947/478 119/247/120 99/274/184 210/418/231 108/286/188 175/379/154 247/532/325 926 ^aBase-pair location in NCBI Build 34.

TABLE-US-00027 TABLE 23 Primers in the AF109294 gene and ESTs used for PCR screening of cDNA libraries (Forward primers: SEQ ID NOs: 95-102; Reverse primers SEQ ID NOs: 103-110). ESTs* Forward primer Reverse primer AF109294 TTGGTGTCCATGCTGTGATGATT GGTTGGGGACCCCTGGTGTA CN277071 GGTTCAAGCATCACTGTTAGGTGT GAGGCGGGCGAATCACGA AW169296 GCTCAGAGCAATTCCAGTGCAAG GGTTCCAGTCCTGGTTCTGC BX100299 TCTCATTGGGGATACGAAGCTCT TCTGGCCCTAGCCTCCATGT ESTs* Nested forward primer Nested reverse primer AF109294 AACTCCAAAGAAACCATCAGAGG TGGGGACCCCTGGTGTAGTG CN277071 CTTTCCCGAGTCAGTACTGCTTTCT CGGGCGAATCACGAGGTC AW169296 TTCCAGTGCAAGTATGGTCTGTGA CCAGTCCTGGTTCTGCCACA BX100299 TCATTGGGGATACGAAGCTCTACA CAGAAAGCTGCAAAGGCCTCA ESTs* names are from NCBI Build 36.

TABLE-US-00028 TABLE 24 Expression analysis of ESTs and AF109294 in various cDNA libraries by PCR screening cDNA libraries Cardiac Endothelial Whole EBV transf. Whole fibro- Ventricular cells ESTs blood lymphoblasts heart Aorta myocytes fibroblasts (HUVEC) AF109294 positive nd nd positive positive nd nd CN277071 positive positive nd positive positive positive positive AW169296 positive positive positive positive positive positive positive BX100299 positive positive nd positive positive positive positive nd: not detected. positive: generated PCR products that were confirmed by sequencing

TABLE-US-00029 TABLE 25 Primers used for sequencing of CDKN2A and CDKN2B (Forward primers: SEQ ID NO: 111-148; Reverse primers SEQ ID NOs: 149-186). Primer alias Forward primer Primer aliasReverse primer CDKA.1e-f.F AAAGAAGCCAGACACGGAAG CDKA.1e-f.R GTAACTGAATCCAGCCAACC CDKA.1f.F GGATGAGGCAGCGTGGAC CDKA.1f.R AAGCCGTGTCTCAAGATCG CDKA.1g.F TCCGGTTTGGCAGCAGTC CDKA.1g.R CTAGCAAATGGCAGAACCA CDKA.1h.F CAACAGTGTCAGAAACGATGC CDKA.1h.R ATCAGTCACCGAAGGTCCTA CDKA.3b.F CTTGATCTCCCAAAGTGAAGG CDKA.3b.R CGACTCTGGAGGACGAAGTT CDKA.4d.F AGATCTCGGAACGGCTCT CDKA.4d.R GAGGCGTGCAGCGGTTTA CDKA.4e.F GGAAGAAAGGAAAGCGAGGT CDKA.4e.R CGGGATCAAGGGGAGTCG CDKA.4f.F TCCTCGCGTAGAATGGTTGT CDKA.41.R AGCCCGCGAGGTTTAGGAC CDKA.4g.F CCTGAGCGCGGTCTAAGC CDKA.4g.R CGTTTTGTCTTGGGTTTGTACC CKDN2A.1.F CCCCTTCAGATCTTCTCAGC CKDN2A.1.R AGCACCGGAGGAAGAAAGAG CKDN2A.2.F CCCGCACCTCCTCTACCC CKDN2A.2.R AGTGAACGCACTCAAACACG CKDN2A.3.F TTGGCAAGGAAGGAGGACTG CKDN2A.3.R TACCAGGCAATGTACACGTC CKDN2A.4.F GGTTCACTAAGTCAGAAACCCTAGT CKDN2A.4.R AGCTTAGGATGTGTGGCACT CKDN2A.5.F AGTCTTCATTGCTCCGCAGT CKDN2A.5.R GACACGCTGGTGGTGCTG CKDN2A.6.F ATCTATGCGGGCATGGTTAC CKDN2A.6.R ACAGTGCTCTCTGCCTGTGAC CKDN2A.7.F CAAAATGCTTGTCATGAAGTCG CKDN2A.7.R GTGAAGCCATTGCGAGAA CKDN2A.8.F TTTCAATCGGGGATGTCTGC CKDN2A.8.R CCACTGAGACTCATTATATAACACTCGTT p14.1.F ATTCCCACCCAGGATATTCG p14.1.R GGTCCCAGTCTGCAGTTAAG p14.2.F CTGCGCACCATGTTCTCG p14.2.R CGAGCAGCACCAGAATCC CDKB.06.F CCCTACTGACTATTACATATCAATGC CDKB.06.R CAGAAAATTAAATATACCTGTTAAGTTCG CDKB.07.F TTTTAACCATTTAAGGCATAGGA CDKB.07.R GCAAACCTCAAACATTATTGG CDKB.08.F CTGCTGATGAAACAGCTAAACC CDKB.08.R GCACTCAATCATTAGAGGCTACA CDKB.09.F TCTTGGAATTTAAGATATAGAGGTCAA CDKB.09.R TGCACAAAGAAGTGCATCTAGT CDKB.10.F GTTAGAGAAAGAAAAGCCACCTTAG CDKB.10.R ACAAGTCATTTGAGAGTGGAGAC CDKB.11.F AACATATGCTCTGATTCTCAACTAAC CDKB.11.R GGGATTTAATTTCCAGGGTTG CDKR.12.F CAAACATTGAGAGAAGGGAACC CDKB.12.R GGAAGAACTACAGCTCTTAAATGTAGC CDKB.13.F TCTGCACCCTGAGACACTCTA CDKB.13.R GGAGACCCTCGCCCAACT CDKB.14.F TAAGAGCAAAGGCCAGCATCC CDKB.14.R CACTCACCATGAAGCGAAAC CDKB.15.F TAATCACTGCCTTCTCCCACTC CDKB.15.R GGAGGGCTTCCTGGACAC CDKB.16.F GGGTGGGAAATTGGGTAA CDKB.16.R GGAAAGTGGATTGCATCAGC CDKB.17.F GGCAGGTATGGGAGATGC CDKB.17.R TCTCCCCTAAACCATTACTCC CDKB.23.F ACAATACAACAGATTTCATATAGTAGCTTAG CDKB.23.R TAGTGGAGAAGGTGCGACAG CDKB.24.F TAGGTTCCAGCCCCGATCC CDKB.24.R GGCTGGCTCCCCACTCTG CDKB.25.F TTCCTGGCGCTCAAGAACC CDKB.25.R CACAAGGGAGCCACCAAC CDKB.26.F CACTGCCCTCAGCTCCTA CDKB.26.R CCTGACAAAGTGGGTTTAAATAGGT CDKB.27.F TGCATTATGGATACAACCCTTA CDKB.27.R TCTTCCTCAGCACTCCGAAC CDKB.28.F CGGATGCTACATTGGATAGG CDKB.28.R GGCTCAAGAATTGGGTCA CDKB.a29.F GAAGGGAACCGGGTAGCA CDKB.a29.R CCATAATGTCCTTTCTATTTGACG

TABLE-US-00030 TABLE 26 Sequencing variants in CDKN2A and CDKN2B. Shown are all SNPs identified through sequencing of CDKN2A and CDKN2B for 93 early onset MI cases using primers in Table 25. Many of the SNPs identified in the sequencing effort are rare, and have low correlation with rs10757278. These SNPs cannot account for the correlation of rs10757278 to the disease. Two common SNPs, rs3217992 and rs2069416 have modest correlation with rs10757278 (r² = 0.36 and 0.37 respectively). rs3217992 is a part of the Illumina Hap300 chip. For Iceland A, rs10757278 gave a P value of 1.5 × 10^-7, while rs3217992 gave a P value of 5.4 × 10^-4. Hence rs3217992 cannot account for the association of rs10757278. Neither can rs2069416 since it is highly correlated with rs3217992 (r² > 0.8 both in HapMap CEU and Iceland). SNP rs1063192, which has r² of 0.23 with rs10757278 in these sequenced individuals, is also an Illumina SNP and did not even show nominal significance in Iceland A (P > 0.05). Rs2069418 is highly correlated with rs1063192. MAF^a A a Position^b Position^d rs names D'^c r²c Location CDKN2A 0.069 A G 21958159 38013 rs3088440 0.5 0.02 Exon3 0.176 C G 21958199 38053 rs11515 0.44 0.03 Exon3 0.005 C T 21960674 40528 1 0 Intron2 0.042 T C 21960916 40770 rs3731249 1 0.04 Exon2 0.005 A G 21961188 41042 1 0 Exon2 0.01 G C 21964859 44713 rs1800586 1 0.01 Exon1 0.356 C T 21965017 44871 rs3814960 0.18 0.02 5'UTR 0.042 A T 21965319 45173 SG09S293* 1 0.04 5'UTR 0.036 T C 21965561 45415 rs3731238 1 0.03 5'UTR 0.057 A C 21965807 45661 SG09S291* 0.49 0.01 5'UTR 0.094 C T 21983964 63818 rs2811711 0.42 0.02 5'UTR CDKN2B 0.005 A G 21957014 36868 1 0.01 3'UTR 0.01 A G 21957207 37061 1 0.01 3'UTR 0.01 G T 21957291 37145 1 0.01 3'UTR 0.005 C A 21957479 37333 1 0.01 3'UTR 0.005 G C 21957838 37692 1 0.01 3'UTR 0.071 A G 21958159 38013 0.33 0.01 3'UTR 0.38 G A 21964218 44072 rs3731239 0.41 0.13 3'UTR 0.005 G C 21964355 44209 1 0.01 3'UTR 0.01 G T 21985044 64898 1 0.01 3'UTR 0.005 T C 21985467 65321 1 0.01 3'UTR 0.323 T C 21985882 65736 rs2518723 0.29 0.07 3'UTR 0.422 T C 21993223 73077 rs3217992 0.78 0.36 Exon2 0.398 G A 21993367 73221 rs1063192 0.53 0.23 Exon2 0.005 C A 21993417 73271 1 0 Exon2 0.005 C T 21993591 73445 1 0.01 Exon2 0.078 G T 21995330 75184 rs3217986 0.58 0.03 Exon2 0.005 C G 21995493 75347 rs3217984 1 0.01 Exon2 0.104 T G 21996273 76127 rs2069426 0.08 0 Intron1 0.005 A G 21996303 76157 1 0.01 Intron1 0.104 T C 21996348 76202 rs974336 0.08 0 Intron1 0.005 G A 21996536 76390 1 0.01 Intron1 0.382 G C 21999698 79552 rs2069418 0.55 0.23 5'UTR 0.011 G A 21999915 79769 1 0.01 5'UTR 0.005 T C 21999953 79807 1 0.01 5'UTR 0.1 del A 21999996 79850 rs2069417 0 0 5'UTR 0.395 A T 22000004 79858 rs2069416 0.8 0.37 5'UTR 0.089 G A 22000412 80266 rs495490 0.03 0 5'UTR 0.021 A G 22000681 80535 SG09S492* 1 0.02 5'UTR 0.005 C G 22001083 80937 1 0.01 5'UTR 0.005 C G 22001158 81012 1 0.01 5'UTR ^aMAF: minor allele frequency. ^bBase-pair location in NCBI Build 34. ^cCorrelation to the refinement SNP rs10757278 based on the 93 sequenced MI cases. ^dPosition in SEQ ID NO: 94 (LD Block C09). *Alternate names used herein for non-public SNPs

TABLE-US-00031 TABLE 27 SNPs in conserved TF bindings sites within the MI region. SNP TF binding site LD to rs1333040 Name Location TF Name Start End D' r² P rs16935754 22002235 PAX2 22002234 22002253 nd nd nd rs35113513 22023540 FOXO4 22023540 22023551 nd nd nd rs35834365 22023550 FOXO4 22023540 22023551 nd nd nd rs17694493 22031997 STAT 22031995 22032004 0.41 0.05 0.03 rs1412830 22033611 FOXO4* 22033601 22033615 nd nd nd rs1412830 22033611 FOXO3* 22033601 22033615 nd nd nd rs4977758 22108480 EVI1 22108480 22108496 nd nd nd rs34974971 22126835 EVI1 22126830 22126839 nd nd nd rs6475610 22131893 AREB6 22131892 22131905 0.11 0.01 0.36 rs10757289# 22150453 MRF2 22150444 22150458 0.14 0.02 0.22 rs10757289# 22150453 SEF1 22150452 22150471 0.14 0.02 0.22 rs1679013 22196986 BACH1 22196977 22196992 0.01 0 0.96 rs1679014 22197036 PAX6 22197025 22197046 0.21 0 0.57 rs10965296 22205659 GATA6 22205657 22205667 1 0.01 0.31 rs7043085 22323165 OCT1 22323163 22323176 nd nd nd rs1969926 22347344 SOX9 22347334 22347348 nd nd nd rs10113901 22364031 HNF1 22364024 22364039 0.06 0 0.64 rs7046709 22366969 MEF2 22366953 22366975 0.13 0.01 0.34 All coordinates are for human genome release 17 (build 35). *Two related TFs recognize the same motif. #A SNP lands in two partially overlapping TF binding sites. LD between SNPs and the rs1333040 is summarized by D', r² and a P value determined by Chi-square tests the CEU hapmap sample. nd: Measures of LD could not be ascertained for SNPs not represented in the CEU hapmap.

TABLE-US-00032 TABLE 28 Shown are all SNP association results from sequencing of CDKN2A and CDKN2B using primers in Table 25 and association results for early onset MI cases and controls. location^a rs names Allele RR #aff aff. freq #con con. freq p-value Variation* 21958159 rs3088440 A 0.7264 118 0.080508 674 0.107567 0.194719 G/a 21958199 rs11515 C 1.0349 118 0.161017 668 0.156437 0.858926 G/c 21960916 rs3731249 T 1.4053 119 0.037815 680 0.027206 0.384391 C/t 21964218 rs3731239 A 1.0712 96 0.619792 87 0.603448 0.748662 A/g 21965017 rs3814960 C 0.8697 118 0.347458 686 0.379738 0.34197 T/c 21965319 SG09S293 A 1.4498 119 0.037815 682 0.026393 0.344886 T/a 21965561 rs3731238 T 1.2498 120 0.033333 689 0.026851 0.582384 C/t 21965807 SG09S291 A 1.7884 120 0.058333 687 0.033479 0.077647 C/a 21983964 rs2811711 C 0.8364 119 0.088235 675 0.103704 0.458559 T/c 21985882 rs2518723 T 1.0818 65 0.323077 49 0.306122 0.784969 C/t 21993223 rs3217992 T 1.3279 96 0.421875 86 0.354651 0.188816 C/t 21993367 rs1063192 A 1.27 93 0.602151 80 0.54375 0.273278 A/g 21995330 rs3217986 T 1.1274 96 0.921875 86 0.912791 0.753194 T/g 21996273 rs2069426 T 1.0602 96 0.104167 86 0.098837 0.866531 G/t 21996348 rs974336 T 1.0078 96 0.104167 87 0.103448 0.982048 G/t 21999698 rs2069418 C 1.4107 93 0.61828 87 0.534483 0.107569 C/g 22000004 rs2069416 A 1.6529 93 0.387097 85 0.276471 0.026641 T/a/g 22000004 rs2069416 T 0.6509 93 0.569892 85 0.670588 0.050367 T/a/g 22000004 rs2069416 G 0.804 93 0.043011 85 0.052941 0.660944 T/a/g 22000412 rs495490 A 1.2051 95 0.910526 85 0.894118 0.600156 A/g 22000681 SG09S492 A 3.587 94 0.021277 83 0.006024 0.206723 G/a ^alocation applies to NCBI build 34. Allele: the allele shown is the one tested for association to myocardial infarction. RR is the relative risk. #aff: number of affected individuals. aff. freq: frequency of allele in affected individuals. #con: number of controls. con. freq.: frequency of allele in controls. Variation*: Shown are the alleles of the SNPs with major allele shown with capital letters.

TABLE-US-00033 TABLE 29 Association to atherosclerosis in other vascular beds. Shown is the association of the SNPs, rs1333040, rs2383207 and rs10116277 to peripheral artery disease (PAD), abdominal aorta aneurysm (AAA), and to large vessel disease stroke (LVD). Study population (n/m)^a Frequency Variant (allele) Controls Cases RR (95% CI) P Iceland PAD (1504/3533) rs1333040 (T) 0.499 0.503 1.01 (0.93-1.11) 0.75 rs2383207 (G) 0.462 0.481 1.08 (0.99-1.18) 0.082 rs10116277 (T) 0.421 0.438 1.07 (0.98-1.17) 0.12 Emory PAD (34/1284) rs1333040 (T) 0.573 0.721 1.92 (1.12-3.30) 0.017 rs2383207 (G) 0.541 0.692 1.91 (1.15-3.17) 0.012 rs10116277 (T) 0.504 0.676 2.06 (1.25-3.39) 0.0044 Iceland LVD (154/3533) rs1333040 (T) 0.499 0.527 1.12 (0.87-1.44) 0.39 rs2383207 (G) 0.462 0.488 1.11 (0.88-1.41) 0.38 rs10116277 (T) 0.421 0.457 1.16 (0.91-1.48) 0.24 Iceland AAA (287/3533) rs1333040 (T) 0.499 0.572 1.34 (1.12-1.60) 0.0012 rs2383207 (G) 0.462 0.536 1.35 (1.13-1.61) 0.00073 rs10116277 (T) 0.421 0.485 1.30 (1.09-1.54) 0.0035 ^aNumber of cases (n) and controls (m). ^bIndividuals used in the initial discovery group have been excluded both from cases and controls. .sup.CFor the combined groups, the allelic frequency in cases and controls is the weighted average over the individual groups.

TABLE-US-00034 TABLE 30 Association of refinement markers to MI, early-onset MI and AAA in Iceland. Shown is the association to MI, early-onset MI and AAA case-control groups for 10 of the markers included in Table 23b. All tests use the same set of 10260 controls. MI (2270/10260) Early onset MI (621/10260) SNP Allele Position Con. frq Case. frq OR P Con. frq Case. frq RR P rs10116277 T 22071397 0.419 0.471 1.23 3.2E-10 0.419 0.496 1.36 1.3E-07 rs1333040 T 22073404 0.493 0.541 1.21 6.7E-09 0.493 0.576 1.40 1.3E-08 rs10738607 G 22078094 0.441 0.497 1.25 8.4E-12 0.441 0.521 1.38 4.0E-08 rs4977574 G 22088574 0.444 0.499 1.25 2.0E-11 0.443 0.522 1.37 8.3E-08 rs6475608 C 22091702 0.683 0.709 1.13 1.7E-03 0.689 0.737 1.26 6.3E-04 D9S1870 X 22093010 0.440 0.490 1.22 2.5E-09 0.441 0.513 1.34 1.2E-06 rs2383207 G 22105959 0.458 0.511 1.24 6.5E-11 0.458 0.535 1.36 1.4E-07 rs1333045 C 22109195 0.503 0.551 1.21 2.0E-08 0.506 0.575 1.32 3.5E-06 rs1333046 A 22114123 0.439 0.494 1.24 4.6E-11 0.440 0.518 1.37 8.3E-08 rs10757278 G 22114477 0.435 0.492 1.26 2.8E-12 0.434 0.518 1.40 1.2E-08 AAA (323/10260) CAD^a (508/10260) SNP Allele Position Con. frq Case. frq RR P Con. frq Case. frq RR P rs10116277 T 22071397 0.419 0.488 1.32 6.0E-04 0.419 0.456 1.16 0.024 rs1333040 T 22073404 0.493 0.579 1.41 2.7E-05 0.493 0.519 1.11 0.130 rs10738607 G 22078094 0.441 0.522 1.38 5.8E-05 0.441 0.474 1.14 0.043 rs4977574 G 22088574 0.444 0.527 1.39 3.8E-05 0.443 0.474 1.13 0.056 rs6475608 C 22091702 0.693 0.752 1.35 1.8E-03 0.695 0.722 1.14 0.110 D9S1870 X 22093010 0.441 0.507 1.31 1.2E-03 0.441 0.471 1.13 0.073 rs2383207 G 22105959 0.458 0.537 1.38 7.4E-05 0.458 0.487 1.13 0.068 rs1333045 C 22109195 0.508 0.580 1.34 4.2E-04 0.508 0.554 1.20 0.007 rs1333046 A 22114123 0.442 0.528 1.42 1.7E-05 0.440 0.472 1.14 0.053 rs10757278 G 22114477 0.436 0.522 1.41 1.8E-05 0.435 0.474 1.17 0.016 ^aKnown cases of MI are excluded from the CAD cases. ^bFor the microsatellite D9S1870, all alleles smaller than 2 have been combined in to a composite risk allele X.

TABLE-US-00035 TABLE 31 Amplimers for non-public SNPs identified in table 26. SG09S293 (SEQ ID NO: 199) GGAAGCAGCCCTCGCCAGAGCCAGCGTTGGCAAGGAAGGAGGACTGGGCTCCTCCCCACCTGCCCCCCACACCG- C CCTCCGGCCTCCCTGCTCCCAGCCGCGCTCCCCCGCCTGCCAGCAAAGGCGTGTTTGAGTGCGTTCACTCTGTT- A AAAAGAAATCCGCCCCCGCCCCGTTTCCTTCCTCCGCGATACAACCTTCC[T/a]AACTGCCAAATTGAATCGG- G GTGTTTGGTGTCATAGGGAAAGTATGGCTTCTTCTTTTAATCATAAGAAAAAGCAAAACTATTCTTTCCTAGTT- G TGAGAGCCCCACCGAGAATCGAAATCACCTGTACGACTAGAAAGTGTCCCCCTACCCCCTCAACCCTTGATTTT- C AGGAGCGCGGGGTTCACTAAGTCAGAAACCCTAGTTCAAAGGA SG09S291 (SEQ ID NO: 200) ATTGGAAGGACGGACTCCATTCTCAAAGTCATAATTCCTAGACCAGAAAAAGTGCTCAGTGTTCTAGAAGCAGA- G TTG[C/a]ACAGTGATCCAAAGACCAGCTTCAAATACTGTCCTGTCTCCTTCACACTTCTCACATTTCTCTTTC- C TACTGAAAATACCTTGCATTTTTCGTAATTATAAAGGGGGAAGGGAATATGAGTGCCCCCTGCTTTATAGGGGT- T GTTGTGAGTTTAAATGATGTATTAATACATATAAGCCTTAAGAACAGTGCCACACATCCTAAGCTAATACCTGT- T AGCTCTTGAATTATCCGCTTTGAGGACTGGCTTGCAATCTTGTTTTGAGGCATAGAAAGAAAATGCTTTGGAGC- A GGACGCGGTGGCTCACACCTGTAATCCCAGCACTTTGGGAAGCCGAGGCGGGCA SG09S492 (SEQ ID NO: 201) TGAATCAACATTTATTACTTAAAATATTTAAAACATTTCAGCGGATGCTACATTGGATAGGAAGAGAACCGCAA- G TTATGGATTTGTTGCCTAAAAACTTTGGTGAGGAACTGCATAAGTGGACCTCTCCTAAAAGTGAACAaTTTTTG- T TTACAGAATCATTTTGGTTCGGAGTGCTGAGGAAGACAAAGTCTTAACAGGAGGGCAATTGCTTGTGTATTGCA- A AATGAGAGTCTTCACATGTTTTTTTTAGGATACCTTAGCTCTGACTCCTCATCCCCCAAATCCCTGTAGAATTA- A AAAAAgCTCTTTCTTTTAAAGGCAGTGGAAGTGCCACCACCATGGAAGTGCTGGTTAGGGCTGAAAATCTACTG- A CAGAGCCTCAACAGAGCTGAAATCCACCTGGACAGG[G/a]AAGGGAACCGGGTAGCATTAATAACAATTTCTT- T TTCTTTCCCATCCAACCCCCATTTCCTAGTCTTCAGTTTCTTAATTTCTCTACCTTTTACTCTTATGCTCTTGT- T TTGACCTTTGAGTTTCTCTGAAACTTATCAGAAAAGTTAGGACAAGATAGTCTGACCCAATTCTTGAGCCATTT- T CTTAGGTAGTAAATATGTCAGAAAAATGAAAGCTGTTTGGAGTTGATAAGGAAATGGAAGATAATGTTTTTCTT- T GAGGGgGACATAAAGAATGGTGATAGGGAAAGAACCAATGACTAAGTAAAATGACTGAGAATCTTGCACGAGGC- A GATGTGTGAGCTTCGCGAAGCAAGTTGACTGAATGAAAAACAACTTTGGGTAGGGAAAACGTTGCCGGGGGCAT- T CGC

TABLE-US-00036 TABLE 32 Association between rs10757278 allele G and arterial diseases Phenotype Frequency Study population (n/m) Controls Cases OR (95% CI) P Abdominal Aortic Aneurysm (AAA) Iceland (14259/398) 0.437 0.515 1.37 (1.18-1.58) 2.6 × 10^-5 Belgium (267/176) 0.527 0.574 1.21 (0.92-1.58) 0.18 Canada (150/206) 0.470 0.533 1.29 (0.96-1.74) 0.097 Pennsylvania, US (447/101) 0.468 0.549 1.39 (1.02-1.89) 0.037 The Netherlands (915/476) 0.461 0.529 1.31 (1.12-1.53) 0.00078 UK (252/478) 0.470 0.545 1.35 (1.09-1.68) 0.0064 New Zealand (442/588) 0.474 0.530 1.25 (1.05-1.50) 0.012 All groups (16732/2836) 1.31 (1.22-1.42) 1.2 × 10^-12 Intracranial Aneurysm (IA) Iceland (14259/170) 0.437 0.514 1.36 (1.10-1.69) 0.0048 The Netherlands (915/644) 0.461 0.516 1.24 (1.08-1.43) 0.0029 Finland (307/320) 0.400 0.469 1.33 (1.06-1.66) 0.015 All groups (15481/1134) 1.29 (1.16-1.43) 2.5 × 10^-6 Peripheral Artery Disease (PAD) Iceland (14259/1764) 0.437 0.473 1.16 (1.07-1.25) 0.00014 Italy (181/179) 0.510 0.499 0.96 (0.71-1.29) 0.78 Sweden (143/206) 0.427 0.507 1.38 (1.02-1.87) 0.036 New Zealand (463/450) 0.474 0.491 1.07 (0.89-1.29) 0.47 All groups (15025/2599) 1.14 (1.07-1.22) 6.1 × 10^-5 LAA/Cardiogenic Stroke Iceland (14259/415) 0.437 0.473 1.16 (1.00-1.34) 0.046 Sweden (734/290) 0.433 0.468 1.15 (0.95-1.39) 0.16 All groups (15012/705) 1.15 (1.03-1.29) 0.015 Coronary Artery Disease (CAD)^a Iceland (14259/3051) 0.437 0.492 1.25 (1.17-1.32) 1.9 × 10^-12 Atlanta (1246/840) 0.479 0.544 1.30 (1.15-1.48) 0.000033 Philadelphia (447/724) 0.467 0.547 1.38 (1.17-1.63) 0.00017 Durham (614/1201) 0.455 0.521 1.30 (1.13-1.50) 0.00018 All groups (16566/5539) 1.28 (1.22-1.34) 1.2 × 10^-23 Association results for rs10757278 allele G for the arterial diseases: AAA, IA, PAD, combined LAA (Large Artery Atherosclerotic)/cardiogenic stroke, and CAD, and for T2D, in several study populations. Also included are the results for each phenotype after combining the study populations using a Mantel-Haenszel model. Number of controls (n) and cases (m) is shown. The results for the Icelandic population are adjusted for relatedness of the individuals. ^aThe results presented for CAD have been published previously ¹(apart from the Icelandic control group that has been increased) and are presented here for comparison of the results with the other arterial phenotypes.

TABLE-US-00037 TABLE 33 Association between rs10757278 allele G and arterial diseases after excluding known CAD cases from the sample sets Phenotype Frequency Study population (n/m) Controls Cases OR (95% CI) P Abdominal Aortic Aneurysm (AAA) Iceland (14259/190) 0.437 0.503 1.30 (1.06-1.60) 0.013 Belgium (267/156) 0.527 0.573 1.20 (0.91-1.60) 0.200 Pennsylvania, US 0.469 0.513 1.19 (0.82-1.74) 0.36 (447/62) The Netherlands 0.461 0.517 1.25 (1.06-1.48) 0.0097 (915/380) UK (252/220) 0.470 0.538 1.31 (1.02-1.70) 0.038 New Zealand 0.474 0.516 1.18 (0.97-1.44) 0.097 (442/360) All groups 1.25 (1.14-1.37) 3.0 × 10^-6 (16639/2017) Peripheral Artery Disease (PAD) Iceland (14259/732) 0.437 0.463 1.12 (1.00-1.25) 0.055 Italy (181/113) 0.509 0.488 0.92 (0.66-1.28) 0.62 New Zealand 0.474 0.491 1.07 (0.87-1.31) 0.51 (463/326) All groups 1.09 (0.99-1.20) 0.075 (14882/1171) LAA/Cardiogenic Stroke Iceland (14259/278) 0.437 0.458 1.09 (0.92-1.30) 0.32 Sweden (734/213) 0.433 0.467 1.15 (0.92-1.42) 0.22 All groups 1.11 (0.97-1.27) 0.12 (14993/491) Association results are shown for rs10757278-G for the arterial diseases: AAA, IA, PAD, combined LAA (Large Artery Atherosclerotic)/cardiogenic stroke, after excluding cases with known CAD. Number of controls (n) and cases (m) is shown. The results for the Icelandic population are adjusted for relatedness. No information on CAD was available for the AAA group from Canada and the PAD group from Sweden. Those study groups were excluded from this analysis. Information on the occurrence of CAD among the AAA cases was available for 97% (466 out of 479) of AAA cases from UK, 86% (87 out of 101) of cases from Pennsylvania, 45% (79 out of 176) of cases from Belgium, 69% (330 out of 476) of cases from The Netherlands, and 98% (575 out of 588) of cases from New Zealand. Among those with this information, the frequency of CAD amongst the AAA subjects was 52% in the UK group, 48% in the Pennsylvania group, 29% in the Belgium group, 29% in the Dutch group and 40% in the group from New Zealand.

TABLE-US-00038 TABLE 34 Genotype specific odds ratio for rs10757278 for abdominal aortic aneurysm and intracranial aneurysm Genotype Specific Odds Ratio Study population (n/m) AA AG (95% CI) GG (95% CI) Abdominal Aortic Aneurysm (AAA) Iceland (14259/398) 1 1.22 (0.95-1.56) 1.85 (1.39-2.45) Belgium (267/176) 1 1.42 (0.91-2.20) 1.52 (0.87-2.66) Canada (150/206) 1 1.04 (0.69-1.57) 1.62 (0.90-2.91) Pennsylvania, US (447/101) 1 2.00 (1.17-3.44) 2.06 (1.06-4.03) The Netherlands (915/476) 1 1.43 (1.12-1.84) 1.76 (1.28-2.43) UK (252/478) 1 1.60 (1.19-2.15) 1.95 (1.26-3.03) New Zealand (442/588) 1 1.22 (0.94-1.58) 1.50 (1.04-2.17) Combined (16732/2836) 1 1.36 (1.21-1.52) 1.74 (1.49-2.02) Intracranial Aneurysm (IA) Iceland (14259/170) 1 1.39 (0.96-2.02) 1.90 (1.24-2.93) The Netherlands (915/644) 1 1.34 (1.08-1.66) 1.61 (1.20-2.16) Finland (307/320) 1 1.45 (1.06-1.98) 1.79 (1.12-2.86) Combined (15481/1134) 1 1.38 (1.18-1.63) 1.72 (1.39-2.13) Genotype specific odds ratios for rs10757278 for AAA and IA cases versus controls. Shown is the risk for heterozygous carriers (AG) and homozygous carriers (GG) compared to the risk for non-carriers (AA), together with 95% confidence intervals (CI). Results are shown for the AAA case-control groups from Iceland, Belgium, Canada, Pennsylvania, US, UK, The Netherlands and New Zealand and for all the groups combined and for the IA case-control groups from Iceland, The Netherlands and Finland. Number of controls (n) and cases (m) is shown. Tests of heterogeneity showed no significant difference in the genotype specific odds ratio between the different study groups For AAA, P_het = 0.38 and P_het = 0.95 for the AG and the GG genotype, and for IA, P_het = 0.91 and P_het = 0.81.

TABLE-US-00039 TABLE 35 Correlation between growth rate of AAA and genotypes for rs10757278 from the UK Small Aneurysm Trial Linear Genotype of Mean baseline growth rate Mean difference rs10757278 n diameter (mm) (mm/year) (95% CI) AA 79 45.3 3.20 0.03 (-0.38-0.41) AG 214 44.8 3.15 reference GG 107 44.7 2.53 -0.46 (-0.93-0.00) Linear growth rates were determined as previously described¹⁶. At least three AAA diameter measurements and growth rate were available for 400 patients who had been genotyped for rs10757278 and n is the number of individuals with the different genotypes. The largest group (AG) was set as the reference group and then the growth rates in the other genotype groups were compared with the mean of the reference group. This leads to estimation of the mean difference [95% CI] of the growth rates in the homozygous groups. The analysis of the average difference was adjusted for age, sex, smoking status, baseline diameter and curvature in growth pattern. In this cohort there were 24 ruptured AAA; 6 with the AA genotype, 14 with AG, and 4 with GG.

TABLE-US-00040 TABLE 36 Association of SNPs in chromosome 9p21 region to MI in African-Americans. We tested 9 SNPs for association with MI in African Americans. These SNPs included 2 SNPs from the genome-wide scan on MI in Icelanders (rs10116277 and rs2383207) and rs10757278, which showed strongest association with MI in Caucasians, as well as six other SNPs that were correlated with rs10757278 in Caucasians. As shown in the Table all, SNPs have greater frequency in cases compared to the control groups and the odds ratios are comparable to that for Caucasians. Combined^a Philadelphia (93/139) Durham (262/243) SNP Allele Position RR (95CI) Pa Con. frq Case. frq OR P Con. frq Case. frq RR P rs8181050 A 22054391 1.30 (0.91-1.86) 0.14 0.921 0.920 0.99 0.98 0.912 0.926 1.20 0.43 rs10116277 T 22071397 1.37 (1.05-1.80) 0.022 0.889 0.893 1.05 0.89 0.870 0.901 1.35 0.13 rs10738607 G 22078094 1.12 (0.92-1.35) 0.27 0.238 0.290 1.31 0.22 0.233 0.254 1.12 0.43 rs4977574 G 22088574 1.20 (0.97-1.48) 0.096 0.175 0.250 1.57 0.051 0.184 0.204 1.13 0.430 rs2383207 G 22105959 1.34 (1.03-1.74) 0.027 0.881 0.877 0.96 0.88 0.872 0.906 1.43 0.078 rs1333045 C 22109195 1.22 (1.04-1.43) 0.014 0.455 0.497 1.18 0.38 0.472 0.525 1.24 0.093 rs1333046 A 22114123 1.19 (0.99-1.44) 0.069 0.227 0.294 1.42 0.11 0.257 0.291 1.18 0.24 rs10757278 G 22114477 1.19 (0.98-1.45) 0.08 0.183 0.257 1.54 0.059 0.194 0.223 1.20 0.250 rs1333048 C 22115347 1.16 (0.96-1.40) 0.12 0.277 0.301 1.13 0.57 0.288 0.321 1.17 0.25 Cleveland (46/81) Atlanta (91/357) SNP Allele Position Con. frq Case. frq RR P Con. frq Case. frq RR P rs8181050 A 22054391 0.887 0.913 1.34 0.51 0.934 0.967 2.08 0.075 rs10116277 T 22071397 0.856 0.891 1.39 0.41 0.886 0.934 1.82 0.049 rs10738607 G 22078094 0.228 0.244 1.09 0.77 0.226 0.220 0.97 0.87 rs4977574 G 22088574 0.160 0.163 1.02 0.95 0.173 0.187 1.10 0.68 rs2383207 G 22105959 0.877 0.880 1.04 0.93 0.888 0.945 2.18 0.015 rs1333045 C 22109195 0.416 0.435 1.08 0.78 0.473 0.544 1.33 0.094 rs1333046 A 22114123 0.204 0.213 1.06 0.86 0.240 0.258 1.10 0.61 rs10757278 G 22114477 0.160 0.152 0.94 0.86 0.187 0.198 1.07 0.74 rs1333048 C 22115347 0.251 0.304 1.30 0.37 0.283 0.303 1.10 0.61 ^aResults for the four African-American cohorts are combined using a Mantel-Haenzsel model. Shown is the association to MI in four African-American MI case-control groups for 9 markers in the chromosome 9p21LD-block (LD Block C09). These SNPs are correlated in Caucasians. The markers include 2 SNPs from the genome-wide scan (rs10116277 and rs2383207) and rs10757278 that showed strongest association with MI in Caucasians, and six other correlated SNPs.

TABLE-US-00041 TABLE 37 Key to sequence listing. Sequence SEQ ID NO: rs7041637 1 rs3218020 2 rs3217992 3 rs1063192 4 rs2069418 5 rs2069416 6 rs573687 7 rs545226 8 rs10811640 9 rs10811641 10 rs2106120 11 rs2106119 12 rs643319 13 rs7044859 14 rs10757264 15 rs10965212 16 rs1292137 17 rs10811644 18 rs7035484 19 rs10738604 20 rs615552 21 rs543830 22 rs1591136 23 rs7049105 24 rs679038 25 rs10965215 26 rs564398 27 rs10115049 28 rs634537 29 rs2157719 30 rs2151280 31 rs1008878 32 rs1556515 33 rs1333037 34 rs1360590 35 rs1412829 36 rs1360589 37 rs7028570 38 rs944801 39 rs10965219 40 rs7030641 41 rs10120688 42 rs2184061 43 rs1537378 44 rs8181050 45 rs8181047 46 rs10811647 47 rs1333039 48 rs10965224 49 rs10811650 50 rs10811651 51 rs4977756 52 rs10757269 53 rs9632884 54 rs1412832 55 rs10116277 56 rs10965227 57 rs6475606 58 rs1333040 59 rs1537370 60 rs7857345 61 rs10738607 62 rs10757272 63 rs4977574 64 rs2891168 65 rs1537371 66 rs1556516 67 rs6475608 68 rs7859727 69 rs1537373 70 rs1333042 71 rs7859362 72 rs1333043 73 rs1412834 74 rs7341786 75 rs10511701 76 rs10733376 77 rs10738609 78 rs2383206 79 rs944797 80 rs1004638 81 rs2383207 82 rs1537374 83 rs1537375 84 rs1333045 85 rs10738610 86 rs1333046 87 rs10757278 88 rs1333047 89 rs4977575 90 rs1333048 91 rs1333049 92 rs1333050 93 LD Block C09 94

Sequence CWU 1

2011201DNAHomo sapiens 1tttcgcaatg cttattttca atttcttcag aaatgcctta aagatattaa tggaggtaac 60aacttaatct caaatagtaa tccatagaca gaatatgtaa magcaatgtt ctctgatctg 120ttctttggct tctattccct agagaaatag ttctctaaga ccaaacagtc tatagataga 180attgtagcaa cagtcaatta t 2012201DNAHomo sapiens 2gtggagagaa aatgattata ctttgagcta tatggctcca ataaacaaag atagatccct 60caatttaaat ttgatcctca gaaaactgag ggtcagagaa yccctcaggc atgacgggat 120aatgtgacag ttaatttggt atgtcaactt ggctaggctg tggtacccag tgtttgagtc 180aaacaccagt ctaaatattg c 2013201DNAHomo sapiens 3agtactatat tacactgttt tttttgtttg ttttgttagt tttttttatt taaagcaaac 60ctcaaacatt attgggtatc aattaccacc tggttgtatt raaatagtaa cttatcaatg 120ccatgtaaaa attaattcca ttttcgaagc cacctggcag acaggtttag ctgtttcatc 180agcagcctaa tatatactgt t 2014201DNAHomo sapiens 4cattatactg ggtcatgaaa aattatccct tgaaatagat atgaaacatg ttacttcatt 60tctggtttaa ataacttgtg gaatctttcc taatgacaac ytgatattaa gggaaactaa 120agaaaatgtt attgtggatc ccacagtact atattacact gttttttttg tttgttttgt 180tagttttttt tatttaaagc a 2015201DNAHomo sapiens 5tgatacaagt tatgaaactt gtgaagccca agtactgcct ggggatgaat ttaacttgta 60tgacaggtgc agagctgtcg ctttcagaca tcttaagaaa sacggagtta ttttgaatga 120ctttctctcg gtcacaaggg agccaccaac gtctccacag tgaaaccaac tggctggctg 180aaggaacaga aatcctctgc t 2016201DNAHomo sapiens 6aaataaaaat aagatacctg acaaagtggg tttaaatagg taagagtgca aacaaagatt 60tactgtacaa atatgatgaa actgggatct cagattctta hagtataatt tttttttgtc 120ttatgtgtgc caggttgcca ctctcaatct cgaactagtt tttttctctt ttaagggttg 180tatccataat gcaaaaatgg a 2017201DNAHomo sapiens 7gtccaagaca aatgtgctat tgtattacat gtgaaatgtc atctttgaag tctggtaagg 60gtgtgctgtg aggtgagcca tctggaaaac acagtgtaga ytgaaaaata attataagcc 120agtttattac ttttttccag ttaagcctac catgacagct gctaaaaaaa acactatgta 180gtataaaggg taaaaagact c 2018201DNAHomo sapiens 8ggggtgcagg ttgttggtgt ggccacactt cttcttgcgg caattgacag cataggggtg 60caggagagca tagcgcttat ggcagatcat cttgtttcag ytgtatttct aggtgagctg 120gaagagtgaa ggctcaataa tgccacctcg caggtgcagc accaggtgcg gggtgggctg 180tttctggacg ttgtagtctg a 2019201DNAHomo sapiens 9tcttaatttt tacacatttt acttttcatt tctttttaaa ctgttattaa taatttattc 60atttgaataa ggattaaaat aaggctagga tattgaaatt ygttgaaatt gctacagtct 120cttgtatctc tctctctctc ttttttttct tataagggac aggtttcatt caccttgtcg 180accaggctgg agtgcaatac t 20110201DNAHomo sapiens 10tgtgattcta gcagccatgg ataattattt catagattat tattttcttg gggatggcaa 60aatggtgata ttctaatttt actattcctt catttactag stggaatgtc tttttaaatt 120atttatttat ttatttatta tttgagacag agtcttgcac tgtcacccag gctggagtgc 180agtggtgtga tcatagctca c 20111201DNAHomo sapiens 11tgcgcgcctc ggcctcccaa agtgctggga ttacaggcgt gagccactgc gcctcgccaa 60cttccttatt ttaaatgcca tttcccacta aaaataaaac magtaattct ttgaaaaaaa 120gttaatatta tgtataggac tggaagtata taagataaaa ctggaatata ttgtcatacc 180agaaatcaaa gattttgtca a 20112201DNAHomo sapiens 12attactgatg tgacaaggta cacaagccaa tgttgacata atgttttcaa aatggggtgt 60ctgctgtaac tgaactaaat ataataactt tattcaagaa ygagtttcaa tgataggaca 120aaacttgata aaatgaataa ataaataatt atatgccaga gttcagtaaa ccctgtgtgt 180acacctgaaa aagctcaaac t 20113201DNAHomo sapiens 13gaacagagca gaagagagtc tggatacaca aatttcacaa ttattggctc ccatcaacat 60atctaactca agcataaagt tgtttcagca gtagtttaag yttggttact aatgcaacac 120ctctttgcat gcaatggccc attaaattat cttcaacttt aaaaggttcc tttgttttta 180aatgcttata atgaacaaat a 20114201DNAHomo sapiens 14tatgtgatgt aaagagcgcc aacatgttta tatcctccta tttcaatcta cttttacttc 60atctacattt ttagcaataa tgtgaacatg aaatcttgaa waattagcta tctgtaatat 120atttactcat ccactcaaaa tattgagccc ccccaataaa tatcatacac tatattctag 180gtacaggtga taaacaattc a 20115201DNAHomo sapiens 15ccagtgaaag ttagagagag gggtctagag ctcagggagg agtgtgtatc cctaatttag 60actaatttgc attaacagct gtagtaatgc aattttctct rtactgaaat gcagacattt 120gagtatagaa aattagcaga catttgaata tagaagaaag atttactttc cttcagaaaa 180agaatagtag agtataaaga a 20116201DNAHomo sapiens 16tcgtgccact gcactccagc ctgggtgagt tgagagtccg tatcaaaagc aaacctacac 60atttttgtgg cctgttttta gctctatcaa gtcagttaca wtcttctgta ttctagcttt 120tttatctgta agctcctgca atgctttatt agaattttta gttcctttgc attttgttac 180aacatactcc tataactctg c 20117169DNAHomo sapiens 17taaaagaaaa aataatccaa atgtcagcaa cctcaaagat tgaaggtaga tgagcccaca 60aagataagaa ataatcagca caagaacact gaaaactcaa wacatcacct ctctggcaag 120cgttcagtac caggctgagg ctgagatggc tgaaatgata gaagcagaa 16918201DNAHomo sapiens 18caagaccact ctgcagatat caagtctgaa aattccccta gggccaaagt ctattatggg 60agcaagttga gcctagaggg atcgccatcc ctgtccatgc wctgctgtag acactcctgc 120actaaaccct ctgggctcca catcagctgg cttgctgctc taccactttg cttgtctctt 180gggggctcca ccccagagag a 20119201DNAHomo sapiens 19gtctcttggg ggctccaccc cagagagatg tgggtcagca atcattcagt tcaatcagcc 60caggatggag agtctgtgct atgggcccaa gccaggggct stctgtctgg tgacgagcag 120ctggggggtg gggtgggacc tgtgggagat ggactggcct cctctccttg agtcaactgc 180tgcttattgg aggtgtggat g 20120201DNAHomo sapiens 20ccattgcaga ggtagtggca gagaggcttt cagttgtccg tggcggctct gtccagggag 60ttgctgagtt gctattggct tgatatctct ggtggggtgt rgctagaggt ccaggcctgg 120aggacctgct cgttgaagag atgtgggaat gggcacccac ataacagtct gttcactttt 180ccatagggct gctgtagtat g 20121201DNAHomo sapiens 21ggggagctta agcaggggtg gaaggggaac cccagcacag aacagctgcc cgacaaaaat 60gtggccacac tgcttttttt ttttttttag caggtcccca rtcccgttcc tcatcactgg 120gtagagtctc ccatctgggg tccccggcta ccccaactgg tgttctctga ctgagagagg 180tttcagactt ccatgggacc t 20122201DNAHomo sapiens 22tgggcaaaag tagctgcgac tttggcaaag ctggaggtta gacccccaaa cataccccag 60gaggttagac tcccatacat accccagaaa agaggctgaa wccagcgaga tcagcagaga 120aggtctacag gccccacttc cacagcgcct cacaggataa gacccactgg cttggaattc 180cagctagcca ccagtagcaa c 20123201DNAHomo sapiens 23aagtggtaag tgaatgcgca actctgggaa tccacactgc tctcacagat ctttgcaaac 60ctcagatcag gagatcccct tgtgaactca ctccattagg sccttcacac acagccacgt 120ggagtctcag cagagcagcc actcaggcat gcatggagac ccaagagctt tagctactcc 180agctttctgg gtgtctgggc a 20124201DNAHomo sapiens 24cttaacagca aagtatcaga ttcatttata aaacaatgtg actgatcttt atgtatggtt 60tgtgaaacat ttatgcagtg tcacttcaga aaactctgcc rttatagatt tgaattgatt 120aaggatatcc actcctttcc ttggcatgat acaaataaat tactaaagta taattgtaac 180aatgataaat ataagtgaca a 20125201DNAHomo sapiens 25caccctttgg ggaaggggat caaaatatag tgattttcta attctaagat tcgttctgtg 60tatattagct gctattcttc tagaaagaag actttcacca ycgtcccttg gatttttttt 120tttaattttt gtatggttta aattgcatca tcattctttt tgatgtccaa attgtcccaa 180attaagccag ttagagaaac a 20126201DNAHomo sapiens 26taatgggatt cctgatggaa tgtttagtct gaatctaatc acatagagac ttgtctgaca 60aatccagatt ttttggatgt tttgcaggac tatttgccac racatttcaa aggattccaa 120gagagaatat tggtgtccat gctgtgatga ttcctcagct cctctcatct gatctccgtc 180ctggccccca tgactttctt t 20127201DNAHomo sapiens 27ctcttctttt atcacacaga cctgaaagat gatggtttcc caaacagcac ttacagcaat 60aggtgtgggc ctcagtggca cataccacac cctaactacc rcaaagaaag tcatgggggc 120caggacggag atcagatgag aggagctgag gaatcatcac agcatggaca ccaatattct 180ctcttggaat cctttgaaat g 20128201DNAHomo sapiens 28caaatctttc cctaagggag atttcagatg aggcccccag ccttggtaga caccttgatt 60gcagtcttgt gagagattgt gaagcagagc tattctcaga rttcatgggt gttttaagct 120atgaggtttt ttttgggggg agaatggtca tttgtgattc agctatacat aagtctacaa 180aagtcattcc agaagtgatt c 20129201DNAHomo sapiens 29tggggctcac aaccacatga ttctacctcc actgaatcac ttctggaatg acttttgtag 60acttatgtat agctgaatca caaatgacca ttctcccccc maaaaaaacc tcatagctta 120aaacacccat gaattctgag aatagctctg cttcacaatc tctcacaaga ctgcaatcaa 180ggtgtctacc aaggctgggg g 20130201DNAHomo sapiens 30tttttatagt gtgactcatt tacatatgca tgtgtatgtt taggtgctat tattaaattt 60tgctggcata tagtgaggaa attgtgattc aaattcgtcc rtatgtactc ctcccccacc 120atctgctctg cccctccatt taccagaagg ctagctttag ctacttgtgc atgtaaaaca 180gaagcaagca acactgtgaa a 20131201DNAHomo sapiens 31gaacatagat actccttcat tcatgtattg tctatgggtg agtctttatt acaacagcag 60agatgagtag ttgtgacaga aactcgatgg ccctcaaaag ygaaacaagc tactatcagg 120acctctatag aaaaagtttg ccaacctcta cactgtagta tgccttaagg atttttagaa 180gattgagtat gataaacact t 20132201DNAHomo sapiens 32gaagggatga tcagtccttc cctcctctat tttcttgagc cccgtttttc acctttcttt 60ttctctctcc tttcttatca tgaagaataa agacaaatga kaacagatct accttaggct 120gatacagggc agggaatcca tttaataata aaacgtgggt caaaattcac ttttctcctt 180ttgaattgaa attatattgt g 20133201DNAHomo sapiens 33atttgatgca acttacacac tgttgttata cctctagaat taaaatgaca attttttaaa 60taattttggg gggcctagat ttgctattta acctatcaaa raattgtgtc ttacagtatt 120attcaaatgt agtgtgtaaa gacttatact attggtccta agcactactg gttgttttag 180gctttttctc tttctctgta g 20134201DNAHomo sapiens 34acatttatat aattaagatg ctaacactga ctgacagaaa tgtcagtaag atgaaatcag 60actgcatggg agttttatgt tacattaatt tgtaaattgt rtatctctgt attcatgtga 120gtgtggctat catgatgtta gacatccagc tacaaaggag gcattcgtgc acacacacag 180tctccaatct tctgtttacc t 20135201DNAHomo sapiens 35tagacaaagt ttaatgttcc cttttatatg ttttcctggt aaacaaaaat tgtctcaggg 60ttattatgca tatatgatat tgtcaagaaa ctttctgggt rctgtggggc aaagtcttct 120ccataaataa gctagggttg attggagttt tcactttgaa aaatatcgca caggaggatc 180tcaacagcta gacaatttcc a 20136201DNAHomo sapiens 36aaattaaatg acatacgtaa agtcctcaat aaataatagc tcttattacc attgctatgg 60ttactatcac tatttctgta ttttcttttg ccattcctca ygcttgaata tgaatctcat 120gggtagagtt tcccaaagca tgatatgtgt agtactacta aaggcaagat tttgggtgca 180tacagacaaa aaaataattt a 20137201DNAHomo sapiens 37aaaccagagg agtaaaattc tactttcacc agtaattagc agtgtggagt tgagtaaata 60aacctctcta agtctcagtt tctacatcta ctaaatctaa rcaaattcaa aacagtgatt 120atttcattag attagatatt ttgattagtc ttaaatgtct aatatataat aaacactcaa 180caggtagtag ctattctatg t 20138201DNAHomo sapiens 38tcatttcttc ttttaaggtc ttaatttctt gtttttcgag tttcatggga gatatccagt 60caccaatcca atccatatcg gggaaaagta caacaaatga rtgaaatttg taaccaacct 120tggatgatgg aataagacat ttgggagaac acaggagaag tggggaggtt aaggagggat 180agctctgtga aaattttgca t 20139201DNAHomo sapiens 39aactaattct ccaaatttgc aatttggcag catcctactg ggactctaga aggctgataa 60atcatggaga gtaggtattc atataggaac tatgaaagct statgtagta aacactactt 120aagaaggcct tacatttcat aaaaagttgg agatttttgt ggagactcat aaaatgcatc 180ctttatatca gtgaagtttt t 20140201DNAHomo sapiens 40actcgtagcc agagctacct tccagatgac ttctttctac cactttcttt cttcccagtg 60taagagaatg caagtatatg ctgatgtttg gagcaagaac rttcaaaaat tttcttatta 120acataacttc taatggaaat acagtatact actatggtgc atacaaagaa gaaatagcaa 180catatatttg ttttagacct g 20141201DNAHomo sapiens 41ataagcagcc ttaaattaaa aaaaaaaaag ttaactcata actaactgtg tgacctggga 60taagttactg accctcttta gggcttaggg tcctaatctg yaaaacggaa attataataa 120taaccttagc tagcatttct tgtgcacata ctataagctg gtgataaaca atttatacac 180actatctcat ttaatcctca c 20142201DNAHomo sapiens 42tccaatgcaa aagaataata ggagcaaaag cacagtggtg agaaattgga ggggaactgt 60gaaaattgcc acatagatta gaggcaggaa aataaaggac rgctaagttt atatagtgaa 120cagtgagccg catggacaca ggtgactgtt ttctcctttt tgaacccctg cttactccag 180agtcaccacc tctcctggct t 20143201DNAHomo sapiens 43tattctgagt attaattcct gtttccaaat agattactct tttaaacata gcactactac 60ttacctaatg aaatttagtt gctattaatg gatgaatttt ktatctaaca ggcttgattt 120tgattatgca ttttaaatgt cagtcagaca catattaata atgatccatg tttgtagcta 180ataggcccaa tatatacttt t 20144201DNAHomo sapiens 44gtaagggctg ggacaaataa acacaagtaa ttttcaaata tattaataat aatattctga 60gtattaattc ctgtttccaa atagattact cttttaaaca yagcactact acttacctaa 120tgaaatttag ttgctattaa tggatgaatt ttgtatctaa caggcttgat tttgattatg 180cattttaaat gtcagtcaga c 20145201DNAHomo sapiens 45tggtggtcct aaagtggcat taaggagcca ataaattgtc attcctacct tagctctgtg 60tcagatgaaa tacacagcat agtgtgggga gaaaatgttg rgcttattgg ggatggggtc 120tttcacataa aggaagaagg tttcagaagg catagtggta tgaaaagagg agaaaccaaa 180gggaggaagg tcaataaagg g 20146201DNAHomo sapiens 46cagcatagtg tggggagaaa atgttgggct tattggggat ggggtctttc acataaagga 60agaaggtttc agaaggcata gtggtatgaa aagaggagaa rccaaaggga ggaaggtcaa 120taaagggtta agaacgaggg gaggcaaatt gactttcttt cagcatatga ggattatagg 180aatggaaacc ttaattggaa t 20147201DNAHomo sapiens 47gaggatttaa tgcaattgtt tgtgggaaag cactttaaca actctaaatt acgatatata 60tgctaggttt tattgttacc cacacctttg atgtatttct stttgtactc ttcactgtat 120ctgtaacaca ttccctagga taattagggc taccctttaa caaagccaag attctattta 180tagtggtaag ctggcacctg g 20148201DNAHomo sapiens 48cttctgctat tgaacgaact ttttgttaag gtagctccca agcaggttca gtagctttgt 60tctattatca cttttctact gacagtgatt tttttccttt saaggcctgg gacatggaga 120ctgcttttct gcagaaacca catcccttgg agtaatgagc tacacctacc tcaattattc 180agtgcagtac aacactccag g 20149201DNAHomo sapiens 49acattgtgca catgtaccct agaacttaaa gtataataat aaacaaaaaa aaccactgca 60caatctctag tattcagatg gagactaagc atgatttttc wtataaaaga gcagatcaga 120atgttgtatc ttttattcag aagactggag ttaatcactg ttatctttag tacttagtgc 180tgccaaggct gtgtgttcac a 20150201DNAHomo sapiens 50acagagtgct tatttaaaga aaaataaaaa gaacacacac acacacgcac gcacacacac 60acgcacgcac acacacacac atgtagctac atgtctagga rggatgtgga gagctgaaat 120atgaaggcaa aataaaacat ctttttcaaa gtatacagcc tacagtggtt agcacagagc 180tggccacata gcaggggttt c 20151201DNAHomo sapiens 51caataatgta gaagcaaaga gcctaaagtg ttttcataaa tcttaagtgg tagctttatg 60ttccagttca gcaaaacaca aatttgaagg caatctgtac rttagggttc aggtgaagaa 120ggcaaaggaa tcaatgaaat tgtaaaagct ttccaaattt gccttttctc ttaagattgt 180ctttctctca ttctcttctc c 20152201DNAHomo sapiens 52tttctgtagc agaagtgtaa gggtgttact cgtaggaggc ctctattgaa ctcttttcca 60gtgacgtagt gtgtggtctt taagtggctt tgcaatgata rtaagatcag cattgcatta 120ctgaatgagc tcctttagta aacgtggata tgtgctttct gaatctattt gtttgttttt 180cccaagtcat aaacagtgaa t 20153201DNAHomo sapiens 53ccatttagag tacttgcctc tgagggaaat aaaaatttgc tagcaatttt ctctaaatga 60cattatcata ggcacttaat tccttgatag gttcttttag rtaatttttt tataatgaag 120caattaattt gattcacgaa agtaagtttc tagtttatat aaagaccaga tctggcctat 180ttcttagctt gtctacattt g 20154201DNAHomo sapiens 54tgctagcaat tttctctaaa tgacattatc ataggcactt aattccttga taggttcttt 60tagataattt ttttataatg aagcaattaa tttgattcac saaagtaagt ttctagttta 120tataaagacc agatctggcc tatttcttag cttgtctaca tttgagtagt tccattgctg 180gaaaatgacc ctggagcttt t 20155201DNAHomo sapiens 55aagttgctct caacatactt aaagttttcc aataactgaa ttaaatatca gtttatcagt 60ttaatataaa caattagggt aaatgaaaat aaaatttcag ytctttggtt ccattagcca 120tggttcagga gcagaatagt cacctgaggc tagtgacaac gcttttggat cacaggaaag 180aagaaaaaaa atcaaaataa t 20156201DNAHomo sapiens 56ttataactaa tgaggcaatg tgtcttgagt attttgaatt aactctctag aatcgattct 60tggggaggtt atttactttg aagtgatgga cagagtgtag kagatttatg agtgaactct 120tgtctgattt ggaaatatag agttgtttag gctaggtatt accaacccaa agttgacact 180tgagtcacct aagttcttct c 20157201DNAHomo sapiens 57tattagttgt gtaatcttga aaaaatctct gacacttttc cctctgactc agtttcccca 60tctggcaccc aatcttttac agtgttatga aaaataggga raatgtagaa aggaagaaca 120tggcacccaa tccttaatgg acactcagtg aaagctggct atcatcatca tttttggggt 180tgttgtgttc tacaaatgta t 20158201DNAHomo sapiens 58tccccatctg gcacccaatc ttttacagtg ttatgaaaaa tagggaaaat gtagaaagga 60agaacatggc acccaatcct taatggacac tcagtgaaag ytggctatca tcatcatttt 120tggggttgtt gtgttctaca aatgtatttt cccaggagtt ttttttactc tgtctcctct 180ttccttcata tacccccagc c 20159201DNAHomo sapiens 59tgggaaggat gaattaatgg

gatggagtgc aggggatgca gagtgcccac ttatggaatg 60atttcattca agagagacag gagggtcaga ggtaagaatg ytaccgctgg gacagagagg 120aaggtacaga tatgagatat ggtaagaagg tatactacaa cagtggctcc caaatctcaa 180tgagtagcca gttctcatgg a 20160201DNAHomo sapiens 60tttgagccca agtctctttc tgactctagg cttagagctt tagggctatt tcacaaaagg 60gctgttccta ggtcaggcat gacaacttct atattacctt ygtaaaagaa gcaatataat 120ctaccactat taaattttgc aggttaattt tatattatgt ttaaatacag aaaactttat 180ttaaaactca gttgaatttc t 20161201DNAHomo sapiens 61gaaactggat ccctgatgac attgaaccat tgactgaatc taccctggaa ccatcaggaa 60ataatcctta gttttttaaa gatgctttta gttgtgtttt ytattacaag tacctgaaag 120catcctaact aatcaatgct aaatgcatct ctcacagttt atgcttattt ttcagaaatg 180cctagtggaa atttctattg c 20162201DNAHomo sapiens 62tccttccact gactgagact atttccttgc cacaatcaga agaactaaaa gaaaggagga 60tatctgttaa tatatgaatt tatctaaatg tcatgcagtg rcttctaaaa tcatctggtg 120tgctctgttt ccccttggag gtgacttagg cctggcatcc caaacaatac atactggagt 180gaagctccag gaaaccctga g 20163201DNAHomo sapiens 63atacatactg gagtgaagct ccaggaaacc ctgaggagaa gagaagggct taaagagcaa 60tcagccttcg attgctggga ttatgaaagg tcgtaagaag ygaatgttgc aatgttttat 120tatacttgat attgaagcaa ggacaagtaa taatttatta ttctctccat gtcagtggta 180tttacctttt tggaatcatg t 20164201DNAHomo sapiens 64ataaaaataa aataaaataa aaaatgaaaa acaaagtcca cttgtaacca catgtcagta 60gcatgtttgc tttcagggta catcaaatgc attctatagc rcaggatgtt ccagtcactc 120taacaaaaga tgtcctgttt ggaacaccaa ctctgtatca gttacttcag acactttctc 180tcattgagtc ccttcagcaa g 20165201DNAHomo sapiens 65aaccacatgt cagtagcatg tttgctttca gggtacatca aatgcattct atagcacagg 60atgttccagt cactctaaca aaagatgtcc tgtttggaac rccaactctg tatcagttac 120ttcagacact ttctctcatt gagtcccttc agcaagccct tttaggttta tgttcttaga 180tgaggaaacc aagtcttaga a 20166201DNAHomo sapiens 66atattttctt gtttttagat gcacatatac gtactttttt agctggtcat ttctttctga 60aattggaatg aatcttacaa tcaatggcat gttataattt mattggcagc attatttgtc 120tcttaagggc ccccaaataa tagtgtgtca cataactgat agcatctcaa attagatgaa 180atacagtagt ccaggcaaga a 20167201DNAHomo sapiens 67gttatgggat aaaggcgata gtattttatt gactatattt tattctttta attattcctc 60taatttctta aaacaacttt attgaggtat aacttccacg stataatttc acccatttta 120agtgcatgaa ttcagtgatt tttagtagag tcattgagta gtgtaaccat tcctacaatg 180gttatagcac atttttatca t 20168201DNAHomo sapiens 68tgttttcttt tatttttcct tctaaaataa tcacacgttt cattgcaacc ctaaccctct 60tcaacacaca cacacacaca cacacacaca cacacacaca yggcttctag attctacatg 120tacaagagtg caaatcaaac taccatagaa aaactaagaa gagaggccta gaagcaagag 180gctgatacac tatctcaggc t 20169201DNAHomo sapiens 69aaccaacact taaaatgcag ggaatttaag ataaaaattt gataaaaatg ggaagatttg 60gccgtattgg gctcatggta actgagatgc atctgaatga yaggcattcc tttgaattgc 120acatttgctc ttgtttttac tataggccac tctcactttc tgtttttttc cccggctttg 180aaacgatcag ttttagtact g 20170201DNAHomo sapiens 70atgactgggc aattatgtca ttatcaccac tgatatatag ctggaagagt ttagtgttgc 60cctgctaaga tctggatttt cttttctgga gcttggctat kggggcattg agaagtccag 120ccaggaggtt ggtcagaggc taacccaaaa agctttgctt aactctgggc tacagctggg 180ggttgccaga gagaagtgcc t 20171201DNAHomo sapiens 71aatttatttg agtagacagc caaccccctg tattgtactc ctttaaaaaa tattttaggc 60tttttaaatg ctgaggcaag gggacatacc aaacactaac rggcacattg gggttttctg 120gctattgaaa taaaaatgtc cttacataac actgatgtac tggaatagca ctgcgttcca 180gtgacggtta ttgcaactca g 20172201DNAHomo sapiens 72ggagcatgat gtgctttgat ttcaactatg ggctttatta cttactaact gggttacttt 60ggttaagttg tttgactctt gttttttgag atggagtcag yctgggagac tccagctctg 120tcgcccaggc cggagtgcaa tggcacgatc ttggctcact gcaacctctg cctcccggat 180acaagcgatt ctcatgcctt a 20173201DNAHomo sapiens 73ctggcacaaa gtaggcactt catatataaa agctgtgatt attgatgaac cagtagtgag 60gtacataact ggggaaggag aaggggccag tttgtgggaa wgctttttta gttattaata 120gtaaggtggt aaaataataa tagtaataat aaccaaaagt tactgaaaac taaatacagt 180gctaaactct ttaaaaggag t 20174201DNAHomo sapiens 74cttctttagc tgtaaataag taattgtatg aggtgatggt taaggtgatt tactaatttt 60acaattctat tattttatga atagacccta gttaggatag yttgaaatag atacttaatc 120cactattatt ctctcttcta agatatagtt actagttgat catacttttc cttaaaggct 180gaactgaatt ctctgatatc a 20175201DNAHomo sapiens 75gaaacatact ggttaatgga attccagaaa ggactgaaca atcaaaccat tttgaaggac 60agcatagagc tggactctag aacagccaaa acaaggggtt maaccactgc gagggatctc 120tctccaactc ttgctcaggc ttttctccct ggcttgactt tcttctcttt cactgtagat 180tggcttctct cacatggcaa g 20176201DNAHomo sapiens 76tattatgtgt ggctgactat ataaaaacat ggatattttc ttggaatcac ttggtttgac 60tgggagaaga ccattctcaa aacaaaggaa gtgcaattta yagaaggtag tagaataggc 120agataaaaca ataattcttc actatattgc tcaaataatc cccatgacat ttttagtata 180ttataaagag agttctaaag t 20177201DNAHomo sapiens 77gagaaagatg ttaagatgaa attagatgtg caagagattc gccgaggtaa accttgtggg 60agaaaatgga gaggtacata gaggagcctg ggcagactgt stggctacta tgtaagactc 120atccccatga aggagaaagg agaggaaggc aaagaagaaa aaccttaaga tttcaattct 180aagaacgttt tgacaaagct g 20178201DNAHomo sapiens 78tgtgcaagag attcgccgag gtaaaccttg tgggagaaaa tggagaggta catagaggag 60cctgggcaga ctgtgtggct actatgtaag actcatcccc rtgaaggaga aaggagagga 120aggcaaagaa gaaaaacctt aagatttcaa ttctaagaac gttttgacaa agctgattag 180gagtatttaa ggcaaagctg c 20179201DNAHomo sapiens 79aaatacttta actcatggcc cgatgatttt cagttaacca aattctccct tactatcctg 60gttgcccctt ctgtcttttc cttagaaatg ttattgtagt rtttgcaaga tggcctgaat 120cctgaacccc ccatcttcaa tgagcaccaa atggtaatta tagattccca gctgtagagc 180tatgtcagac aaaggaaact t 20180201DNAHomo sapiens 80ctcttccttg gtggcttaaa gttaggctga agaagattta cattatgttg tgcatgacct 60ctttagtttg gttctactta tactttcaag gagggaagac yggggaaggt gtcccttagt 120gagcatattt tgtacaaatg aaaacagggt actaacactt atgccaggac gcatgcataa 180actaggatgg ttctgagaaa a 20181201DNAHomo sapiens 81agaaccttaa tgggagcaca ggtcccaccc accccttgct accccatgta cttgttccca 60tcttcaccca agagaggaaa cactctggaa ctagggcagc wtaagtgaag cagagtgaaa 120aggaatgtga agttttgaga agaaagaaaa ggctaaagtg tctatctttc cacattgctt 180ttttcaggtt tctcttcgga a 20182201DNAHomo sapiens 82gatgaaaaat tcatattcat ctgaatttta taagtgaatc atgagaactc aaagatactt 60agcccttggg accatttttt actcctgttc ggatcccttc rgctaagcat gattatttac 120tattttcagc tattagttat gtcttgttga aaaagtatga aaagagctgc ccaataaatt 180agagtgtatg ctcaacattc t 20183201DNAHomo sapiens 83ttcggatccc ttcagctaag catgattatt tactattttc agctattagt tatgtcttgt 60tgaaaaagta tgaaaagagc tgcccaataa attagagtgt rtgctcaaca ttctcttagc 120ttctttatct ctttccaaaa ttggatcaaa tgacattgga catgatcaac ttcttactgt 180tttgacaaac atctgaggat a 20184201DNAHomo sapiens 84ttatttacta ttttcagcta ttagttatgt cttgttgaaa aagtatgaaa agagctgccc 60aataaattag agtgtatgct caacattctc ttagcttctt yatctctttc caaaattgga 120tcaaatgaca ttggacatga tcaacttctt actgttttga caaacatctg aggatacttt 180tataattgat aatttggact a 20185201DNAHomo sapiens 85ttttgtgcct cagtttcctc attcaatatg ggtgtaataa ctgtgcctgt cttgtaggat 60tattgtgagg cccaagtgca ataatatata gtacactgtg yctggcatct agtaagcatt 120cattaagatg acatgaagat aacacagata tatcttaaca tgtaattatg attttgctta 180ttcaaggcca agcattccaa t 20186201DNAHomo sapiens 86gaagaagaag acagtcagag agaagtgagg gcttactttt catgtttaaa gtctgttatg 60tggtaaaggg attagattta tctgtgttgt tccaggggac mgaaatagga caaatggatg 120caaatagagt gaggaagatt taaaacaaat ggagaagaca ttctaaaatc aactacaatg 180agcgtaaaca atgacaacgg a 20187201DNAHomo sapiens 87tcatatgcat agacaaatac accaaactga tgaatatttg ccttgtataa tctttttgta 60gtttttttat gaacatatat tactcaaaca atttagaaca wttggcaata tatatatatt 120tcatttataa aaggttagga agattaatta cactttctga ggtcgcaact aaaagccaag 180attttaatcc atttctattt g 20188201DNAHomo sapiens 88agtgtcactg gaaagtgaca aagaggacag ttaagttagt tggaactgaa ctgaggccag 60acagggctgt gggacaagtc agggtgtggt cattccggta rgcagcgatg cagaatcaag 120acagagtagt ttctccttct ctctctctct ttaattgtaa cgccttttat aacaaacaaa 180tattatgctt atttctgtct t 20189201DNAHomo sapiens 89cagttaagtt agttggaact gaactgaggc cagacagggc tgtgggacaa gtcagggtgt 60ggtcattccg gtaagcagcg atgcagaatc aagacagagt wgtttctcct tctctctctc 120tctttaattg taacgccttt tataacaaac aaatattatg cttatttctg tctttaaatt 180ttttgtagta atttctcatc a 20190201DNAHomo sapiens 90ttttctagtt gagctatcat tcatatttat tatgtggaac tagaggtagt cctggctact 60tgggaacagc gtggagtcta gccatgtcag ggccagaagt sgtctcagct aagttagaat 120gtgataccat tgtttacaca agtgtggcct gccttcaaga tagggtgagg tgttttatga 180ccacaggctt tatgagttat a 20191201DNAHomo sapiens 91tgactctgaa gatcataccc gaagtagagc tgcaaagata tttggaatat tggtaatatc 60caataaagaa tgaccttcat gctattttga ggagatgttt maatgtcgaa ttattgaaat 120atttataaaa tacaaataaa ctaactctgc ttcatattcc aacttgtgta tgacacttct 180taggctatca tttcattcca a 20192201DNAHomo sapiens 92ttccaacttg tgtatgacac ttcttaggct atcatttcat tccaaattta tggtcactac 60cctactgtca ttcctcatac taaccatatg atcaacagtt saaaagcagc cactcgcaga 120ggtaagcaag atatatggta aatactgtgt tgacaaaagt atgcagaagc agtcacattt 180atacagtagt gaaggaaatg t 20193201DNAHomo sapiens 93aattacagta tatctaaaaa aagaataata tataacaact gaaaaaataa aatagttgat 60ataagcagat attccaagat ctgccagaca tattgttaaa ygaaaaatct agatacaaaa 120ttgtttatag ttctctttca tactatagcc aaagaaaatt cagaaaaaac tacttacagt 180tgatccttga ataatgcagc a 20194229836DNAHomo sapiens 94gtaaactcaa aattctcttt ttttgggaaa atgaaaccaa gggagctaat cagagccaaa 60ccccatgtac ccaagtgtta gcaggcatga atgtagctac cagctacctg ggtgtgttgt 120catccttggt atttttgggg gctgtcctca tctcttcttt tgttttgaca tctctacttg 180tcttaaaacc caaggagcct tctgtgtttg tggccaatca gtttaccaat gcctcctcat 240taaatggact ggaacttgta ccatagatta tgtacccctg gacatcttta tactccctgg 300caatctctct cttccagcac caatccatgg gaattctatc ttgcccaggg tgaaaagggc 360tatccaatta attccccttc ttatgggcct cagcattata gctggtatgg gaacctaaac 420tgccggaatc tcaaaagcct ccttgaccta tagccaactc tgaaaggaaa tagccagcaa 480gtttaatatc atggctaaaa cctcaaccat ggccagagca aattaacact ttagcagttg 540tagtcctcca aaactgtcaa ggactagata tgttaatggc agcacaggga ggaatttgtt 600tagctttaga tgaaaaatgt tgcttttggg taaatcaatc agtaaaagta caaaacaaca 660tcagacaact cctaaatcga gcctccagct tacaagaaca agcctctcgt ggttagttag 720attggtaagg aacctggaaa tgggatcttc cctgggttct tcccttttta ggcccacatg 780ttagcctcta cttttgctcc tttcagtcca tgtcttcaaa aatctaataa cccaatttgt 840ctcctttctc tcacctttag atgatcaagt tccagatgat cctcagtgag ggataccatc 900ctttcaatat tcaagagtca cccttctaca gaggactcct agacttccca tcagtgggac 960atggcagagg tgaaatcctg cccctgtctc ccttagacct ggctggatac tgcttccaac 1020aacccatgca gccaccctgc cctgacagct agcaagaggc caagacccac agaacaatca 1080ccatcacacc tctgtcagca ggaagcagtt acagaagact gaccttcatc cagtttccca 1140aagaattggg tcatggattt ttgcggggga aaatgttaga gtaggtaatt aggcagacat 1200gagtaaggga ggagagaccc cctccaacta ggaatgtcag gtgagcatca gatgatcatc 1260aggtggttgt taaactctct ctctaaaata ataataggtt gcaactggca gcagggaaag 1320acaatctccc aatagataga aaagtcctga agctggtgat cagcagcttc ctagtaagat 1380ctcaggattt gggcaagcag gctcaaacat gggcactaag aggcaaaatc gtggagttta 1440actggtatac agacttcctc taaaaacaca tgactcatgc acatgtggac agcctgcccc 1500aaggaaaaat caaaagagga gagatgcaaa accccagaag catgccaata tataaaaccc 1560caagtctaag gtcaaacagg gcacttggat ttctcaagtt gcccacttgg ccctcttcta 1620agtgtacttt atttcctttc attcctgctc taaaactttt taaatttcac tcctgctcaa 1680aaacttgcct cagtctttca ctctgcctta tgccccttgg aagaattatt tccttcaaga 1740tggcaaaaag caagctgctg cagacccata cagatttgct gctgctaaca ggaggataac 1800ttgagcccag aaggttaagg ctgcggtgag ccttgattat gccactgctc tccagcctgg 1860caacagaatg agactctatt tttttttctt ttaaaaagac tttttacaaa aggcaaaatg 1920ataatggaac taaaaatgta cgttgactga cttaactcca actgcttctt ccctcaattg 1980aaaccacctt tgcaaaaatt ataacagtga gaaaattatg gcagtagggg tgatctgatc 2040aagccaaacc ccatcttgcc tttagccttc aagctgccca taattattcc tgggcttagg 2100ccaagctaac tttgggagac acttggtcta tagtttaaat gataatagtc cttccttaaa 2160attcaaccac ctcagcaaag ctgatgagag gccaccaggc aaggaggata gaggagtcta 2220aattctgcta aggtgtagat ataaacagtt tccagccatt attctggagg tcacaaaatg 2280tgcaacttct tcaattactc ctgcagataa catcagtatt ttagaaccta agattggcct 2340tttgagatgt cttttcaggt ttttttgtgt gtctgactac cgatggctcc acctggaccc 2400accaaccact cctgtggccc catccagaag caactcagca tgcataagga ctatttccca 2460cacccctatg attgcacccc caaccaatta gcagcaagga cttattgcct aaaacagccc 2520cattcatccc ccaaaccatc catgaaaaac cctagctttc aaatttccgg ggaagctgat 2580ttgagcaata ataaaatacg tctcccattt agccaactct acatgtataa aactctttct 2640ctattgcaat tcccctgcct tgataaatga taaatcagct ctatctgggc agcaggcaag 2700aagaacccgt tgagtcctta caatatcctt ctttctaccc tcctctgcct aattactctg 2760aatctactaa ctttttcact cagttatttt tccactttga agacaaaaag ttagaaaaaa 2820aaatgcctta tgaaattagt ccctcagaat aaaccagctg ggctttcttt agccacctgt 2880atgctttagt caaaatctaa gctcagaggc aatagtgaaa ggctttctta tcccaaagga 2940aaactctcag aaatttgctg aagctatcca cactgagtgt aggtatagaa catgctttgc 3000cctatttatt catgggcacc atcctgaact cagtaatcta gcttttttct tttgaagctg 3060gatggggaag acacagatct agctgaatta gttgccaaaa tatgctatct ggcataaaga 3120ttattttgag agagttattt tgagactctt tgtaagagaa atttatatct acaaaggaag 3180tctccattta taagcttgtc tctctgcatc aggaagaaaa gaaggactaa atcaccagac 3240actcttaacc aatggagaag gagtttaagt aacaaacctt acctttgttt aaggtgcttt 3300ttctggctct ctgccattaa gatctacatt ttccaccctg tctcctctag gacctgaggg 3360ttatctcttt gatatgcaaa tgccagggag attactcacc agaagaagaa gaagaaatag 3420agctaattgg aaattgagca aataaaaaaa tcttgttttt tctcccagaa acagtgaaaa 3480gctttagcca tcctttagat aatcttaact tgttccatct gccagaaaca caatttggat 3540tcagaaattc tttatgaact gtttttgtat tattgtacct ggcacatggc tacagttttc 3600aaatgaaaac tgtgaaatct gcttctgtct gtattttatg tatgtctgtg tatgcatgta 3660tgtgtaatat ttttctacct ctagagacta tcctaaaatt aacttataaa gagctgtatt 3720taattgcctt aaagaaaaag cacttataca aattaagtat tttttaaact ttcagaaaaa 3780taagacctag cgcaaatgtt cttcaagttg atattgttaa aagaagaaac ttcagccaaa 3840ttaaacttaa agaagtttaa ttgagcaatg aatgattcac aaatcaggca gcctccagag 3900ttacagctga ttcatggaga ctccagggat gcctcatggt cagaacaaat ttatagacaa 3960aaaaagggaa gtgacataca gaaattagaa gtgaagtaca gaaagagctg gactggttac 4020aggttggtgt ttgccttatt tgaacacagt ttgaacactc agcagtgtct aagtggttga 4080agtatggcta ctagaattgg ccaagactcg gctattgtta caggaacgta ctcctaaatt 4140aggttttcaa tcttgtctac ctgttaagtt aggttacagt tcatccacaa ggactcaaat 4200atagaagtac ggagtccttc tcaggctatc ttcagttctc tttaacagta tgatacggga 4260taatcttcag taaataaaaa tttctttaag tttgttggat taactaaagc aggcatgtct 4320tcagagttgt caacattaaa tataatacat acatacagtt tttttctacc aggggttact 4380aggcaaataa gtttgttatt gtaactagat gtttaagatt ataaaactgt cagtttaatc 4440taagagcaaa agtgaaaatg tggtagctat tttattaagt acagcggtaa agcaagtata 4500tattaagtat agcagtaaag caaaaaaaca aaaaaaaaca agtatttaac ttttttttgg 4560tttttttttt tgagacggag tctctctctg ttgcccaggc tggaatgcag tggcacaatc 4620tcagctcact gcaacctcca cctcccgggt tcaagcgatt ctcctacctc agcctcctga 4680gtagctggga ttacaggcgt gcaccaccat gcccggctaa tttttgtatt tttagtagag 4740atggtgtttc accatgttgg tcaggctggt ctcgagctcc tgacctcatg atctgctcgc 4800ctcggcctcc caaagtgctg ggattacagg catgagccac caagcccggc cttaactttt 4860ttttaggttc ttgcttttgt gatatttggc taacatacat atgctgtaaa aattgttaat 4920aggaaaatat taataatgag atgttgacta gctttgtctg tctaatgaaa tttcataagt 4980caattaaaat taagaacaat tgaattatag aatagaattc aattgaattc tattgaatac 5040acttgctgaa tacaacaatt gaattgtaaa tagaatagaa attataaatg aacttttcaa 5100tagtaattat tttttaatac gggtacttaa aattgtgtca acttcttaac aaaagaaatg 5160gaggcaaaat tagtataaac agtttatttg ggccaaattt gagaactgca atgtgggaga 5220cacgtcttca agttgctatg aatataaact ccaattagca gcagttacaa gcggtttttt 5280ttttttaaag aaggggcagt tctttagttg catataaact attgattggc tatacatttt 5340tttttaacca taaattccag gagcatgaac ataatgggtg agggtcacat cccctgggca 5400tggatttggg gcaggatgtg acaaaaatct catactcatg tctctctggg cctgataaat 5460tttgcatact ttatatagtt cagactcttc tgagctacgt ttctttctct tccttttggt 5520tgagtttttt tttcttctga aagtattgat gatcaacatt ttagatgtaa gtttgtccca 5580tgtcactgga agacttagtt ttagttagtc tcatcccaca ttggaggaag agaggagaga 5640taaaatggct taagaatgca gtgaagtctc aaggccaagt tgattggcaa cacaaaggga 5700cagggcaatg gtatttcagg tcatctgctt acaaaggagc tatggcatgt tggatcattt 5760ctaagcatct agctatcatt attttagtgt ttttgttgat tttggacatc tagaagtgca 5820aagtataatc aatttgagaa taaaagacat gatgcaaata aagacaatta ctaacaaaag 5880ccagatctga aaaatgtttt tatttccgaa ggcgaccaaa taaatatgtt ttctacttct 5940tgtgctgatc taaagatcaa tgtataggag atctccagtg

atgagtttgt ccactcaggc 6000agagctgcct ttttaaaata aaaattatga atgcataagt caatgtattt gaatttaact 6060ccacaagtat tggttaacaa tacagatatg gtcgcttcca aggtgtttgg agggagtttt 6120gtatttgatg gcattccaca ttggaggcca tgctatttga tgtcttcatc tcctggaacc 6180acactgtatt gtttggacat atctatccag acagatgatg ataaattttg catatctcac 6240atagttcaga ctgctctggg ctacttttct ttctcaatag cttctcattg ttaacttatg 6300cctgtagagt tttgctaaac taaattagat aatggacatt tattaaatat ttagatcatt 6360tccaaataac ataaaatgct gaaacattaa ttgcttaaca taagttaatc tacttttggt 6420ttttattaca aaggaactaa atatatttac atctgttaaa aaacacttta aactgtacta 6480tgagaaagaa tatacttcta tagaaattat aaaatggtat atttatagat ttaccatttt 6540atggaatacc ccataaccgt tcacaatttc ttatttccta gttttcacta gaaattgaag 6600ttactaagag ttaacaattt taactaatat agagtagtta aaaagactaa aaataataag 6660ggagataact atatgcaaag aaagtaagac atgtttttgg taaggaaagc cataaggtat 6720aaggatgtgc ttttttttaa ggaaaaggaa gaataatttg gtctagtttg gaggttattt 6780aaaggttgtt tcagaatgaa tgaaagataa aatctaaatg gatacaaaaa ggaagagaga 6840tgacacacac acaaaatgaa tgactcttgt atggacaagt tggctagaac tgaatgtatt 6900ataaggtttt aaaaatgagt cttgaccaag cactgtggct cacgcctgta atcccagcac 6960tttgggaggc caaggcgggc agatcatgag gtcaagagat caagaccatg gtgaaactcc 7020atctctacta aaaatacaaa aattagctgg gcgtggtggt gcgcacctgt agtcccagct 7080actagggagg ctgaggcagg agaatcgcat gaacccagga ggcagaggtt gcagtgaact 7140gagatcacac cactgcactc cagcctggcg acacagtgag actccatctc aaaaaaaaaa 7200agagtcttaa tatcaaaagt aaactgatgc aaaactagaa tttggtcttc tctgtgaaaa 7260tgacagtttt ctttttaaag agtattgctc cagtttttaa aagtgattgt gaaaaatttt 7320cctttccctt gtaactaatc ggcctacaaa atgaagattt tgtgttttct caaaataatt 7380ctttgtgctt cgtgttgcct ttttttggtc tttaattact taagaaaatt gaatcttccc 7440aacaaaagag ctagttttgt ttgttttgtt tttacagtta ttaaactttc tctatttgcc 7500tttgaaacct cttagttgtt actttttgtg tcttcacagt gacttttgat atatttaatc 7560aagtgtttaa aacatttgat atttttgcca gacttcctaa aaccaaattc taaactaaat 7620ctttttttta acctcaagct aagtaggatt ttccagatgg attcctggaa tatctcaaaa 7680gactttgttt tctttcctta tagaaagaga ggtcaggcac agtggctcag gcctgtaatt 7740ctagcacttt gggaggccaa ggtaggcaga tcacttgagc ctgggagttt gagaccagcg 7800tgagtaacat agggagaccc ttctctacaa aaattagcct ggcagcccag cgtggtggct 7860catgcctgta atcctagcac tttgagaggc taaggtgggc tgattgcctg agctcaggag 7920tttgagacca gtctgggcag caaggtgaaa ccccatctct actaaaaata caaaaaatta 7980tctgggcatg gcggcgtgtg cctgtagttc cagttacttg ggaggctgag gcaggaggat 8040tgcttgaatc cgggaggcag aggttgcagt gagccaagat cacaccactg cactccagcc 8100tcggcaacag agcgagagtc cttctcaaaa aaaaaaaaaa aaattagcct aacatggtgt 8160catgcctgta gtcccagcta cttgggaggc tgaggtggga ggatcacctg aacctaagga 8220ggttcaggct gcagtgagcc atgattatgc tactgtattc cagcctgggc aagaaagtga 8280gaccttggaa aaaaaaagaa agaaagaaag ggaaaaagaa agaaagaaag aaaaaaagag 8340aattgcatag gaagttgtca aataagggtg atgtttaacc ttcttatgtt ataatattat 8400tcatgtaagt tttccagatg ttctgtgaac ttctacaact ccgatatgtc ctgatatgtt 8460atcagtcata attttagtta ccttaaaatg ttgtgtttct cagaaataac aaattacatt 8520gtcaattgca ttataatgaa ctttcatcag atctttaacc atggccattt ttaagtctgt 8580tgtcatccac aaacagtagt tttactctga tactttcctg aaagttattc caaatgcttt 8640gtttgcagga agatttatgg aaaatattga aatgtgtggg tttctggtaa ctttaagatc 8700ataacattgg actgcataag aatttccagg actctattgg aaaaactaaa tttataaaat 8760tgctaaccca agatcaagta gaagaaaaat taattacatg gtgatatggt ttggctgtgt 8820ccctactgaa atctcaactt gaattgtatc tcccagaatt cccacatgtt gtgggaggga 8880cccagggaga ggttattgaa tcatggagtc tggtctttcc catgctattc tcgtgatagt 8940gaataggtct catgagatct gatgggttaa tcaggggttt ctgcttttgc ttcttcctca 9000tttcaccatc aggtaagaag tgcctttcag ctcccgccat aattctgagg cctccccagc 9060cacgtggaac tgtaagtcca attaaacctc tttttcttcc cagtctctgg tatgtcttta 9120tcagcagtgt gaaaacggac taatgcacat gggataaaat gtattgataa taatgataat 9180tttatgactt ttcgtttgaa acattgctgt ttctttaatg tctaattttt cagatttaac 9240gtaacttttt ctttctttcc ttaagctatc tatagcttac agaaatttag cagattatac 9300ctttatcaac agaaaagaag catatacttt ctctcttacc tgatccctcc agaattcaga 9360aactattagc aagtattatt atttccaagg caatatagtt atatgcataa ctgcaataag 9420aatatgttct tctgggctgg gcgcagtatc tcatgcctgt aatcccagca ctttgggagg 9480ccaaggaggg ctgatcactt gaggccaaga gtttgagacc agcatggcca acatggtgaa 9540accccagctc tatgaaaaaa taataataat aataataata caaaaattaa ctaggtatgg 9600tggtgcacgc ttgtaatccc agctactcag gtggctgagg cacaagaatt gcttgaacct 9660gggaggtgga ggctgaagtg atctgagatt gtgccactgc actctagcct gggtgacaga 9720gtgagactct gtctcaaaaa aaaaagaata tattcttcct ataacaggac acaattagaa 9780acactggtta tattaccaag gttttaaata gaatatcata cttaaaaata tgtgtaaaat 9840tttatatgac cagccgggtg tggtggctca cgcctgtaat cccagcactt tgggaggccg 9900aggcaggtgg atcacctgag gtcgggagtt tgaaaccaag cctggccaac aggaccctta 9960aggaccctta aggagatttt aagaacctaa tgaagaagag aattcaccca aaattatagg 10020cattgcagat gaagtctgat gacaagtcct tggcttgcct tcctagcttg gaaagacttt 10080ttaaattcta atttgagact ccttattaaa agtcccagca aagtatactt tgaaaaagct 10140tatgtaatga atcactattc ttactatact tatgtaagta atcaggccaa gtgtaacggg 10200actaggccta ttttgcaaac aaatcagttt tactgtgatt atttttggaa tgggcatgac 10260tataaagaga aaaactatat attagtagaa aactatagca cacccattgt tagattctag 10320cctagttcac tgtctttgag gttttgttat ctacttgtaa actgaactgg atcctgaatt 10380ctaatttcct ccagtatctg gctatgactt ctaccgagct gactacaaat ttgagggttc 10440ccttgacctc ttcctcatgt tcaataattt actaggacaa ttaacgggaa ctcaggaaaa 10500cacatatgat tgccagttta taatgaaaaa tacaatttag gaatagccaa gtggaagaga 10560ttcatggggc aaggtatggg ggctctttct tccatgcctt ctccaggtgc accatcatcc 10620tagcacctca ttgtgttcac caacccagaa gctctctgaa ccccaaagtt tagaggttag 10680tatggaggtt ttattacata ggtatgatta gttaaattgc caaccattgg tgcttgaaca 10740ttatctttac tgcctttctt cccccaaccc ccagaagtgg aaaggggtgc taaaagttac 10800aaccctctta tatttgcttt caggtgacaa ctttcaaagt gagttggagc aaagaccaaa 10860catatatttg catgaaatca tgacatccta tagtaatatt tgattttcaa actctgcatg 10920tataatagtt acttaaaatt taaattaaat tttaaaatgt accagttatg cagctgaatt 10980ttggtacttt ttcccttggc tttgtctggt atctgaatcc accatcattt ccctgtacaa 11040tatctgccat tggagatcca attgggaaaa tacatttaaa gaaaaaatct aagaagcatc 11100tcataggttg tggttccctt gcatccacac tcattatcat ggtattatct tccccaaggt 11160gggtaatagt atatccctgg ctaatatcaa gattagcact agctgtctgt agataccatt 11220tagaaaagtt ttctctacat gtcctctctc accactccta ttcaacatag tattggaagt 11280taaaaaaaaa gttttctcta cttgaaacta aaatttatgg cagactatat gcttccgaat 11340gttctaaaac cttactagaa gacaaacatt gtcaaaggta ggaatgtggc caacatgtca 11400ggtaacgcct ataacaaatt aaaatctggc gattgctgcc aagataccca caaaactatc 11460ggaggcaact gctgctaaaa gaccataaag atgattctgg agacaaaggc ctgtggaagt 11520caataaaata atggtcaaag tggacaagat ttaaaaaaat taggattcag aaagaagcca 11580attgtcattt aggaaacaat tatctgataa caaagctcag tgccctctta gggctgacat 11640tcatgtacat attaaatatt gtagaactga taaggcttgg tggattatat ttgacaaagg 11700ttatttgtat ttcaaaaagg aatcaacttt tgagacaaag gaatgcttta attcattcaa 11760caaatatttg ccaagtacct actttaggga tatgatggtg tgtaaaaaaa tttttgctgc 11820tatcatggag tttagaatat agaggtaagg ccaatattaa tctagcaaca ttaaatcttg 11880tgtaattgta aactgaggta gataagtgct caagaaaaaa aggttctgta aaagtttata 11940tcaaaagatc ctgatcaaag aagtattcta ggggaaataa tcattaaact gagagctgaa 12000ggaagagttg ggttgaatgg cataaatctt aaaatgagac agggtttata cctgagggtt 12060ggtatattag tttactaggg gtgtataaca aagtatcaca aactgggtag tttaaataac 12120agaaatgtat tgcctctaag ctctggaggc taaatatctg agatcaaggt gctggtaagg 12180ctgtttcctt ctgggttgat gagggagatt ctttttcatg actctctcct agattctagt 12240gatttgctgg aaatctggtg tttcttgact tgtacacctt tgcctttgtt atagactgat 12300gttgtctccc cctaaaactt atgtgttaaa atcctaaccc ccagtgtgat gggattagga 12360ggtggctctt ctttggggaa ataattaggt aatgagtgtg caaccctcat caatggaatt 12420agtaccctta gaaaaatgac tccagaaagc tctctcatcc cttctgctat gtggggacac 12480agtgacaagg gggccatctg taaagcagaa agcaggccct caccagacac taattctgcc 12540agtgccttga tctgggactt cccagcctcc agaaccatga taaataaatt tctgttgttt 12600aagccactag cttatggtat ttttgttgtt agtccaaaca gactgagata gccttcatct 12660ccacatggca tttttttctc tgtgtctttg tgaataaatt tcttcttttt ataaggacac 12720cactcatatt tgattaggag tctaccctaa tccagtataa gcttatctta atgaattatg 12780cctgcaatga ctctatttcc aaactaagtc acattttgag gtattgcagt taggacctca 12840acatatgtat ttttggggga gacacaatac aactcttacc agttgagaaa gagacaatgg 12900gagcaaagaa gatttgaaat ttacctgctg acttagctag gttaatcatg agagaacaaa 12960aagctttcat ttgaaaacgc ttcaggaaat tcagtgttct caaaggagag ttggattgtg 13020tttataccaa gaagggggct gaaactatct gaggaggagg ttcaggctat aaagattata 13080cagattgatt attgagaaaa gtacaaagga gcacagtgca aagtttggga ggtggagaag 13140tttgagtcaa aaataaggaa gtatagagag cattattggg atgatgggaa ggtaaaataa 13200actggccagg attaattgct tctattcata tctctgcctg atgaaaatgg gagtgagaag 13260tgtgatggct ttagtctcaa atgccttctt gagaaaggcc aaagaattta gactgcccag 13320tccagaacaa tgtcagtccc aataggtata gtctctgttc tcctggccag aactagaatc 13380aattactggc tccatcattc actagatgtg tgcgtttggg ccagttacag tacctctcta 13440agaccgagct ttctcattct taaaatgagt ataataataa cacttagttg aggaagcttg 13500tgtagtacgt ctcagtatca ctattgaagg gctggaggat tctcatgccc tcgataaact 13560gtgtgatctc tcagatcctc tattttctga ttttaaaact gtcatagtaa tgctttagag 13620tactgtaata acaacttatg gagatcttat ttataaaaag taatttgaga aatagaaaag 13680taacacctag ttactttttt cctagttatt ttgggccagg attgtgttct gtgactgtgt 13740ctaaatgcac catgagagga cgcccaggga aggcacctcc actccattct atctcattcc 13800tctttcctag tgtgagttca tcctgtgtgc tgatttattt tccttaatcc acctggtcct 13860atcaaagggc catttcagtt agttgctcca cttcagttta tgggagataa gtcttgtcca 13920gattttccta atggccaaaa aagtcaaatc cttatcctct ttgggcttta ctcaaaaatg 13980cttgttcagt tagggctcta gttttattcc ccagagattc tgcatgtttt atactgatct 14040tgccagggcc ttcatctttt gggctagtct ctggaaaatc tacctctggt cctgtgcact 14100tttccccctc tagattctag aaggaaaagc aatgaatagc gtctcccaca aagatatttc 14160caagacctaa cccccagtac ctgtgaatag tgagagtaaa atgattagtg gctgccagag 14220gttcaagaga aggagagaaa tattgaatag gtgaaggaca ggggattttt tagagcagtg 14280aagttattct gtatactgta attgtgtatg catgacatgt tttttcataa cccattggac 14340tttacaatac aaagaatgaa cttaaggtat gcaaaattta aaaatcactt aggagggggc 14400agggccaagg tggtagatta gaagcagctc atgtgtgctg ctctcataga gaggaaacaa 14460aagggctagt gaacattgac cctccaggct gatcatctga aaaaccatgc tgggatccat 14520caaggcagtg ggtgaacaca gagtacagag atgagcaaag ttgggcacca gcctttcagg 14580actcagagtg aagccaagag aacctctcca acatgggaaa gggtgagtga gtgagagccc 14640ccagaggaat tcacactctg cacagggacc cacacaagac ttggaatggg agaatccccc 14700tggaccccct ggacacctgc caccaccatg ctcctagact gaggcagaga gccaactaga 14760tgttttgcag gggcaactct tgagtccaag gggacctcta caagccttgg ccccttgagt 14820agaccagcac tggttccaca gccccaaaag aggccacagt tgcagtgcct gggagaagta 14880agattgcccc gccccctctt gctggacagg gcttgatggc agcttctggc ccagcagtcc 14940cacttcagcc tgaacttgtc tggccactcc aatcacccct caccactggt atcctggcgg 15000gcaaccctcg atagagcttc cagcccagta gtcccacttc tgtgtcaact tagcccatgg 15060acacagcctc ctgttgtccc aggaagcact cagacattag ggcaggagaa tgtacccatc 15120ctcaccactg atagccaggt ggcccagtgc tcctacttca atggggactc agctggaggg 15180ctcagcctcc cattgtccca agaaatgcat agacagcagg gtgtgtagcc ccaaccatcc 15240ctgccactgg tagacaggcg ggcaatgcct cctagacctt ctggcccaga ggtcctatat 15300ctgtgggaac tcagccagtg cgcacagcct cctgctgtcc caggaagtat ctggatggta 15360gggtgggtgt ccccaaacac ccctgctgct ggaagccagg tgagccatgc ctgttagaac 15420ttctggctca gtggtcctac ttctgccaga atttgctgag ggtcacaacc tcctgctgcc 15480ctggaaacac ccagagagca gggtgagcaa ctccactcac acctgcctcc catagccaga 15540cagggcccac ccaatagagc ttccaaccca gcagttctgt tctacctgca ctctgtgaaa 15600aggcacaagc ccgtgtttct ccaagaagca catggatagt atattagtgc tgacttggca 15660aggatacagc ttgtctgcca acagcagctc ctgcctgagg gaacaccatg gacccgaaaa 15720cccaacaaaa aacataggca cagagacagt aattggaggg ggctcctcca agacccagga 15780gtggactaga attgaaacca gtcaaccaaa gccaccttat acaataatga aacccccaag 15840ggcatcaaag aagaaaaaag caaaaaaaaa aaaaaaaaat ccactcaaat tacagcaatg 15900ttaaagactg aaagaacaac agcccataca aatgagaaag atccagcaca agaactctgg 15960caactcaaaa aaccagagtg ccttctttac tccaagcaac tgcactagtt tcccagcaag 16020ggtccttaac taggctgaaa tggctaaaat gatggaaata aaactcagaa tacagataag 16080aatgaagatc attgagattc agacaatgtt gaaacccaat ccaagtaagc taagaatcac 16140aataaaatga tacggaaatt gatcgatgaa atagccatca taaaaaagaa cccaactgat 16200ctgatatagc ttaaaaacac actacaggaa ttgcacaatg taattacaaa tattaacagc 16260agaacagacc aagctgagga aagaacctca gagctcaaag actggctctc tgaaataact 16320cattcagata aaaaattaaa aaagaataaa caaaacctac aagaaataga agattatgta 16380aagagaccaa ttataggact cactggcatc tatgaaagag atggggagaa agcaagaaac 16440ttggaaaaca tattttagga tgtcatacat aaaacttcct caacctcatg agacaggcta 16500acattcaagt ccaggaaatg cagagaaccc ctgctgacat tacacaaaaa gaccatcccc 16560aagacccata attatcagat actccaaggt tgaaatttaa aaaaaaaaaa aaaaagacaa 16620aggcagctag agaaaacggg caagtcgctt gcaaagggaa tcccatcagg cttacaggag 16680acctttcagc agaaactcta caagccagaa gaggtttgga gcctatattc agcattcttt 16740ttttatgaga cagagtctcg ctgtttcacc caggctggag tgcagtggtg cgatctcggc 16800tcactgcaag ctccgcctcc tgggttcaca ccattctcct gcctcagcct cccgagtagc 16860tgggactaca ggtgcccacc accatgcggg gctaattttt tttttttttt tttttgtatt 16920tttagtagag acggggtttc accatgttag ccaggatggt cttgatctcc tgacctcgtg 16980aggaggtcct cctgacccgc ctcggcctcc ccatatattc agcattctta aagaaaaaat 17040ttacaatcaa gaattttaca tctggccaaa ctaaacttca caagtaaaaa gaaataagat 17100cattttctta caagcaaatg cttagggaat tcattaccaa cacacctgcc ttataaaaag 17160tcctgagagg agcactaaat atggaaagac cattacaagc cactacagga acacatttaa 17220gtacacagac cgatgacact gaaaagcacc cacagaaaaa aaagtctgca taataatcag 17280ctaaaagcat gattacaaaa tcaaatccac acatattagt actaagctaa tgggctaaat 17340gatccaatta aaaggcgcag agtggcaagc tgaataaaga agcaaggccc aatggtatgc 17400tgtcttcaag agaaccatct cacatgcagt gacatctata ggctcaaaat gaaggggcgg 17460agaaaagtct atgaaacaga agaaatcaga ggttacaatc ttaatttcag acaagatgga 17520ctttaaacaa acaaacatca aaaaatataa agaagggtat tatataatac ccttcaattc 17580aatggttcaa ttcaacaaga aggtataact ctcctaaata tgacagacat ctaacacaag 17640agcacccaga ttcacaaaac aagttcttag agacctacaa agggacttag aacccccaca 17700caataatatt gggagccttc aacatcccac tgacagaatt agacagatca tcaaggcaga 17760aaattaacaa acatatttaa gacctgaatg caatacttga ccaaagggac ggaatagata 17820cctatagaac ttgccatcca aaaacaacaa aaaatacatt cttctcattg ccacatggca 17880catactccaa aatcaaacac aaaattggac ataaaacaat actcagcaaa ttaaaaaaaa 17940aacagaaatt ataccaacca caatcttaga ccacagcaca acaaaaatag aaataagttc 18000taagaacata actcagaacc ataaaattac ataggaatta aacaatctgc tctggaataa 18060cctttgggta aacaacaaaa ttaaggcaga aataaagaaa ttctttgaaa ttaatgagaa 18120aaagatataa catatccaaa tctctgggaa acagctaagg ccatgttaag agagggaagt 18180ttatagcact aaatacccac atcaaaaatt tagaaagatc tcaaattaac gacctaacat 18240cacaaccagg agaactagag aagcaagagc aaagtaagac cccaaagcca ccagaagaca 18300agaaataacc aaaatcacag ctgaactgaa gaaaactgag acactgaaaa ccatacaaaa 18360gatcaacaaa tccaggagtt ggttattaga aaatattgat aagatagata gactactggc 18420tagactgata aagaaaaaaa gacagaagtt ccaaataaac acaattagaa atgacaaagg 18480agacgttacc actgaaccca cagatataaa aaaaaacatt gaagactact ataaacactt 18540ttaagcacac aaactagaaa atttagaagg ctgggtgtgg tcgatcacgc ctataatccc 18600agcactttgg gaggccaagg agggtggatc acaaggtcag tagatcatga tcatcctggc 18660caacatggtg aaaccccatc tctactaaaa tataaaaaaa aaaaaaaaaa ttagctgggc 18720ccagtggcat gtgcctgtag tcccagctac ttgggaggct tgaggcagag gaatcacttg 18780aacctgggag gcggaggttg ctgtgagctg aggttgagcc actgcactcc agcctggtga 18840cacagtgaga ctccatctca aaaaaaaaaa aaaagaaaga aaaaagaaaa gaaaatttag 18900aagaaatgga taaattccaa gacacataaa ccaggaagaa actgaatccc taaacaaaca 18960aacaatgagt tccaaagtta aatcagtagt aaaaagccaa ctgtattaat gcattcttat 19020gttgctataa agaaatacct gagattgggt aactataaag aaaagaggtt taattggtta 19080acagttctgc aagctgtaca ggaagcatga cagcttctgg gaaggcctca gggaactttt 19140aatcattgca gaaggcaaag ggaaagcatg tatgtcttac atggccagag cagggggaag 19200agagagagag gggaggtgct acatactttt aaacaaccag atttgtgaga attctatcac 19260gagaacagca gtagtgggat ggtgctaaac cattagaaac cacccccatg atctaatcac 19320ctcccacaag tccccacctc caacactggg gattaaaatt gaacatgaga tttgggttgg 19380ttcacaggta taaaccatat catctactaa acataaaaag cccaggacta cacagattca 19440cagccaaatt ctaccagatg tagacagaat agctggtgcc attaataatg aagctattcc 19500aaaaaattga ggaagaggga ctcctcccca actccttctg tgaggccagc atcatcctga 19560taacgaaacc tggcagagac aaaacaaaaa aagaaaactt caggccatta tccttgatgc 19620acatagatgc aaaactcctc aacaaaatac tagcaactga atccagcagc acagtgtaaa 19680gctaatccac cactatcaag caggctttat ccctgggatg caagattggt ttaacataga 19740caaaacatat gtttgtgtga ttcattacac aaacagaact aaaaatgaaa accacatgat 19800aattccaata catgcagaaa aggcttttga taaaattcag catcccttca tgttaaaaac 19860tctcgataaa ctatgcattg aagaaacata cctgaaaata attagagcca tgtatgacaa 19920atccacagac aacatcatac tgaatgggca aaagttggaa gcatttccct tgaaaactag 19980aacagccaga cacgatggct catgcctgta atctcagcac tttgggaagc aaaggcaggc 20040agaccacttg agcccaggag tttgagacca gcctggtcaa catagggaaa ccctgtcttt 20100acaaaaaaat aagaaaaatt agccaggcgt gatggcacac acctgtggtc ccagctactc 20160gggaggctga aatgggagga tcacctgagc ctgggagctc aaggctgcag tgagctatga 20220tcacactact gcactcaagc ctgggtaaga gtgaaaccct gaccaaaaaa aaaaaaaaga 20280aaagataaaa gaaagaggcc aggcgtggtg gctcaggcct gtaattctag cactttggga 20340ggccgaggca ggcggatcac ctgagattgg gagctcgaga ccagcctgac caacatggag 20400aaaccctgtc tctactaaaa atacaaaatt agcgggcgtg atggtgcatg cctgtaatcc 20460cagctgctcg ggaggctgag gcaggagaat cgcttgaatc caggaggcag aggttgcagt 20520gcgctgagat tgtgccattg cactacagcc tgggcaacaa gagcaaaaaa aaaataaaaa 20580taaaaaataa aaaataaaaa aaaaataaag aagaaagaaa agaaaactgg cacaaacaag 20640aatgctctct ctcaccactc ctatttgaca tagtattgga agtcttggct gcagcaatta 20700ggcaagagaa agaaataaaa ggcatccaaa taggaagaga gggagtcaaa ctatccctgt 20760ttcaaatgac atgattctat acctagaaaa ccccatagtc tctgccccaa agcacattaa 20820tctgattcac atcttcagca aagtttcagc atacaaagtc aacatacaaa agtcagtttc 20880attcctatac cccgatagct ttcaagctga tagcaaaatc aggaacacta tcccaccaca 20940attgttataa aaagaacaaa atacctagaa atacagctag ccagggatgt ggaagatctc 21000tacaacagga attatataac actgctcaaa gaaatatgag

atgatgcaaa caaatggaaa 21060aacattttat tctcatggat aagaaaaatc aatatcatta atatggccat agcgcccaaa 21120gcaatttaca gatgcattgt tattcctaac aaactaccaa tgccattagt cacaaaacct 21180aaaaaaataa aaaaactgtt ttaaaatcca tatgaaacca aaaaagaccc ttatagccaa 21240ggcaatctta agcaaaaaga acaaagctgg aggcatcacg ttacccaact tcaaactatg 21300ctacggggct acagtaacca aaacagcatg gtactggcac aaaaacaggc acatggacca 21360atggaacaga atagagagcc cagaaataag gccacaacca ctggatattt gacaaagctg 21420acatcattct accataaaga tacatgcaca caaatgttca ttgcagcact attcacagta 21480gcaaagatgg gaatcaacct aaatgcccat caaaggtaga ttagataaag gaaatgtgat 21540acatatacac cacataatac tatgcagaca taaaaaggaa tgagatcatg tcctttacag 21600caacataaat ggagctggag gtcattatgc taagcaaact aacacaggaa cagaaaacca 21660aaataccaca tgttcttact tataattggg agctaaagga tgagaacaca tggatactag 21720gaggggtaca acagacactg gtgcctactt gagggcggag ggtgggagga gggagaggat 21780cagaaaaaat acctgttggg tattatgctt attgcccagt gatgaaattt tctgtacacc 21840aaacccttct aacacacagt tcatctatat aacaagtctg cacatgtacc cttgaaccta 21900aaataactat tacaataagt aaatacatat ttttaaaaat catttagaat gtcagaaaat 21960tccaggattg tattagtctg ttcttgcact gttatgaata aacacctgtg actgggtaaa 22020tttataaaga aaagaggttt aattggctca cagttccact ggcagtacag aaagcatgac 22080agcttctggg gaggcctcag gaaactttca atcatggtgg aaggcaaaga gcaagcaggc 22140atgtcttaca tggccagagc aggaggaaga gagaaggtag acgggctaca cacctacaca 22200accagatctc gtgtgaactc tatcacaaga atagcactag gaggatggtg ctaaaccatt 22260agaaaccacc cccatgatcc aatcaccaga cccacaagga cgcacctcca acattgggga 22320ttatgattga acatgagatt tgtttaggga cacagatcca aactatatca aggatagagt 22380gtagaatatg acaaaataat ctaactgtat tacaaatgtg tgaaacaacc tcactgcagg 22440tggtggtaaa agaagtgcag acctaagtaa cttttggaaa ttagtggagt ctgtaatact 22500aaatgaaaaa ctgtttataa acgccacact cttgtttttc acagggatat gggttaacaa 22560ttctaatact tctatacgtg tgtattggaa ttgagcagtt aagtaaatta tggtaaattg 22620tgggtagtga ggctggtttc tctctgctgg agtgagagtt tatgcctaat caaagggagg 22680gagctaaaat aatctctgtg gtaatggatt acagttggat atattaatat taaatcatat 22740ttggcttaat gtagatacac atggctacat acacgtacac atggctacat atagacacat 22800atagatatgt gtacatacat gattagtata cacaaacgtt cccttccatt gacaaatgag 22860aaggcctaga agcaacagta ccccagtagt aacaagcaca tctggcatcc agttcatggt 22920ttgtaatagc actctgcaat aaagggaaac agggcttctt agaaaaattg gtgtttctag 22980gactagggca ggaaatatac atgatgagcc tgtaacattt tgtagtgcca gaaaggaaag 23040aagtgctaac aacaaaaaca agcccacaaa gatggggctg tgtcaaatag atgtactgaa 23100agagccaata ccaagaactc ctgacgccaa atctggaaca ctttggggaa acaaataaag 23160cagtattgaa ttgtaacaca aagtataaaa taaatagcca tgagtctaca ctaatataag 23220taaataagtg aataaataaa taaatggggg caaagaaaca atcttccatg cagaaaaact 23280ccaaatgatt tatgtagata tgccaaccta aaggagataa agcataactc ctcactgttt 23340cagttcaggc cacacatagt gactttcttc caaagagtat agtatgaaaa agggaaataa 23400aagagtaact tgtgatggaa aagcctgaca agcacaaatt acctcagcag agtgatcagg 23460gtcaacataa acagtaataa atcatatcaa cagtatgttc tcttgatatg atacgatgaa 23520aatcatctag tcatcctttt ttttttttta gatggagtct tgctcttgtc acccaggctg 23580gagtgcaatg gagtgatttt ggctcactgc aacatccacc tcctgggttc aagcgattcc 23640cctgcctcag cctcccgagt agctgggatt acaggcgccc gccaccatgc ccagctaatt 23700tttgtatttt tagtagagac agggtttcac cactttgacc aggctggtgt cgaactcctg 23760accttgggtg gtccactctc ctcatccccc caaagtgctg ggattacagg cgtaagccac 23820cgcgcttggc tgaaaatcgc ccttaacctc tgtagtcttc ttccccaaaa aaacattatc 23880cctgtctaat aatgacaaag acatctaaca aatcccaaaa gatagatatt taaaaaatac 23940ctgacccatt cttctcaaac tgtcaagatg accaaagcaa ggaacaactg aaaagctgtc 24000ataaccaaga ggggcctgag aagacatgat gatgaaatgt tatatgatat tctggatggg 24060ttcttggttt gcaaaaggga atttatgcaa aaactaagga aatttgatta aaacatggac 24120tttcagttat ggtaatgtct tgatattggt tcattaattg caataaatat accttgctaa 24180tgtaatatat tcataaaggg gaaactgggt acagagttaa tgagaactcg ctagactata 24240ttctaatagt tctgtaaatc taaaactatt gtaaaaatca agtttacttt aaaaatatta 24300ctgactgtct tggttctgtt ttactacttt ttttttttct tttttttgag tcagggtctc 24360cctctgtcac ccaggctgga gtgcagtggg gtgatcttgg ctcactgcaa cctctgcctc 24420ccgggttcaa gcaattctcc cacctcagcc tcagaggttt gaataatact tctttgtttt 24480aatcattcag ctcagattaa aaacaacgcc taatttctta atgtcaacta ttgccttgcc 24540ctctgttata tcctaccttc tcccattcgt tatagtcact ctctagtatg gtattgagtt 24600ggggatgtgc atctgcccaa caaattttta tattttttgt agagatgggg ttttgtcatg 24660ttgcccaggc tagtctcaaa ctcctgagct caagcagtcc gcccaccttg gcctcccaaa 24720gcgctgagat tacaggtatg agccacattg tccagccatt tccatttact tttctttccc 24780attgagccca attcttaaaa acatccagtg gcagcttagc ttgggtgtct tggctcagct 24840ctggaggttt gaatgatact tctttgcttt tctttgcttt aatcattcag ctcagattta 24900aaaatttctt aatgtcaact attggcttgc cccctgttat attctacctt cttccattcg 24960ctatcctaac tctctagtat ggtattgagt tggggatgtg cacacacagg caaacacaca 25020cacatacaca tccccataca tatacagtgg tgtgctgaaa ctgtgtcaga ccagctagag 25080agacccaatt gttaaatatt caagaatgag gcaagccagt tattaagcac atccattatt 25140aaaaattaaa ggataaagtt acaattaagt aaatcatatt aaaaagaaag gttataaata 25200atatcattac ttctatttat tttactatta tctatacttt ttgaggttaa gtctactgta 25260tttctataat ggaattacta catactggtg tgctacttct tgattccgta tttggtgatg 25320tcaccctgat atgacatcat atcattgata tgatatgaaa tagaccatgg gtggagtatt 25380tgtaccatgg atattgaaaa aacttaaatc agagcttgag ttattgtttt gttgattttc 25440tactttaaaa agatggatgt gcttaataac cggccttaaa aagatggggg aaaatgttat 25500cacggttaat actgtaggtt aagctctaaa atgtttgtag ctgttacatt tgaatagcac 25560aaaatattga ggaatattct ttaagtgttt gaaaacagtt ttaaactcag caaagaggtt 25620aactgatatt gttaacaaga ttcaacttca ttcaattcta ttgttatact ctcatcttac 25680tcgtcaatat aaatgaaaat gtcaattgat attcatttga gagttactct catttgttaa 25740ttgcaaccat aggttaacta aagatacaag agtttggcta aatcagtgag aacattgtat 25800gagaataagt tcattataca gaatagagaa tattatatat tttattatta tttgtaagtt 25860ttgtattaca tatcctttat gtcagtaaaa tttataataa acatgtacat atttattttt 25920tgcagtttgt tattaaacag ttactagcaa attgctatgt acacacattc cttatcaaaa 25980atgtgggaat tatttgcaac ataaatgaga acatatgagg ttatacgtag taggtacaat 26040cttaaagaga caaaccacaa gtatgattga tacttccact agacatcttg tcaagagaat 26100tatattccca aataagtatc accaaaaatt ttgttgaaac tagacctttc cacaagctat 26160gggctcctat aaatacatat ttttaccaga gtttcttcat ctaattaggt ttttaaattg 26220tggtaagaat aagatacaga taaatgaatt agatgcagcc tggccaatat ggtgaaaccc 26280catctctact aaaaatacaa aaattagctg ggtgtggtgg cagacgcctg taatcccagc 26340tactcgggag gctgaggcag aagaattgct gggagccggg aggcagaggt tgcagtgagc 26400tgagattgcg ccactgcact ccagcctggg cgacagagcg agactccaac tcttaaaaaa 26460aaaaaaaaac aaatcaatta gatgtattaa ttaggaatct gctatgaact gaattgtgtt 26520cccccaagat ttacatgttg aagcgctaac ctccaatgtg gcaatattta cagatcgggc 26580ctttaaagag gtaattgagg ctacaagagg ttgtaagggt ggagccctaa tccagtagaa 26640ctggagtctt tacaagagga agacacacca aaggtgcatg ggcacagaga aaaggccatg 26700taaggacaca gtgggaaggg gccatctaca agccaatgag agaggcctca ggagaaacca 26760aatctgtcaa catcaacatc ttgatcttgt acttccagcc tccagactat gaaaaaacaa 26820ctattgtttg agccgccctg tctgtggtat accatgtacc atggtgtttg tagggaagcc 26880ctagtaaact aaaacaaaat cttagattgt aagtaataga aatcaactgt aggtagatta 26940tagcagaaag aggacagaaa tgcaggtaaa agttacaact ggaaactgca gtgctatagg 27000aagcccaaga tgttctcttt ttctgtatct cctctctgct atagcctatc tattttattc 27060tgaacatctt tattccacac atctttattc cacagctata ctgtccaata tgatagtcac 27120aaggaacatg cggcttttta aatttaataa aattcagttc ttcagtcaca ttaaagatat 27180tgcaaatatt aaatagctac atatggctac tgtgttggac actgtagata tagcacacct 27240ccatcattgt agatagttct tttggacagc actggattat aggattacca gagatcaagg 27300taaacttccc ttgaagttga aggtaaactt ccatttaacc attaggacac ctcagctgta 27360tcactccctt ttaaggccta tatttagttt tgaatttata attttttatc atttttctta 27420gggactgata tcaccagtga cctctaggga aaggattagt agtgaggaga aacattattt 27480tgtattgttt gaatgtaaat acatccatgt acaaactgca taatattttt taaggtattg 27540gagttttgta ttgctcatca ttgtatccaa acacccagta tagtacctta acaggtaatg 27600ttaggaagtc gaagagatgg acatacggtt aatgctaaat cctgtgatgg tgagaagatg 27660ctctggttat gcctaattct ttctgcttca agcccagcta ggtctgggaa ttgcttgggg 27720aaactggaag cctgaaccag aggactgtgt gcatgtgtgc atgcgtgcgt gcgtgtgtgt 27780gtactggtag gtaataaata actactgtgt atctgacact atggtagttt atacttttta 27840tgtctactct aaacaacaac actacaaagt agtcaccctt gtacccattt tataaatgag 27900gaaactaaga ctaactcatt tatcctggtg tgttcttttt tcttttcctg ttagtgcaat 27960ttgacagtta cacaattgtt actaaataga atgtagccag ttctagagaa acttcattct 28020accagtgttt attttattat tttatttttt attagataat tcatactctt ggatcaaaaa 28080ctggtagcaa attgtattta gcacgaagta aatcttcctt cacacactac cctcaggcaa 28140ccgtcaacaa cttcttgtgt gtctttacag aaatatttta tgtgtataca acacatatac 28200gaatatttct aaaatttaat ttggagtatt ttacatactc caaatctttt ttttcacttg 28260acaatatatc ttgaaaatca ttatatatta ctagatctgc tgaatttctt ttaatagcta 28320tatgttattt gttgtaggaa agcctcaaaa tttattcaaa tccctactca tttatgattg 28380ttgtttcata tcttttgtta ttacaaagct tcagtgacca ttcctataaa taggccattt 28440tgcacatgtg gaaatatatc tgcagaataa atttctagag gtagagttgc tgagtcaaat 28500ttaaaggcaa agagtcttta aactcttcat agatattgct aatttttatc catagatgtt 28560atacaaatat acttcccctc agcaatgttt atccataccc tttccaatac taagggaacc 28620ctttcttgta caagagaaaa agaaagaaag aaaaatcaat ctaatttgct tataggcacc 28680taaagatttt tttttttttg gccttgccca gaagttatgc atttcagtga accctaccct 28740caccatcccc atttcctgga ataatattaa tactactttc caactgaaac tctgagatca 28800cattctttct tttctatttt atataatact ggcctacttt atatatgact gggatggagg 28860ttgttcattc tgctcatctg tgtattatgc aaatttgcct ccaagcagat tggcctcttg 28920caaccctggt gagaggtgac agcatgctgg cagtcctcag agccctcgct tgcacctccc 28980ctgcctgggc tcccactttg gcggcatttg aggagccctt cagcccccac ctgcactgtg 29040ggagcccctt tctgggctgg ccaaggctgg agcccactcc ctcagcttgc agggaggtgt 29100ggagggagag gcgcgagcgg gaaccggggc tgcgtgcggc gcttgcgggc cagctggagt 29160tccgggtggg cgtgggcttg gcggccccgc actcagagca gccagccagc cccgctggcc 29220ccgaggaatg agggacttag cacccgggcc agtggctgcg gagagtgtac tggatccccc 29280agcagtgccg gcccaccggc gctgtgctcg atttctcgcc gggccttagc tgccttcccg 29340cggggcaggg cttgggacct gcagcccgcc atgcctgagc ctcccaccca ctccatgggc 29400tcctgtgctg cccgagcctc cccgacgagc accaccccct gctccacggc gcccagtccc 29460aacgaccacc caagggctga cgaatgcgag cgcacggcgc aggactggca ggcagctcca 29520cctgcagccc tggtgcagga tccactaggt gaagccagct gggctcctga gtctggtggg 29580gacgtggaga acctttgtat ctagttcagg gattgtaaac gcaccaatca gcgccctgac 29640aaaacaggcc actgggctct accaatcagc aggatgtggg tggggccaga taagagaata 29700aaagcaggct gccggaggca gcattggcaa cccactcggg tccccttctg caccgtggaa 29760gttttgttct ttcactcttt gcaataaatc ttgctactgc tcactctttg ggtccacgcc 29820gcttttatga gctgtaacac tcagtgcgaa gatctgcagc ttcactcctg agcccagcga 29880gaccacgagc ccatggagag gaacaaacaa ctccagacgc gctgcgttaa gagctgtaac 29940attcaccgcg aaggtctgca gcttcactcc tgagccagcg agaccaggaa cccaccagaa 30000agaagaagct ccgaacacat ctgaacatca gaagggagag actccagacg cgtcatctta 30060agagctgtaa cactcacggc gaaggtctgc agcttcactc ctgagccaac gagaccacga 30120acccaccaga aggaagaaac tccgaacaca tctgaacatc agaagggaca gactccagac 30180gcaccacctt aagagctgta acactcaccg cgagggtccg cggcttcatt cttgaagtca 30240gtgagaccaa gaacccacca attccggaca cactgggtca ctttctgact gcactttctt 30300gaagtattcg tctttggtcc tgtggtagta cccagtggac aacctcactt gcctgtaaac 30360tacttccttg aggtattttc cctaacaacg tgaaatacat tccatttctc tgcttgctct 30420tttcatgact ctcatttcaa tggtccttag aaaacacttt ttttgattat tattcagctt 30480tgtaatactt atttcttcag ttccccatcc ataaagtctt tgatttagag gtcaaatctg 30540ttttgcttta ctattcctat ctaaagcttg aaagtatggt aattaataaa aacattccac 30600atgttaaatt agctttaatg ttagctttaa aagaagatag cagttaatca gtcttgatga 30660cgtagaggtt gacaggtaga aggatcctaa aatttaattc ctgggctgct aacttcaaat 30720ctcatctgta tcaacagttt tctcacttaa gtcattaaca tcgaaaatta ttttattaaa 30780tgatttataa ttgggagagt actatttctc tttctcccca cctccagtta tgagaagata 30840cttattccca gctttttctg ggtagagcta ttcaattttt tttttttttt tttttttttt 30900tttttttttt tttttgagat ggagtttcac tcttgttacc taggctggag tgcaatgctg 30960caaaatctgc tcactgcaac ctccacctcc caggttcaag cgagtctcct gcctcagctt 31020ctggggtagc tgagattaca ggtaagtgcc cccacgccca gctaattttt gtatttttag 31080aagagatggg gtttcaccat attagtcagg ctgatctcga actcctgacc tcatgtgatc 31140cacccgcttc tgccttccaa agtgctggga ttgcaggcgt gaaccaccgc atccagccca 31200atttgttttt taaatctttt tggcactcta ccaaatcacg aaggctcttc ttagttaggg 31260gaacagaagg gatttagtct taataaattt ttctccatgc catggggaag actctctcag 31320aaggtagcat ctagaacaga acattgaaaa gtttataaac aacaccagta cttcatactt 31380ttgttttatc ttccctttga gatagacgtt tagtccttta ctgttattac ctagcacaat 31440atctggcaca cagtaggtgg ccactgatta tttcttgaat gaagtaagga atgagaatat 31500tacctacaga gttagagctc tgcgcattac ttccttccag atttcataca tcttttttta 31560gtaatgaatg caaacaggct ctggggcagc tacattatcc ttctgaatca agacagggat 31620ttcgcaatgc ttattttcaa tttcttcaga aatgccttaa agatattaat ggaggtaaca 31680acttaatctc aaatagtaat ccatagacag aatatgtaac agcaatgttc tctgatctgt 31740tctttggctt ctattcccta gagaaatagt tctctaagac caaacagtct atagatagaa 31800ttgtagcaac agtcaattat gatgttagct atttgagaga cggttgagaa ttcagaaaaa 31860actactgaaa tgttgtaaga caactcactc aaagaacagt tcaaatagtg gaaaagggaa 31920atgatgatgt atccatttat tttgttctat tttttccaat ttcataggat agcaaatgct 31980gcccatttat ttattttttt atttttcata agttattggg gtacaggtgg tgtttggtta 32040catgagtaag ttctttagtg gtgacttgtg agatatgggt tcacccttca cctgagtagg 32100atacactgaa ccatatttgt agtcttttat ccctcgcccc ctccatctct tccccgtaag 32160tctccaaagt ccattgtatc attcttatgc ctttgcattc tcatagctta gctcccacat 32220atcagtgaga acatacaatg cttggttttc cattcctgag gtagttcact tagaatagta 32280gtctccattc tcatccaggc cactgcaaat gctgttaatt cattcctttt catggctgtg 32340tagtattcca ttatatatat atatatatac cacagtttct ttatacactc attgattgat 32400gggcttttgg gttagttgca cgattttgct attgtgaatt gtgctgctat aaacatgcgt 32460atgcaagtat cttttccaaa taatgattcc ttttcctttg ggtagaaacc cagtagtggg 32520attgctggat caaatggtag ttctactttt agttctttaa ggaatctcca cactgttttc 32580catagtagct gtacttgttt acattcccac cagtggtgta aaggtgttcc ctgctcacca 32640cacccatgcc aacatctact gttttttgat tttttgatta tggccattct tgcaggagta 32700tagcattgtg gttttgattt gcatttctct gatcattagt gatgttgagc attttttcat 32760gtttgttggt cagttgtata tcttcttttg agaattgtct tttcatgtcc ttagcccact 32820ttttgatgaa attgtttgtt tttttttctt acagatttgt ttgagttcat tgtagattct 32880ggatatcagt cctttgtcag acgcatagat tgtgaaggtt ttctcccact ctgtgggttg 32940tctatttact ctgctgactg ttccttttgc tgtggaaaaa ctctttagtt taactgggtc 33000ccagctacgt acctttgatt ttattgcatt tgcattttgg ttcttggtca tgaaatcctt 33060gcctagtcaa tgtctagaag ggtttttcca atgttatcgt ctagaatttt tatagtttca 33120ggtcttaggt ttaagtcctt aatccatctt gagttgattt ttgtataagg tgagagatga 33180ggatccagtt tcattctcct attatgtggc tagccaatta tcccagcaac atttgtttaa 33240aagggtgtcc tttccccgtt ttatattttt gttcgctgtg tcaaagatca gttggctgta 33300agtatttggg tttatttctg agttctctgt tctgttccat cagtctatgt gcctattttt 33360atactagtac atgctgtttt ggtgactgtg cctttatagt atagtttgaa agcaggtagc 33420atgatgcctc cacatttgtt ctttttgctt agtcttactt tggctgtgca ggctcttttt 33480tggtttcata tgaattttag aattgttttt tctaattctg tgaagaatga tggtggtatt 33540ttgatgggga ttgcattgaa tttgtagatt tttttggcgg tatggtcatt ttcacaatat 33600tgattctgct catccatgag catgggatat gtttccattt gtatgttgtc tattatttgt 33660ttcagcagtg ttttgtagtt tttcttgtag aggtcttttg actccctggt aaggcatatt 33720cctaagtatt tgatttgatt tgattttttt tttttttttt ttgccgctac tgtaaaaggg 33780gttaagttct tgatttgatt ttctgcttgg tcgctgtttg tgtatagaag agctactgat 33840ttgtatacac taatcttgta tccagaaact ttgctgaatt cttttatcaa ttctagtagc 33900tttctggagg agtccttagg gttttcaagg taaacgatca tatcatcagc aaacagtgac 33960agtttgactt cctttttact gatttggata ccctttttat ttttctctct catctgattg 34020ctctggctag aacttccagt actatgttga agaggagtgg tgagagtggg catccttgtt 34080ccagttttca gaggaaatgc tttcaacttt tcccattcag tattatgttg gctgtgggtt 34140ttcatagatg gcttttatta cattaaggta tgtcccttgt atgccaattt tgctgagagt 34200tttaatcata acaggatgct gaattttgtc aaatgctttt tctgcatcta ttgagatgat 34260catgtgatgt tttgttttta attctgtttt cgtggtgtat cacatatgtt aaatcatccc 34320tacattcctg gtatgaaacc cacttgatca tgtcatggtg gattattttt tgatatgttg 34380ttggattctg ttagctagta ttttgttaag gattttagca tcaatgccca acaaggatat 34440caatctgtag tttttaaatg tgcttttctg gaccggcacg gtggctaagg cctgtaatcc 34500caacactttg ggaggtcgag gagggcggac cacttgaggt caggagttcg agatcagcct 34560ggccaaaatg gtgaaaatcc gtctctacta aaaaggtgtt gtggcgggcg cctgtaatct 34620cagctactga ggaggctgag gcaggagaat cgcttgcacc cgggaggcgg aggttgcagt 34680gagccgagat cgcaccactg cactccagcc tgggcgacag agaaagactc cgtctcaaaa 34740aaaaaaaaaa aaaaaaaaaa gttgttttct gctatttcct gaactttatt acgtaaatga 34800gacacgtgag atctggaagg aggtggaggt gaagaccctc ccacctggcc tgcatccaga 34860gtacttgggg tgtggcactg gcgtgggccc caggaaggat cccagccagt tttggtgctg 34920gaggcccggc caaaggaagg gctgctctcc cgtcccgcgg gctccgaggt cgccgcaccc 34980gggcgcgcct gggcctcgtc acccgcgctc gtgacgcgtg cttacaaagg aaacttttac 35040aggtttcggt gggcagggcc ttttattgcc cttctgctcc acagcccccg tgcttaatcg 35100gttggttggg aggtttcttt cgtccgtggt tttggaaagt ccccgcctcc aaaccgcagt 35160cccgcagtca gttctgcagc ctcagggcct cgaacagcca tgcttagaat ccgtccttct 35220ttcctgctcc atctaccctt cccctctggc ttcttttttt tcactggaga aagcccaccc 35280gagtctctca gcctgcttcg gaggttactg cggcctcctc cacgggtagt tctgggaccc 35340gggtctagtc cgcggttccg gagcaggtcc ctccctggag tcgtcaggcc cagtatgcgt 35400gtgctcagtg tgctcgggaa acacgcgtgg gctttaacag cagatctcca taaaagggtc 35460ccggagatag cctctgcctg gcccgaggcc cagtgcctca aagcggacgc ctttgcgctc 35520ccggaggtgc tcacaccaca gcggagcctg ctggcgagtg gagcgtagga ctgcgaacca 35580gcaatctccc gagaagcggc gagggggagg ggaatgtctg tgaatcggtt atccctccca 35640cccccagcag aagtcgggga aatgggggtg gaagggggaa aaagggagag aacaggagtg 35700gggttgagga agggtaagga ggaaggtgag cttcctacag ctgcggggga aggtggagaa 35760aattttcagg gggacagctg agtggtagag ctagcgagct tcagagaaat gttgacagac 35820agatgcccag aaagtgagga tgccgggcat gggcactgcg taccaggcac aggagatata 35880tggaggcagg aaattggcac atcataagca tttgaccatc ctgccctaaa acaaaacaaa 35940ttgaacaaca acaacaacaa aagataatag caaaagtggc acagtagtga gctcgcaggg 36000cccattccta tatagaaaca cagaaaaata agcaaaagct gccagaattg acttcgtggg 36060aactctggga aacagtaaga aagttttaca gcaaccaagt

gagtgctgaa ccaaggcaaa 36120ggtaactgaa acgcaatgat agagaagagg ggcagggaag tgttgggtag acaaaggcgg 36180gtccctggta agggccctcc cctgggcctg tgcccactgg acctaggtga ggacaggcac 36240tccttccttc acgcccaaat gttgcatatc ccaagaccac cctgtcccgc cacgccccca 36300tcctttgcct atgaaaaccc tgagacccta gcaggcagac acacaagcgg ctctatgtcc 36360agaggaactc atcggaggaa ctggacgtgg agcggggcac cccagcggaa gggagcacgc 36420cagtggaaga gcacactgac agaccatagg agtcagtctg ttatattatc atagtataat 36480attataaaat tattataata caataaaaat ataaaaatat aaataatgta ataaatatgg 36540ataaaaataa taattacata tttatattta tatgagaaca ctatgaataa ttttaagcca 36600aaaaacaact cgatgttcat cactggatga gtagacgagc aatttccagt atattcatac 36660aatggaatat gattcagcca taaaatgaaa tgaggtactg atacatgctg cagcaggaat 36720gaacccccaa aacactacac ttggtgaaag aagccagaca cggaaggtca catattgtat 36780gatcccattt ataagaaata ttcagaatag gtaaatccat agagacaaaa ggagttttgt 36840agttgccagg agttggaggc aagaagagtt taacaggtat gcttaatggg gcctcctatg 36900cagttgacga aaatgttttg ggctagatag gagtgatggt tgcataacat tgtactaaat 36960gccactgaat tctactcttt aaaattttta gttttatgtt atgtggcgtg taccctaaaa 37020aaaaaaatag aggtgcagtg ctccagcacg ggatgaggca gcgtggacag gagcatctcc 37080caacctcagt gaagtctgag ccgcgtgcct gcaacaatcc cactgtggca gagaaccgca 37140gagttccttc cggtttggca gcagtcattc gcaacctcac agccctctgg aaccccagcc 37200tgggggtctc agaacgccga ggcggggact gggagccgag tcggattccg agactatggg 37260ccagggttgg ctggattcag ttacctggct gaggcctggt gagcaaaata tcccaaacct 37320cgcgtgatct ggaaggggaa gccggataaa tacggatctc cagatgtgcc agtctcgagt 37380ctatcgatat gaggtccccc tagagtttct attcatcatt ttaaccgcat ttcatcgatc 37440ttgagacacg gcttttgata ttttatcacc tcaagataaa tagtgttaga tgtctaatag 37500cagcgttttt ctaagagata catgaaacaa cagtgtcaga aacgatgctg tcttccatgc 37560gatgaaattg ttgtaatagg tgctcaataa atgttgacaa taaatgagtg aatgaatgaa 37620aattatttta tttttatttg agctttggtt ctgccatttg ctagcagtgt gactcaagag 37680aagccagtaa cccccctgag cttccctagt tcacaaaatg cttgtcatga agtcgacagc 37740ttccggaggc tgcgaggctc gcaagaaatg cccacatgaa tgtgcgctta gggcgtgagt 37800gctcactcca gaaaactcca acacagtgaa aaggcagaag cggtgttttt cttttttaca 37860tttttataag aatatataaa aaatgatata aatggacatt tacggtagtg ggggaaggca 37920tatatctacg ttaaaaggca ggacattttt aaaagctcta ttttctaaat gaaaactacg 37980aaagcggggt gggttgtggc gggggcagtt gtggccctgt aggaccttcg gtgactgatg 38040atctaagttt cccgaggttt ctcagagcct ctctggttct ttcaatcggg gatgtctgca 38100gagggcagaa agaaaacagg cgttagaaac ctgaggtcaa agatgtgtgg cacatcccgc 38160cctcctctct tgccgtccct accggcattg aaatacttat ggataaagtt ctcgcaatgg 38220cttcacgtgc atgtacccgc cgccaccgct ctcccacacc tccctggtcc agcagctagt 38280ccactgcccg cctggctgct ccaggcgcgc cgaccgctca agcgctccag gtccacccgg 38340cggagggcag agaaagcgcg accgcgcggc ccgcagggtt gcaagaagaa aacgagtgtt 38400atataatgag tctcagtggt tgctcacaat gccaggcgcg aaggcgtgaa gatgtggcct 38460ttcccttccc gcatccccag gcatcttttg cacctggtgc ggagtgagcc agccagcttg 38520cgataaccaa agggcgcctc aggctctggc gctcctcggc ggaatcccgt agcttcccta 38580cgcatgcctg cttctacaaa cccacaaatg gtttccgatc atttctgaaa caaaatggat 38640gctcatttat tcatgtgctc tggcttctgc cttcctctct aatctcgttg cgtatgggct 38700ccagctcgcc gttcggttct cccgaggcag catttacact tgagagtctc aagattattt 38760tattcctgag ggagcatttg cacttgaaag tctcttttta cgtttattcc tgaggcagca 38820tttgcacttg agtttctttc tcccgtagct tgcattagat tctccgacca ctctttagct 38880tctcctccta ttcacacttc atatttaccc attgcattgg ttttataaac tcgctctctg 38940aaaatagatt gttatcttcc ttaacgtctg tttcccaggt cgggcaagat agcttgggac 39000tgtaatccca gtactttagg aggaggaggg gggatgatcg cttgagccca gataacatgg 39060tgagaccttc gtctctatta aacaaacaaa caaacccagg cgtcgtggcg tgcacctgtg 39120gtcccagcta gtcgggaggc tcaggtggga gaaccccttg agccagggag tttgaggctg 39180cagtgagctg tgatcgcgcc actgcactcc aggttgggca acagatcgac tctgtctcca 39240aatgtaaacc ccatgagggc aagactcttg tttggtctca ttcaccttgg cgtgcccacc 39300acctagaaca gggctgatca cgcagtagaa tctaaccata taattaattg tgcttgaaga 39360gggggtgttg gggagtaaga gaaggaaggg aggagggaag aaatgaaaga cttgtgtgtt 39420tggattaaat atattaggtt tggttaagag tcgttcagtt tattcatttg cttgtggccc 39480aattcagtag ttttactccc tctcccactt ggctcctcag gctttttgct cagccctgga 39540accgcgctgt aattggcagc tccttctaaa tcgggacccg gatgctagct gtaactggag 39600ccgaagtctc cttcttcacc tcccgggacc tggatgctag ctgtaactgg agggaattgg 39660cgggggggag gggaggaggg gccgagtaaa gaagaacttc gcgtctttaa cttcgaaggt 39720gattttgcgt tctgtattta cagcatctcc aagcagaggg cttagagcta actcttcacc 39780ctgtcctccc cagctcccct atggcccaag gagcccaatg cccccgttct gggccaaaat 39840aagatggatt tcataatctt caaggtcatg ttttacctta aatattcgtg ttaattcccg 39900tgtactgttt catatatcta ttttgtttca aaaaaaaatg ttcctccccc cagaaacaat 39960tgagtaatgt tggcagtttc agcagacagc tgtgggagta gggaactggg gccatggaat 40020gggggcggag ggaggatgct ttgagatcac aaaaaggaaa ggcaagggca aggaggacca 40080taattctacc ttcatcgctc agcgatctct tgcacaagtt taagagggaa aggagccaac 40140tccggtgcac agactgccag ggtcagcgaa gtcttggtcc tgatgtcccc agaaccccct 40200ggggcagctc tggaaaactc taccgcataa agcggagggt cagattagct gaggagggtc 40260agattagttg agttgtgcag aagagccgag atcgagagat ctccagatga tgccacgcac 40320aattgggttt ggaaatcctg aggttggtcc agccagcttg gtatgcaaat gaggaaacag 40380acctggtaag tggatgcaac tggccctagt ttggaggaag agggggcact agacctctag 40440cctcttgagt cttcattgct ccgcagtcta ggccttgaac tagcagaggg taggtgtttg 40500ggtggtggta tgctttggga agtataatgt acaaaatggg ctttcacgtg cgcaagtcca 40560tttcgggatt atttcccatt tgccgccctg gcggggcagg gcgataggga gactcaggcc 40620gtcccaccga ttggcgcgtg agctgaggca agaccggaga ctggtctccc gggctgaact 40680ttctgtgctg gaaaatgaat gctctgagct ttggaagctc tcagggtaca aattctcaga 40740tcatcagtcc tcacctgagg gaccttccgc ggcatctatg cgggcatggt tactgcctct 40800ggtgcccccc gcagccgcgc gcaggtaccg tgcgacatcg cgatggccca gctcctcagc 40860caggtccacg ggcagacggc cccaggcatc gcgcacgtcc agccgcgccc cggcccggtg 40920cagcaccacc agcgtgtcca ggaagccctc ccgggcagcg tcgtgcacgg gtcgggtgag 40980agtggcgggg tcggcgcagt tgggctccgc gccgtggagc agcagcagct ccgccactcg 41040ggcgctgccc atcatcatga cctgccagag agaacagaat ggtcagagcc agggtggggg 41100ccggcatgac ggaaaggaag cttgtgtaga gccccctcac cgccaagcag acccccacac 41160aagccccagg tgtctaatta cccctacatt tgcttccagt ttccaatttc cttcttgagt 41220tctctatcca ttcttcagta cacaatgaat tccattatat cctccgaact tctgcggagc 41280tgtcgtcaca ggcagagagc actgtgaggc acgggcaaaa tagcaaaggg gcagggacag 41340actgactttt actccaggct aacttcctgt atttcccctg agatacaact actgaaattt 41400cttcctgaaa ttatgttagg cctggagatt tttttttttt tttttgttca ctgctgtata 41460tccaagcgca gaatgtggta attgttaaaa agagaaaact tgtttgtttg ttaaaacaaa 41520ttctcacaaa acttttaagt tacacttagc ttctgggaat gttgaacttc aatttctttt 41580tcattatatt agttttaaaa ttatatattg ggatagtaca gttgtatata tttatgtggt 41640acaatatgaa gttatgatct ttgaacacaa tggggaatta ttaagtcaag ctaagtaacc 41700tatccatcat ctcaaatatt tgacattttt gtcaaatgag agcatttggg atttactatt 41760tagctatatt catcatgcta tgaaacacat ctcaaaaaaa acaatcaaac ttattcctcc 41820catcttaact gaggctttat atcttgatta ccatctcccc attcctccca ccccccagct 41880ctagtaacca ccattctact ctttactgct aagaatgtaa ttgttttata tttcacagat 41940aagtgagaac atgtgatatt tgtctttctg tgtttggctt atttcattta gcataatgct 42000ctccaattcc aaaacttcaa tttcttcaag tataaaataa gaaggctagt ttaattaacc 42060ctaaaattcc ttcctgtggt aggctgaata atgccccccc acccccaatg tctatgtcct 42120aatcctcaaa aacttttaat acattaactt atgtggcaaa agaggctttg cagatgtgat 42180ttaattaatg gtcttgaggg agattatcca gaattttcag ggtgggccca acataacccc 42240aagtgttttt attagagggt cacagtcaga gagaagatac aagaatggaa gcacaggcca 42300cagagaaaat acagagacca tgagccaagg aatttgatgg tcactagaag ctggaaaaga 42360caaggaaaca gattgcccct tagagtttcc aaaaggaatg aaaccttgtg gacccatttt 42420tgacttctga tctctagaac tgtaaaataa taattttgtg tttgttttag ctaacacatt 42480tgtgataatt tgtaacagca gcagtaggaa actaaaacac ttcccaggtt tatgatttga 42540gagttcatta aacaagagat ggtcacctct ttggttccta aatcatcttg gaaacaaagc 42600catttccaga gaggaatttt aaaatactgt ctgcagtcat agcaacctta aaatttgagt 42660gctgcatggt ggaagtagac aatttatttt aggataactg ttatttgtta tattagtttg 42720aggatggtgg tgttaaagag gagttactta tttttaggta catttcatac taaacacaaa 42780ttgcataatt tgcctaaatc aaggaattat actaaattat attatggtta ttaaatcctg 42840tcctgagaaa gtgaaactga ctcagttttc aaagagacaa agagaaagta taagcaaacc 42900aaattgcagc tacaaaaaga aagacaaaat gttgcagtat atttattgtt ttgtgtattc 42960aatgaagtcc ttcgtcttgg tcataaaact agccttaaag gtttttctta tatttcatag 43020tatgaaaaat ctaaaaagta acccatatgt aaatatttaa atcatgatag aaatccaaag 43080caaaaagaaa atgaatcaat tgaattaaaa tgtgtaggat gcttaaaccc atttgataat 43140atatccattt gataatatac taatatgaat ttagtacttt aaaatgttat ataaataaat 43200gttcctatat taaacaccaa tgtagttagg attctaagcc aacatcattt ccccttttct 43260acatgttctt ctcccgtctc cattaaaaat tgtcaaaact atccactttt ctttttcctt 43320tttgttttta aacaaataag gtctcttcta agatattgta ggactacaaa gccaaactcc 43380cgggttcaag ctgttggcaa aattttagag atgctaagtt acccatgtat taattacttt 43440taaatcctcc cctaactccc tcacaaaaca ggagtaggga gaggagaaac acctctgttc 43500aaaaatgagg aattgaaaac tcttatcaca aataaactat atcaagtaag ctaaagatag 43560taaaagagca aaaatgttag cagatattcc caaaatggta actacatatt acctctggaa 43620tgatcacatg aatgtggctc attatttcct aagttcctac agcaaacata tatttatttg 43680ccctactcag ttaaaaataa acacaatatg tagttgcttc tgaataattt ttctctctct 43740ctttctctct ttctttcttt cgacaaagtc tcactctgtc acccaggctg gagtgaagtg 43800gctccatctc gctgttcact acaacctcag cctcccgggt tcaagcgatt ctcctgcctc 43860aacctcccga gtagctggga ttacaggcgc ctgccaccac ccccggctac tttttgtatt 43920tttagtagag gcgaggtttc acctgttggc caggctggtc tcgaactccc gacctcaggt 43980gattcccccc gccttgatct cccaaagtga agggattaca aggcgtgagg caccgcgccc 44040ggccgcttct gaataatttc gatcaaaatt tatattcgat atttattcca acatacacca 44100cagatttcca ctgataatcc ctcctagtaa gaaagataag ctccatccag gtatctgtga 44160attggaggct aagtagtccc agcacatctt acatttcttt aagactccct ttttatccca 44220aacgttcgta aattttgtat ctgataaaga gcatacttcc atctaataca aatatgttcc 44280ccccttcaga tcttctcagc attcgagaga tctgtacgcg cgtggctcct cattcctctt 44340ccttggcttc ccaagccccc agggcgtcgc caggaggagg tctgtgatta caaacccctt 44400ctgaaaactc cccaggaagc ctcccctttt tccggagaat cgaagcgcta cctgattcca 44460attcccctgc aaacttcgtc ctccagagtc gcccgccatc ccctgctccc gctgcagacc 44520ctctacccac ctggatcggc ctccgaccgt aactattcgg tgcgttgggc agcgcccccg 44580cctccagcag cgcccgcacc tcctctaccc gaccccgggc cgcggccgtg gccagccagt 44640cagccgaagg ctccatgctg ctccccgccg ccggctccat gctgctcccc gccgcccgct 44700gcctgctctc cccctctccg cagccgccga gcgcacgcgg tccgccccac cctctggtga 44760ccagccagcc cctcctcttt cttcctccgg tgctggcgga agagccccct ccgaccctgt 44820ccctcaaatc ctctggaggg accgcggtat ctttccaggc aaggggacgc cgtgagcgag 44880tgctcggagg aggtgctatt aactccgagc acttagcgaa tgtggcaccc ctgaagtcgc 44940cccaggttgg gtctcccccg ggggcaccag ccggaagcag ccctcgccag agccagcgtt 45000ggcaaggaag gaggactggg ctcctcccca cctgcccccc acaccgccct ccggcctccc 45060tgctcccagc cgcgctcccc cgcctgccag caaaggcgtg tttgagtgcg ttcactctgt 45120taaaaagaaa tccgcccccg ccccgtttcc ttcctccgcg atacaacctt cctaactgcc 45180aaattgaatc ggggtgtttg gtgtcatagg gaaagtatgg cttcttcttt taatcataag 45240aaaaagcaaa actattcttt cctagttgtg agagccccac cgagaatcga aatcacctgt 45300acgactagaa agtgtccccc taccccctca acccttgatt ttcaggagcg cggggttcac 45360taagtcagaa accctagttc aaaggattcc ttttggagag tcggactgct ctctccttcc 45420cctccccttc ccctcctgcg tgtaaaacgg ctgtctgggg caagggtttc tcagacgtgt 45480acattgcctg gtataagagc agactctgaa aagatgaggt ttatttaata cggacggggg 45540agaattctgc ctgtaggcag ataggaaaat ggggagggag tcattggaag gacggactcc 45600attctcaaag tcataattcc tagaccagaa aaagtgctca gtgttctaga agcagagttg 45660cacagtgatc caaagaccag cttcaaatac tgtcctgtct ccttcacact tctcacattt 45720ctctttccta ctgaaaatac cttgcatttt tcgtaattat aaagggggaa gggaatatga 45780gtgccccctg ctttataggg gttgttgtga gtttaaatga tgtattaata catataagcc 45840ttaagaacag tgccacacat cctaagctaa tacctgttag ctcttgaatt atccgctttg 45900aggactggct tgcaatcttg ttttgaggca tagaaagaaa atgctttgga gcaggacgcg 45960gtggctcaca cctgtaatcc cagcactttg ggaagccgag gcgggcagat cacctgaggt 46020caggagttcg aggccagctt ggccaaaatg gtgacacccc gtctctacta aaaatacaaa 46080aattagctgg ccatggtggc gcacgtgtgt aattccagct actcaggagg ctgaggcagg 46140agaatcgctt gaacccggga ggcagaggtt gcagtaagcc gagatcgcgc caccaccctc 46200cagcctgggt gacagaatga gactccgact caaaaaaaaa aaaaaaaatg ctttggatag 46260aattatcact attacataaa aggaaagtcc ggatgcggtg gctcacgtct ataatcccag 46320cattctggga ggccgagaca ggcggatcac ctgaggccag gagttcgaga caagcctgac 46380caacatggcg aaaccctgtc tctactaaaa aatacaaaat tagcggggct tggtggcgca 46440tgcctgtaat cccagctact cggaggctga tgtaggagaa tcgcttgaac ccaggagaag 46500gcggaggttg cagtgagccg agatcgcgcc attgcactcc agcctgggag acaagagcga 46560aacttggtct caagaaaaaa agaaagaaag aaagaaagaa agaccaagaa gaacttactc 46620cctgaaaaga ttatgggcac cctccaccac cctcacttac aaagaaaagt taaacagcac 46680taaagagtat aacaagcgca aggaggtaaa agttctaatt tttcctgtga ctactacttt 46740ttaagcttat caaaaacatg tactacgttt taaaaaatgg attgctcaga ctttgctgat 46800gccttaagca catgcttaat ctgcctactg gataatccag ctctgtttaa aagttatatt 46860tcaatccctg gttgacttaa accttgtaga cccagtatat cttgtacttt tagtgtctgc 46920ttgattttaa aacatgtagt ttttaaaatg aagccaatga aaacaatttg ggatgtcaag 46980tatgttatta aaatctacaa tgcattactg taccatttat attttcctcg gggtacctct 47040caattagctg tgtagcaatg atagggaaaa ttcaaactat cgataaataa aattatttta 47100gtttagttta agatatttta tgatggagga ggaagaaagt ggttgccagg atgggaggga 47160gggaacacat ttccatcact aatacaatgg ttctttcttt ttgtttgttt gttttgtgtg 47220tttttttgag atggagtttc gctctgttgc ccaggctgga gtgaaatggc accgcacgat 47280ctctctcggt tcactgcaac ctccgcctcc cgggttcgag caattctcct gcctcagcct 47340cccgagtagc tgggattaca ggcacatgct gccataccca gctaattttt gtattattag 47400tagagacggg gtttcactat gttggctagg cttgtctcga actcctgacc tcaggtgatc 47460cacccacctt agcctcccaa agtgctggga ttacaggcat gagccatcgt gcccggccta 47520cagtggttct taatgggggt gggagagtgg gaagagtagg ctccttcaag agtctgttga 47580aataaatacc ttcttctcaa aaaagaaagt aggtaatgat tttttttaaa aaagatgtgt 47640tcacttgcac atgtatttct agataaaact ttcagtgaat tcagggattt ctctgaaact 47700ctaccatgga ttcctacatc aagaactctt tcagctcttg tgaaaaatat atatagctat 47760tggtgaagaa gatgggagat gcaaccatat aaaaacaaca tttggatgca ttataaacag 47820gtgtaaaagt tgactgcttt ggaaatacca agaacaagtt ttagatatgt atatctcata 47880tcttgcagta gagctctgga aggattatgg catccttggg tggggccatt ttgctctaga 47940aattgaagtc cattatccat tataaatctt atgtaggggg gaggggggag ggatagcatt 48000aggagatata cctaatgcta aatgatgagt tgatgggtgc agcacaccaa catggcacat 48060gtatacatat gtaacaaacc tgcacattgt gcacatgtac tctaaaactt aaagtataaa 48120taataataaa attaaaaaaa tattatgtaa ataattaata atagtgggaa aactttccta 48180gtttttctgt taaagagccc attatactcc cagtttactc atacatatcg acctgaggtg 48240caaaatccta gaagaatgaa aatataaagt cctggatctc tgtgctcctt atgccagtct 48300cagatttcct atgtgcaaaa tgggattata atatatttca tgtggccata aaatatgata 48360atgtatgtcc aaaagctttt aatgtaaaaa tttactacat ttactaaatt tactaaagtt 48420tgttggttat tgttattatt attctcacac ttacttttcc tctttcctga gaatgccatt 48480ctttttttag atttgcactg cctttgcagt tttgaaaatt ctacacgtga aatttaaacc 48540tgtcttaatt ctgatcagtc ttataacaaa aaaagactac cacctgttca ttcattcaac 48600aagctcagaa actaagggca gacatggggt gggggcagag gggagtaggt caaacatagt 48660atctctacag tcagactgcc agggttcaaa cctcaactgt tccacttatt ggttctttaa 48720cttttatcaa agttactcaa catgtctggg cctctgtttt ctcatttgca tgattaggat 48780aataactgta cttgcctcaa acagttgttt agggattaaa tgaagcatgt aacgctctta 48840gaagagcaaa ataaagcaca gaatgataca agaaaatgaa aaggtgacca aactcattct 48900catttgtctc tagtaggcaa aggcttccgg atgctgagag ctgatcccag tcttgaagaa 48960tgatgtgaga gtttaaagat ggaaaagaag gagaaagata ttctaggcag aggtaagagg 49020atgtgcaaag gcatagaagt ttaggaaaac tgaaagtgat tcatttagac ttattcctga 49080aaaccagcct gtgaaggact cctcagagag ccaaaagaaa aactaggata atgggatggc 49140aaggaagtgg ggacactgcg ttgactactc tttcatagct tggttgtgat agttcaaggc 49200cctatgccat gaagtgaggc agatggaagg tggaggagac ctgagcacac atatacctgg 49260aagggcaagt gccaagtgaa gagaagggaa agttagaaaa gaataaaaga aaagttaagt 49320acacaggcaa gataggatat ttttgaggac ttgaggtccc tcaaaaataa tgaagaaata 49380gaactcaaag tacagcggtg gttatagatt ttgtcacaag agatacatag atttgggagg 49440gagaaaaggt cagaacgggg aggaagttga ggcacttcct tctatgaatg aggaggttag 49500cttgtttgca gagtgaaaat aagatggtcg gttaggaagt ttgagaatcg taaaggtttg 49560gaatacctct tatgagtaga gaggatgggt tgagtaagac tcagacagag aagccttttg 49620ttttgttctt taaaaccaga ctggagaacc cagctgaggg tggagatcat gacacagtag 49680ggacacctga ttactttctt taaactaaag aaagccctgc agtggtgcta ctacttcagc 49740aaccctacaa atcaaagact agtcataata gatgtgaata ttaattcaac atattaccat 49800aaagagacag aaagatactt gagaaggtag tgttccagag ttgggttctg gttctgatgc 49860ggcattgtag gattggcaat atgcacgtat ttcatgggat aagcaagatg attttgttag 49920gaaaataaag ggagttgagg caatagctct acactgagac caagtgacag ttctcatgta 49980tctaatgaac tattttttga ctgcaaaatc ttttgagatt atttctagat tcattgtcca 50040taattttcaa aatgggctct ctcttgttct attgtttacg cttgaggtga gataatacac 50100acatatttct ttaccagttt caatattaac attattatta aagataattg ttttaaatat 50160agcttggtgt taaaaacaaa atatacatag aatatctctg gggagataca ggaaaagctg 50220ttacctgtga ggtaaggaaa tgaagaactg ggatgggcat gtgacttact tttcacattc 50280catgatttat attgtttgaa ttttgtacta tgtccatggc ctttctaatg aattaaataa 50340acataataaa actagtagac aaataagtta cttttattag aatcatcatt cataacttta 50400gttgaaaaag agtaactgag tacctaatat atgtcaggca ctcggcttaa agttgtcaat 50460attaattaag aaagaaggtt tcttagtcaa gagcatgtat tggtaacaac catcaatata 50520tttgcttctc tgccaggcgc ggtggctcac gcctgtaatc ccagcacttt gggaggccga 50580ggcgggcgga tcacgaggtc aggagatcta gaccatccta ggtaacacgg tgaaacccca 50640tctctactaa agatacaaaa aattagccag gcgaggtggc gggcacctgt agtcccagct 50700actccggagg ctgaggaagg agaatggcgt gaacccgggg ggcggagctt gcagtgagcc 50760gagatcgcgc cactgcactc cagcctgggc aacagagcga gactccgtct caaaaaaaaa 50820aaatgtatat atatatatac acgtatatat atatacgtgt atatatatat atacgtgtat 50880atatatatac gtgtatatat atatatacgt gtatatatat atacgtgtat atatatatat 50940acgtgtatat atatacgtgt atatatatat atacgtgtat atatatatat acgtgtatat 51000atatatatac gtgtatatat atatatacgt gtatatatat atatacgtgt atatatatat 51060ttgcttctct ggaggaggaa ggtggtcttg aactgggatg agctcttgag tggagcctac 51120agtaatcatt tgaggaggga agactggggt gatgcattct

gataaatgac acctcacact 51180tgtgttacca ggaaaaaaag atttcagagt ctggaaaagc tcccataatt aaagagaatt 51240ccttaggaag tagcttatga gagcgagata tatgccctgt aatggagctc ccaggtacag 51300ctgtgttaag ccttcataga tgagttctag aataggatgt tgggtgcaat agataattat 51360ttgaaggcaa aggcaatgga ggaataattc catgcatccc tttaatttag aaaagcaata 51420atgtaaggaa attagagtcc ctgtcctagt tctaccacct actttgttac cctgaaaaaa 51480tgactttttt ttttttttac tagcttcaat gtcttgatct acaaaacggg tataatcaca 51540aacatgtaaa aacagattgt ggtttagccc cgaagtgcca aagtgctcct gaagctgccc 51600cggataaaaa ttctgataat cgagtccaat gtgggtggta agagcatttt aaacgggaaa 51660gaaacacttt cttaggtaaa taattgcaag gtatttaatt acttatgttc cacaaggaaa 51720aaagatagct tcagcatgaa agggagacct ctgagaaagt agagcagacc tccaaacaga 51780tttgctaaga aaaaacaatg tgtccctggg agtagatctc tagaagtttc aaaacattgg 51840atgtttcttt ctccctttta ctattctcta tttaattaaa ttcaatatag cacaattatt 51900tagtatttgc tataaggaag gtactctttt agaaactctg tgccaacttc cctcattcag 51960aattactgta aaatttatct tcctactcaa actggatctt agtaaggagt acaaaatgca 52020aaattctttg atgtgttgta gatttaatgc ataattatag ttaagtcaca attttcaacc 52080ttagtttcca aaatgttaac tgggtataga attagcagta cctattatca tcttcccaag 52140aatattttga aggaaactta aaagtatatt acttattata tagcaggtat cttttctaaa 52200ttatgtgcaa aacaaatgtg attttaaatc tatgtgagaa atttactatt aaaatatctc 52260tagggtgtac tcttgtgaaa tgagggatct ttgcagctca tggagacaat tattccttaa 52320cttttttgta aatttttttt atgttgataa attacttgtg gcgaattact tatatctatt 52380tgtagctatt tgatcagctg agaacactaa aagattagca cagtatgtat gtatgtacat 52440actatatgca catatttggt atatatgtat attatgtaca gcacagatat tgagaattga 52500cctcatcctg aggaacaaaa taagtaataa acataattag aggagatagg cagaaagaaa 52560tagagataat aaaaaattca ttaaaagttg ccaagaaaat aatggctatc attttttcaa 52620cccccagcta tgtgacaagc atcaagcagt tttatatgtg taatttataa ttccacagct 52680gtcccatggg atagagagta ttattctttc ttcataatgc agacaaaaaa aaaagctcag 52740agtgcttaag taataaggaa aagaaaagtt caaacttaag gttctcagtt ctgtttgaga 52800ggtcctcact ctccctacta caatatgttt tcctaatgat aatttatcca gtacattgtg 52860gacaactcat caatgcttcc ttttctttga ggactctgct ttagagcaag ttgcaaaacc 52920tgggccaaga ttactgactc tccattttca gaaactactg tgcttctatg attattcttc 52980agtagtaata catagtgata gaaatttgga actcaaagac acgcaaagtc ccctgaaagt 53040cacttaattc agtcccctca tttttgaatg atttgctttc ctgattaaag ctcacatatt 53100taaaaataat taaggaatta gctgcacata gaaaatgaaa aactacccca cacaaagcaa 53160taattattaa cattttgaaa tacttcttcc tttttctttg cttaatcttt acattgtgaa 53220tattatgcaa ttttgaaatg agctttttct aacttattac agcattttcc aaacttctcc 53280aaaaacactt cataaatgct acttttaaca gctgtaacac atcccactgg aaaaagttat 53340aatttactta atgatgtccc tgttgtcaga tatttaaggt gtttctaatt gctactaaaa 53400atagtattgc agtttttcaa agggtagaag gctcttgaat atattgtaaa actgcttttt 53460aaaaagccac cattttgatt tatagataac aaaatggagg agtggtacat attgaggaac 53520tatgtagcta tggttactca gctaataaat gtttgctgta gctgttgaag tcagttcctc 53580tctccattct ccattctttc tatggccaca gctacttaat tggacttaat gtgggtggcg 53640ggaaatgcca accatatcct taatcataat tttggaaatg acacatatgc aagtgggaca 53700agcctagtct ttaaactcag atagaactga cctctcattt accagctctg tgggcttgaa 53760taagttatgt aaactttctg agcctttatt tcctcacctc acaaagtggg gaaaataaaa 53820tttaccccat aaggttactg tgaggaataa agaatgtcag atatataaaa atccgggtgc 53880acggtaggct ctcaataaat ggtgcttttt aattttttga gaatatatat gacatttact 53940atgaagttat tcatttaggt catcaaaata aatgtccttt tgagtaattt ttcattaatt 54000cctgtacatt ctagcaggta tctgtggttt caacaagcaa attctcttct aaaaggtatg 54060atgctacctc tgaattctaa ccctctgaaa aaacagcttc tttgtaacaa agtttcccat 54120gttatgacag aagaatttcc aaaaaaaacc cctcattaaa tcatgagaag tgacactgga 54180gagtgtcact gtgttcagtg tttcctctgc attcattgct acccacctcc actgcttgga 54240gtgcatttca agtggaaggt acaatggaga aactacagtt aaaactgagg aattgcaaaa 54300tttactttct ctaaactact tttcctaacc tccctctttt tcattcttga taggacagat 54360tttcccctct caaatatgct gtccttttta attgctaaca caagcatata taatatctca 54420tttctgctta tgctgctgat gtacgcatgt gctgttagag ttctgagata atgttgaaag 54480tcacagataa ataataatgt attcggtttt cactactggg agtggaggtt taatattcat 54540gtttcactga taggtttaac actggtttag gatactctaa tttcaggggc accatctaca 54600tggaagcttt tctcatcaaa tggagaatgg ttgtccccct tttgcccctc taaaaaacta 54660tcctttaaaa gtagcttgct ttcttgggac tctatagtct tactgttatg ttcaattttc 54720tgtgtccttt cctgaactta ggagagttct gaagccaatc tcccctctga tattattaaa 54780gattgcaaga aaattttctt gtgttagacc attcttcccc aaatcacatt cttcacctga 54840tatgtgattc aactccactc aagggaatca acttcttgat gaaatataat caactttgat 54900taaataagta actgcttcct attcatgttt tagcactttt cacatacaga tttaacattt 54960ccactcatgt tttcctttga gtctctgggt tgagggtaga gttttatctt ttgtgttgtt 55020acggttaaga tgataacttc cataattaat ttttcaaaaa ggcaatgata acagaatata 55080ctgtatgttt actctgtact gatttaaaac ccccaagtca atttagcctt aagaaagcat 55140actatttagt gtattttgtg ttactctttg atatcctact tctaaataac ttcttcacat 55200ttgcataaaa ataactgaag gtcaccctcc aaggtaggca ttttgaatgt cgtaaggatg 55260acagtaatgt ttctgcctat cattcctttc atcacacaga cacacacaca cataattttt 55320tatactaaag aatttttaga aaattgtttt ggtcaaaact gttgattcag atattcagac 55380tgtgacaacc attctgaagg aattaaaaat ccagttatct tcagtgattc ctttggaaat 55440tattattctg ggttattaga tagatagact aataactttt tttccagttt tctaaagcta 55500ccttgatttc ctgtcttaga aaacaggggt tcacaaacac tgcttaatat ctctttaatg 55560attatgaata ctagaatagc ttagaggtat accctaaagg ccaccatata gatcttctgt 55620acagatgtga atttaaaagt atgcaaattt acactgattt tacctaacac cttggaacat 55680accaggagtc tgaatacata aatatatttt tattatgata tgtatatttt taaagtggag 55740tttagaaatt tctagctaca ctgaaaaatt ataatgaagt aggtatttac tgtaaaaaac 55800taatgtgctt tcttaagggc atagtttaat taggcactat aataactgac aaacgtacac 55860tgtgtaaaag tttacagtga ctcttcacac atactatttt atctacctct tattacggga 55920ctaccatagg gtctcaggtt tacagatgag aacatgaaag cactgagagt ttctcatact 55980tcattctggt accatgacag ctaataagca aaagaaatag aatctgctca caggtcatgt 56040gaatgctaaa gaaagtaatc tttcaactgc acgcttcaag tggttcctgt gctggtgaat 56100aggtatccca cttattgctt ttaaattaag gtaggaataa gtaatttata tgtacagtca 56160tatgagaatt tttcactggt tttattttgg tcaaaaaata aatttttgaa agatgttaac 56220ctcctttcaa ccaataaata tttactgtga cttatacggc tgatgcttga gtatagtaga 56280ggcccaaagg ggttaagcga ctttcaaaat aatagttaac taaaagagat ggaactgaaa 56340ccatatacat atttatagca ctccatgggc aaccaagttc aactatatat gaattactag 56400tcaatgactt ttggtaggcc atgcaaccta tctgagcctc agtctccaga tctacaaaat 56460gaaaaaatga aacattgaaa acataaggat attgtgataa ttaaattaga taatggaagt 56520tgaagtgtcc tattattgtt aagctcctcc taattgtttt tgaagaaaac aataacttta 56580ccatgtgatt taggaagaaa gtttcaataa gcttttaaaa attaaatgtt aaatataata 56640tattcaactt caactattca gcatgtaaat tgcatggagt aaaattcaaa gtgtccgatg 56700ttggacattt aacaattaga tgttcaactg ggggagtcat tgttctctag acagctgctg 56760tttctttaaa ttgggtgaga gagttataca attgctgagt cagatgatct ggcagcctga 56820aagagaatga gagcaagaaa atggtggcac tcgagaaaag aaagcaaaac aagctttttc 56880ctaatacatc agcaaagtca ctggtgtaat attagacaaa ttttagctta aaagcagaaa 56940aatgatcatt tgaaaggcat gatattttag tttttcttat aattgttact ttttagctta 57000catttttcat ctatatttcc ccccccatca ctgtgctttt acagagacat aaagacccat 57060cattttgtcc ataaatgctt tattctgtta tggctacatt ttcctgcaat cttgccctga 57120tcttagataa gcataagtta aacctgtgaa acacttgtgc tttgattttt cttttttaca 57180taattttagg ttgtcatgtt tattacgagc ctggtctgga tcataaaatg aaagaaaccc 57240cttattacaa cacacacaca cacacacaca cacacacaca cacacagaga gagagagaga 57300gagagagaga tccattcatc ctgcacgaac agaaagaagt gtatatagtg ttttaaaaag 57360acaacgtatc ttatatagct tatgtggaaa ttttctgtct ggttctgtaa gctttaaaac 57420acaaatatat cttgttatat ttttttctct caaactatgt tctgactgta aaaatgtggt 57480atctacaaga cattcttttc caattcatac aaagggtcac ataataataa agggtctcct 57540tcatttggtg aaataactcc tccactgatt actcagactc tcctccctgg gatccagtaa 57600actgactcta aacttaaaat cttacctaaa atcctggacc tcaattcaaa gataaagaag 57660cagaaataag gtttaaaaag taaaattggt catatttgtc aaattgtgtc ccaatgggcc 57720acttgtatta gtatctcctt caagtgttta tttaaaatgc agatttctgg gacccacagc 57780aaatctgaat caaattttct gaacgtgaac cccagaaata tgtattttta aaggcagccc 57840aggtaataat gctgttgtta acctttgcca tacttttaaa atttctagtt actcacataa 57900ttcaattaag aaagcagagg cttttttatt tacgttacct tgattgtacg attttattag 57960tttcaatttg cttaagagat tacatgtctt tgttcatgta attctgaacc tctataaaac 58020ttttctctct taaaaaaatc ctactgcctt cacaaccatt taaataattt atgatatttt 58080attttgaagg tgaaagagaa aactgagaaa tagttgaatt aaaaaatcct ttgtgataac 58140atgtttatat tttcatgaac aaagccaata agtcataaaa attaaaaatc aacatactat 58200tttttgaaag gacctctgat gctttgggaa tttcaatcct gtagttgatg gctttcactt 58260ttttttccct tttattactt ctttttgatt gtagagttct gcccaaatga aaccatcatt 58320ccagggctca tgaattaaat gaatgcactg agagacactg acaagcactg agaatttctt 58380caaccaccct ttttaaaaaa caaatgctaa ttggacataa atatgagaac aatagacatt 58440ggggactact agatggagga gaaagggaat gagcgagggc tgaaatacta cctactgtgg 58500gtactgtgct cactacttga gtgacagatt cagtcgtact cgaaacctca gcatggtgca 58560atataccttt gtaattaacc tgcacatgtg ccctctcctc ctaaataaaa gttgaaaaaa 58620aatctacgag gcactatatt tttaaaaata ccactatgta caaggcactg tgctatatct 58680ggaactacaa atattagtta aatagtccaa gattcagtgg gttcagagac tctaagtatt 58740tgccattccc tttagatgga aacgttcttt ggtccaccaa gccctatcgt tctgctcttt 58800ggaaattctc cctcactttc ttcataatgc cgtccttgac taactctcct ctagcaatac 58860tattggtttt gtatgtgatt taaaatcatt cctgtaattt cttctgttta tatggcttcg 58920tacaagagat tcacattcaa caaatagaaa aaaaacgcta ttgacatttg gtagcttcga 58980caattgtaaa cacatgtggg tttgctgaat acacattaaa atagcatgaa ttaggatatg 59040gtaaatctgt tgcggtccca agttggtggg tttttctagg aagagtcaga ccctttaaaa 59100ggacctttta tcatctacca aacaaatcct tcatttatta attcccaagg ttttctccat 59160cggttggctt actgtcatgg aaattgatct tgttttaata gctacttact tttttttatt 59220ctaatcaatg atttcatttg aaaagaaaat tttcaaacat ggggaaagct gcaatataag 59280aagaaaacaa tggagagaca tcgtcactgg aaaaatacta cgggccactc tctataccat 59340cctgcacccc cagatggaga aactgaggga agtcgtggcc tttcaacact cttgggtctc 59400catctggctt ggaagggaac gaaatggctg tcaagagtct cagaagcgca ctttccccgt 59460ggttcctccg ggtaaccctg actcactttt catctaccca tcccctccaa aacaaggcct 59520agccagttcc aagctggaga ggtgacccag agttgccttc tgtcatgtcc tgcctttcgt 59580ctcgagtcca ctaaccccac tcagactctg tctgctccca cccccaccgc ggccagtgaa 59640atcccaatcg tcttccacgt ggaaccccag gtccgcagtt atgataacgg atcacatcgc 59700tcctgcggaa agtgcgcgcg gtggagtgat aattggacct agcgtctaaa ttcttgttgg 59760aggacctcgt tccagctgcc agttaagcct ctgggatccg cagcgtctct aggaattgag 59820agagtgggga agttaggatc caggaggagg atggtggggg ctgaggagtg gaggagcagc 59880gtgcatctca tctcttgtcg ccgggcgggc gctctttcgg gtccagggcc cttgcacccc 59940cagcgtggct ccggaggcgg cgagacctgc ctgaaattga ttggagggga ctagagtgtg 60000cttgtggggt ggggtagtgg gggcggagag aagagatccc aagaagggcg ccaagtgctg 60060tgaccagagg cctaacacga ggcaccttgg aaacaggtat agctacggat ttatgggttt 60120taaaatggaa cgtcttggtg aatggacata gcgtgcattt cacagtctga cgtcacagcc 60180ctcgcaggtt ttcccagacc ttaaagccac gttctcgtgt atgacactta aacaactcag 60240tttccttgtc tttcctccct ccctacccat ctaagggtag agaagctctt agttcatcca 60300ctgtgtagga ctgttaccgt gtgtcaaagg ctttggaaat gtatatttta ctgatgatgg 60360tcatagcact ttggaaaact caaaagtgaa acgaagaaaa taaatatcac caaacttttt 60420cccaacccct ctcatcctgc ggaaaccatt ataactaatt tggtgagaga gagagagaga 60480gagagagaga gagagagaga gagaaactgt ttactgtttg gaatcttgct ttaaaaaaac 60540ctgactttat aatgcaatca tttaacagtc tatgaaatat tcttcagata cctgatgatc 60600cagaatgtaa ctgtaccata atttaacact ttattgctag aattttatgc agtttttgat 60660ttcttgctac tacttatcca tctgtattaa tctttgtcag aacctttctt tccttaggat 60720gatgcctgaa tataaaatag ctgaatgaaa gtggatgggt tcattttaaa atacaaaatt 60780gtttttcttg atggtgaagt gtttaagagg tggattaatc tcattgggca acaaatagag 60840aagatattag tagttaggta tatgagaatc agaattcaga taatttgtct taaaaattca 60900tattcaatgt aaaaatttta tatttagaaa atgaaactgt acccattgtt tatataactt 60960aaactgccaa aataaagcac cacaaaaact ttttatcacg ttggtttttg tatcaggctg 61020ggctttgcag cagatggagg agctagggca agcttgtcca acctgtgggc ccgagggtca 61080catgcagccc aggatggttt tgaatgctgc ccaacacaaa ttcatacact ttcttaaagt 61140atcatgagtt tttttttttt tttaagctca tcagctattg ttagtgttag tgtatttaat 61200gtgtgtccca agacaattct tcttcttcct atgtggccca gggaaggtaa aagattgaac 61260acccctggcc tacagtgttc tactatgaag tttcagtttt agttcggcct agaatgtttt 61320agtacagaag gcaagtgaga ttttctctgt ttctccaagg acttttgaaa aagtgtaaaa 61380gcactgggcc cactgttgaa ccttgctata aaaaagtatt tttgatacca tttgtatcac 61440tttagtaata ggagtttttc atatgttggg aaaatggttt agcttaactc tatcatggta 61500gttgatagtg atgaactaac gtggaataat agatctgtaa accatcatag acggtaatag 61560gctatgttgt tgctacctta ggatcataat ggactttcta aaattcaaga gtactcaaag 61620aagtaaaatg aatataagtc ttgatttctg aaagggctat ggttcacttg gaacacaata 61680caaactgtga atcatgtaca catggggaat aatggtttat actaactgca cagtgcttac 61740cttgagagga ctctgtgcta ttaaagaaaa aaataacctg agccttctga agtagctata 61800aacaaatgaa tatttaactt cataataaaa atatgactat tttgtaaatg caccaaggta 61860gaagtaacaa atcaactatg gcaatttttc aggtttctgt ggttaagaaa ctggtaacgt 61920ggaattttag tatatgtatt tccaatcata taaaaataaa aagtcataat aaacatattt 61980gcagaaactt aaaaaaagtt aaaataacat cttatttgca atgatattaa ataattcata 62040caagtaattt ttagcacttg tgcctctcaa ggaattgtat gaatcctaac ataattagta 62100tccatatata ttcccaaatc aatatagcca tgggcataaa atatattaat gtgaaatata 62160taattacata tcattataat taacaccgct agattttata ttatgtatat cattttacat 62220atgaaattgg aaaattgcat atatttcaag acattctatc caagctgtgt tctatcttga 62280gaaacttcct gaagattgcg cttttcacat acgtcctgaa aattgattta tacctaaata 62340acaaaaaatg atctatttca atgaacctat catttaaata tttttgcatt tcatgcatat 62400acattaacat actataaaat attttctcta acttaaaatc accacaatgt tatgttttat 62460aggcctaaac taaaaaatac ataattatgg catttatata cattgacatg ttctactttg 62520ttactacaga ttttcagagg caacttaata atttaaacaa aatgatttta tatagaataa 62580tattaactag agtaataaat atttttatat agacaataat attaagaact atattcatac 62640agttaccggt cacagtggct aaacttttgc tgatacggat aaaccactgt taaaaaaaac 62700aacaaccagg gtcttgtcaa tgtttcaaaa tgaattaaaa tcaaatccag caacaggccc 62760tgaaatcctt tataagctcc tttgactaaa ttaaaaaaat taacttgcat aatatgaaaa 62820gtaaaaaata aaatgtgcat ttatcctata gattataaat ttttgctaat agaaattgag 62880acactaaatt aaacactgat agttttaaca ggtttatatt tccatgtcaa agagacaatt 62940aacattgcag taaaaaaata attacccctc cgctggcctt tgctttttga agctatatat 63000tcctggcgaa gcataccaca aggacggtca taaaagtgaa gcctcattaa attactttta 63060gacttattac acaagtttta attagcattg tacatatttt aactgtacat atattctttc 63120agttttcctg gttataggaa attacactgg ctgtgtcaac atttgtcaat gtgaggacaa 63180aactaccttg gattctgttt ttcaagaagt aggcctcatt tttaaactgt gctaactgtc 63240gtctgagatg actaaaatac tatcagttgg gatttctcag gaacagttct acagttctgt 63300cgtttgctaa acatacgagc attgtcccga gcagtttcaa tcactcaggc cgccggacct 63360ctacctctaa ctcacaaaga aagcccattt ccctgttggc tgcaaaactc ccccaagaag 63420caagtgcttg ctcctcgcag cagtaactga tcctacgatc cttgttagca tttcaggaag 63480tcgctgcctg cgtgccccgt atctcacggg tcctccactc tcctggaagg tgggagaggg 63540tgaccccgcc gggaggctgg ggagaaaaaa ggccgcctcc agaaaactta gatggttagc 63600aataattctc cccaaggaga aagaaagtgt gcttgaaata cacctttcct actgtgtgtg 63660tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtc ttagtcattc ccacccagga 63720tattcgggac tcactgactt ctgaggtggg tttagaagct ctgttcgcct cagtttccca 63780cgattgaggg gctgtgtgaa gggaggtcca ggttcaatgg tactgcgaga accacatgtc 63840taagtcgttg taacccgaat ggggaagcct ccaccggcgg ttatctcctc ctcctcctag 63900cctgggctag agacgaatta tctgtttacg aaatcacacc aaacaaaaca agtgccgaat 63960gcgccccgga cttttcgagg gcctttccta cctggtcttc taggaagcgg ctgctgccct 64020agacgctggc tcctcagtag catcagcacg agggccacag cggcgggcgc ccctggcgct 64080gcccactccc ccgtgagccg cgggatgtga accacgaaaa ccctcactcg cggcgggccg 64140cacgcgcgcc gaatccggag ggtcaccaag aacctgcgca ccatgttctc gccgcctcca 64200gggccgagct cggcagccgc tgcgccgccc tttggcacca gaggtgagca gcgccactcc 64260tgccccctta actgcagact gggacccacg caccgccccc tgcccatctc cgccccgcag 64320gcgcgcaccc gccttccctg agcgcgcccg ccccccacct tcacccccac ccccacccca 64380cccccactcc cacccggacc tccaagatct cggaacggct ctgagccctg cgcacgcggg 64440aagggctgcc ggaggcgccc gtagggaggc gcgcgcgcgg gcggctcagg gcccgcgttc 64500ctctccctcc cgcctaccgc cactttcccg ccctgtgtgc gcccccaccc ccaccaccat 64560cttcccaccc tcagcgcggg cgccccgcgg tgacggccca ggggccggac gcctggaacg 64620caactccagg cagctcgccc cctagctaca tccgtcacct gacacggccc taccaggaac 64680agccgcgctc ccgcggattc tggtgctgct cgcgtccccg ctcccctatt ccccttattt 64740tattcctggc tcccctcgtc gaaagtcttc cattcttcaa actagattat ttaaaaatga 64800aaaaggaaga aaggaaagcg aggtcatctc attgctctat ccgccaatca ggaggctgaa 64860tgtcagtttt gaactaaaag ccgctccgct cctcttctag atttggaaaa caagcgaaat 64920taaactaaac cgctgcacgc ctctgacgcg acatctggac acggcgcggc gctggcgctg 64980ccggagctgt cgacccggcc tggcgccgga ctaggtaggt ggagtcgcac ccgggggtcc 65040cagctgggtc cgggcgccca ttcccctccc agctgcccgc gtcgccgagg gcgcctggct 65100gggacaagca ccgagtcctt tgtgtctagc ccatttttat tttcggtttt aaccttcacg 65160acagccgcgg agcatctgag cgcttcttcc tctttcctct tcccccgcgc tcccctcccc 65220tgctggccgc tcccctcctg tcgccgcgtc ctcgcgtaga atggttgtct tggcgaccgt 65280tggccgctgc cgcctccacg ctctgccccg cgcccagaca ccccgactcc ccttgatccc 65340gccgcctgac tcctcggcgt acgttctctc tccggtctcc ccctccatgt cccctcctcc 65400ccttttcttc cacatcaccg atcctttctg gactctctcc cttcctcctt tccagctggg 65460agacaggaaa agcggtcctg tttgggaaca gtaaaagcag ggcaaggaaa ggaaggagcg 65520gcagaaagga ggggtgagtc gaggacacag gggcagccgg agaatgcgga ggagccgggt 65580cctgagcgcg gtctaagcga ggctcggctc tcgtccagga actcggacgc gggctcgccg 65640gctctccgcg cgcgggaagt cgagcccagg acgccgcctt caggccggcg cgctgacccg 65700gtgccccgac ccggagcctg cggtctgcct ggatccgtcc taaacctcgc gggctggacc 65760cgcggcctga gtgggtgggt gtgtgccaga ggattcggga ctaggcccag ctccgggaac 65820ctggaaatgt ggcccgcttc tcagtggctt cctgttcatg cgcttgggcc tagtggccta 65880gttgaagaag tggaaccaca gcgtgagccg acagggcctt acagatcaga cgtcaagccc 65940cccagacctt acaggggagg aaagtgaggc ctgcactggc cgagccaccc acttaaggcg 66000gtgcggtagc ctagaggagc ggcagacttc tctttcccca tcccccgccc catcacttga 66060cgttgctgcc ggacctcggt acaaacccaa gacaaaacgg ggccctttgg aaaaagtgag 66120atttagcgat cactcttacg tagccactct aaatatctat ctagatattt acaaatgcac 66180ctccccggta ggtagatttc actcagaatt tacccaacac

cgtgctttgt gctggggcca 66240catgccacct ttctgtctag tatggctgct ctttctccct cttcgcaaat atagctcttt 66300ttccttcagg tctcttctga agtaagtagc ccttcctcag aaatgcttcc cttttcaggc 66360accctcatac caccgtgatt tttttcttta tagcacttag gacgaagaga ttattttact 66420tatgtacttg tttacttgtt tgttgtgtag aatgtcagct ctatgggaac cagatccttt 66480tatgggtctt cctctgcacc tatgccacgc ccccagcatt cccctcctac caccaccttc 66540agccggcctc cgcctctgta ggggggcatt aggttttctg tcccacagag gaagggcgct 66600ttagaaaggg ttagttcatc ctggaagaaa aacgatgtcg gatgccagca tagtgtcatt 66660taaagatact ggaggaatgg agtgggagcg gtgagggttt cttgggccta gacaatgtaa 66720ctagttgttg caataaagca tggtggggaa aggagaaaag gcacgtatta aacatctttt 66780gaagtcgcta tctatatcag tcagttctcc agggaaacag aacccattgt gtgtgtgtgc 66840gtgccagtac cacacatatg tatatgtata tacacaccgt catggggttg cttaacaaca 66900gggatacatt ctcagacatg tatctttagg cgatttcatt gttgtgcaaa catcatatac 66960aaacctaggt ggtatagtct attatacatc taggctgtat ggtatgggct attgctccta 67020ggctgcaaac ctttacaaca tgttactata ctgaatactg tagataattg taacaaaatg 67080tagttttata tctaaacaca tctaaacata gaaaaggtag tatgttgtgc tacaacttta 67140ggacagctat gacatcacta ggggatagga atttttcaca tccattataa tcttatggga 67200caccaccaat atgtgactgt ggttgactga agcatcgtta tccagcacat gactctgtgt 67260gtgtatacaa ttttatatat acgtacatta tatgtctaca cacacatatg tgggggagag 67320aaagagaggg agggagagag agagagagag agagagaaag agaaagagag aaaatactta 67380ttttaaggaa ttgtctcaga aaatggtggg ggttgacaaa ttggagaccc agggaagagt 67440tgttgttgca agacttgaat ccaaaggcaa tctggaagca gaatttcttc ttccttgagg 67500gacctcagtc atttctctta agctcttcaa ctgcttggat gaggaccacc catattattg 67560aggataatct gctttttcaa gtctactgac ttaaatgtta atcatatcta aaaaatacct 67620ccacagcaat atttagactg gtgtttgact caaacactgg gtaccacagc ctagccaagt 67680tgacatacca aattaactgt cacattatcc cgtcatgcct gaggggttct ctgaccctca 67740gttttctgag gatcaaattt aaattgaggg atctatcttt gtttattgga gccatatagc 67800tcaaagtata atcattttct ctccacagga actagaccta gggataaggg taattgctta 67860tttcagagga atgccatctg aataaaagga taattatata gtaagctctc tgttcaaaaa 67920atgtaaatat taaagtttga acatctaaat tccatcttgg tttcccccac tgccgctgcc 67980caatacctgt tctctttcag ttgcagtatg caggggaatt ctaagtttaa tattagtctc 68040agcaaaatac aatggtgaag atgactcttt ctagcataac aatgggtatg tggtattcca 68100aatacttttg gaatgcggag tgactattgg ctatgtgctc ttcaaaaaat taataatgaa 68160gaactgagca tgtaatttca cttatattac ttattttatc ctcacagtgg cctttcaaaa 68220ttgggattat tactcctgtt ttacaggtgg aaagaatgag gcctagaaag gctcaaatct 68280tgaacacttc atggccagca agagccaggg ctggaatcat caggcaggcc tttgggttac 68340aagccttgtg ccttttctgt tgtcccaaag gccagggtca atagggagtg agttatctgt 68400gggtcactta tgcagacaga atcactgaat attggaagtt tttggggttc tcttccactg 68460gcctaaaaac ctgagttaat tgagtttttt ttaacagggg taaataattt tctgttttag 68520atcagcaaat tcattccata ggcagggata ggggagaaaa atcttactga atatcccttg 68580tcttgttctc ctcctcccca aacttaatgt cctatgacac tagctttatc ccttaggtaa 68640ctcttgatta tccaaatttc atgagaaact ttcctaacat tgcacatgct caaactcaaa 68700accccaaagt cataagaaaa aagataacat aagcaagaat aaaaaacaat tatttgatca 68760tatatgtcaa aagattaatt actagactat ataaataaat acataatcca gtaaaacaac 68820aatccaataa aaaaggcaaa ggatataata gtttatagta gaatatgtgc aaatagtaaa 68880aaataaaaag ataatcttac tcattaataa atgtaaacag aaacaatggc atataaccac 68940aagtgtggca aaaagaaaaa agactacttt gacaaagttg tcaggaaaca atcactctta 69000ctattacaac ttggtgtaat tgttttgaaa ggcagcatta caatatctag tcaaaactgt 69060atgagaatat aggtaccctt tgactcagct attccactat tttaagtatg taaagacaca 69120cacaaataat gtatggaaat atatatacac atatatacta tatagtatat atagttcata 69180tgtatgttat atgtttgtgt atatatctat atacttatat acaccctttg actcagcaat 69240tctattccta taactcatgt atgtaacata tataatacat atctttatat acacatatgt 69300acacacatat ctgtaagtat gggaagatgt atacacatgt acacatatat atacatacat 69360atgtatatat gtattttatg tatggataca tatgtatata tggatagatt ttacacctac 69420agacacattt agatatgtaa cttcagctaa agcaattcac tcctatataa attgctacag 69480ataacttgta taagtatgca gaaatgtttc tttatagcag tgtgtattag caaacaaagt 69540gcaagaaaga gaaaaatgat tgacatgctt gtgaggagac tttttttgtt gttgttgttg 69600ttagggctca ttcataaaat aataaaactg tgcatccata aacaataatg aagcacatct 69660atatgcactg acaatggaag ttgtcaaaga tctattgcta attaaagaaa gcaagtgaca 69720gaatagtatg atcccattca tgttttccaa atatgcatgc tgggggagag atgtttgcaa 69780ttatatgtac ttatatttct ggaaggataa ttaaatattt gtaatagtgg ttacctttgg 69840gtagtaagaa tgagggtggg aaaaatttca gatttttgct tactactttt tgctttctgg 69900actgtttgaa agtttaccat gagcaagaat tattaaataa caaccacagg aatattgggg 69960ctcaaaccta gagattctaa ttttgtagac ctggagctga tcaacaagtc taaatgttaa 70020aacatcctca cgggtgattc tgacatggag ccaggattga gaaacaattt tctgaaatgg 70080aaggggtttt aaacttgttg tcctcaaatg actactgagg caaacaccat tcttatagac 70140ataagacata cttgggagca aatgtataat aaagtggtat gcttccctag aaaggggacg 70200accttaaatc tttctgttta tggtggtatt taaacatatt aaaaactact aattttggaa 70260tagtcttact gtgataagtc taactatcaa aggcagtcca gagattagca aataatagag 70320gatgatcaaa tgtttttcag aaaatattat aggtggcact ttggcaggag attctgagaa 70380tggtgagagg gtgcctctgt gccctaggaa aggtgataga gcttagaaac tcagaactca 70440gatggaatga ggagccatgc catatacatc tttacaacag tcaccctcta gaagaaaact 70500ctgtgttgac aataatctgc tgacttgtct gtgggttttt gaacagaata aactgtttct 70560tcttttatgt ttgtgtatta ttgcttataa atatattcta aaatatataa taacaaacaa 70620taacagtact tgcagcttaa ttaaagaaaa aatgcaagta tcttatttat actaagagaa 70680gagagaaacc cgaagaacaa tggattatcc ttacatattt ggtttgggat tacattgaga 70740gctacctaaa taccagacac tcattcttgg tcctgactcc tactctgtta tccatagctc 70800agtacctagt atctggcgca gaaagaagtg gaatggaatt atcagggaga cccagttttt 70860agccaagact aaaaggtttt agccaagggg atggaagaat ttgtgcatag atagacggca 70920gatgggaatt cgtttaaaat ggaatggaga cccagaggtc acataagaca gggttcagag 70980gaagtagccc caacaacatc ataatagaga acattgataa tgagaggata gatagattat 71040gcatttgggg aggaggccaa atatgagaaa taagacatgg tttacttact gtaattggtc 71100ttaaagtttt gagtggaact ctgttgtaaa atattttctg tgccagagct gactccatat 71160atctactgga agtctaatgc caggggcttc tgagtgtgaa gtggattaat aggtgtttgg 71220ggtcctttgt aaacttctag tgtaatgtga atagctgtga ggtagtcagt gtgtcatctt 71280aatacattgt tcttagttct ttttccagca aactcttttg ttttacattt agttcacacc 71340acaaattagt aagtcaggct tggtgctttt tgacccatac attaattttc attactgtgc 71400ttaatataca atccatgcca attacatatt attaattagt ggcactagta ttagttcata 71460ttttctttta ttatgtaatt aatagggcct atatgtgaaa gttactgtgt ttctgtaaaa 71520tgaagtattc tttttcctta cgcaaggaat gacattaaaa tcttctgagt agggaattta 71580agaggcaaga aaggagtaat ttcatttgga tagctgaaat tgagaaacgt tttatagaaa 71640cttttcaggt atgaaggata gtagtagaga tgttacatga gttagcactc atatattgaa 71700ttagttaagg aaccaatgtg ggaatctagg tcttctatct tccagtcaag tccttgtttc 71760acttttcttc attccctctt tctttcctgt cgttataagt agaataggaa aatattgaaa 71820gtattgaggc tcaactgttg ttgccccttt aagtaatttc taaaattaaa attgtcttat 71880tttcatatat gtgtgattgt gtatctaggt atctctttgt agcttagtaa ttgaacactg 71940tgaactacac caacctaagc attattctcc aagttttcat caaataacta gacagtttct 72000gttaatactg aaaatctagt aaacgtgtca gaatttggtt atgattagtt gctgacataa 72060aacatgaggg cagacctcac tgtactttag aagatactgg ctttcacatt tgccccagta 72120ggtagttcac atgagtgctt cttcagataa tgtctctaag ttttgcatat cattagttct 72180acttgctcca cttttgatag agtggcaatg tattgaacat tgtaaaaatt atgctctatg 72240atttaaaaaa tccatctctg gtaaagcata aaatgagtat atgttttact gtttaaaata 72300attgaggggt aattatagaa tcagcaaaaa gaaaaaaaaa ccctactgac tattacatat 72360caatgcacac agtgtgttaa tattttcaaa aaagggaggg caatctcagt gtaagtgtaa 72420atgaaattag tttttgtata tatttgctga agatcagtta cctagcttca tatgataaat 72480tatttggtgc tggtcacaat attgtgcttg ccatattagg gaaataaaat atcatgaaag 72540tattcctaag tatacatttt cccagaggcg tttggggttt tatcagtctc gagctctcct 72600cttgaaactg tttcattcct tagttatgaa attactaatt ttaaccattt aaggcatagg 72660aaattttaca tagattttgc tttaacagca aaacaccctt taaaaaattc atccacttag 72720gtgaaaaata aaagataaaa atgaagccaa atgaatgtta ttaaatttat aaatttattt 72780aactttccag atcttcttgg aataaatgtc aggtagtaga atttgtacaa accttggtaa 72840tgtcttaggt ttagatacga acttaacagg tatatttaat tttctgtatt ccacaatgga 72900gctagaagca ggactcatga aaatagtaac tatatgtttt gcatgtatcc ttcaaagtga 72960aatccttaac aaatttaaca gtatatatta ggctgctgat gaaacagcta aacctgtctg 73020ccaggtggct tcgaaaatgg aattaatttt tacatggcat tgataagtta ctatttcaat 73080acaaccaggt ggtaattgat acccaataat gtttgaggtt tgctttaaat aaaaaaaact 73140aacaaaacaa acaaaaaaaa cagtgtaata tagtactgtg ggatccacaa taacattttc 73200tttagtttcc cttaatatca ggttgtcatt aggaaagatt ccacaagtta tttaaaccag 73260aaatgaagta acatgtttca tatctatttc aagggataat ttttcatgac ccagtataat 73320gcaactagca aatttaaaca tcttggaatt taagatatag aggtcaaatt aagggatttt 73380ataaaccaaa tgggagattt taaagtatca actgacttct tttatataga atgttttcta 73440ataattgtaa aatactgtaa ctttaaaaat attattcttg tagcctctaa tgattgagtg 73500cttaagtgat aactagaaat atattttctg tccctgtgct tcagtttgaa aatggaggtt 73560ccattatctt tgttccaaaa atttgggttt ttataggtgt gttggggggg gttattctcc 73620atattgttga cattttaaaa tagttttcaa acaaaccgtt tatatttact agaagttaga 73680gaaagaaaag ccaccttagg agcttacaag ggagatcatt gtgtatttct gctttttttt 73740aaaaaaagtt atcttcatgt gtatcattca tgattttgga ggacaagctg gtgcaatggg 73800aagaaaagca agacaaccat aatcagctgt ggaactagat gcacttcttt gtgcatccat 73860ggaatgaata tcttgtaacc tttggcaagt tacttgatat ttctttgcct cattgtcctc 73920atctgggaaa caatacctat ctctcaggtt taaatattaa attaacaaat atattttaat 73980gcatacctgg tacagattat gtgtcaataa acatatcctt tccccaataa catatgctct 74040gattctcaac taactttccc cagtaatatg ttcattttgg gaataggaat tggtagagaa 74100gtaaagattt gtgtattcaa ctcaaatgta ctccttctta taagtctcca ctctcaaatg 74160acttgtttct gttccttttt tctcttttaa atgtgtatct ggtagaatga gcatttagaa 74220gcataataca tgtatacact ttgtgtttaa ttttctatgg cataagtaag cagtttttat 74280gaattgctgg tattgcttat gagcaattat tacaaacatt gagagaaggg aacccctgtg 74340aacctttaac atttctcagg agttagtggt aaacccatga acatgtattt ttaaaccaaa 74400ttacccacct cttggagttc aatctctgtt aattctttat taaagtagtg aagtatcagt 74460tgttccaatg atataatgat caagcaaccc tggaaattaa atcccaaagc agtgcacctt 74520tagtttgttc agtgatagta ggacatccca cgagccatca tatattttca agtttttata 74580ctcaatctac tttttcagca atcttttggg aactatccca agataattta ctgcataagt 74640gcatctatct tctaaaagac atttggaata tttcttagtc tgacctctgc accctgagac 74700actctataaa ggaaacaatc agaaaaattt aacaaagaaa taaataggtt aagaagaaag 74760caatctaggc gtttgcactg agtttgcaac agtgccattg ctacatttaa gagctgtagt 74820tcttcctcac attttaactg agagccacta gttatgttac ttaaaatctc cccattaaat 74880aagacagttg ctgaacaact aaaaagtaca aaatatcaca aaatcaaaaa gtagcaagtc 74940ataaggggat ttccgcatcc tagcatgtgt gtgtgtgtgt gtgtgtgtgt gtgtgaaaga 75000aaacgttaca gttaaccgtt acaattgctc tcactccact ccaccacctc atcctgtgta 75060gtctgcctgc ggaacccgcg ggaatctctc ctcagtgtag taagagcaaa ggccagcatc 75120ctgtgcaaag gtgctctgca gcgtcgtgat ccagggattt tagcatctgt cgtcgcttgc 75180acatcctctc ttacccctct gctatctggt ggagttgggc gagggtctcc agggcttcca 75240gagagtgtcg tttacgcatg tgacttgcca tgcgctcaaa ctaaagcgcc gccggggact 75300tactgaagcc cacctcggcc ctcctccact ttgtcctcag tcttcaggtt ttcctttctg 75360ccgctagggc ctaagttgtg ggttcaccat aactcctcag cagacattgg agtgaacgca 75420tcgactgccg tcacccaagt gctaatcact gccttctccc actcagcgct ggagtgggag 75480attcatccat cggaagattc gtagccacca ggtccagtca aggatttcat atgcactttc 75540cctcagaaaa ccctgaaaag caaacgaccc ctggaatgtc acacactcct aaatatccct 75600ggaaatccgc ttctctgtgt ttcgcttcat ggtgagtgtc gagggccaga taagacaaag 75660aaaaaaatgt atggaaggtt attcccggtc ggctcctcct tcctgtgagt ctcagacagg 75720cttgcaggct tacaggcttt ccgccgctcc ccgttggcag ccttcatcga attaggtggg 75780tgggggtggg aaattgggta agaaaataaa gtcgttgtgg gcggctgggg aacctggcgt 75840cagtcccccg tggctgtgcg caggtaccct gcaacgtcgc ggtggccccg ctcctcggcc 75900aagtccacgg gcagacgacc ccaggcatcg cgcacgtcca gccgcgcccc ggcccggtgc 75960agcaccacca gcgtgtccag gaagccctcc cgggcagcat catgcaccgg tcgggtgaga 76020gtggcagggt ctgcgcagtt gggctccgcg ccgtggagca gcagcagctc cgccacgcgg 76080gcgctgccca tcatcatgac ctgccagaga gagcagagtg gtcagagcca gggtgggggc 76140aggtatggga gatgccggcc ggggcaaggc aggtggagcc atttaaagaa acacctaatt 76200gcaaagtttt cacccagtgc agaggtgttc aggtctctga tgtctggtgt ttcttcattt 76260gctgatgcaa tccactttcc caccccacct tcaggttata ctcagtacaa attaaatgcc 76320attttattct ctaaacgtgc agagacaaga aagttgatgg taaagtgatg atcatcatta 76380tggaaaaaca aatcttgatt tccattggaa catgggaatc tattttgtta aatgatttag 76440gggcagagtt aaatttattc ggcttttaaa gttttaaatt atttgccttg ctgacccctc 76500ctccataatc caggtctaca aatatttatt aggtagtcaa ctactgtttg ttagaagttg 76560ggagtaatgg tttaggggag aaaataaaca actaagtttt tttctttctt ttttttttaa 76620tttatttagt tctcatagca aatcccgtgc ggaaggcttt tgtttgtcat gtgtctgagc 76680tcataactgg cttgtagtgt gataatttga gccaaagttg gagattagaa gggaaaagta 76740aattaaatca tgcaaaatct tataaaatta taataaatga tttttcctta acagttcatc 76800attttaaatt tagactataa tatttttaat gtaatataaa actaactata tttgtatact 76860acaggatttt ataatagcta agatttaaaa atgttaaaca gtaaatattt tgctatataa 76920aaagagcttg ggccaggccc agtggcttat gcctgtaatc ccagcacttt gggaggccat 76980agcaggcaga tcacctgagg tcaggagttc gagaccagcc tggccaacat ggtgaaatcc 77040cgtctctact acaaaaaata aaaaattagc tgggcatggt ggggcgtgcc tgtagtccca 77100gcaactcagg aggctgaggc aggagaatcg cttgcatcct ggaagaggtt gcagtgagct 77160gagattgtgc cactgcactc cagcctgtcc gacagagtga ggcctcatct caaaaaaaat 77220aaaataaata aataaataaa tagagcttgg atgttagcag tcaatcagga tgatgcataa 77280cttagaaaaa atgatgtttt gcaggagtaa tcctgtagca gccatttgtg tacatgaaca 77340ttatgaaaac atttgctgtc atatttaaag tcaattataa gacaattttt ggtaactaaa 77400tgtctaaaat cgagttattt gttatgggtt tatgcacttt aaaatatacc atttaattga 77460aaggcagtat acttctcatg ttttgttggc ttgtttcatt aatattagaa atgttcattt 77520catctcttaa aaaccgtgat aagttatatc tactagtgat gtaaggatat tttacataga 77580aaaaaagggg aaaatagctg ctgttagtat ttcagaaaat ggtgaattac atatataact 77640tgtttttata attattaata aaattttaag tttttaagat gcactttaca atatttttgc 77700tcctttaaaa atccctcatt tgttatacca ttattctaag aattcaaaag aaatgaacac 77760ttctttaaaa tctatactat taacaagatc ccttaatatt agcttagttt tagagggtga 77820tagtgaggtg agtactgaat atgaccacta gccaacggta aagtacaaaa gagttgtccg 77880agattgtaaa agaaataaaa aatatcagta ctaattaaag caggattcgt acttaaacat 77940tgaataagtg tattttaaca atgaagataa agatgcatta tttatgaaga tcctttgcca 78000ttcaaaaagg acctaacagt tgctgcagga atatttttgt aatctgggca ctgagtatga 78060taattaaaga atgagaaacc tatagaacta tatatttttt ctcttatgca tcactcataa 78120gacactgcta acataaaagg aactaagtac tgtggttgag gaatcccgtc tcattctcaa 78180ttaacctcta tgagaaaaca atacaacaga tttcatatag tagcttagaa gtttacattg 78240attttttcca tgtactatga ttttgtagaa ttccttaaat ccaatctaga atgcgtaact 78300tatactttac ttatctttat cgttgaaagc agacagacaa gataatcttc ttccctaaat 78360aagctttcct tttctccttt tctccccaat tcagtctatt ccttgcatct ctgatcatga 78420gatggcagaa caaaaaccac taaaaaaagc ttaaacagtg ggtttttcaa tgtctctctt 78480taggattttt gctgggtaaa agcctgtttt acgcgtggaa tgcacacctc cggccaacgg 78540agactcctgt acaaatctac atcggcgatc taggttccag ccccgatccg ccgaggccgc 78600gccccgcgtt cgcgcgcccc ctgccggcga ggccctgggg ccccagctac ctggatcgcg 78660cgcctcccga aacggttgac tccgttggga tccgcgccgg cttccaggag ctgtcgcacc 78720ttctccacta gtccccgcgc cgcggcgctg gccagaccct catcgctgcc gcccccactg 78780ggcatgccct tgttctcctc gcgcattccg cagcccccag acgcgcagcg gcccggataa 78840tccaccgttg gccgtaaact taacgacact cttcccttct ttcccacgct gctccggcgc 78900actctctcct tcctaggaga cctgggctca gcttcattac cctcccgtcg tccttctgcg 78960gcttggggcc ccgtgcagtg gccgagcggc cggtcgttag ctccgggctt ttcctggcgc 79020tcaagaacca gcgggcgcgc ctggattgct tctgggaaaa agcgcctagc gcggacgcag 79080ccgagctcaa agccgctctg gccgcagggt gcggacgcgt cgcggagtcc tcactgcccc 79140gcctcgctct ggcagagtgg ggagccagcc ggcaaagaat tccgttttca gctgggccaa 79200ggggccggcg tctccccacc cccttaggct ccgccccctg tccgctgtga tcgccgggag 79260gccaggcccg ggccgacgcg tcacgagggc ggggaagcct gcccaaagat gctaggacgc 79320atgcgccaga gactgggcca gggagccgcc aggaatgctg gctgcactgc tcgctggatg 79380tccagtaaag ccaaggctaa tattttggga atgttcacca ctgccctcag ctcctaatcc 79440ccagtaggcg gagcagagga tttctgttcc ttcagccagc cagttggttt cactgtggag 79500acgttggtgg ctcccttgtg accgagagaa agtcattcaa aataactccg tgtttcttaa 79560gatgtctgaa agcgacagct ctgcacctgt catacaagtt aaattcatcc ccaggcagta 79620cttgggcttc acaagtttca taacttgtat caaacttagc aattttctct tggatgtgtc 79680tttctgtttg aattagtcaa ccataaaaat agagaaaaat cccgagaatc atgttttgcg 79740tgtgcttttt aattctttcc atttttgcat tatggataca acccttaaaa gagaaaaaaa 79800ctagttcgag attgagagtg gcaacctggc acacataaga caaaaaaaaa ttatacttta 79860agaatctgag atcccagttt catcatattt gtacagtaaa tctttgtttg cactcttacc 79920tatttaaacc cactttgtca ggtatcttat ttttatttat catgagtaat aaaggaaatt 79980tatgcagtaa taatgaaaca tcataagaga ggggtgtggt gctgggcttg tcattaaaca 80040ggctgaacct gtcattaaat tctcttctga agatttaaat gccaagtgct ttttttcccc 80100ttcctaatct tcctaggtga gtttgaatca acatttatta cttaaaatat ttaaaacatt 80160tcagcggatg ctacattgga taggaagaga accgcaagtt atggatttgt tgcctaaaaa 80220ctttggtgag gaactgcata agtggacctc tcctaaaagt gaacaatttt tgtttacaga 80280atcattttgg ttcggagtgc tgaggaagac aaagtcttaa caggagggca attgcttgtg 80340tattgcaaaa tgagagtctt cacatgtttt ttttaggata ccttagctct gactcctcat 80400cccccaaatc cctgtagaat taaaaaaagc tctttctttt aaaggcagtg gaagtgccac 80460caccatggaa gtgctggtta gggctgaaaa tctactgaca gagcctcaac agagctgaaa 80520tccacctgga cagggaaggg aaccgggtag cattaataac aatttctttt tctttcccat 80580ccaaccccca tttcctagtc ttcagtttct taatttctct accttttact cttatgctct 80640tgttttgacc tttgagtttc tctgaaactt atcagaaaag ttaggacaag atagtctgac 80700ccaattcttg agccattttc ttaggtagta aatatgtcag aaaaatgaaa gctgtttgga 80760gttgataagg aaatggaaga taatgttttt ctttgagggg gacataaaga atggtgatag 80820ggaaagaacc aatgactaag taaaatgact gagaatcttg cacgaggcag atgtgtgagc 80880ttcgcgaagc aagttgactg aatgaaaaac aactttgggt agggaaaacg ttgccggggg 80940cattcgcgct tactagcacc acggacagcg ctttgcttat actcaggcct gggtggtcct 81000aaccagctcc agacagaatt ctaaagcttc acacttgatc ttccaaagcc ccttttctcc 81060cgtcaaatag aaaggacatt atggaagctc aatgaatttc tttgaaaaac caacctgctc 81120aacctggttt tcaaatatga ttggatttta tctaatattc tctgtataaa gaatattata 81180tagtctatat ttagaagacg agaagagaaa tcaaacttat tgtgtactct gtacgaagtg 81240ctttacagct gttgtttcat ttaatactca taaaactcct

ctgtggcatg tgtccatatt 81300tcaattttac agacaagcca aaaggatcag agaatttgag tgacttgtat actagctaat 81360cattgttgga ggtgggtata acttttgcga cttcagagtc tttttaccct ttatactaca 81420tagtgttttt tttagcagct gtcatggtag gcttaactgg aaaaaagtaa taaactggct 81480tataattatt tttcagtcta cactgtgttt tccagatggc tcacctcaca gcacaccctt 81540accagacttc aaagatgaca tttcacatgt aatacaatag cacatttgtc ttggacaata 81600gagtgagatt atgaaacatt ttacctctcc ttgaaaccca gctgtctcta gggtgaaaca 81660caatctgttg ttaatgcttt aaacacattt aaaagatgaa gtggatggga acatagtggg 81720cagctgaaac ttggaattgt cagagccatg tcttttaata aggtggagaa tttataattg 81780agaagaaaga aagagaaagt taatggtaaa ttggcataga attttggagg tcagtagaag 81840ggaatgagtg gcatccattc caatgttgca cataactcag atcactagta ataatatttt 81900tatattctag ttggtgaaat tgtctgtata tgaccttgat atagaagtat gaacagatct 81960gccatcctct ttttcttcag cgaggcagcc gagctgcaga cacagagatg cagatctttg 82020tgaagaccct cacgggcaag accatcaccc ttgaggtcga gcccagtgac accattgaga 82080atgtcagtgc gaaaattcaa gacaaggagg gtatcccccc tgacaagcag cgtctgatat 82140ttgccagcaa acagctggag gatggccgca ctctctcaga ctacaacgtc cagaaacagc 82200ccaccccgca cctggtgctg cacctgcgag gtggcattat tgagccttca ctcttccagc 82260tcacctagaa atacagctga aacaagatga tctgccataa gcgctatgct ctcctgcacc 82320cctatgctgt caattgccgc aagaagaagt gtggccacac caacaacctg caccccaaga 82380aggtcaaata aggctcttcc ttcctcggag ggcagcctcc tgcccaggcc ccatggccct 82440ggagcctcaa taaagtgtcc ctttcattga ctggaaaaaa aaaaagtatg aatagaactg 82500gttgactggc caagagaaac agcgacctaa ccttgccctc atttatgcac acttttgcat 82560atgattagga ctaagatagt gtttataagt gagaagagaa ggaaattcat aatcactttt 82620ggggcttttt caaatttttt atgaacacac cttcccacca agaggtttga ttttctccat 82680tttatgagtt gggtttattg ctccgtgatc cacagtatat ccacttctat attcccatgt 82740atttttcaag attaattaaa tggtggactt gttcatcatt ttagtatccg tattagtttg 82800ctagggctgc cataacagaa taccacagac tgagtagctt aaacaacaaa tatttatttt 82860ctcagagttt taacttctcc tgaggcttct cttcttgact tgcacatggc catcctactg 82920ctgcctcttc acatagtcat ccctctgtgc acacgtgccc ctggatctct tgtgtgtgtc 82980caaatttcct cctcttttga ggacaccagt cagattggat tagggcccac cccaatggcc 83040ttattttaac ttagtcactt ctttaagggc tctatttcca aatacggtca aattgtgagg 83100tattgggctt aggactttaa tataaaaatt tagaggtgac agaatttaac ccataacaac 83160agcatcttaa tttttacaca ttttactttt catttctttt taaactgtta ttaataattt 83220attcatttga ataaggatta aaataaggct aggatattga aattggttga aattgctaca 83280gtctcttgta tctctctctc tctctttttt ttcttataag ggacaggttt cattcacctt 83340gtcgaccagg ctggagtgca atactgtgag caagggtcac tgctgcctcg aattcctggg 83400cttaagggat gctcctgcct catcctccag agtagatggg actacaggtg ttggccacca 83460tgactggcta atatttttac ttttttgaag agatgaagtc ttgccatctg gcccaggctg 83520gtcccgaact cctgggctca cacaattctt tcacctcggc cccccaaagt gctggattgc 83580aagtgtgaac cactgcacct ggcgtcttgt ttcctcttaa tctacagttt cccccttttg 83640ccttcttttt ttttctttca atttatctat tgcagaaatt ggctttatct gtagttttct 83700aaagcttgga ttttgctgaa tgcttcttta taatgacact taacattttt ctttgtcatt 83760tgtatttctc ataacttatt atttaggcct agagtctgta tgtgattcag gtttgatatt 83820tgggcaaaag tatttaataa gtgggattac gtactttcac caagagacac ataatatggt 83880tgtctctttc tgtgattcta gcagccatgg ataattattt catagattat tattttcttg 83940gggatggcaa aatggtgata ttctaatttt actattcctt catttactag ctggaatgtc 84000tttttaaatt atttatttat ttatttatta tttgagacag agtcttgcac tgtcacccag 84060gctggagtgc agtggtgtga tcatagctca ctgcaacctg caactcccag gctcaagtga 84120tcctcccacc tcagcttccc caatagctag gactacaggc acacatcacc tggctaattt 84180ttaaattttt tgtagagatg agggtcttgc ttttttgccc aggctggtct ctaactactg 84240ggctcagcct cctaagctcc tcctgcttca gcctcccaaa gtgttgggat tacagacata 84300agccactgtg cctggcctgg aatatttcta tatagaaagt tctcttcatt atctacttca 84360ttgctttcag gtatatgtaa gaaagacagg ataaaccact agattttgaa atgtatttat 84420aaattttcaa aataatgagt tgagtcctag aatctttctt ttattattat tattattata 84480ctttaagttt tagggtacat gtgcacaatg tgcaggttag ttacataggt atacatgtgc 84540catgctggtg tgctgcaccc attaacttgt catttagcat tagatatata tcctaatgct 84600atccctcccc cctcccccca ccccacaaca gtccccagag tgtgatgttc cccttcctgt 84660gtccatgtgt tctcattgtt caattcccat ctatgagtga gaacatggcg gtgtttggtt 84720ttttgtcctt gtgatagttt actgagaata atgatttcca atttcatcca tgtccctaca 84780aaggacatga actcatcatt tttatgactg catagtattc catggtgtat atatgccaca 84840ttttcttaat ccagtctatc attgttggac atttgggttg gttccaagtc tttgctattg 84900tgaatagtgc cgcaataaac atacgtgtgc atgtgtcttt atagcagcat gatttataat 84960cctttgggta tatacccagt aatgggatgg ctgggtcaaa tggtatttct agttctagat 85020ccctgagaaa tcgccacact gacttccaca atggttgaac tagtttacag tcccaccaac 85080agtgtaaaag tgttcctatt tctccacatc ctctccagca cctgtttttt cctgactttt 85140tttttctatt tctagactct ttattaagat tcattttcct atgaaaaagt ccattcttta 85200gtcagttcta cactgtcttg attaaggtag ctttatagga agtttttaaa tcaggtaatg 85260taacccctcc aaattcatcc tcccttttcg aaattgtttg gtcattctga atcctttact 85320ttttaatata aatttaaaaa ttatcttgcc aaataatctt gtttgaattt taattgggat 85380tgtgtggaat ttatagatca atttggggaa gactgtcatc taaaaatatt gaatcttcaa 85440ttcattaaca tgaatttatt cccccattta tttttattta tttatttatt tttctttatt 85500attattatac tttaagtttt agggtacatg tgcacaatgt gcaggttagt tacatatgta 85560ttcatgtgcc atgctggtgc gctgcaccga ctaactcatc atctaccatt agtttcctga 85620ctgtttaatg attgccattc taactggtgt gagatggtat ctcattgtgg ttttgatttg 85680catttctctg atggccagtg atgatgagca ttttttcatg tgtcttttgg ctgcataaat 85740gtcttctttt gagaagtgtc tgttcatatc cttcgcccat tttttgatgg ggttgtttgt 85800ttttttcttg taaatttgtt tgagttcatt gtagattctg gatattagcc ctttgtcaga 85860tgagtaggtc gcgaaaattt tctcccattt tgtaggttgc ctgttcactc tgatgatagt 85920ttcttttgct gtgcagaagc tctttagttt aattagatcc catttgtcaa ttttggcttt 85980tgttgccatt gcttttggtg ttttagacat gaagtccttg cccatgccta tgtcctgaat 86040ggtaatgcct aggttttctt ctagggtttt tatggtttta ggtctaatac aagggacgtg 86100aaggacctct tcaaggagaa ctacaaacca ctgctcaatg aaataaaaga ggatacaaac 86160aaatggaaga acattccatg cttatggata ggaagaatca atatcgtgaa aatggccata 86220ctgcccaagg taatttatag attcaatgtc atccccatca agctgccaat gactttcttc 86280acagaattgg aaaaaactac tttaaagttc atatggaacc aaaaaggagc ccgcattgcc 86340aagtcaatcc taagccaaaa gaacaaagct ggaggcatca tgcaacctga cttcaaacta 86400tactacaagg ctacagtaac caaaacagca tggtactggt accaaaacag agatatagat 86460caatggaaca gaacagagcc ctcagaaata acaccgcata tctacaacta tctgatcttt 86520gacaaacctg agaaaaacaa gcaatgggga aaggattccc tattgaataa atggtgctgg 86580gaaaactggc tagccatatg tagaaagctg aaactggatc ccttccttac accttataca 86640aaaattaatt caagatggat taaagagtcg tagcatcttt caaaggtgac taatgatttt 86700aacattatta ctataaacct atagatttaa acataattgc tatgttttaa cccattatag 86760ttattattcc tgttgatgat caagctctat ctttggccag tgggagcctc tgcaaattga 86820ttagtgaatc tttttgacat ggaactatta gtctttgaca aaatctttga tttctggtat 86880gacaatatat tccagtttta tcttatatac ttccagtcct atacataata ttaacttttt 86940ttcaaagaat tactggtttt atttttagtg ggaaatggca tttaaaataa ggaagttggc 87000gaggcgcagt ggctcacgcc tgtaatccca gcactttggg aggccgaggc gcgcagatca 87060caaggtcagg agttcgagac cagcctggcc aatatggtga aaccccatct ctactaaaaa 87120caaacaaaat tagccagacg tggtggcaca cacctgtagt cccagctact caggaggctg 87180aagcagaaaa aaataaataa aataaggaag tctgcctata tgggttatct acctcttttt 87240tagggctcaa cctacccgtt tcacacaaac ccaactgaat tcggactcta tatgtgctag 87300gcaagtttga gctttttcag gtgtacacac agggtttact gaactctggc atataattat 87360ttatttattc attttatcaa gttttgtcct atcattgaaa ctcattcttg aataaagtta 87420ttatatttag ttcagttaca gcagacaccc cattttgaaa acattatgtc aacattggct 87480tgtgtacctt gtcacatcag taatgtacag ttctcattta ccagaaattt ttatatgaac 87540aacatattga agttattaag ttaatgaatt ctgccaaggt attggtatat atttgttcat 87600tataagcatt taaaaacaaa ggaacctttt aaagttgaag ataatttaat gggccattgc 87660atgcaaagag gtgttgcatt agtaaccaac cttaaactac tgctgaaaca actttatgct 87720tgagttagat atgttgatgg gagccaataa ttgtgaaatt tgtgtatcca gactctcttc 87780tgctctgttc ttaatggatc tagtgttaat gttagaatct agtgcatttc acaactgttg 87840ctattataga tggaatatca ggaggggtag tgaggtattg agatagatga aaacattttc 87900taaaagtggc tcacgcctgt aatcccagca ctttgggagg ctgaggtggg tggatcacct 87960gaggtcagga gttcaagacc agcctgacca acatggtgaa accatgtctc tactaaaaat 88020acaaaaatta gctgggggtg gtgtcaggca cctgtaatcc cagctaccag ggaggctgag 88080gcaggagaat tgcttgaacc caggaggcag aggttgagtt ttctccacag ctttggatcc 88140tgatgacttt ttttttttta attgttactt tcaacttcct tgctttgact gaagccatac 88200ttacatatta ctgataacat atgccatggg ccgcgcatgg tggctcacgc ctgtaatccc 88260agcactttgg gaggccgagg cgggtggatc acctgaggtc agcagttcag accagcctgg 88320ccaacatggc gaaaccccgt ctctactaaa aatacaaaaa ttagctgggc ttggtggtgg 88380gctcctgtaa tcccagctac tcgggaggct gagggaggag aatcgcttga acctgggagg 88440cagaggttgc ctgtgcactc gggccactgc cgtccagcct gggtgacagc gcaagacttc 88500atctaaaaac aaacaaagaa aaacataatc catgtatgtg atgtaaagag cgccaacatg 88560tttatatcct cctatttcaa tctactttta cttcatctac atttttagca ataatgtgaa 88620catgaaatct tgaataatta gctatctgta atatatttac tcatccactc aaaatattga 88680gcccccccaa taaatatcat acactatatt ctaggtacag gtgataaaca attcagagag 88740tattaatttc aaaacatggt aagtgcatag tgagagagct gatctggtct ggtggttgag 88800ggaatcaaga gatatttgag ttgaggtctg cagtattata gaaaattaac taatcaaaag 88860agaggcagtc attccaagga aggggatgtg agtcagaaga aactgcatgt ggcaagctct 88920gaggtgggac aaagcaagga catattgaag gaattgtgac tggagcatag ggatggagga 88980aaacattgta gctagctgag aaataagcat ggaaaaatgt tgtagagctg tataggccat 89040gttaggactt ttgtctttat cttaaggata agccattgat gtgtttataa agacacatga 89100tgtgatcaga ttttcagtta aatttaaaaa atacttggaa tgcattttgg agaatggttt 89160aggggagagg caagagtgga ttctgtgggc cagtagttca gaggataggt tatggtagct 89220tggactaaag tgcctgagcc aagatggaga gaagtagatt gctttaagac atatttaaag 89280aataacatca gcacttagca atgaactgga gatggaagat gagggaaggg aaggtgttag 89340gcaggttttt acaatgagag aggttggtga tcatggtcac caaggtaggg aatgctggat 89400gaggatgcag tttaaggtga agattatgag ttcaggttca gcaaaactga acttgagaca 89460tggtgaacta tcaaggtgga gatatccagt gaaagttaga gagaggggtc tagagctcag 89520ggaggagtgt gtatccctaa tttagactaa tttgcattaa cagctgtagt aatgcaattt 89580tctctatact gaaatgcaga catttgagta tagaaaatta gcagacattt gaatatagaa 89640gaaagattta ctttccttca gaaaaagaat agtagagtat aaagaataat atttaatcct 89700aggaattaat accaaaccct ttaaaaaaaa cttttaagtt caggggtaca tgtgcaggtt 89760tgttacatag gttaaacttc tgtcatgagg gtttgttgta cagattgttt catcacccag 89820gtattaagtc tagtacttgt tagttagtta tttttcctta ttttctccct ccacccatct 89880tccaccttct gataggcccc ggtgtgtgtt gttcccctct gtgtgttcat gtgttctcat 89940catttatctt ccacttataa gtgagaacat gtggtatttg gttttctgtt cctgcattag 90000tttgctaagc ataatggctt ccagctccat ccatgtccct gcaaaaggac atgctattgt 90060tcttttttta tggctgcata gtattccatg gtgtatatgt accacatttt ctttatccag 90120tctatcactg atgggcattt atgttgattc aatttttttt ggctattgtg aatactattg 90180caataaacat acacatgcaa gtgtcttcat aatagaatga tttatattcc tttgggtgta 90240tacccagtaa tgggattgct gggttgaatg gtatttctgt ctttaggtct ttgaggaatc 90300atcgcacagt cccccacaat ggttgaacca atttacactc ccaccagcag agtctaagtg 90360ttcctttttc tccactacct caacagcatc tgttattttt tttgactttt taataatagc 90420cattctgact tgtgtgagat agtatctcat tgtggttttg atttgcattt ttctaatgat 90480cagtgatgtt gagcttttct tcatatgatt gttagccaca tgtatgtctt cttttgaaca 90540gtgtctgttc atgtcctttg cccatttttt aataggggtg ttttattctt gtaaatttgt 90600ttaaggtctt tatagatgct ggatattaga cctttgtcag atgcatagtt taaagaaatg 90660ttctcccatt ctgtaggttg tctgtttact ctgttgatag tttcttttac cgtgcagaag 90720ctttttagtt taattagatt gcatttgtca attttttctt ttgatgcaat tgctctgtgt 90780cttcctcatg aaatctttgc ctgtacctat gttctgaatg gtactgccta gactgtcttc 90840cagggttttg atagttttgg gttttacatt taagtcttta ctctatcttg agttaagttt 90900tgtatatggt gtaaggaagg ggtccagatt taatcttctg catatggcta gccagttatc 90960ccagcaccat ttattgaata gggaatctgt tctccattgc ttgtttttgt caggtttgtt 91020gaagatcaga tagttggagg tgtgtagtct catttctggg ttctctgttc tgttccatta 91080gtctgtgtct gctttttttt atgttcttaa cttttattta tttatttatt catgtattca 91140tttattttta ccagtgccat gttgttttgg ttgctgtagc cctgtagtat agtttgaagt 91200caggtaatgt gatgcctcca gctttgttct ttctgcttag gattggtttg gaaaattagg 91260gcactttttt ggttccatat gacttttaaa atagtttttt ctagttctat gaagagattc 91320aatggtagtt tcataggtat agcactgaat ctataaattg ctttggccag tatggccatt 91380ttcacaatac tgattcttcc tatacatgag catagaatgc ttttccattt gtttatgtta 91440tctctgattt ccttgagcag tagtttgtgg ttctccttgt agagattttt ttttgtatcc 91500tgagactttg ctgaagttgt ttatcagctt aagaagcttt tgggctgaga caatggggtc 91560ttctagatat aagatcatgt cacctgcaaa gaaagatagt ttgacttcct ctcttcttat 91620ttggatgcct ttatttcttt ctcttccctg attgcccttg ccagaatatt caatactatg 91680ttgaatagaa gtgttgaata gaaactaatg ctgcaagcat tagtttcaaa gaacttcttg 91740atttctgcct taatttgatt gtttacccaa aagtcattca ggagcaggcg tttcactttc 91800cgtgtaattg tatggttttg agtgaatttc ttagtattca tctctaattt aattgtgctg 91860tggtctggga gacagtttgt tatgatttca gttcttttgc atttgctgag gagtgtttta 91920attccaatta tgtgatcaat tttagagtat gtgccatgtg gtaatgagaa gaatgtagat 91980tctgttgttt ttcactggag agttttgtat atatctatca ggttcatttg atccagtgtt 92040gagttcaggt cctgaatatc ttggttaatt ttctgtctcg gtgatctgtc taatattctc 92100actggggtgt taaagtctcc cactattatt gtgtgggagt cagtctcttt gaaggtctgt 92160aagaacatga ttatgaatct gggtgttcct gtgttgggtg tatatatatt taggatagtt 92220agattttctc gttgaattga accctttacc attatgtaat gcgtttcttt gtcttttttg 92280ttcttgttgg tttaaagtct gttttgtcag aaactaggat tggaaccctg cttttttctg 92340atttgcattt ccttgatata tttttctcca tccttttatt ttgagcctat ctcattgcat 92400gtaagatgga tctcttgaag acagcatacc gatgggtctt ggctctttac ttggcttgcc 92460gctctgtctt ctaattggtg catttagcct atttacattt aaggttatga tcctgtcatc 92520ataatgctag ctggttgctt tgcagacttg tttttgtggt tgctttatag tgttactaat 92580ttgtgtactt cagtgtgttt ttatagtgac tggtaatggt ctttcctttc cacaattagt 92640gcttccttca ggagctcttg taaggcaggt ctggtggtaa ctaattcctt cagcatttgc 92700ttgtctgcaa aggatcttat ttttccttct cttatgaaac ttagtttgac cagatataaa 92760attctgggtt ggagtttctt ttctttaaaa acattgaata ttggcctcca atcacttctg 92820gcttgtaggg tttcagctga gaggtctgtt gttagtctga tggggttccc tttgtaacct 92880gggctttctc tctggctgcc tttaacattt gttctttcat tttgacctta gagaatatga 92940tgattatgtg tcttggggat gaacttatta tggggtatct tactggggtt ctctgcattt 93000cctgaacttg aatgttggcc tctctggcta ggatggggaa gttctcatgg atgatatttt 93060aaaatatgct ttccaagttg gttccactat cttccatttt tttcaggtaa accaatgaat 93120tgtagatgtg gtctctatat aatcctatat ttctaggagg ttttgtttat tcatttttat 93180tcttttttct ctattcttgt ctgcttgtct aattttggaa aggtagtctt caagcttgga 93240aattctctcc ttcacttagt ctattctgtt attaatactt gtgattgcat tatgaaattt 93300tgggggttgg gagtggtggc tcacacctgt aattccagca ctttgggagg ctgaggtggg 93360tggatcattt gaggtcagga gtttgagacc agcctggata atgtggtgaa accccacctc 93420tactaaaaat accaaaaaaa aaaatcatag ctgggcatgg gggaacatgc ttataatctc 93480agctactggg gagactgagg caggagaatt gcttgaacct gggagatgaa ggttgcagtg 93540agctgagatc gtgccactgc actccagcct gggtgagttg agagtccgta tcaaaagcaa 93600acctacacat ttttgtggcc tgtttttagc tctatcaagt cagttacatt cttctgtatt 93660ctagcttttt tatctgtaag ctcctgcaat gctttattag aatttttagt tcctttgcat 93720tttgttacaa catactccta taactctgcg aacttcattc ctatccatat tctgaattct 93780gcttctatca tttcagccat ctcagcctca gcctggtact gaacgcttgc cagagaggtg 93840atgtggtcct ttggaggaaa gaaggtactc ttgattattg agttttcagt gttcttgtgc 93900tgattatttc ttatctttgt gggctcatct accttcaatc tttgaggttg ctgacatttg 93960gattattttt tcttttatcc tatttgatga ccttgagggt ttgattgtgt tataaggtca 94020attcaaccaa ctagctttgt atctggaaga ctttaggggg ccatcgttca cctcccaact 94080cctggactgc atgttctaac tctggatgac ttgtattggg ccccaacttt gttctctggt 94140tcctcgaggt ttggagtcta ctttgttgga ggaccaaggt gtggcagctc cagctgggtg 94200ctagcggatt caggggtgcc tgcctccctg caggcattca ccatgctagt gaaggcaagg 94260catttttgtg gggaacagga ggctcctgct atagactgtc tgtgcttttg cactggtgat 94320ggtgttggtt tggtgagagg cactgaccag tgcagatctg agtgccttct tggtcacctg 94380caagcaggag ggattgctca gggtgtggga ggatcctctg ttctccatgc agcattacca 94440caagagtgag gcactggcag ctgcagggct tgctggctgt gtgctgctaa ggttctgtct 94500gcaatggtgg ttgacagagg tcaaggggca tacttccctc ctgtatgcta gtggggcaac 94560taaagcaaat tccacctgtg cagacatgtg cctgcaaagt gatgtgggga gttgccatgg 94620gctcagggga agttgcagta tgggtagcga acacccggct ggtgtgcgca gtaagggctg 94680tcttgctgga gttctccact ggtcaggcat ggcccactgg tgcagaagct attctgtggg 94740ccaccacagc acccaagatg gccctagaag aggccagcag accaaggagt gctcaggttg 94800caccagccct gactgatgta caagaccact ctgcagatat caagtctgaa aattccccta 94860gggccaaagt ctattatggg agcaagttga gcctagaggg atcgccatcc ctgtccatgc 94920actgctgtag acactcctgc actaaaccct ctgggctcca catcagctgg cttgctgctc 94980taccactttg cttgtctctt gggggctcca ccccagagag atgtgggtca gcaatcattc 95040agttcaatca gcccaggatg gagagtctgt gctatgggcc caagccaggg gctctctgtc 95100tggtgacgag cagctggggg gtggggtggg acctgtggga gatggactgg cctcctctcc 95160ttgagtcaac tgctgcttat tggaggtgtg gatgagacac ttagggtctt tgctccttta 95220ttagtcagag ggtagcaagg acagttccat tgcagaggta gtggcagaga ggctttcagt 95280tgtccgtggc ggctctgtcc agggagttgc tgagttgcta ttggcttgat atctctggtg 95340gggtgtggct agaggtccag gcctggagga cctgctcgtt gaagagatgt gggaatgggc 95400acccacataa cagtctgttc acttttccat agggctgctg tagtatgctg ggggccagct 95460ccagtccctg gtcactttag attttccagt acctggaggt gtcaccagtg aaagctgcga 95520aacagcaaag atggtggcct tcctttctct ctgggagctc catccctggg aaatacaggc 95580ctgttgctgg cccgaacaca ctggtaggac atggctgaag acgctagttg ggagacctca 95640cccagccagg aggaatagga tcagggacct gctttcaaaa gtagtcttgc cccattttca 95700tagaggagtt gtgccatact gggggtatgc tttagcccct gattgcctca gacactctga 95760agcccaaagg ctggaatggc taagttgttc taacagcaaa tatggtgggc tgctcctctc 95820cctgggacaa aggtcccatg gaagtctgaa acctctctca gtcagagaac accagttggg 95880gtagccgggg accccagatg ggagactcta cccagtgatg aggaacggga ttggggacct 95940gctaaaaaaa aaaaaaaagc agtgtggcca catttttgtc gggcagctgt tctgtgctgg 96000ggttcccctt ccacccctgc ttaagctccc caaagcctga aggctggaat gggtaagttg 96060cccaaacagc aaagatggca gcctgcccct ccctctggga gctctgtccc agggagtttt 96120cagatctctg tcagctggag aacactggca ggtgtggctg gaggccccag ttgggaggtc 96180ccgcctgtaa ggatgaatgg gatcggggac caacttaaag cagcagtctg gccacatttt 96240aatagagcaa ctgtgctgtg ctgggggatc tctttggccc ctggttagtt tggactctcc 96300aaagcccaaa ggccataatg gctaagttgc ccaaacagca

gagatggggg cctgcccctc 96360ctcctgggag ctttgtacca gggaggcaca atgttgctac tggtggctag ctggaattcc 96420aagccagtgg gtcttatcct gtgaggcgct gtggaagtgg ggcctgtaga ccttctctgc 96480tgatctcgct ggattcagcc tcttttctgg ggtatgtatg ggagtctaac ctcctggggt 96540atgtttgggg gtctaacctc cagctttgcc aaagtcgcag ctacttttgc ccagacaccc 96600agaaagctgg agtagctaaa gctcttgggt ctccatgcat gcctgagtgg ctgctctgct 96660gagactccac gtggctgtgt gtgaagggcc taatggagtg agttcacaag gggatctcct 96720gatctgaggt ttgcaaagat ctgtgagagc agtgtggatt cccagagttg cgcattcact 96780taccacttcc ctgggaaggg gagtttccct tgactccacg tctttcccaa gtgggctgtc 96840ttcctgcctt gatttgctct ggtctccgtg ggtcgagttg tttccttgat tacttccaat 96900gagagtacct taatgtttca gttgaaggtg ctatatttag tcaccccttt ctttccgccc 96960tgtgagagtc acacacatta actgcttcta gttggccatc ttggccactc ctgccctaaa 97020cctttctagc aaaaaaaaaa aaaaaattaa taacatgttg atctaccgct tctctctctt 97080taaatttatt taatcattat gaattttttt acatttattt acattgttaa gctgttttat 97140tttaaaaatt ctaggtccag ctcttcctgg attgctttta tataaggaac atatctcatg 97200aaataaataa aattcacatt caaatgcaga agaatctatt ggaaaaaact cagaggacag 97260gataaaagca ctcagaaaaa atgccaggag aaggcgttta tcacataata tcgctgataa 97320gagtctctcg aaaatttttc tctctattca ttcttaccaa atatagaaag tgaacaaaac 97380aatattagta ttagaaaaaa catccaaaaa taatgacctt tctgaatgaa gactgctttt 97440ttcatggtta ctctttttgg ggtacagttc tatgttgatt tatccaattt atcaaatagc 97500cattcagcaa atatttattg agtgtctgtt atgtcacagg cactcttttc ggtcctcaaa 97560atacatccgt gacaaagagt aaaagattcc tgttcatggc tcttacattc caggagggat 97620agcaatttct tttgtaaagt taatcacaca acagaaatgt gaaataatat tgatgctgta 97680aggaaaggaa aaataaatga aataaattga aaaagaaatg tgaaggaata attaaaagag 97740gctatatttt attgaataaa aataaaagag gctatgtttt attgaatatg ctccatgttt 97800tatactatat cataaaacat acaagatctg gcttttaaga aatcaatatc ttcatcaata 97860tcttcattca gactcatcta gattagatta ctctgaatct aatcacatag agacttgtct 97920gacaaatcca gattttttgg acgttctgca ggactatttg tcaggatatt tcacaggatt 97980ccaagaaata atattggtgt ccatgctata atgattcctc agctcctccc atctgataaa 98040atattgattt cttatacata taaaacatat aaaaatattt aaaatatttt ttgttatatg 98100agtgaatcaa taataaaacc actatctcaa taatcatcaa ctgattgcaa actgattgtt 98160catctcagaa aaaccttggc agagttaaaa taaaagtttc aaaatacaga acttagtacc 98220aaaattaagg cagtgttagg tttctaattt tgctattcac atgttaaatg aattttcaaa 98280attcagtagc taatactagc tagggtttta aacaagacat agttaaaatg aaactttaaa 98340aaaagaatca taaacttcag tatcatcatg atggcagttt taggatttta atgttgacac 98400cctagtctca aatttgtact taatgtggtt atatagctag gcagtgctgg agtgaaagtt 98460tcaaaacaaa ttaaaatcaa aagttaagaa aaaaatatga aggcaatttt aaggtgttta 98520atttggcact gtagtttcaa aatagtacct gaaacttaac agcaaagtat cagattcatt 98580tataaaacaa tgtgactgat ctttatgtat ggtttgtgaa acatttatgc agtgtcactt 98640cagaaaactc tgccattata gatttgaatt gattaaggat atccactcct ttccttggca 98700tgatacaaat aaattactaa agtataattg taacaatgat aaatataagt gacaatacca 98760ccatattact atgaaacaca gattgattat ggtataatac aatttagcat ctccatattt 98820ttgaaaatga acttgtttct ctaactggct taatttggga caatttggac atcaaaaaga 98880atgatgatgc aatttaaacc atacaaaaat taaaaaaaaa aatccaaggg acggtggtga 98940aagtcttctt tctagaagaa tagcagctaa tatacacaga acgaatctta gaattagaaa 99000atcactatat tttgatcccc ttccccaaag ggtgacaaaa ccattggtag acagtggttg 99060agaaacagaa tagtctcagg atatcactcc gtagatttat tcattaatta aaaagagaaa 99120atgtgctttg agagagagaa agctattacc gtctttatca aataggagag cctgatcatg 99180tgtggtctga agtttatcta atgggattcc tgatggaatg tttagtctga atctaatcac 99240atagagactt gtctgacaaa tccagatttt ttggatgttt tgcaggacta tttgccacga 99300catttcaaag gattccaaga gagaatattg gtgtccatgc tgtgatgatt cctcagctcc 99360tctcatctga tctccgtcct ggcccccatg actttctttg tggtagttag ggtgtggtat 99420gtgccactga ggcccacacc tattgctgta agtgctgttt gggaaaccat catctttcag 99480gtctgtgtga taaaagaaga gccttgggga aatgttctct tccaaattta atctttacat 99540tattagaaaa tattttgatg acctgttttc aaatattttc ttataacttt ccattttcat 99600gtgtttattc tgacagttta ttttatcttg tatttataat cactaagatg ttagtattgt 99660aatattaata ttacatgatt taaattagga aaaatgtgtt ttctattaca aaatggatag 99720tggataattt aagtatagaa agtaatattt tctatatggg actatttcac tctctgtaat 99780atcctgaatt ctaattccca ctgtagtgag ctataacttt actaatcagt tttcttacaa 99840tcgattttaa gtctattttg ttagatctaa agacataaag ccaaaagttc ttcttgaaga 99900gaagcacatt tcagttacgt ttataacttg aaatatctgg ttttactcaa aactcacatg 99960tcatactgaa aaacagaagg gagatgttgt cttttcttga ggagagactt ctctgcagtt 100020aaacagctca ccacatgttt agagtacata gacaatacac ttcctctttt gtaatgtaga 100080tttcagcttt ttgcttgtag aattatcatt ggcgtggagg ttatacaggg gaagtagtga 100140aaaatgtagc caataccagg aaccttagga agtgtctgaa cttcatcttt tctgtgttcc 100200tttgccctta gggggtcagt gtaagagttt gggctaggaa gagattgctt cttttactct 100260atttagtttg tacttcctat ctgggtattt gacaataaat gactcattct ctttgtttgc 100320cctggtgttg aaaaattttc ccatatgcca gagaaaaaat gttacagtga cacaatgtaa 100380aattgtaaga ggtggaaaaa gatgaggtat ggacatagtg aatggaagtt cagcccttta 100440aaactactgg cagagtagat tttactcagg cttcaattaa gtagacctga atgtaaattc 100500aggtctagct ctgcaactta ctaggtaagt gactttagtc ctctttaaga tttagtttcc 100560tcattacagg atataataat actatttttc ttatgaggta agtattaatt gaaatagtat 100620atgtacattc tagcatacag tgatccccta ataaatggaa cttatcatta atacattgct 100680aggaaaagaa aaacacatca gggaacaaaa gatataactg tcttattgat aacaggggat 100740ggattcttgt ggacaaaaaa atttagaatt gaattttcaa ggggtcattt ctttcaccag 100800gtgtagttag gtttgctctt atggtaacaa tgaatatgtt tgtttagctt cttaaaccgg 100860catcatggaa cgttaattaa taaacagaat tcaatgtatt tgtggggcat tttatttttt 100920atgcaatcat ttgtatatgt caccttcaca atgcatgcca cattctcaga ccacctatta 100980tgttattttc ttaacatttt tcttcaaatt cactcaccct tttaaaaact ttactgaagt 101040ctcacttaag cacataattt gtaaaatcat gggtttgttg tgcaagtttt gtttttctaa 101100tacactctaa aacaaatacc ttaaaagagt tacacctaca gtccatatac cacccataat 101160catctcaagt acctccagtg cttgttactg cactttggaa aacactaaca tacattattc 101220tcattagttt ttataatagt tatatgaggt gaatagagaa ggcataacta tacccatttt 101280aaagatgaga aaagcaggtt catggataaa atctcatagt aaattgctag aattggtcct 101340gatactcatg ctttctttag atcaacccag tgctcttact gtaattgata ccaaattctt 101400taaggaaact tagagctaaa agtaaaattt tttgtattta gacctgatta ttttgtggta 101460atttgaatat aggtcaatat gaaaaaaaat aaaagatgaa acaaagaaac tgagagcaga 101520tcaccaagtt gcggtaggtt agcctaagat agcttttggt tttctcagcc ttctactatt 101580cacagctttg tgtaatcccc tccacttgag tatcttgctc ataccaatag aatatggtag 101640tagagtagag gtcacctctc tgataagttt acagaagatt gcgacctccg tcttgccaga 101700gtacttcctc tcttgctggt tttgatgaag caggctgcca cagaagagag gctcacatgg 101760cagggacctg agggcagcct ctggccaaca gcaagcagta aacagatgcc ctcagttcaa 101820tatccctcaa agaaatgaat cttaccaaca gccagttgtg ttagctggga agcaaatctt 101880tccctaaggg agatttcaga tgaggccccc agccttggta gacaccttga ttgcagtctt 101940gtgagagatt gtgaagcaga gctattctca gaattcatgg gtgttttaag ctatgaggtt 102000ttttttgggg ggagaatggt catttgtgat tcagctatac ataagtctac aaaagtcatt 102060ccagaagtga ttcagtggag gtagaatcat gtggttgtga gccccaggca cttggagttc 102120tgatagaatt gtgacttcta acactggaca ccttttcttt ttctcttatt ctcccatttt 102180tctcctttcc ccttttcctc ccttccttcc cttcattcct tctacttttt ccgtacttta 102240aattaataga gcagttggaa acacaaaagc aatgtctgta tctacaaaat gtcattattt 102300atactttgta tccacagtgt gctgcctagg gcttcatgcc tgaggtgcat ctgtagaagg 102360tgctcaacaa aggcttggct gttggtatta ttgaatcact gtggagttta ttcattgttg 102420tccatgccat tttgagtttt cattttttta tttatgggag tgtctttatt cttttaaaga 102480gctttgtttg tacactcatt ttctctctct ctcttttctt ccacaggcaa tttatagcac 102540tgatctgtca tcaataccac ttgctgtctt ggatgtgaag atgatttttc ctgcagggat 102600tccctctaca aaattaaaaa cactgggcat gtggaaataa tattcatgct ttaaattgtc 102660ttttctcttc actacaccag gggtccccaa cccctaggcc acagactgtg gccctagtgt 102720agtgaataga aaagacaatt taaagcgtga atattatttc ctcatgccca gtgtttttaa 102780ttttgtactg gtctgtggct tgttagaaac caggctgcac agcagaaggt gggcagcagg 102840tgagcaagca ttactgcttg agttccgcct cctgtcagat cagcagtggc attagattct 102900cataggagca caaaccctat tgtgaactgc acacgcaagg gatctaggtt gtgcgccctt 102960tatgagaatc taactaatgg ctgatgatct gacgtggaac agtttcaacc cagagcaccc 103020cccacccacc tgcagaagaa ttgactttta cgaaaccagt ccctggtgcc aaaaaggttg 103080gggaccaccg ctgcactaca ctacctaaaa gattttcact ttcacagtgt tgcttgcttc 103140tgttttacat gcacaagtag ctaaagctag ccttctggta aatggagggg cagagcagat 103200ggtgggggag gagtacatac ggacgaattt gaatcacaat ttcctcacta tatgccagca 103260aaatttaata atagcaccta aacatacaca tgcatatgta aatgagtcac actataaaaa 103320cttttaacaa gtactggcaa gtcagatggc agacttaccc tgaaacctgc cactccaata 103380aaaacctcat aattaaaaac aaggctgtct ataaagcata acatataata acaattattt 103440gcaactggta caaggctaga ttagaaagtt gaaagttatc tttctcaggt aaaaatgctt 103500ttcctataca gtatgcagcc agcagattat catccatagt ttgagtagtg agatgccact 103560tgctccaaca attaacacct gctgatgttg gtccaagaag agactgaggt gatgcagttt 103620cacctgtttt gtaagaataa cgctggtgtt tgccatctat tgacagagtg cctactacgt 103680gccagatgct ttgttggcac tgaatgtgct atctcattcc agtttcttta tactcaatga 103740aaaaccaact acatttatat tgcattgagg cttaaagtgg tttactgact tgcttaagat 103800tatacaagta gtaggtggct acagcagggt ttgaacccaa gtatgcttga ttccccaaac 103860catgcttttt aaaaaatcaa aggtgtaact tcgataaaag acatgaagtt aatgaatata 103920tgaaagatgg tgaatagata cagatacaat gtggccttag gccagatcat gttgaacatg 103980tggtgggata gataagagaa ggttcttctt tgttgttacc tggttctcaa ttggttatta 104040ctttatgtgc tttccatatt aaaattctat tattctggtc tataaattca cccacccaga 104100cttgcctaaa ctaattaaac cctgaagttt ggcatgtctc ttttttgggg tgcctctatg 104160ataggtggta gaaatgaaaa tggaattaaa agttttgtga agctatagca ctactttttc 104220attgtgttcc cccctgactt tctgccttag gtgtttactt tggtgagata tcctgggaga 104280aattgaggtg aaaagaagcc cgagttagga ttagggaaga gatgaagtag tcaataaaat 104340tcaaattctt gtattctgaa acgcaactat tctttctcca acttggtttt ggacagaatg 104400tcttagtgta gctgttaaca aagaaattga tgacaattaa ctcccatttc tcagaatttc 104460atcattcttt gaaagtgttt atcatactca atcttctaaa aatccttaag gcatactaca 104520gtgtagaggt tggcaaactt tttctataga ggtcctgata gtagcttgtt tcgcttttga 104580gggccatcga gtttctgtca caactactca tctctgctgt tgtaataaag actcacccat 104640agacaataca tgaatgaagg agtatctatg ttccaataag acttttaaaa ataaaattag 104700gcagcaagac tgatttgaca taagggtcat aatttgctaa cctgtggtat agtgaaagga 104760gttcaactag agtttgatta tggctgtgcc attctagttg ggtagtttta ggaaagttat 104820ttaatttaga tttgatgtag ttttctcata tgtaaaatgg ggataataaa acctgcttca 104880caagactact atgaggagta agctatgtag ctaaatatag caaaatatct ggcatctaat 104940agatgcctaa taaatggtga ctataatgat tcttatcatt actgtattat tttaaacatt 105000tatctttttt ttttaggttg ttgtctaact aaggtattta gagaaaataa gtgctgctga 105060gggcagctgg aactgttttg ctggttcatc actgaaattc tagttcttgt tggtgcttat 105120ttcataatta tgaaactaat tcttttgaaa agaacttgaa gtagagcaac aagaactaag 105180atagaactaa taccattctc tctcagttct tattgcttta cttcaagttc ttttgaaaag 105240aattacatag atatgggtgc atgtgtttgt ttattttcct tgttgggtaa tcgtgaatat 105300gttgattggc gtcaaacatg ggtctcacct atacccatgg cagtaagctt ctattgattt 105360gaattcagac tagccctggt ggccctgtga gtgggaaagt ctaggtgtgc ctagcttggt 105420ctgtggttcc acgaggggtt ggatgcatct gttctacttg tggaatgttg gcaccaatat 105480attggctgct tctccgagta tttgcctttg tcttctttgt gaaaggtcac tggctggttt 105540gagctattgg gctgtttatg ccacatcctg tgcatgccac actggctttc tttctgtggt 105600gtttccagag ataagtttgc ctgatagaag tcagactctg tggcttttta tcattataga 105660tttttctaga aggagaagag gccatgatca catctgagga tcctgagtca ttgtagacat 105720gtactgaatt aaagagaatt ttttgactaa aggagaattg catcaatcac ggtgaaggag 105780atgccacagg acagggcctg aggtgttggc ttagccacag atgtaagggc tacagttaac 105840agacaacttt cagtttccac tattggaagg gatgatcagt ccttccctcc tctattttct 105900tgagccccgt ttttcacctt tctttttctc tctcctttct tatcatgaag aataaagaca 105960aatgagaaca gatctacctt aggctgatac agggcaggga atccatttaa taataaaacg 106020tgggtcaaaa ttcacttttc tccttttgaa ttgaaattat attgtgcatg ggctaattag 106080attgaatgct gtaaacatga agataatgct tgcaaagtag ctacagagaa agagaaaaag 106140cctaaaacaa ccagtagtgc ttaggaccaa tagtataagt ctttacacac tacatttgaa 106200taatactgta agacacaatt ctttgatagg ttaaatagca aatctaggcc ccccaaaatt 106260atttaaaaaa ttgtcatttt aattctagag gtataacaac agtgtgtaag ttgcatcaaa 106320taacaaagtt agtctacagc ctaaattgtt tcgtcctgct tttttcactt ctatgcatat 106380ttttatactt ccatgctaga gctacctcat tcttttaaaa ttgtgagata ttctataatt 106440tatttgtatt cccctattaa tatattttta gcttattagt ttacttaaaa agatttatgt 106500ttgccttcta atgtcaaagt taggagtcat ctgtccattt aacaggtggt gttttcttgt 106560gtaactcctc tgccttcatg caaacctttg agaacaatct cttgaaacaa ggctaaaatg 106620cctttggaga ggtattatag atgatcatat ctactttgtg cctctttcca ttacttagct 106680gcattagagg cccagctgtg taggtgtaac tcaaaatcca ccaaaactaa tactgtggtt 106740agattctggt caaacaagtt gccattaatc cagatgtaga atgggattga aaggtggctc 106800ttccacaccc tgacatcaat gtaccagttt ggctctgtgc attctttctc cccttctccc 106860tttaccaccc tcatataatt gtttgtgtac atgtctggtt tcgtcactac gctgatggca 106920aggatcatgc atgccttatt catatttgtg ttattcaagg attctactct gggttctatt 106980atggggcctg gcctaaagtg gttgttcaag aaatgtgtgt tagagaaatc atacataaac 107040tagcaattct catttggatt cctgtatctg aacaactaac tttcagcttc ttcagtggga 107100taaagaagaa aaatggggtt taaagtacat actattcagt attaatgtag aatttaacag 107160ctgccatcca agtgcagaat cctctgtagt ttcccagtgt taacctcact tctatctcta 107220gccatgtctc agtgctgggt gactctctcc tggcatgttc tggcaagact ctacctggtt 107280tgcgtaatct acatcggctt ctagtttcca caagaattgt ttatatgcat ttaattttag 107340ctcttgggct ataacatgtc attgttcttt ttacttatct cctcttactt ctggaaacag 107400ggcaggcatc ttcaatactt gctgttcctg tttggtgtgc tcttagatta attttaactt 107460tcctcttcag ctttcatgac acttcaagac attttccagt catatttcct gtataagaaa 107520atacagacta tgtcaccaca aagggtagtg gagattgggg ggcataattt aattcattca 107580gggaactcat attttggtgt gaatggaaat taaagcaagg tatttggatt aatttacctc 107640atttggttct atattccatt tagaggataa cacattaagc ttttattcaa ttttatctgt 107700tatggtcaca gtgaatctgg aaaaaaatat atatggggct tagttttcat atttagggga 107760aaatgaatat cctagagaat aataataaaa gttagggaaa ataatgtttt cctaagagta 107820ggcaatgaaa atctgaaggt actcaaagca gtcttgcaca agtgctttga aaagcctctt 107880gcacaatttt atttctttat agtacttaca caatcatatt tcataatgac ttgctataaa 107940caatgttctt gacaagaagc ttaaagatac aaaactgaag gaagcacttt tgggagaaaa 108000tacttttata tttgcttact tctacactac aacagacata aaattatgga tttttttttc 108060agtgcaattt tcatatgtca gttctaggag acaggaaatg tgaaacactg taggaggtat 108120gagtttgcca cctagaggag agaggtgaaa ttcaactttt ctccaatttc tttagtataa 108180ttcattaatt tatttaatta tttactcgtt taattattca aaaataatta tctaccaagc 108240ttaactattt tgccagcgca gatttgataa atctgttcaa gatttatgag ctcaaagaaa 108300ccacaaagtg catcttactt taattgctca gctgcctctt ttaaaaatct tttactttta 108360agagagtata gcacaaatat ctgaacaact ctaaatatcc atacttggga tggatattac 108420tttgagctct tgcactataa taaaacttta ttcttttgta ctaattcagt ccttttactt 108480tttctttttt aatgtttaag aaacaagttg gatatggaca agatgtaatt tcttctgtca 108540aggaacccac aggataatag gttaatgata gagaccaaca atgctgatgc atttttaatg 108600acggagataa tgtctagaaa aaaatccatt atttggtaaa gacaaagtat gcatatgtat 108660tcctttgttt caattatttt taaagttaaa aaacaactgc ttatctcctt ttgtactaca 108720agcaatatct ggtatagtgt atgcatagta agtattctag aaatagtaat ttcattgttg 108780acttgattat attggagtgg aacttactct ggaagagatc ctaactttca tttatctgag 108840aaaatttcca gttaggacat ggaaattttt tccttgtcaa tatttattct taatgtgttt 108900agaattttag aaaatgggtt tagggattta gaaatttctt tactaaataa ctctagggaa 108960cagtacctta aaaatattca aaatgacaaa aacttaaaat gacatctaat tttttaaggc 109020caagaatcat taaaaaggga tccaaatctt tagactttgt tgctcggtgg aactagaatc 109080attaatatct cagtcagggg aagccatgtc aacttactgg tttaatttcc tgtgagcttc 109140ccatgttctc tccctgcaag gaccacctca aatccctcag tagtcctgtc tttatgaaac 109200cagtataatt tttcttttcg ctcttgtcct tcaccttcct gtggcaacaa gagtcaattc 109260tccatatata aatactcggc ccctgtttta gctgtgtctt aattgcgcaa catctgttta 109320ctctgtgttt taacatctgt gtggatagca ttgttgttgt aatattttga ctgtaagctt 109380ctaggaggta gaggccagca ttattttctc catttttgga atgagaaaat acagattacc 109440acaatcaaag tagaatggca gcttatagta gttatttgga taatttatat agtctcttaa 109500aaaaacagat tatagtaaga agtggctgag caattagcta tggcacactg cacggttttt 109560ctgacctctc agctcctaaa taaactttgc caaatcttca ggccctcaaa attttttcat 109620tccatttgtt atgggctgaa ttgtgttccc ccgaaatgac tatgctgaag tcctaactcc 109680tagtgcttca gaatgtgacc ttatttggaa acagggtcat tgcaaatata attagttaag 109740atgcgatctt actgacatag gagaagctcc taatcatggt gtccttataa aaaggagaat 109800tttggccata gagacatgca ctgggagaat gctctctgaa gactggagtt atgctgctaa 109860aagtcacaaa attaacagaa gctacggaag agaccttgaa taaattcttc cctgtagcct 109920tgagggagag gatggcccag ccaactgcta atctcagacg tctagcttcc agagctgtga 109980gacaatttct ctttttaggc cactcagttt gtggcacttt gtacagcagt cctagccgac 110040taacacacca ctctaactgt tgatcaaggc aagagcctgt gatcatgtat tatcttgctt 110100attccttatc agcattctat ggtgtagata ttagtgccat ctatatacaa attaggaaat 110160ggagcctcat agaaattaaa tgacaagttc aaggtgtcat ggctatttca ttatagtgcc 110220agtgtttgaa cacaaatcaa tttgactcca aaacatcatt actctactca attctagttc 110280aatccagatg ttcacaaaca accagactat agtggagatg tgggtggtgg gttgagaagg 110340agatcataac caacatcaga ctgtcagtga agcagactgg gagaagtttt atgaagccaa 110400gcagctgtgc aaggtacagt agagatggtc agattgttca tgtgtatgga ttccatcttc 110460tgaggaatga actccttgat attcctgagt tagtccagtt taggcaggag taaacagaag 110520gtaaacagaa gattggagac tgtgtgtgtg cacgaatgcc tcctttgtag ctggatgtct 110580aacatcatga tagccacact cacatgaata cagagataca caatttacaa attaatgtaa 110640cataaaactc ccatgcagtc tgatttcatc ttactgacat ttctgtcagt cagtgttagc 110700atcttaatta tataaatgtg gaaactgaaa tactcaagag gttccctgac ttcccaggcc 110760acacagtaag ctttggtgcc agaatgtatc tctaggcttt ctcatctcaa cccagcattc 110820attatactat tgctcactgc gtgtagaatc agatttgatt tctctgactt ttcttagtca 110880cttctgtggt tttgtaccac tccctctctc actaaataac tgcctgcaaa agtaaaaatt 110940tccatgaaaa cagaaaacaa atgtaccaga aatgttgatg gtgtaagaga taaaactggg 111000ataaagagaa aatgtgttgg aaagtggtgt cctttaatgc aacagaaaag tatattggga 111060gaaaaagaaa agagagaaaa atagacaatc tgaagtgatg agaagagcaa atgctacaga 111120tgtacctgaa cctcttcagt aggtgtgatc ctgaagagtt gtgtataaca acaatgaaca 111180aaaataaaat gtactgtgga aattgtctag ctgttgagat cctcctgtgc gatatttttc 111240aaagtgaaaa ctccaatcaa ccctagctta tttatggaga agactttgcc ccacagtacc 111300cagaaagttt cttgacaata tcatatatgc ataataaccc tgagacaatt tttgtttacc 111360aggaaaacat ataaaaggga acattaaact ttgtctagtt

ctactgcata aacatgtgat 111420aatgtgcatg gtgaccttct gttgtaaatg gaaagagtta agctctctga atctactgct 111480gaaaggtgaa aacactttct tagggctttg aacttcattt gaaatcttac tgaaaaaaca 111540ctacagactc tattttcttt atatttgaag atactttaca taaaaatcta aagcattttg 111600acttatgttt tcatctactt gagaaggaaa ctcacagact ccaaagcaac tgttgtctgt 111660tttgaaaaaa atttcagaaa tcaccagaag caatagggag tggccttgat tcctgttctt 111720gtatttatgg gtagctaaag ttcatatttc tcaacatacc ataatctctg tgtaattggc 111780caaattccat ggtggataat tagatctagc ttaccagggc agatttggat ggtgagagca 111840gtcacactgt tctgggaata tgttagccaa gtttactatg ttttacatga gttgacagac 111900tcacctcact tgctgaagga ctagcccagc aggttctacg ggtgagatca ctgctagctc 111960attcactgct gggcctggta ggcacaagag gccaagaaat aaataatgtg aatttgggct 112020tcagaagttc tctttcctat tttctttcct aaaccctttc ttctaccagc tgtctagggg 112080ctaaaacatt tgttcatacg tttattaact aattcaacaa atatttacca accatgtttc 112140aggcactgga cactagaaat ataatagtga actagacatt ttctgccttc aagggtctat 112200gaacaattat aatattctga aaaatattac aattcacaga gctcagtaat ccaaatcctt 112260attatttctg tctttaaaaa gcagaaagtg aaaaatgctc ttaaaagagg atggcataga 112320aatgtattta tgcattgcaa cagataaaat taaggaatgc atgaagactg gttcatctgt 112380gtggttgtga gtcaagaata aatcccaccc tccctgaagt actcagactc taccttgccc 112440catggccacc actgtggccc aatggaagca ccagtccagg gggtctccat tcatgctgtc 112500tttggatgtc ttcagaatgt tgtttcacaa gtactcagac ccaacagtaa gattttaaaa 112560attgtccata atattaacct tggcattatt atgttaaaga aagcaaaaca gatatcactg 112620agtttacttc tcaaaaaaac cttgcgttcc tgcaaaagtt tcttgaattc tgactcttgt 112680cacacaatca cacaagaatg gctatactta aacccttcta atcaattata tccttaatat 112740gtatgactga gtgatgtgtt ttcatgacta tgaaatgtat acatgtttgg aaaatctatt 112800cacaatagag ttttatgata ttcctgttaa caggctgtca ttgtaacact gtttatgcag 112860gaattgtaat tctatctgtt tttattttta gcgtcttttc tctccatccc ccaaatttta 112920aggagctatc aggtctgtat tttatttggt tttgaagttt taggttattt gtagttataa 112980tagccatatc aattattcat ttagcaaaca tgtattgagt gctactatgt gcttagattt 113040ttccaatgtt gtgaaggata attggctaaa acttttccac ttttattagt aatttgagag 113100tttttttctc catggatttt agtcactggt aaaggctgtt tcatattcat agattttttt 113160ctacggtaag aaacatatga tgttgaataa ggtatgaatt acaaattaag gcttttccac 113220attcgctgcc tttataagat ttttttttct tcatcaaaat ctattcacac acacacagac 113280acacatgcgc tgttttgatt ttcttcaaat atatccagtg ttcagttctt gggcacatat 113340taatatactt gcctagatga agactatgtg tcctcaggaa tttataatct agcaggtgaa 113400agatttgctt ctttcaaaat gtgactctac ttccccactc cttaggttgt gaaagcagtt 113460gtttacgctt tatttcattg ttttccaaac tttagttatt tatgtgccat cttcatgatt 113520atgctattca cataccacct atactattat gcttctgaaa atatactatg attttcaact 113580taattaaatt tgtttagtaa taacagtagc tgttacatca ctaggttgat gtgctagtta 113640aaaattttta aatatacttt aatataaata tgttactact aaattatttt tttgtctgta 113700tgcacccaaa atcttgcctt tagtagtact acacatatca tgctttggga aactctaccc 113760atgagattca tattcaagca tgaggaatgg caaaagaaaa tacagaaata gtgatagtaa 113820ccatagcaat ggtaataaga gctattattt attgaggact ttacgtatgt catttaattt 113880tattttatcc tcacaacaaa ttttagccat gagtatcaga taaatatgag gcaaaagggc 113940aggaaagaag gaacagtgga agtcaagctt tttttcgcct aggtcagcta taactaacac 114000gacaagatgt tttagtattt gtactttatt tttagtcagc tcagatttca cacctgacta 114060ttttacaaaa atttggatgt gatggtggca gattaacata attactttta gcaattatta 114120tgggacaaat tagttaaagg ttgtaaaatg cctagaaaca gagtagaata tcctagtagg 114180atatcctaga atatcctata attaagttat caaacaatta ctctgattat ttttcacagt 114240agttcaatca aagtgtaact ttgggtctgt tagtatacat gagtgtgaat actctggaga 114300tttgatcttt ggctttcctg tgtaagttca tatatatttt tgttattatc ctgtaaataa 114360ctgaattata gtacagtgat tctgtaaaaa acactttagt tattaatatt ctttggtgtg 114420aagttcacat taaaaattgt tatatttcca gaacctggtt tttacctgtg aaagtcaatg 114480catccttctt ttaatcctct gcattggttt tgcatagctt gatgaaatat gacttgcttc 114540tcctccctcc ccctccttcc tgtgcctgta tccccatcat ttttttttct attcctcttg 114600gtatctggac ttctttttct gccaaatgag tcagtaagag aggaaatgtt taacccacat 114660ttgtcatctt ggctgggaaa gaagtttgaa ggcaaaaggt gcctgaatat gtttcactag 114720gatgctgaca caaccttttt gactctctcc taagaatact actctatatt caagttataa 114780agtgctaaat gatctatttc caccatgtat acatttcata tgatcaatac ttattttgta 114840acttttttct ttgaggagaa gtatttttct tttggaaaaa tattatttat ttgtgtgtgt 114900gtgtgtgtgt gtgtgtgtgt gtgtatttat tttcttttaa tatgtggtct ccctatgcaa 114960aggatttgat tttataaaca gaagcaatag gattaagagg ataaaggaaa aataggagaa 115020ggggaaatat gagtatcatg ataaggtaaa aatgaattgc ttgtattcta acatagaata 115080gctactacct gttgagtgtt tattatatat tagacattta agactaatca aaatatctaa 115140tctaatgaaa taatcactgt tttgaatttg cttagattta gtagatgtag aaactgagac 115200ttagagaggt ttatttactc aactccacac tgctaattac tggtgaaagt agaattttac 115260tcctctggtt ttctcatcca gcacatcatc actataaccc ttatagtttg cttttggcac 115320aagtattcat tattaatgga aatgcatagt attatctcag caaatgtaca aatagtttag 115380cttcactaaa ctagtcaatt ttttttttct aaacatcaat gcttaggaag caaaacaggc 115440tgggggaaca gtagttgtac tggtggcagc tgtggtgctg atggaggaag tggtggaatg 115500cataggctgc tcatgctttt tgccacaatg aaggtcaaaa agtagatcac ttaaagtcta 115560aagttaacct tgggggtcat attcttcacc aaaaactatg tttatacata tagacttagc 115620agtatgctat aaaagtgaag atatagcact ataaaattcc accataaagt aaattgttca 115680agattgtggt ccaagctctt caaaatgctc ataaatcaga aggtgtattt attaaacaat 115740attttatatg tacctataat aatacaatac tatactacac aaattggacc taaaatgaat 115800tctcttgcta tattaaatat taaacattaa ataggcagaa attttgtttg cactggactt 115860agaatataag aagaaaattt gggacaacct gaatagttga ggtctcttga gaaacccttc 115920agcttctttt cctccaaata aatttctctg tagcaaatgg aagccatcca aatgattccc 115980tagctacctc aaagtactgt aatttgtcta cttcacaaag tggaggacta tatctagcaa 116040taattcaaga aaaatgcagt gactcccatt atatcttagg cactatgcta ggaagtttat 116100gcatatcatt ttgtttgatt ttaatagcaa cttcatgaaa taaatcatca taataaatca 116160ctatttcaga tattgagaaa ccacagaaag agagaagtta aataattttc ctgtcaaaga 116220ccacatcaat gatgaagcca gaatttgagc tcatgtactt aaccactgga ctacctgcct 116280gccctgtcga ggaacagcta aggttgtcat agagtcttga ctgtgtatag atagttgttt 116340gaagagagaa aaaaggcagg aggatctggg gcatatgttt aaatcaggca ttggcatctg 116400tactagaatt gaaaggtgga actattattg tgttctattt attgagtata ggtataccat 116460attcaatgta tttctctgct tcatacacta tccaaggtga taaaagtgtt tatgaagagg 116520gattaggaaa tatctgctgt gtttaggtca tagtccaacc aaaggattaa ttaacatttg 116580cctctttttt ctcctacatc cagtgtccct tttgatgaga agaataagcc tcattctgat 116640tcaacagcag agatcaaaga aaagacttct gttttctggc caccagatat atgttatctg 116700tgcttaaaga attgaaaaac acacatcaaa ggagaatttt cttggaaaga gaggtaatga 116760gatacagtga aagagaatgg agattcttta aatcacagag acctaggatc aaatcctgtg 116820attagcactt tttagtaatg tagcctactt catttctttg agccctcgtt tatttttctg 116880aaaatgaggg tgatctaaat tacgtctgga gtagtaataa agattaaatc catgtgatac 116940aggtaaactc atgacaataa tagacatgaa acaaatagtc tttcatctcc ctcctttgct 117000caagcattgc tctgctcttc tcacctcctt tcccttcctt tttcttttct cctctttatt 117060ttgtctgtac ccaatagctt ttcccaagcc ttaaaactat gtataggtat attgttgcag 117120caaaatgcat aaaggagaca ctcattattt gcatccattt atatgctgat ataaatattt 117180catcctcaca agtttcagag ggaaagacca catgctggtg atttggtgag aaagaagcaa 117240ctatttctgt gatttaattt caacctgagc attaaagagg caccctttca ctactagtgg 117300taactccatg cttccaagaa ctaatgagct gaagaactta gcacttgtga tgaattagtc 117360aagcaaaaat tatgaagcga gtaatctata acattatagt acattacaaa tgctgaaata 117420tattagttat tatttattat gattcttata gctcatttat actgtacaaa attcttctgt 117480cattttatga agatgttaca catatacata acaaaactta gctaattaga tacaaagact 117540atagaaccaa ataactcttt tctaaatatt ttccctttaa ggaggttttg caatccagct 117600ttgctgtggt tagacactgt tgatgagaaa actttttttt tctttctttt ttttttttag 117660acagggaatc attctgttgc ccaggctgta atgcagtggc acaatcatgg ttcattgcag 117720cctcaacctc ttgggctata gtcgtcctcc tgcctcagtc ttctgagtag ctgggactat 117780ttgatgtgca ctcccatgtg cggctaattt ttgtattttt ttttttttgt agagatgggt 117840tttcaacatg ttgcctaggc tggtctcgag ctcctaggct caaggtatcc acctgcctca 117900gcctctcaaa gtgctgggat tacaggcgtg agtcagtgcg cctgacctgg atgagaaaat 117960attgagttgg aaacccaaaa tatgacataa ataattggta tattttagag ctggatttca 118020acaacttttc aacactgtca tcctgtaaat gtctttccgt cctaatccca ttgcccatgc 118080actcagcaga agtgtgtgcc tctaaggtgg atgctggtat gaaatatctc agctggggca 118140ggctctgaaa gggagagatc tggttaaagt gctcatacca aacaaagctc ctcatgatgc 118200tggcctaact ctcccaatcc tgcatttctc aacaaaactt tttgctcttc tctttcacat 118260aactcccgtg gaataatttc cattgaattg catggaagag gctgttcatg gggttagtct 118320ggcagataag aggtctccac tggatttttt cattttgcaa tcagtttcat acatatacgt 118380acatactttt cttggagtca tagttcattc tcaggtcttt tagagttaaa tatctttcat 118440ttcttctttt aaggtcttaa tttcttgttt ttcgagtttc atgggagata tccagtcacc 118500aatccaatcc atatcgggga aaagtacaac aaatgagtga aatttgtaac caaccttgga 118560tgatggaata agacatttgg gagaacacag gagaagtggg gaggttaagg agggatagct 118620ctgtgaaaat tttgcattac tcttgcctga ggtctactct tccttgtcat gttggtggct 118680gttttgacaa tgagaaatat ttaatggcaa acttagtctt ctaatttgaa aatggaaatc 118740ataacagttc ttgcctctta gggatagtgt gagacaagtg aaataatcca tgtaagaggt 118800atagtactat gcttgccatt ctttaagagc tcaacaaata ttcacttttt acctattagt 118860atcaatctta attctaaaat tctattattt aatattttcc agtggtgttt ctaaataata 118920tctaatgact aggctaatac actatgtggt tcttctaggg ttcaagcatc actgttaggt 118980gtgctggaat cctttcccga gtcagtactg ctttctagaa gaaaaccggg gagatctatt 119040tggaatgtat ctaactccaa agaaaccatc agaggtaaca ggtaggagat atgaaacgac 119100cttttagata tgaaccctaa ttgaataaaa gttgccaaac aactgttccc aaacatctaa 119160agaagagttt tagtctaagt ggaatggctg gagagtatgg gaagagttct ttcctactct 119220gtccaaacac aagcctctgt gacatttatc aaagaaatgc agccctttaa atctgggtat 119280aagtccgaaa ggtgctttcc ttgtgaagct tcttttgtcc tctgctttta ggactctctg 119340cacactgcat cctctatgtc accctccagt acatctgctc ttacacaagg ggccccacag 119400ggactggccc acacaccagc cagggcacat gggccaactt ttaacagcaa aaggaaatgc 119460taaatcctag agtagggcag atgagaaaaa tggcattctt cagagagctg ggatgactca 119520cattaagatc aagggccctg aagtaagaca gacctgagtc tgaatctcaa ttccaacaat 119580aaatttgttt atacacttaa ggcatcatgt atagtattgt taaatagata ctttacaaga 119640ttgtaactaa gaggaagcaa aataatatct gtaaagcgtt tcatagattg gccagcatat 119700agtaaacatt taataattag tagctattat tatttttcct taaatatttt ttttctggct 119760tcctagcaat cataaaattt agtcttgtat agactccatg gctaggactt gcagaattaa 119820aaatggtctg aacaatttag acattgcctt tttgtcctca aaccaagggg tgaattttta 119880ttctaaaata tccagattgt ccatatcact taaccagttg attgctaagt ctgtatttct 119940cttttatgca attgggaaac attaaaaagt tgaatgtata tactgtacac atacatgcac 120000acacatagac ttaagtacat aaatgtgtat gtaccttcca tagcacttag ctcatctgtt 120060ctttcctatg accttttcta taatcctgtg aagtaggttt tatattatcc tattttatga 120120ttaaaggaga agggaagaca gaaaagcagc ctggcttggc cagaggcctt gcaattgatt 120180acgtatagag ccagggagtc ctgacccctt ttcagttttt cttcctctgt actgctgtga 120240tgactgtgga agtgaagtac ttctttggct gccaaggaag tcccagctga aaggtaacca 120300aaggaaagga gtatttggga gcagcatggc tgaaatccag ttaacagtta aaatcccgtt 120360gggcaatttc tcgttaattg acaacaggaa ttgctgtcac tgtcctgtct agccactttc 120420aaacggtggg gatgttagca agagctccca gtgaatgctt cctaggagag cagtgattgc 120480tttggctagc ttcttctgta gcagttttct ggcggtgaaa agtctgtact aagacaattg 120540gaggtggtaa tcattttcta ataaccacct caggcttttg gcacctaatt cgctggcact 120600gtctagggaa gctccttatg ctaactcatg cttcttgcca tgtcaatctg cttatctaat 120660tttgctggga aatctgatat cacccttcaa atagttcacc tcagtgggat ccagtgtgtg 120720acctgcaaag tgctcaagga agagtctgat cagctctgac aagcaaacag cagaaagaag 120780ttttgaaaaa acggctaccg tttttgcagc tttttcactg tggttccatg gtgtttgaaa 120840tcagaatgta atattgagtt aatgacacaa ggaaacactt ggatgttcat attgtctact 120900tggttttcat gaacctcaca tggactggct tcatcctgtt tcagagtcca ttcaactgta 120960atttccactc tacttcctgt gcaggccttc ctctggtttg tgggctgtac atttcagcct 121020gctcctttaa ggggccccct gagctgaaaa tgaaagagac attttgttgc ttctgctacc 121080tgcttatcgt ccaatcccaa tctcagattt tctttttcta ttttttaaac ccgagtagca 121140cttttccaac tagtgtgtag tttttctttc aattctctgc tcttcacagt aattaaacaa 121200gagctagcct ccttttccaa atcttgtttt tgtaatacct ttattcccaa agagttatgc 121260ttataagagt aacataaatg tgttaaactt ggtattgatt tgatgatttc ataaacccca 121320gactccttga aattctgcag gtttttgtga aaggacttgc ttaaaatctt tgctaatcta 121380cctgaatttt cttccaaagg cagttatata caatgtttct taaaactaat tctccaaatt 121440tgcaatttgg cagcatccta ctgggactct agaaggctga taaatcatgg agagtaggta 121500ttcatatagg aactatgaaa gctgtatgta gtaaacacta cttaagaagg ccttacattt 121560cataaaaagt tggagatttt tgtggagact cataaaatgc atcctttata tcagtgaagt 121620ttttgcttct aggtatatta tactcacatc gaaacactcc agggattttg ttttcagcct 121680gcatatacca cgtatattta ttatctggat agataaatta gacgtataca tttaaaggag 121740tttgcatcag ctgctgctag gaagtttttc ttgtgttagt taagatcctg tgaaacaacc 121800cttgacattt cactagctgc acagtttgta ataaaatcca ttttagcctg aggttaaatc 121860atgactgtgg tcctcacatc atggtggggg atcctggtgg ccagattaaa ggaaactcca 121920cattctcatt tctgacttcc ctacaacctt gtattaagac cttaattgaa aaacttattg 121980cctctctcac caaaatattt caaattttaa tagtttcccc caatgaaatt acaagtacta 122040ttttactttt ttcagtgccc ttggaatttc gaggctggat ggggggcttc aatgtctgac 122100tcattaagtg ttctatatac aaagccctac atggtcccta gagcatagca ggcattcagt 122160gaatgaaatg aatgaatgaa aagctagagt cacattttag tgacctaact gtatattttc 122220agagtaatgt agtgcttaaa aaaggacaat gataacacgt ttctacaaag agatgcatga 122280cagataacac ttctcaagaa gaaggaattt agcttctgtc atttgatcta ggttttcaat 122340tacagaagca ttgagaattt cctgtggctg gataagggcg aatctttaag gcaagttgaa 122400gacccaggct gcccatgtgg acatcaatac tcccacagag cactcttcat gaagaaaagt 122460gtgggcttgc tgtcttttca tcaaaactcg tagaatttgg ctgactgcct ggtttatccc 122520aggacattag tcagcccaca aatcccgcat ttgtttattc agtccagagc aagtgaatac 122580tgccattttc tcatctcctt tgttggcaac actttgttaa cctgaattgg gttctcaaca 122640taaaatgaag tgactaatct tttggggggt tccccctccc aggttcttgt atgagcaact 122700aaatctacac accacaaagc cccatgctgt cattttttct catcctgccc ctttattttg 122760atgattccac attgtagttc atgaaaccaa taccttctag agtgtggctg aactggcgcc 122820agcattaaga aaaggagttt ccaaactttt tagttttgtg agaaaatgtt agaggaagag 122880ggaggttagg ttgactattt atacttatgt aatcttctgt gaatttgcag tagttatcac 122940cttgtactct caaaagtttt ctagctctga gtatgtgaat ctgaaagtgc aggaagtagg 123000aatcttagca caaaacaacc agtttggatt atcacacaat taatatggga cggagctgga 123060ggatggacct gaacagaatg tatattcttt atcactaggt tatttatcta tctacagatg 123120tctagaaaga cctgggcttt tttagcaaac gtttgagaat ctaggtttct aagtttccat 123180tgaccatgaa agagtgatta gttttagaag acagttgggg gcaacattgt gcaagtcaga 123240agaggggatg aagaaaatca taaagctaaa catgtttgcc ataggcccag gctgtttttc 123300agcatgtttc acctagcagc ttggcagata attcccagtg atcattaggt ctgtggaaat 123360tctgtttggt ttataaagtt ttggccctga ctatgtgtac cactgataac ttgtttttct 123420ctctcttccc ttttcctcca actcgtagcc agagctacct tccagatgac ttctttctac 123480cactttcttt cttcccagtg taagagaatg caagtatatg ctgatgtttg gagcaagaac 123540attcaaaaat tttcttatta acataacttc taatggaaat acagtatact actatggtgc 123600atacaaagaa gaaatagcaa catatatttg ttttagacct gattgctgta ttttattcct 123660taggtcctcc ttgatgtctt gtagaccgtc actagctaat tgttacagcc atcgaaggaa 123720aaaataagga tttttactta ggacatacgt aacagaaaaa gagatggttt agcaaaaaag 123780cacaggcttt gcaataagca gccttaaatt aaaaaaaaaa aagttaactc ataactaact 123840gtgtgacctg ggataagtta ctgaccctct ttagggctta gggtcctaat ctgcaaaacg 123900gaaattataa taataacctt agctagcatt tcttgtgcac atactataag ctggtgataa 123960acaatttata cacactatct catttaatcc tcacaacaat cctgtgagat aggtactatt 124020atcatttcta ttttacagat gaagaatcca gacataagaa gtgaagttaa gtaactttct 124080caaggtcgca cagctaccat atgatggagc tggaatgtga atctctgcag tttgacgcca 124140gagtgcatgc tcttagtcac tacatttgtc tacaaatcta aaacacgtaa gacacatagg 124200aggtgctcag ttagtggtat ctattattaa atcagactat aaataatcac caggcaatac 124260ttgaaaggcc acaaacaatt tcttaggatt tgtgacaata ctaataatta taactgatta 124320tgagcatacc ttgtgtcagg cacttctttt catagtattt cagtcattat ttaagagatt 124380tattcttatt tttatttttc tagtgagaaa actgaggctc aaaaaagccg acaaatttgt 124440ttaggattac aaaaatatca aatgatagga ttgaaaatca aatccatatc ctttctatgt 124500gaaaacctgt gttctttcag ctttttttat ttttattttt ttatttttta tttatttttt 124560taaattttta tttattttat ttttttattt tataagcctt tttattttta tttattttac 124620tttatttgtt gttgctggtg tttttttctt gagacagagt ctcactctgt ctcagctcac 124680tgtaacttct gcctcccggg ttcaagcaat tctcctgcct ctgcctccca aggagctggg 124740attacaggca cctgccacca tgcctggctc acttttgtat ttttagtaga gatggggttt 124800caccatgttg gccaggctgg tctcgaactc ctgacctcaa gtgatctgcc tgccttggcc 124860tcccaaagtg ctgggattta caggcatgag ccaccacgcc cagcctgcct gatttttaaa 124920attattaaat tcatatttgt tatttatcag atgcctctgc cactttattt tttaaaaatt 124980tatttttatt aaggtatagt taacaaataa aaattctata tatttattgt gtacagtgga 125040atgttttgat atatgtatac attgtgaaat ggttaaatca aactaagata tctgtcatct 125100catatgcatg ccatattttt gtggtgagaa catttatgat ctactctctt agcaattttt 125160aatattctgc tgtttgactt ttaaaccaag gcttggatta ggacagtctt tgtagcttag 125220ttttaggttc agggataaca aaagttgttt tatcctttgg gcttttgcaa cttgccattt 125280tcttaatgaa gatctgggag aaaaattagt ttaagtggtt tttaaaatag ccattagctc 125340aggacatact cagccaaggc aggataagta gttttgccag cattcttctg taggtaggtt 125400ggttgttttt tgtttttttg ccacagtctt tttaaaaaat ataactttaa aaaaaccttg 125460gttttctgtg attgatcttt ttcactattt tttatagagg gccaggaata tgagtaaata 125520attcttgggc ttgggtgcag atgatccacg tgctggcaga cagaaatcta aagggacaaa 125580agaggctgtc ctttgaagat acttttcctg gcttgggttt tatatttttg gatttgattt 125640agtgaaaatt tttattgagg acctactgca taccagacac tcggctacat tatgagaggt 125700ttggggggcc tatattggca tatagggagg atgaataaag aatacaaaca attatagtac 125760aaatcagaat aaaatttggc atgcaacggg ctatcagata gtatggagga agaaagcata 125820ttttattagt ggagctagga aatacgttac aaagttgata gcattcttga tgggtcttga 125880aggttacata gatttttttt tctttttttt tttttgagac ggagtcttgc agtgtcgtct 125940gggctggagt gcagtggtgc aatctcacct cccgggttca agtgactctc ctgcctcagc 126000ctcctgagta gctcggatta gaggctcctg ccaccacatc cagctaattt atatatgtgt 126060gtgtgtatat atatatatat atatatattt tttttttttt ccagtagaga cggggtttca 126120ccatgttggc cagactggtc ttgaactctc gacctcgtga ttcgcccgcc tcggcctccc 126180aaagtgctgg gattacaggt gtgagacacc acacccggcg gatagagaga attttgacag 126240gtgaggaggt attccaatgc aaaagaataa taggagcaaa agcacagtgg tgagaaattg 126300gaggggaact gtgaaaattg ccacatagat tagaggcagg aaaataaagg acggctaagt 126360ttatatagtg aacagtgagc cgcatggaca caggtgactg ttttctcctt tttgaacccc 126420tgcttactcc agagtcacca cctctcctgg ctttctgcca

atcttcttgg ccacagtttc 126480tcggtcttct tttctggctt ctcttccttg gcctgaatgc tacatgttaa gtgatgtcag 126540cttcagtttt cttaacctct cttctcttaa gttgctatca tttaaatatc tttaaatatc 126600atctacatcc aagtgacctc taaaccagta attttaccca tgacccatct cctcaactcc 126660ggattgtata taaaactgtc tactcaacat cttcactttt gatgtctaaa tctctatgtc 126720caatttagaa ttcttgattc tttgctttcc ctccctcctg gaaatcctgc tcttaccagt 126780cttccccatc ttaattaatg aacctgacat tcacctagta gcttagtcct caaaactagg 126840gattaatcta gatttagtca tttttcttac tcttgccata taataacata ttattctgag 126900tttaccttta cccgacccca aataggtaac tgctgttttt gttataagat agtaatattt 126960gcctctgagt gtatgtgaat tattttgata aaaataaata ttatttttaa aatattaatt 127020ttacagggat tgtctcttga tttctttcca aaagttaact cataagttgt tcagcagagc 127080tatgtattct tcagtatgtt ataatttcgt tccatcttcc aaaaggcctt cacattctct 127140tggcttacag actcagatgc tatggattag atacacaagt acatgttcct gtatatctat 127200tatatagtga acataacaat tatgattgtg atcttccaaa gctcgtattt ttaatcaaaa 127260ttaattaaat attttaagcc aaagaataaa ggtagatgca gcatctagtc aaaaggatat 127320ttctgctggc cacactcagg aagacataaa gatatagttg tagaaagtga tatagtattg 127380gccaggtgtg gtggctcaca cctgtaatcc cagcactttg ggaggccaag gtgggctgat 127440tgcttgagct caggagttcg aggccagctt gggcaacatg gtgtaaaccc catctctaca 127500aaatacaaaa attagccagg tgtggtggtg ggcacctgga gtctcagcta ctcaggaggc 127560agaggtggag gattgcttga gcctgcgagg tggaggttgc agtgagctga ggtagtgcca 127620ctgcactcca gcctgggcga tagagtgaga ccctgtcttg agaaaaaaaa aagcaaccca 127680gtgataggct gggcaaggtg gctcatgcct atatttctag cagtttgaga ggccaaggcg 127740ggtggatcac ctgaggtcag gagtttgcaa ccagccttgc caacatggtg aaaccctgtc 127800tctactaaaa atataaaaaa ttagccaggt gtggtggtgg gcacctgtaa tcccagctac 127860tggggaggct gaggcaggag atttgcttga aaaaaaatta gccaggtgtg gtggtgggca 127920cctgtaatcc cagctactgg ggaggctgag gcaggagatt tgcttgaatc cgagaggcag 127980aggctacagt gagccgagat tgcgccattg cacttcagcc tgggcagcaa gagcgaaact 128040ccatctcaaa aatgaaacaa acaaacccag tgaaaaccag tattgaaaat agattgcctc 128100tcccttgctt catggtctgt tcttacgtaa ttttcaagat aagttcattt tggcgggtac 128160tgacaaattt ccatttattt acttttttcc cttacattca tttcttctca gtctctccaa 128220tgaacgcctt cactgatatc caaagcatga aggacacacc agggaaaaac atagacctaa 128280cacaggacaa atggaattat tagaaacatt ttctagcaga agaacactat tctgttgcca 128340tttgaatctt tgcttctttc taggtttgac aatgagccta tcatataagc ccaaatgtaa 128400acagaaagag gttgaatcag tcacgataag cccaattatg ctgtggtaac aaacaacctc 128460aaaatctcat tggcttaaaa tatacagaat tattcttact catggcacat atccatctat 128520catctgcagg ggatctgctc actgaagtca cttaggaact tggactgatg gaacggccac 128580tttttggtca ctatatgtat taatctgttt taatcctgct gataaagacc caaaattggg 128640aacaaaaaga agtttaacta gacttacagt tccgcatggc tgaggaggcc tcagaatcat 128700ggtgggaggc gaaaggcact tcttacatgg tggcagcaag agaaaaatga ggaagaagca 128760aaagcggaaa cctctgataa acccatcaga tcttatgaga cttattccac tatcaagaga 128820atagcatggg aaagactggc tcccataatt tacctccctc tgggtccctc cctcaacatg 128880tgggaattct gggagaaaca attcaaggtg agatttggtg gggatgcagc caaaccacgt 128940aatttcaccc ctggcccctc caaatctcat gtcctcacat ttccaaacca accatgcctt 129000cccaatagtc acccaaagtc ttaactcatt tcagcattaa tccaaaagtc cacagtccaa 129060attctcatct gagacaaggg tagtcccttc tgcctatgag cctgtaaaat caaagcaagc 129120tagttacttc ctagatacaa tggtggtacc agtattgagt aaatacagct gttccaaatg 129180ggagaaattg gccgaagcaa aagggttaca gggcccatgc aagtccaaaa tccagcgagg 129240cagtcaaact ttgaagctcc aaaatgatct cctgtgactc caggtctcat atccaggtta 129300tgctgatgca ggaggtgggt tgccatggtc ttgggcagct ccgtccctgt ggctttgcag 129360ggtacagcct ccctccaatc tgctttcacc ggctggtgtt gagtgtctgt ggcttttcca 129420gatgaatagt gtaagctatt ggtagatcta ccactctggg gtctgaagga cgatggccct 129480cttctcacag ctccactagg cagtgcctag ggactgtgtg tgggggctct aaccccacat 129540ttctcttctg cactgcccta gcagaggttc tccatgagag ccccgcccca gcagcaaact 129600tttgcctggg cattcaggca tttccataca tcttctgaaa tctaagtgga ggtttccaaa 129660cctcaattct tgacttctgg gcacccacag ggtcaacacc acgtggaagc tgccaaggct 129720tggggcttcc accctctgaa gccacagcct gagctatata ttggcctctt tcagccacag 129780ctggagcagc tgggacacag ggcactaaat ccctaggctg cccatggcgc agggaccctg 129840ggtccagtcc atgaaaccac tttttcctct tgggcctctg ggcctgtgat gggaggggct 129900gccatgaagg tctctgacaa ggcttggaga cattttcccc atggtctcgg ggattaacat 129960taggccccat gctacttatg caaatttcta cagctagctt gaatttcttc ccagaaaatg 130020ggtttttctt ttctattgca tagtcaggct gcaaattttc tgaactctgt ttccctttta 130080aaactgaatg cctttaacag tacccaagtc acatcttgaa tgctttgctg cttagaaatt 130140tcttccgcca aataccctaa atcatctctc tcaagttcaa agttccacaa atctctaggg 130200cagaggcaaa atgccaccag tctctttgct aaaacctaac aagagtcaca tttgctccag 130260ttcccaacaa attcctcatc tccatctgag accacctcag cctggatttt attgtccata 130320tcgctgttgg cattttggac aaagccatta aacaaatctc taggaaattc taagcattcc 130380cacattttcc tttcttcttc tgagcctttc aaactgttcc agtccctgcc tgttacccag 130440ttccaaagtc acttccacat ttttgggtat ctattcagca aagccccact ctactggtac 130500caatttactg tattagtctg ttttcatgct gctgataaag acatacctga aactaggaac 130560aaaaagaggt ttcattggac ttacagttag ttccacatgg ctggagaggc cttagaatca 130620tggcaggagg tgaaaggcac ttctcatgtg gcagtggcaa gagtaaaatg aggaggaagc 130680aaaagtggaa acccctgata aacccatcag atctcgtgag acttacttca ctatcaggag 130740aatagcacga gaaagatcgg ccctcgggat tcagttacct caccctggat acctcccaca 130800aaatgtggga attctgggag atacaattca agttgagatt tggtagggac acaggcaaac 130860catatcacta taccacaagt ttttttaaaa aaacaaactt ttgagaatct tgtactgata 130920attaatatct ggtctggaag tgaagcacat ttctttttct tgcaactgat tggccagaac 130980cagctagatg gccccaccaa gccaacattg ggggagaact gaaatatttg gcaaacagca 131040accatgacca tcacagctgg aagttctcag tctggaactc cttccccagg cctcccattt 131100ctggaactct gagaacaaca atccaggaat ctgatgacat cttttccttt actagccaaa 131160atctgatgac attttttcct ttactagcca aaagggagaa caataagcaa ataaattcaa 131220ttttctccca tttatacttt taaatctgag aacgaattgt gtgtttataa gaaagtgagg 131280gttgagcatc atgaagaaaa atataaagat ctttaaaaag tatatattgg gcctattagc 131340tacaaacatg gatcattatt aatatgtgtc tgactgacat ttaaaatgca taatcaaaat 131400caagcctgtt agatacaaaa ttcatccatt aatagcaact aaatttcatt aggtaagtag 131460tagtgctatg tttaaaagag taatctattt ggaaacagga attaatactc agaatattat 131520tattaatata tttgaaaatt acttgtgttt atttgtccca gcccttacaa ggtgtgtggt 131580aatggttaag gtatttctcc tctatatgcc tgagttttct tctttacaaa aggggggagg 131640gaataatagc acctgatttt acttttgttg tgaagattaa atttgtacat atataaatct 131700atatatctat atatacactt atatatgtat gtaaaatatg taggcttgtg cctgacatta 131760aatactaaaa aatactagct attattttta tcctcatatt atcagatatg acacattcat 131820aatttaaaca gaagcctacg aagaactcat aaattaaaag aagataatct tttcacaagg 131880taacaaattt tggaacaatt ttttagagtc tctagacatc tgttactgac gttgtgagtg 131940aaatgggtct gtgaagggaa gatacaggtg gaactgggcc agtgtttgca gaggaccatg 132000atatttctat atctctgctg gctccctatc agttctagag ctagttcaag tgaagcctcc 132060ataacctctg gacaataaaa atgcaccatg ctattgttag catgatgaat gaatttattt 132120ttgtttagct tacagaaagt tagtagtttt caaaagggtc tttatgtata caattgaaga 132180tactacattc ttgaaaagga aatctttaca gcatacaggt ccctggcact aatacctcat 132240ttctgggcac agcttgatat ggaggtatag tttgtgtttt atctgaggaa aatttaggtt 132300ggtgttatgt tttgggctag ctctgctgaa acattattct cttttctttt agagccaggg 132360ctgtgggctg tgtcacttgt gacttggcag cccttaatgg ggctacatga ggaagacatt 132420tccttacatg attccaagag tctttctctg gggttctgag gtagtctctg tgtttcttgg 132480agatatcgtt ggctctaaaa tttcccctaa gtgaggtgat attctgtcat ctcatgcatg 132540ggttttggag gctgaggggt gtctgggttg gctccaccac ctaccagttg ggtaatattg 132600tgtagttttt tttttaaacc tttctcagct ttagtttcct tatttgaaca gggttaaaaa 132660ttgggcttga gagaaggatt agagataata ttagtagata ttgttgatga attgggcgaa 132720gcagagggag ggggcaaagt tgactacctt tgtttctgtc tcaaacaagt aggtggtgat 132780gcctttgagg agataagaaa agtgacttgt gtgtgtgtgt gaaagacaga cacacacaca 132840tatatatata tagagagaga gagagagaga gagagactta taaattttgg atatatggtt 132900tcaaggcact tttctggatg cataagtgta aatgttcagt tgaagtttta atggtgctta 132960ggagagagat gtgaacgata atagagattc caaaggcctt tacatcaaga ggataactga 133020agctatagga gcagatgagg cacacctgta aagatgagac aagaagaaag cctagggtag 133080ctctgagaac tttgctattt agtgtcctca tagaggggat ggaggattct tcacaaaaag 133140ttcagttttg tgacaccaca ttcccctgat tttactctta cctcttgaga caccaatttt 133200ttaatgaaga agaaaattat gttgcctgct taaagtaagg aaagcaggtg ttggtgggat 133260tccttaatag aaatatagag gtttaaaata cctacaagag taggagatag aattgatcaa 133320gtaaaaaaat tgaagagatt aattgaggac ttaacatcag agaccatatg tttgttgtga 133380caataatcca aattattgta ataatgtgtt taggagtatt tagccttgta ggtaccaaga 133440ttgcattgat cctgtgttag gagtttgcca ggtgtgtgca atagtgagaa agacatgaag 133500ggatttgagg ttgctgatga gtgaccagtt tagatgacaa ctactgtttc ttcaactctt 133560tcttcaactt caactgtctg ttttgggaaa ggctagtggc ctgtgaggaa acgaagaccc 133620cggagctgga ggactcaaag agtttggaga gcagacgtgt gcaagtgagg gttttgtgag 133680cactggagga caggcagctg gggaagagag tgtgttattt gcagttatga tattgggtgt 133740ggagctattt ttggtggcag caaagctcag gatgtatttt tttattattc ccataggtga 133800tggaggcttt ttattttgcc acaaaaccac tggtgacgtt gcctgtggcc accttggaga 133860agacactgga ggtacacagg atgtatccct ggaagtggca gggggtataa gtttagtagg 133920agatttgtta ctgagtattt aaggtctagg aacagattga gggtgttggg tggattgccc 133980actaagacac tgggttttct agcatgatga cagaaattgg agtttggggg gagaagagtt 134040ctattgtgtc ttgaagaatg tgatcaggag gtatttctaa tgacacaaac atagaagtat 134100acacactggt atagtcagat ggcatgagta ccaaggtgga agtgtggtgg tcctaaagtg 134160gcattaagga gccaataaat tgtcattcct accttagctc tgtgtcagat gaaatacaca 134220gcatagtgtg gggagaaaat gttgggctta ttggggatgg ggtctttcac ataaaggaag 134280aaggtttcag aaggcatagt ggtatgaaaa gaggagaaac caaagggagg aaggtcaata 134340aagggttaag aacgagggga ggcaaattga ctttctttca gcatatgagg attataggaa 134400tggaaacctt aattggaatt aattgaccac aaatattcca aagatggagt gaatcagttc 134460gagacagaga tatctgaggg tctgagggtc tgaagtagga tttgtcccag tcgtgtgtgg 134520gtgggttcac tgtgtggagc ctggggtctt gaggatctga acatgggctg cctcctgtgt 134580gcacggtgga ggcatctggc ctgttctccc tggggtggac tcatgatgag ctgagtggcc 134640aaacacacaa tggttttcat ttaacatctc atttctagcc taacgacaaa cctaaaaggt 134700gggcataaca ataatgttaa taaaacatct gcatttctcc catccttgga gttgtgagga 134760tttaatgcaa ttgtttgtgg gaaagcactt taacaactct aaattacgat atatatgcta 134820ggttttattg ttacccacac ctttgatgta tttctctttg tactcttcac tgtatctgta 134880acacattccc taggataatt agggctaccc tttaacaaag ccaagattct atttatagtg 134940gtaagctggc acctgggctg attctctcta gtgattatgt agttttgatg tggactggca 135000ttcttccctg gagtttgagt acctccgtca gcacttctcc cgtccagaag ttccatctct 135060gtgtttttct attacaaagc ccagacaccc atctaggcca cccaccaggt tcctctttcc 135120agtcttaagg acatctttag ctcctggctc atttgtgaga tggagtggac tgacatgccc 135180taagcaaaga ttgccagcct ggtctagttt tccaggtctc ccttgactcg acaataaagt 135240aaccactaga ctttgagaat tgcagtttta cattgtctag agtcttctag actttcatga 135300agataggcaa atatgattct aaccaagatg tattaatacc tcctacttcc tttgaaatgt 135360aactgagact gtacttgaga cgttacaatt tcttggaagg ggaaaggaag cttctgctat 135420tgaacgaact ttttgttaag gtagctccca agcaggttca gtagctttgt tctattatca 135480cttttctact gacagtgatt tttttccttt gaaggcctgg gacatggaga ctgcttttct 135540gcagaaacca catcccttgg agtaatgagc tacacctacc tcaattattc agtgcagtac 135600aacactccag gtcagctatt aagaggtgca cacattattt ttagaaaatg tgagtcagtc 135660ttggggaaaa caaatctatg ctatatgttc tttttactca cttgatttac aacatactgt 135720gatgtattct ttttctattc agcatctttt tgtacccgta gctctttgtt ctgagcataa 135780atgtgacctt ttggcttcag gtagaaactc tgtctcatga gcactccctg gacacggaag 135840ttctttgaaa tagcattgat tttgtttaag ccttcatgtt cccctggaag gctgattaac 135900cttagtgcct tctttctgta atagctcata ttgaattatc tccctctgtc tgattatatc 135960catttgaatc acctgcaagt ttcttttaca tgtctagagt gaggacaatg tgggtgatga 136020agagctgaaa tcttctaggt aaacattaga tttttaaaaa ttctattttt ttttttttat 136080ttttaagaca gggtctcact ctgtcaccca ggctggagtg tattggcatg attacagctc 136140actgcaacct tgaactccca ggctcaaacc tgagcagctg ggactacaga tgcaccacca 136200tgcatggtta gttttttaat ttttttttgt agatagaggt tctcactatg ttgcccaggc 136260tcatctcaaa ttcatggcct ccagagatcc acctgcctca gccttccaaa gtgctgggat 136320tacagacatg agccactgca ctaagccaaa aactcttgtt caaattacat tttctgcctt 136380agtaatgctg ctttcctagc ttctgagaat ttctaagacc caatggtaac tctatgctaa 136440aattaaaata cgaatgtcct tttcaaaact gcacaatatc tttgctattg tcaataatgt 136500ctcaataaac ataaaatagc aaagagattg tgcagtttta aaaagaacat tcgtatttta 136560attttagcat agagttacca tcgggtctta gaaattctca gaagctggaa aagcagcgtt 136620actaaggcag aaaatgtatt cacaatagca aagacttgga accaacccaa atgtccatca 136680atgatagact ggattaagaa aatgtggcat atatacacca tggaatacta tgcagccata 136740aaaagggatg agttcttgtc ctttgtaggg acatggatga agctggaaac catcattctg 136800agcaaactat cgcaaggaca gaaaaccaaa cactgatgtt ctcactcata ggtgggagtt 136860gaacaatgag aacacttgga cacagggtgg ggaacatcac acaccagggc ctgttgtggg 136920gtggggagag gagggaggga tagcattagg agaaatacct aatgtaaatg acgagttaat 136980gggtgcagca caccaacata gcacatgtat acatatgtaa taaacctgca cattgtgcac 137040atgtacccta gaacttaaag tataataata aacaaaaaaa accactgcac aatctctagt 137100attcagatgg agactaagca tgatttttct tataaaagag cagatcagaa tgttgtatct 137160tttattcaga agactggagt taatcactgt tatctttagt acttagtgct gccaaggctg 137220tgtgttcaca atgaggatag gatgtcaaat aaatgaagct tcatagaaca agagcaggat 137280tgagtcatgt aggcaactgt ttcagcttcc tcacctaact tagcaccaaa atgtgttatt 137340gtcattacag agtgcttatt taaagaaaaa taaaaagaac acacacacac acgcacgcac 137400acacacacgc acgcacacac acacacatgt agctacatgt ctaggaagga tgtggagagc 137460tgaaatatga aggcaaaata aaacatcttt ttcaaagtat acagcctaca gtggttagca 137520cagagctggc cacatagcag gggtttcata aatgcttgtt gattaaactc ttttttttga 137580aaacaataat gtagaagcaa agagcctaaa gtgttttcat aaatcttaag tggtagcttt 137640atgttccagt tcagcaaaac acaaatttga aggcaatctg tacgttaggg ttcaggtgaa 137700gaaggcaaag gaatcaatga aattgtaaaa gctttccaaa tttgcctttt ctcttaagat 137760tgtctttctc tcattctctt ctccctattt caggaatgca aatatcctgt ttcatcaatc 137820ttttgttttc tgactcaaga taacaacaat aatttattga gcacaaacca tgacttttgg 137880gtctgtgtag ccccgaagct tcatagttca atatctgaca cataagaggg gcttactcta 137940cacttaaatg ttagttttgt cctcactttt ttctctttct cagagatctc ccttttcccc 138000tacttgtata agcatgaaga aatctttctt ttcattctct ccaagtttaa tcagacaact 138060ccacatacat acatctttgt tcacaactat gaacaagaca gaaaagttgc tggacctcaa 138120ggactttaca atcaatctgg gaaggcaaac attgaacata taatgtccag tctgataagt 138180gttagggaag gaaagctcag aatgcaaggg aatataatct aatctaggag atcgtgggaa 138240atatcactgg ggaatttgga actgaaagaa aaataagatt tgattagggg aaattgaagg 138300atcagggagt caggcggaga agaatgtccc ggcagatgag acactatgta ccaagcccga 138360gtttgacaga gagcgtggtt tacagaagga atctaaaagg tgtagtttct gtagcagaag 138420tgtaagggtg ttactcgtag gaggcctcta ttgaactctt ttccagtgac gtagtgtgtg 138480gtctttaagt ggctttgcaa tgatagtaag atcagcattg cattactgaa tgagctcctt 138540tagtaaacgt ggatatgtgc tttctgaatc tatttgtttg tttttcccaa gtcataaaca 138600gtgaatcaag caaatgaaac ataatcaagc ttggatagta tcttccacta atttccttgg 138660tcttaagtaa gactgacagt aaactgatgg tcaacctgtt caatgggctt taacaagtag 138720tagccacatc caagtcaaca aacagtacag gcaatcaggg cccctggcct acagtgaatc 138780atgggaatta ccccagggac ctatgctttg gggactcgtc cttcctggca gctatagatg 138840ccatcagaaa ctcatttgca cactcttata accaagataa gggcaatggt tagtcccctg 138900tcattgcatg ttagctttct ttcccttttc taggcttttt cagatgcctc ttttacatta 138960ttacttttcc tgtgtgaaaa taatgcgtgg gaaatgggta ggtcatacag agcgataatt 139020tcattcctgg gcccctgtct tgcagctccc taagtaaagt tttgcgcctg gcactcctct 139080ggcatagtaa cctctgacaa acccttgggt aatagaggag tagcaaaacc catgggtaat 139140ggaggagtag caggaatatt atgattagct aacaaattca caaagtacat agaaattttt 139200ttctcgaata accactatag ctgaggaata tagattagtg acaaaattgt gcactcaacc 139260aactctatta aaagtatttc attattcccg tgaaaaaact cctaggaaaa tgattcactg 139320agagatatac gattgtataa gtattgagaa acagtctttc ttttttgctt tttatttatt 139380tatttaatag acattatagt tacacataat tatgggatac aatttgatgg ttcgatacat 139440ttttatgttg tataataatc caatcaaggt atatttagtg tactcatcac ttcatgcatt 139500tattattcct ttttgatgag aacattcaaa agcctctctt ctagctcttt cgtaatatca 139560ataccttact gttaatcata gtcactctac tgtgcaatag aatgctagaa tttattcctc 139620ctattgaatt gtaactttgt acctgtcgac cagcctctcc ccatcttctt ccccttcctt 139680cttgcttccc cagtctctgg taaccactgt tctattcctt tttttgtttt ttctttttgc 139740agagttcgct ctgccgccca gactggagtg cagtgcacaa tcttggctca ctgctacctc 139800cgcctcccag gttcaagtga ttctttctat tttttgggaa tgtgcgttat ctaatactta 139860ggtgcctcag atttaatggt ggtaaatctc actcatttta tgaaaaccaa atgaacacta 139920tcctcacaat ggttagaaag caagatcagc tcaactttat gaaaatatga ctataaaacc 139980atttattatt gccaagtggt tggagtggag ttgacagaaa gatgcattat tttaaattgt 140040gttttagatg acagaacagg agtcagtaat gttccagttt ggaggaatta gagttaattg 140100gttaattgat tgattcgatt cagtcaaatt tattgaatga ctgctgtttc agacactgta 140160tttggtcctg ggaaaacaca gataaataat atataattgt attataaatt aataaaatag 140220ttttttccct ccaaatgtca gtagtccttg gaaaggacat gtaaacaatg aatataaagt 140280gacacatagt ccagtcaaga taggtaggaa ggtctaagta caattgagtg gtcaatttca 140340cttcagggaa gggcaatgat cagggaagat ttcccaggga aagtgatgct tgggcaaata 140400agtaagcatt ttacaaagag acaaggaagg atagggcgtc ctgggcagag gaaggagtgt 140460gtacaaaggc caagtgacat atgacaacat tgtacatgaa ggaaactacc atcaggcaga 140520gctgaaatgt tggcacatgg tgaagtgcta gttaccggtc ccagccatga cagtagtgta 140580acaaatgcct gcctctggtg cacagcaaga tattaagatt cctcaaaaca gttcatatat 140640tttataaatt aagatagaca ttaacagaag ctcatagaat caattaatgc aaatgtaagt 140700gacctaagag gcattttgtt cagcatagtt attgattttg cctgacccag aggatttgaa 140760tttaggaaga tgtaagccta gagtagctgt cagttatctt gtgatacatg ggccttggaa 140820gcaaggtaca gggacacagt ggaccaatgg gggaagatta ggtcctggtg atgtgattca 140880agccactgga ttaagccaca tctgaaacgt ctatttctgt actcttcagt tacaagagat 140940gttagtttga attatttgct taagtcagtt tttaaaaaat tcaattgcaa cttaggagat 141000acatctggcc tcttcatttt acaacttagg agactaatat ctagtatgac aaagtgactt 141060gccaccaaat ggctggttaa aaactgatac caggacccag atctaatgac tcagaggcca 141120ggcttagaaa tatctagctt tttttttttt tttttttttt ttttttttta gacacggagt 141180cttgctctgt tgaccaggct ggagtgcagt tgcgcgatct tggctcacag caaattttta 141240aagcatctac atgtgagggc ctaagtatac gagtacctag aaatctattt tgcagcaact 141300atatatttga tagagtgatt gagtttagtt taaagatgac atttctaagt ggtagtgctg 141360tcaaaagagc attgcattga atcaagaatc tggcattctg tgttcatagt tcacttttgc 141420cactaattat ttttgtgacc ctgggtattt ctttctggga ctgtattcat tggatatgag 141480tatctctaaa tcttcttcaa cttctatgat tctaaatgga

agtacactca attttcaagt 141540atccattgtg gattttatat actgctatgt atcctgagaa aatcttcctt ttgaattatt 141600tttcgtatta atgagttcaa cttcacaaat atttactgaa caccaactat gagctaggtg 141660atgtaaaagt gaatagttac ttctagtcag tattacttac ttacttttgt attccacagt 141720gcagtttgat attgtttgta gttccaaagc attaaacaat gccttttaat ctaggacatg 141780tggaatcttc aaataagagc agaattacaa agagttttag actgccactt tgcatcattc 141840tgagaggcaa taccataagt gttcagcagt cagaagaagg gacaggggaa agtcctgagc 141900agtgcaggtg gattaagaac taaatatgcc tacaaaagca cattcatgcc taaatgtcat 141960tgcatttgga tcacaggcct tgagaagatc tgtaccatca ctgtgggtaa cttgggccca 142020tttagagtac ttgcctctga gggaaataaa aatttgctag caattttctc taaatgacat 142080tatcataggc acttaattcc ttgataggtt cttttagata atttttttat aatgaagcaa 142140ttaatttgat tcacgaaagt aagtttctag tttatataaa gaccagatct ggcctatttc 142200ttagcttgtc tacatttgag tagttccatt gctggaaaat gaccctggag cttttcaatc 142260tcatttgaag agtccagggg acagacagag acactagtta tgcagtttac tagagccagg 142320ttccatttca tctctaataa tttttgcctg tgtgcgcctg cacatgtagc ttaagctatc 142380taagccttag ttagttttgt catcagtcaa aggggaatag tgatatctcc ctctaagggt 142440tgtacaacat ggtggttatt tatagcacag cttgaataaa tgttattaga tgatatagtc 142500tcagtcaggt tttccttgga ccatgtttta gtgacatatt agactccaaa gaagcaaaat 142560gctaggagca caaggcagcc taacttgtga gttgatgtac agtgtgaaga tgcaccacag 142620atttagaatt tcagttgact agaagaataa gtggtagaat ttgtccctgg ttgactactg 142680tcttaacttt gtgtctttgg ggaaatattt aagctctcca gacttctatt tcttcatgtt 142740taaatcggga ataatattcc tttctcattt cgtagaaatt gaaaggagat aagtatgaaa 142800gcgtttatga gagtagaaat catgagtgtg aaagttcatg ctattatggc acaattgatg 142860ttgaaagtta atattacaga ccattccttt tttgcacagt gaaaattgtt ttatatccat 142920attggcccct gtcacatatt aaaatattat tttctcttat taatttctat gagaataata 142980ctgccttcat acttttataa agggacctag gaaaccaata tttgtctaat gtttcaggct 143040aaagagtaaa aaggaatagg tatactcttg aaaatagatg gctattgtca atatttttcc 143100taccaagaaa ataattcctt ctctataaag aactgttact gtttagagca atattttcac 143160gattcaaaaa gattatctga gcatgtgtcc aaccataact gacccctgca aaatatttct 143220aaaagcactg tgcatctagg ctgggaagta tgcaaaatta gcaaaaatcc cctagcattt 143280tcacaccaag ccatgtgtat ttaatataca ccacctcaaa gaggaacatt accaccctag 143340cactatgagt gaggtgagac agagagattt ctaagaatat atgggtgtaa ttttctgtta 143400actgagagtg attgacagtt cgtggaaatc tgccctccaa aataacctgt tttgcagcac 143460ccttagtttt atttgatatg aagaaactgc ctgctgtttt gacccattta gctactagga 143520actctattta ctaccctaac tgcctaaatc cctatggata aattaggcag tatctgttta 143580ttttagttta gatttatttt taaaaccagt gttcctttga ctgttcttac tatttctatt 143640tgagagttgg ttgaaataag atcatgtaaa taaaaataca atgtagtcta gatctaaagt 143700cactgtacat acctagataa tttttttttt ttttgagaca ggatcttgct ctgtctccca 143760ggctggagag cagtgttatg atcacagctt actgcaacct ctggctccca gattcaggtg 143820attctcccac ctcagcctcc ctagtagttt ggactacagg tgtgtgccac cacacctggc 143880taatttttgt atttttgtag agatggggtt ttgccatgtt gcccaggctg gtctcgaact 143940cctaggctca agtgatctgc tcatcttggc ctcccaaatg agaaggatta caggtgtgaa 144000ccactgtgct tggcacctag aggatttcaa taaaatttga ggtcctataa ttttaagatc 144060acatttccaa aggaaggagt tttgcttctt ttcaaatgca tggacaatga gcaactatat 144120tgttttggta aaactagtag tcccaaataa gaaagaggtc ctactagtcc ctagtagtct 144180agtcccttga ctagaagaaa aagtcaagcc caatttattt tatctgcagg acttggttta 144240agggggatta taaaactatc accacataaa gtctttgatg aagaggacat agggggatgt 144300agggagtact tcagagatgc atctggtcac tctcgaatac ataacacatt tacataaata 144360tatatatcca agtaaacttc agacttcaca tatttgtttc cttttgtttc cttgttgaaa 144420atctttatcc aagctgacaa tcacagtaca ctgctcatgt agattccact gctgagagct 144480ggaagctgag agtagagtgg gctggggagc gactttcttg ggactattat gcttttcttg 144540cactttacta ggttcctgtt cttccccacc cactacctct cctgggcact gattccaggc 144600aagtgagatg catatctgtg gactatggtt aagtgaaagc ctttgttctg gaaagctcta 144660tctggtttct cttaagccag acagaccagc ttgccatgaa ggctttcata ggctctggtc 144720cacactttag acttccaact ggtctgctac tgacattcta ggctattgtt tctccaagta 144780atgaatgagt ataccattgg tggtggaaga gagaatttta gatggtacat agacaaatgt 144840ttttattgtg attgttatgt atttttaatt catatgagaa aaatgttttc cattcatggt 144900agcaatatac agtttcttct ttaaatacat ttacttaaaa atgtgagttg atttaaagag 144960aaatattaat aagacttctg gggaaactca ggcatgacaa aatacatgaa ggtgacatgt 145020gagtagttga ggtttagaaa gcactgcaat gttatagact ctaggctagc tccctgccta 145080tccccaggcc agttaactag ttgaattctc tcaagagtca ggatgtcttt gcctgttggc 145140cttcacctta agaaagtcag gcaatgatga ggaatcacac ctgaggagat tgtaggagac 145200ctttaactta aagagtggtg atgaatatga aagaaagagt catagtatat gatcaaagca 145260gagaggactt tgagactcag cgattgggat gtaggaaggt ttcctgtaaa aataaagtct 145320taactgggct tcaaaggatg aacaggaatt atcctgtgga gaaaagtagg agaagaatga 145380catatgccaa gtttgtttct taaaaccaca acccccaaat tgtgagctct gggtcttaat 145440ttggtgggga tgggaagcgc caatctatct gtgacttctt tcctgacatg ggctttcaag 145500tgcatgtaac ttgacattta tgatttcctc tgcaaaagaa gaaaggaaca gggtgatggt 145560gcctctgtga tcagttgcat ttatgggtgc aacagcaaag gaggtgggac acctaaggga 145620caaccgttca cgtgaaatga agcagggatg agaagaaatg cccgtttgta tttaatacat 145680cccagaaatg aaccccttta ttttctggga ctgttagagc agggaaacta tatatttcta 145740agaatggggg ctctgctcaa atctttgtat tacagtacaa agaagggtga ggacaggaag 145800cagtggtgat cttgctcttt ttggaagagt ttgtgtctgt ccttttaaag tcaggtatga 145860ttgataggaa agtcaagtac tggcatcctc agattggaga ggttttattt tattttattt 145920tttttaatgg agtcttgctc ttgtcatcca ggctggagtg caatgccacg atttcagctc 145980actccaacct ctgcctcttg ggttcaagca attctcctgt ctcaacctcc caagtagttg 146040gattacaggc acctgccacc atgcctatct taatttttgt atttttagta gagacagggt 146100ttcaccatgt tggcccggct ggtcttgaac tcctgacctc aggtgatcca cccgcctggg 146160cctcccaaag tgtgggatta caggtgtgag ccaccacacc tggcctgagt ttaacataaa 146220caaagaaata aaaataatat aatctctcaa aatagcaaag aacagggttg tctaatcaaa 146280atatataact atttattttt aatagccaca ttacaaaagt aaaaagaaac aggtaaaatt 146340aatttaattt aattttaaaa atatatttta aggtatacaa cacggtgcta tgggtaaaat 146400ggttattaca atgaaacaaa ttaacatctc catcatctca catagttacc tgcttccctt 146460cccactccaa acccctcatt gcaagagcag ctatagttta ctcatttagc aaaaatcctg 146520aacgcaatac accattttta ttatttttta aatttatttt tttgagacaa ggtctcactc 146580tgtcacccag gctggagtgc agtggcgcaa tcttggctca ctgcaacctc cacctcccag 146640gctcaagcaa tcctctcacc tgagccttgc gagtagctgg gactacaggc acgggccacc 146700acatttggct aatttttgta gagacagggt ttcaccatgt tgctcaggct ggtctcgaac 146760tccttgggct taagtgatct gcccacctca gcctcccaaa gtgctgggat tacaggcatg 146820agccatcatg cctggcctac aatgcactaa tattaactat agttggcagg ttgggcatta 146880gatcttcaga cttgttcatc ctacatattt gctactttgt atcctttgag gtacatctac 146940ccatttcctc cacccaccct acctctggta atcactattt tattctctat ttctgtatat 147000ttgactttta aaaaaattct acatatatgt aaaataatgc aatagttttc tttttgtatc 147060tggcatattt tacttaatat aatttaaata atatacttca tttaactcaa tatatttaaa 147120gtattttaac atacaatgaa tgtaaaaata ttgaaatgtt ttgcactttt ttcatgtaaa 147180tatttaaaat ttggggtata tgttatagta catgccattt aggacattaa attgccaatg 147240gaaataatat tcagatttta taacatttgc agttgaaaaa gtagatacat gtatccaagt 147300tgctctcaac atacttaaag ttttccaata actgaattaa atatcagttt atcagtttaa 147360tataaacaat tagggtaaat gaaaataaaa tttcagctct ttggttccat tagccatggt 147420tcaggagcag aatagtcacc tgaggctagt gacaacgctt ttggatcaca ggaaagaaga 147480aaaaaaatca aaataatttt tcttggtcac atttagctcc ttttcttcca ggatgattac 147540ggagctagga atttcctacg aagctgggtg ataaaaggac attggacaaa aacacagata 147600gcttcattct ataccaggat ccatcactga ttagctgtat tatatttgtc tctactgtaa 147660tttgaggaga atgatacctg cttctctatc ttgttgggtt ttacagatga tgtattgaaa 147720gttcaataaa atctataaac aatagatctc tgtggcttga atggtcctca gatatcttga 147780ccaatgattc tcaaatgctt accatagacc ataatttttc cccacatgac actgcttcat 147840atttttaagt tttttttcac caaatatttt gttttactat ctccaagccc tgaaactttt 147900tttctccctc aaacatgact tcaactttac tatcctggtc cctttctatt gaatgtgttt 147960tgtttgtgtc tatatttctt atagtgtctt gaactgattg tacttacgat atgacttgac 148020tagcataaga tagaataggg cagtcatctt ctttgatcta gactagatgc tatccttcta 148080ttaatgcagt tgctagtttt gtatttgctt gctttcaatt tttttttttc agattttggt 148140aaccactgtt acttgactcg tatcaaactt atcagtagct aaaaccccca ttttccctct 148200tcctgtgctt atttgactag ttttgttgcg ctttctgaaa tgtttctcac ttgtttttga 148260ccaaaaaaat aaaaataaca aatgccattg attctgtgtc tatactattt gaggcagtta 148320ggcctttact tacttcttcc aacattttaa gcagtgttgc attcaatttg aacaagagga 148380ataaaaaggc ttgagaaatc ttagggaagt gtgtctcaag ctttagcaaa caaacaacag 148440atctgcagga gatcttgtta aaatgctaaa ttctgattca gcaggtctgg agtagggtcc 148500aagattttac atttctagta agtttctatg gattatgttt tgagcaacaa attcttagag 148560tgtctgaaag gtttttaaaa taactgattt cccttcaaaa tcttcttcat taggagtaaa 148620atatacatct tctcactctg taaatcagct ctgagatctt ctataatctt agctgaggtt 148680tgggtatgca gagttttgaa actcttattt gcttaagaga ggagccatgt atgatcttct 148740tttgggtttc cccattgtct ggtaaaatga ggagcattac taaacggcac tcacttttac 148800tgagtttgtt tggatcccac agagaactga aaaagtcacc attatggaag ccttatcaga 148860gagatgggga caagtcgccc caaagcagtt gtcaatatct ggaagatatt tttctagttg 148920gccttatatt tcatttctat tttcctcagt tctaattcag tttatcacaa ttaaaaagaa 148980accaatgaaa aacataaata ttggagatca tttgatttca ttggaggctg gaaaggatag 149040aaaggctgaa aagtggccgg gtgcagtggc tcacgcctgt aatcccagca ctttgggaag 149100ccgaggcggg aggatcacct gaggtcagga gttcgagacc agcctggcca acatggtgaa 149160aacccatctc tactaaaaat aaatacaaaa attagttggg cgtggtggca cgtgcctgta 149220gttccggcta ctcgggaggc tgaggcagga gacttgcttg aatgcaggaa gtggaggtta 149280cagtaagccg agactgtgcc tctgtactcc agcttgggtg acagagcaag acagagtgtg 149340acagagcaaa acaccatcta aaaaaaaaaa aaaaagggaa agaaaaaaaa gaaaagctga 149400agggtgtgct gggtcctgtc ctgggtgagg gaacaacttg tggaaaagtg aattgaggct 149460tatcggaatg tttggggctc ctcaataatg ttggcactct gagatacaga ccaaaagtga 149520ggtaaaaagc gagtgtttcc tttttttcag aataggactt tactccagat tttcttactc 149580ttctcttgat tccttcacca tccttgatcg acattcacct cagatgccca tgtcccttct 149640ccaccggcat agcttgtttt cttcttaatc ttcttgtgtt catctagcct cacattgcat 149700ttgtcacact tcgttgaaaa cctactgttt gtcaaagtgt ctttctagta atccagatat 149760ctcttccccc atgcctttgg tgtggtttcg gtagagtcat acagagcagc aatgccttat 149820gaaaacgaat tttacagaat ctgcctgttc atcaaaggag gccagacagg aggtgagaaa 149880aaccaggtgt gtcccacacc agtctcaatg aagccttttg gggtgtcttg tgctcttgac 149940taaatctcag atggtactga atgaataatc accaaaggcg tgagctgtta aggaatccca 150000gtttggctgg ctctgtgcag tcagatgtag ccagccctgt ttatgtgtga aaggattggg 150060ttttccccaa gctgtttggt aatgttgcaa gaacagactt tcccctccct ggctccctgg 150120agtaaaatgg ctgccaaagt attttggaac agaaacttag aaatgtaccg accactagaa 150180gagagtaaca agggtccttt gatattttcc gtgttcacta tgatcaagct ggcatcgttt 150240ccttctgagc taaagattct gagctatcat tggctgatgt gagcttgtga cctagctact 150300tctgttcaca atacactgtg gaggggcagc gggggcagcc ctatttgggt tgagagtctt 150360taaggagagc tttacagatg agttctagtg aagcccatca gggagaagaa aatcaaacac 150420aatgggaaat gtttaacaat taaaaccagg ctttgcctgt gtggtcctgt gttttaccac 150480atcactctat ggaaatgggc tgttggaagg aagactgtat ttctgacagt ttgcagagcc 150540aaaaacctgt tgaaggcttt ttgtaaggta gtggagaaaa tggcaaaacc tttaaaactt 150600aagggaaatt acttgatagt tctgatgacc acaggccacc agactgctgg gtcatggaat 150660tatagctaca tgacaaagaa aataggaggg tgggctgagc cagactcaga aactattcca 150720aaagtactat gactttttag gaagctagtt ctttttattt gaaatatttt gtgttttttt 150780gcatgagaat tagcctatgc ttcttaaaaa tatcataaaa tgtcagctag tagaaaaata 150840aagagtttaa tctccactcc gactacctag agtcaaccct tgttcatact gcagtacatt 150900tttttctttt agttctgttc tatgctttaa ataaaaatac aattaggtcc atatggcaat 150960ataattttga ctccttttaa aactgtagct tatatcataa gtctatttga tgttgttttg 151020aagttgtcat gtacattttg tcatacaagt ttttaatgac tgtttttatg gggttgtgcc 151080ccaagttact tattcattcc catgttatca gatattttgt tctttagctt tttttttttt 151140tttttttaca ttataactaa tgaggcaatg tgtcttgagt attttgaatt aactctctag 151200aatcgattct tggggaggtt atttactttg aagtgatgga cagagtgtag gagatttatg 151260agtgaactct tgtctgattt ggaaatatag agttgtttag gctaggtatt accaacccaa 151320agttgacact tgagtcacct aagttcttct ctactccaga gacttggccc tgcctggcct 151380gatcccagga aaagagattt tagggattac agaaatggga acaagttgtg ggtctgagca 151440cagcatgcaa attaattcaa cacagcccct gggacaggcc catgatcagt gagctgaaac 151500tcccccttca agtgctttca tgattagact ccagcctagg aagcttgtct attagttgtg 151560taatcttgaa aaaatctctg acacttttcc ctctgactca gtttccccat ctggcaccca 151620atcttttaca gtgttatgaa aaatagggaa aatgtagaaa ggaagaacat ggcacccaat 151680ccttaatgga cactcagtga aagctggcta tcatcatcat ttttggggtt gttgtgttct 151740acaaatgtat tttcccagga gtttttttta ctctgtctcc tctttccttc atataccccc 151800agcctgtggc tggggtcttg cttcaaccac catgcacctt tctgaaaccc aagttttact 151860ccctgataaa ggtattgacc tcttgttggt ctcatcctcc agacctacct atacttaaga 151920aaatgacatc tctttaaact ggtccccagt tcacttgttt tccctaacat tttaattcac 151980aagattaatc acttccctta caggccagtc ttactgcaga gttgattttt ataattttgg 152040gcctgttggt ctggttgtac ttttctcttt ctgctggtct gctagttata gcgggtcttg 152100aaagcagtga tatgttatga cattgtcatc accctcatta ttgctcttta tataacagta 152160gcagcataac tgtgttttga tttcttgtac aaggcataaa gtgtgctagt ggctcactat 152220tcacatcaat ctcatcagaa aatgttattt cctccttttg ttgatcatga tatagaggcc 152280cagtgacatt aggtaacttg ctcaagatca cacatgtgga aagctacaga gccagacttg 152340gaactgagtc cattatatct taatcccact gcactccaaa atttgttgaa tgaaggaata 152400gataaacgta tcatgatttt gatgttctga ctaattcgta gccagtactt tattgctatc 152460ggagcttaag ctttaagtac tggctaggaa atagtcagaa ctttattttt aaggaggagc 152520atataattat gtatatttta tacctgtagt aaattgggaa ctatagaaaa catgtagagg 152580attgtgttta ccaacttcat gtagagtgag gatacccgac tctagcttgc tggtagttag 152640gtaagtcaga catgggcagg ggataaacca aattagacta tttccatttg actaagccat 152700ataatcaggt gtaagccacg gaaagaaatc tggaaagaca ggtgcaatat tagaagatgg 152760ctcatgatag tgatcattag aggttcaggc ttgagaaagc caattggaat caagaaggcc 152820taatcctggg gttctgtcac agaaaagaag gctggtagca ggaagaggac atgtaacatg 152880aattacatga ttagatttgt gtcataataa caaaaacaat aatgataata acactaatag 152940cttgttatat gccatgccct gtactaagaa ctatacgtat gttatcccat ctaaatcaca 153000tttaatagat tcccattttt ctcatgagaa aattgcatca tacagagatg aactaacttg 153060ctcaaggcta tagacctggt aattagcaaa gcagggattt gaatttagat gtatttttct 153120ctgaaggctg ggtttagata aatggatctg gaagcactgg gaaggatgaa ttaatgggat 153180ggagtgcagg ggatgcagag tgcccactta tggaatgatt tcattcaaga gagacaggag 153240ggtcagaggt aagaatgcta ccgctgggac agagaggaag gtacagatat gagatatggt 153300aagaaggtat actacaacag tggctcccaa atctcaatga gtagccagtt ctcatggagg 153360ttttgttttt atttttgaat gaagattccc atggcatacc ttgaatattc tgaatcagaa 153420tctctggaat acaacttggt attcttataa agcaccctag gtgatgctga agctctgcca 153480ggttcaagaa ccacagctcg atcagcctat atttagatgt ttggggtgga gaatgagaga 153540aagaaaagat tttagggtgg catccaggtt tctgaatttt gtgactcagt gaagtttttg 153600gagggtaggt aagatgctga gttcagtttt ggatgtgttg agatggactg gtcctgtgga 153660tttagttgga tattagagtc taacgcttag aacagaggtc aaggctgtag atttagatat 153720ggaggacact ggtgtttggg tggtgatggc gctatatatt acatggaatt ttcaaaatac 153780tcaaaacttc agttttccct caataattaa tcactttaca tctttgtgat cttaaatctc 153840tttctgacca ttgattgaaa cttttgcttt taaaatttac attacctttc ttaacagttc 153900cttaagattc atgcattgtt gtaagtagtt acttgcacca tttcattgga ttcacaccaa 153960caattgttaa agtaaaattt atttttcctg tgttttagat gaagagattt aggcaggtta 154020tgtaacacac ccaaggtaat atagtcaaat aattgagcca gaatttgagc ccaagtctct 154080ttctgactct aggcttagag ctttagggct atttcacaaa agggctgttc ctaggtcagg 154140catgacaact tctatattac cttcgtaaaa gaagcaatat aatctaccac tattaaattt 154200tgcaggttaa ttttatatta tgtttaaata cagaaaactt tatttaaaac tcagttgaat 154260ttctcttgag aaattggcca tgtagtaaat tatatttaat agaagagttt gtgtacttcc 154320cagggagcag agtattggcc tgatcaaagc acctttcagc ctttgtctaa cagcatgtgg 154380gtaggctaca ttttttttac tctcagagaa agggggtggg caggggtgtg atatgggttt 154440ttgtctctgg gagttctgtt gcatgatttg acctcccaaa ttgttttgtg gggcatatcc 154500aactttgggt tgaaactaaa atgggttctt ggtaatccca gattgaaaat atgtctcagc 154560agtaacattg tttatcttta ggtttaggta aatacagaca tttgccatgt cttcttggta 154620gcactgtaag aatgagtagg gctgtgaaaa atgcacaggg cattcattat gaagactggc 154680tggttaaaac tgatacacta aagaaattgc attcttttcc acaagctgag tcatacagct 154740gaaattgtgg aatcatctga gccagcagct gtaatatgat acttaatctc cataagtgac 154800agatatctaa gataacacga acacccagac gacaactcag gcaaccccag cacagtgttt 154860tggtatgaga acaggagaaa tgttagtaga gtgaacattt ttccacagag aactcaaata 154920tggtaacatt ctcatagctt tgataatccc caataaactg tggttactaa aatgcatgac 154980aaaaagaact tctatctata aagaacttct ttatacattt ccaatacttg ggttatgatc 155040aaggagaaaa aagtttatca gttaattaag agttaggtag ctagtttgcc cacagattaa 155100tttgtatgag gtaaaggaaa tctcacctaa ctgggaaaaa gcaagcttac cctcaaggta 155160tgcttatccc aaccccaccc tgccaagtgc attccttatt cctcaggtgt gcctgtttat 155220cccaaggacc tagccacacc tacatcttgt tctggcccca caccaaggaa catataaaag 155280ttccctctct ggccgggcgc ggtggctcac gcctgtaatt cccagcactt tgggaggctg 155340aggcgggcgg atcacgaggt caggagatca agaccaccct ggctaacacg gtgaaacccc 155400gtctctacta aaaaatacaa aaaattagcc aggtgtggtg gcgggcccct gtagtcccag 155460gtactcggga agctgaggca ggagaatggc gtgaaccctg gaggaggagc ttgcagtgag 155520ccgagatcgt gccactgcac tccagcgagg gcaacagagc gagactccgt ctcaaaaaaa 155580aaaaaaaaaa aaagtccctc tctttatatc tcagggtatc ttggagtcac tactgatcct 155640tgacctccct cctttctctg accatgtcta gacaagtgtc caggtctcct gtgccaaatg 155700tctatttgtt gcctggatta ggttttgact tgtttttcta tttctttgca tctcgtagcc 155760catttctttg attcaatttc acaatctctt gattttgtcc ttaagtattt ggcaacacaa 155820accctcgaga ggcaggatag ttcaacagaa agaagatgaa ccttgggggt cagaagattc 155880aaacttccag aatttaaatc ttcattctgc tattactaga tttataaact ttatcaaatc 155940actctcctac tctatccctt aattcaacat atttaaaatt ggaataaaaa tctcaatgtg 156000gtagagttat tattgagatg aaaatcagaa tagatacaaa gaacttgata gccccaagga 156060gcttgatcag tgtttgttta atggcccttc ctctcttctc atatctcagt tcagatccta 156120ctcagccatt tattttattc tgctcctttt ggagtagaga ataaagccaa gaattatgct 156180taaaaagtag cataattaaa agtatttaaa acacaagtaa cttgagaaag gtgagttgga 156240agtttatatc taacctcagt tttttttgga gagaaattta cccgtcaggg ccagattaaa 156300acatttacaa gtcccaagca cacgtgagat gaagatgccc ctcacttatc tcacatgtaa 156360gttgaaagtt aaaaagtgaa aatgtctact agagttcaat aatattcttt ttttcccatg 156420acttctctga agcttttaga aaatatgaaa ttcttaaaaa caataacagt aacccacatt 156480tttattgccc tggtttgccc tatcttatct ttctcctgct cacagggtct gaggcagctg 156540ggatagggga gaatgattac cagccaatca atattttttg

aaccccagag attatttatt 156600tatctatcca tttatttatt ttgagatctt attttatctg gaatcttaat aaacgattag 156660tttccaaact gtatctactg tgtgtatttt atccatatgg cccagatttg tattacttat 156720ttgtgattct gaataatatt ttttccaaca ttaattatca gcctctctgt gcccctccag 156780aattgttaca acctatgtta atgcacacta tggcaagcca tgtgaattgc ctacgcaggg 156840aagttttctt catacttcct tgccaagaga accccattat tggtcagtta ctagtcacat 156900gatcttcttt agcccctcct tagcccctgt agtgaatcag gagtagccta aggccatggt 156960ggtaactccc ctttttcttg gaaatgtttg atttagatat ggagaagagg tgcaactttg 157020cttatgaaat gggagggcaa atatgggaaa ctttaaggta agttttcttt ccccttgaag 157080gggaccaaaa agttgtggtt tatactttct tgactctggt cactgttggg tgaagagttg 157140gtgctatgga agccatcttc agaccatgag gggacaagtc tgaggataca attacatgct 157200accggtggca gaggacagta tagcaagaaa ctggatccct gatgacattg aaccattgac 157260tgaatctacc ctggaaccat caggaaataa tccttagttt tttaaagatg cttttagttg 157320tgttttttat tacaagtacc tgaaagcatc ctaactaatc aatgctaaat gcatctctca 157380cagtttatgc ttatttttca gaaatgccta gtggaaattt ctattgctga ttataatatt 157440tgtcctaaat aaattgaata gactgtcaat cttttgaaaa taaaagcatg acttgattag 157500caattgttta gtctgatgtt ttcctaattt ctgtcatttg cataccactt ctttgatttt 157560gtcatatcct tgtatcatct gcactaatag aaatattttt ccttaagttg tctctccttt 157620aaaaaattat atccatttat tttgaagaga aactttttca ctaactataa attgaaaacc 157680gatatcattt gccttaaata gaagattgtc ataaaaagaa atgccatgag tgaaataatg 157740ttattaaata tttgccagat atagtttcct atgaagactc tgagcttgtg gcttgctgtc 157800tctgttgaaa ggagagacta gggagtgtta tagaagtggt aaaataatcc ttccactgac 157860tgagactatt tccttgccac aatcagaaga actaaaagaa aggaggatat ctgttaatat 157920atgaatttat ctaaatgtca tgcagtgact tctaaaatca tctggtgtgc tctgtttccc 157980cttggaggtg acttaggcct ggcatcccaa acaatacata ctggagtgaa gctccaggaa 158040accctgagga gaagagaagg gcttaaagag caatcagcct tcgattgctg ggattatgaa 158100aggtcgtaag aagcgaatgt tgcaatgttt tattatactt gatattgaag caaggacaag 158160taataattta ttattctctc catgtcagtg gtatttacct ttttggaatc atgtgcccca 158220ttgagaattt ctggaaaacc atggttcttc tactcaggag aatgcacaat tgcacacata 158280cacaaatgtg caagcacaca cacacacaca cacacacaca gaattgccac agaaggtcag 158340taggttcaca ggccctaggc taagaaccag cattctgtat attttacatg tgttctctta 158400caagttaccg tgtgattcag ttcactccaa actgcggtta agtgcaaaac atggttttga 158460atatttctat caattagtaa gagtggtatg ttaatttaaa tacaccaaag tggagaatta 158520ctgtcctctc aatagctact ttaaatagac ataagttaca gtgatattgc cttccaggag 158580gcttcaagaa atgagatcag gctctataaa agaaaatcac ccaaccctat aaagtcatct 158640ttatgaactt tgaaacacca ctgtatgtac ctagtaaaaa ttattcctgg gtaagcagac 158700tcccaggcct gggtggagtt cacatgagtc cctttgctaa aataaacaga agtgactggg 158760aactttggat tgcctttgtc tgaacttgag tgtctggatg gatcagcatc agcagcatac 158820cacacacctg cttgtccagc caaagagaaa cccaaagact tggcatttgt tttttacatt 158880gtcaactgtg caaaaatatc acgattctaa tttatgaggg tccatgagtt ttaaaaacac 158940cccctgacat ttttctagcc aaataatttt tcctttaaaa ggcacaggat gagcaacaag 159000attaggtaga tcacttcaat ctctaatttc aaaagataat agttaaaaat tcaactgtag 159060gactaacaca ttaactatgt aataagaccc agaatagtct ttggagcaaa tttcagtgga 159120tacttgatca aaataatgtt gaagacaaaa tcttgaattg atgatattta tctgatacaa 159180ttatttacat aacaaatgtt aaaagaatta gaaaaatttc ataggtaaga tgttcattat 159240cttcaagtga agttacttgc tttatattaa gaaccacaaa aacttactaa actttttttt 159300ttaaaagggt ctcactctgt cacccaggct ggaccggagt ggctcaatca cagctcactg 159360cagccttgat ctacccagat tcaagtgatc ttcccacctc tgcctcccaa gtaactggga 159420ctataggcac atgccaccat gcctggctaa tatctctctt ttcttttttt ttccccttat 159480tttgtaggga caagttttct ccatgttgct gaggctggtc ttgaactcct gggctcaagt 159540gatcctccta cctcagcctc ccaaagtgct ggagttatag gcatgagcta ctttgccccc 159600tagcagacgt cttacttttt tttttaattt ggtattagat tgagccaatg actaatttca 159660aacatttata aattactaaa ttcttttttt taattatact ttacgtttta gggtacatgt 159720gcacaacgtg caggtttgtt acctatgtat acatgtgcca tgttggtgtg ctgcacccag 159780taactcgtca tttaatatta ggtatatctc ctaatgctat ccctcccccc tccccccacc 159840ccacaacagg ccccggtgtg tgatgttccc cttcctgtgt ccatttgttc tcattgttca 159900attcccacct atgagtgaga acatgcagtg tttggttttt tgtccttgtg ataatttgct 159960gagaatgatg gtttccagct tcatccatgt ccccacaaag gacatgaact catccttttt 160020tatggctgca tagtattcca tggtgtatat gtgccacatt ttcttaatcc actctatcat 160080tgttggacat ttgggttggt tccaagtctt tgctattgtc aatagtgcca caataaacat 160140acgtgtgcat gtgtctttat agcagcatga tttataatcc tttgggtata gacccagtaa 160200tgggatggct gggtcaaatg gtatttctag ttctagatcc ctgaggaatc gacacactga 160260cttccacaac ggttgaacta gtttacagtc ccaccagcag tgtaaaagtg ttcctatttc 160320tccacatcct ctccagcacc tgttgtttct tgacttttta atgatcgcca ttctgactgg 160380tgtcagatgg tatctcattg tggttttgat ttgcatttct ctgatgccca gtgatgatga 160440gcaatttttc atgtgtcttt tggctgcata aatgtcttct tttgagaagt gtctgttcat 160500atccttcacc cactttttga tggggctgtt tttttttctt gtaaatttgt ttgagttcat 160560tgtagattct ggatattagc cctttgttgg atgagtagat tgcaaatatt ttctcccatt 160620ctgtaggttg gctgttcact ctgatggtag tttcttttgc tgtgcagaag ttctttagtt 160680taattagatc ccatttgtca attttggctt ttgttgccat tgcttttggt gttttagaca 160740tgaagtcctt gcccatgcct atgtcctgaa tggtattgcc taggttttct tctagggttt 160800ttatggtttt aggtctaaca tttaagtctt taatccatct tgaactaatt tttgtataag 160860gtataaggaa aggatccagt ttcagctttc tacatatggc tagccagttt tcccagcacc 160920atctattaaa tagggaatcc tttccccatt gcttgttttt atcaggtttg tcaaagatca 160980gattgttgta gatatgtggc attatttctg agcgctttgt tctgttccat tggtctatat 161040ctctgttttg gtaccagtac catgctgttt tggttactgt agtcttgtag tatagtttga 161100agtcaggtag cgtgatgcct ccagctttgt tcttttggct taggattgac ttggcaatgc 161160aggctctttt ttggttccat atgaacttta aagtagtttt ttccagttct gtgaagaaag 161220tcattggtag cttgatgggg attgcattga atctataaat tactttgggc agtatggcca 161280ttttcatgtt attgattctt cctacccatg agcatggaat gttcttccat ttgtttgtat 161340cctcttttat ttcattgagc agtggtttgt agttctcctt gaagaggtcc ttcacatccc 161400ttgcaagttg gattcctagg tattttattc tctttgaagg aattgtgaat gggagttcac 161460tcatgatttg gctctctgtc tgttattggt gtataagaat gcttgtgatt ttcgcacatt 161520gattttttat cctgagactt tgctgaagtt gcttatcagc ttgaggagat tttggctgag 161580acgatggggt tttctagata tacaatcatg tcatctgcaa acagggacaa tttgacttcc 161640tcttttccta attgaatact atttatttcc ttctcctgcc tgattgccgt ggccagaact 161700tccaacacta tgttgaatag gagtggtgag agagggcatc cctgtcttgt gccagttttc 161760aaagggaatg cttccaggtt ttgcccattc agtatgatat tggctgtggt tttgttatag 161820atagctctta ttattttgag atacatccca tcaataccta atttattgag agtttttagc 161880atgaaggttg ttgaattttg tcaaaggcct tttctgcatc cgttgagatt atcatatggt 161940ttttgtcgtt ggttctgttt atatgctgga ttatgtttat tgatttgcgt atgttgaaca 162000agccttgcat cccagggatg aagcccactt gatcatggtg gataagcctt ttggtgtgct 162060actggattca gtttgccagt attttattga agatttttgc atcgatgttc gtcagggata 162120ttggtctaaa attctctttt ttttgttgtg tctctgccag gctttggtat caggatgatt 162180ctggcctcat aaaatgagtt ggggagaatt ccctcttttt ctattgaatg gaatagtttc 162240agaaggaatg gtaccagctc ctctttgtac ctctggtaga attcggctgt gaatccatct 162300ggtcctggac tttttttggt tggtaagcta ttaattattg cctcaatttt agagcctgtt 162360attgctttat tcagagattc aacttcttca tggtttagtc ttgagaggat gtatgtgtcg 162420aggaatttat ccatttcttc tagattttct agtttatttg catagaggtg tttatagtat 162480tctctgatgg tagtttgtat ttctgtggga ttggtggtga tatccccttt taatttttta 162540ttgtgtctat ttgattcttc tctcttttct tctttattaa tcttgctagt ggtctatcaa 162600ttttgttgat cttttcaaaa aaccagctcc tggattcatt gatttttttg gagggttttt 162660tgtgtctcta tttccttcag ttctgctctg atcttagttg tttcttgcct tctgctagct 162720tttgaatctg tttgctcttg cttctatagt tcttttaatt gtgatgttag ggtgtcaatt 162780ttagatcttt gctcctttct cttgtgggca tttagtgcta taaatttccc tctacacact 162840gctttgaatg tgtcccagag attctggtat gttgtgtctt tgttgtcttt ggtttcaaag 162900aacatcttta tttctgcctt cattttgtta tgtacccagt agtcattcag gagtgggtag 162960ttcagtttcc atgtaggtga gcggttttga gtgagtttct taatcttgag ttctagtttg 163020cactgtggtc tgagagacag tttgttataa tttctgttct tttacatttg ctgaggagtg 163080ctttacttcc aactatgtgg tcaattttgg aataagtgca gtgtggttct gagaagaatg 163140tatattctgt tgatttgggg tggagagttc tgtagatgtc tattaggtcc gcttggtgca 163200gagctgactt caattcctgg atatccttgt taactttctg tctcgttgat ctgtctaatg 163260ttgacagtgg ggtgttaaag tgtcctatta ttattgtgtg ggagtctaag tctccttgta 163320ggtttctaag gacttgcttt atgaatcttg gtgctcctgt attgggtgca tacagattta 163380ggatagttag ctcttcttgt tgaattgatc ccttaccatt atgtaatggc cttctttgtc 163440tcttttgatt ttgttggttt aaagtctgtt ttatcagaga ctaggattgc aacccctgcc 163500tttttttgtt ttccatttgc ttggtagatc ttcctccatc cctttatttt gagcctatgt 163560gtgtttctgc acatgagatg ggattcctga atacagcaca ctgatgggtc ttgactcttt 163620atccaatttg ccagtctgtg tcttttaatt ggagcattta gcccatttac atttaaggtt 163680aatatgttat gtgtgaattt gatcctgtca ttatgatgtt agctggttat tttgctcatt 163740agttgatgaa gtttcttcct agccttgatg gtctttacaa tttggcatgt ttttgcagtg 163800gctggtagtg gttgttcctt tccatgttta gtgctttctt caggaactct tttagggcag 163860gcctggtggt gacaaaatct cttagcattt gcttttctgt aaagtatttt atttctcctt 163920cacttatgaa gcttagtttg gctggatatg aaattctggg ttgaaaattc ttttctttaa 163980gaatgttgaa tattggcccc cactctcttc tggcttgtag agtttctacc gagagatcag 164040ctgttagtct gatgggcttc cctttgtggg taacccgacc tttctctctg gctgccctta 164100acattttttc cttcatttca actttggcaa atccgacaat tatgtgtctt ggagttgctc 164160ttcttgagga gtatctttgt ggcattctct gtatttcctg aatttgaatg ttggcctgcc 164220ttgctagatt ggggaagttc tcctggataa tatcctgcag agtgttttcc aacttggttc 164280cattctgccc gtcactttca ggtactccaa tcagaagtag atttggtctt ttcacatagt 164340cccatatttc ttggaggctt tgtttgtttc tttttattct ttttcctcta aacttcttgc 164400ttcttttcat tcatttgatc ttccatcact gatacccttt cttccagttg atcgaatcgg 164460ctactgaggc ttgtgcattc gtcatgtagt tctcgtgcct tggttttcag ctccgtcagg 164520tcctttaaag acttctctgc gttggttatt ctagttagcc atttgtctaa ttttttttca 164580aggtttttaa cttctttgcc atgggttcga acttcctcct ttagcttgga gtagtttgat 164640catctgaaga cttcttctct caactcgtca aagtcattct ccatccagct ttgttccatt 164700gctggtgagg agctgcattc ctttggagga ggagaggcac tctgattttt agagtttcca 164760gtttttctgc tctgtttttt cccatctttg tggttttatc tacctttggt gtttgatgat 164820ggtgacgtac agatggggtt ttggtgtgga tgtcctttct gtttgttagt tttccttcta 164880acagtcagga ccctcagctg caggtctgtt ggagtttgct ggaggtccac tccagacgct 164940gtttgcctgg gtatcagcag cggaggctgc agaacggcga atgttgctga acagcaaatg 165000ttcctgcctg attgttcctc tggaagcttc gtctcagagg ggtacccagc cgtgtgaggt 165060gtcagtctgc ccctactggg gggtgcctca cagttaggct actcgggggt cagggaccca 165120cctgaggagg cagtctgtcc attctcagat ctcaaactgg tttcaaagaa catctttatt 165180tctgccttca ttttgttatg tacccagtag tcattcagga gtgggtagtt cagtttccat 165240gtaggtgagc ggttttgagt gagtttctta atcttgagtt ctagtttgca ctgtggtctg 165300agagacagtt tgttataatt tctgttcttt tacatttgct gaggagtgct ttacttccaa 165360ctatgtggtc aattttggaa taagtgcagt gtggttctga gaagaatgta tattctgttg 165420ttttggggtg gagagttctg tagatgtcta ttaggtccgc ttggtgcaga gctgacttca 165480attcctggat atccttgtta actttctgtc tcgttgatct gtctaatgtt gacagtgggg 165540tgttaaagtg tcctattatt attgtgtggg agtctaagtc tccttgtagg tttctaagga 165600cttgctttat gaatcttggt gctcctgtat tgggtgcata cagatttagg atagttagct 165660cttcttgttg aattgatccc ttaccattat gtaatggcct tctttgtctc ttttgatttt 165720gttggtttaa agtctgtttt atcagagact aggattgcaa cccctgcctt tttttgtttt 165780ccatttgctt ggtagatctt cctccatccc tttattttga gcctatgtgt gtttctgcac 165840atggtgatgg gaggtactgg tattacaaaa agcttctccc ccgtgggtca aatctaagct 165900gagtgttgag acataattga aattcactag atagatagga gataggggta gggaattcta 165960atcagaggga atagcacatg taaggcaaac aatacagtgc atctgggaaa gctatacaat 166020tttattgtta taggacaaat gttggggaat gttgagagat ggaactggag agtgaggcag 166080aagttagcat ttattcattt attcagcaga cctttatcta ttacctacat tgcactaagt 166140actgtgtgag cattagagag aaaaagatga atgagattgg acaccattcg ttcattcctg 166200actatgaact tggcattgtt ctaggtacca gagatataat aatgagaaac agacatgctc 166260cctcccctca ttgaggttac agcttagtgt ggagacacac agatgcctaa cgcactatgg 166320tatggaaggt gctatggaca cagtgctcaa atccatgatc tacataggta tgagagtgac 166380ttttctacaa cttaaatctg atcttgttat tccctgctta aaatcctgca gtagctccca 166440gtagtgcctt ctggttaaaa tacaagatat atagtatgac ctctcaagga cctttgttat 166500ttgtctctgg ccacctctcc aatttttcac catgaccctg gccctgtccc actggcattc 166560catctccaat cacacggaac tatgtggagt tattaaaatg ccctatgtta tttcaagact 166620cagagattta gtgcctcagc ctgttttgtt ccctctcccc tcctccacct ggccttctcc 166680agctcactca tcaatctatt agactcaggc atcatctgct tgccttcgta accctcccca 166740ccccgctcac cttgctggat tctgtgcctt tgcttgctgg ttcccagaga tccctgccct 166800tatttttctt tgcctgctgg atttgcagtg ttgtgtccta tatggtgtag aaaaccagct 166860caggctccca cttctctggg cttatgtggt cagatgcaga cctgtcttcc atccatacca 166920aaggccatca gggagtttct tttgtcctct tcaccagccc attcttaatc tttctgataa 166980attttctgca ctgtgtgcgc gtgacaaatt gggtcaaggt gatggtaatt tacagcatga 167040gatggtgaac ttgctgcctg tgctgatgag cccattggat ttcccctaac tagtctgttt 167100ccctacccag gtggagaact tcagtagagg aagtggcagg aatttgggaa tgaggagcac 167160agtgattaaa ctggggccat tcatatgaga gtttaagaac tcagaccagt gacttaggtg 167220agtaaaaata tcagaaaaag ggaaagagga taagagcaac ttgggccata attaaacttg 167280tcaatgaaat gaaggtctgt tattctaatg cctacatttt gccaaacctt tgtgcttata 167340acttcatcat ttgctgtgat taacaaagtt gaaagaataa taactactta caaggcccac 167400atcacctcct tataccacta gcttttgctt tccgtacaga catagcttta aaaagtgcaa 167460atcctattct gtacctgagc cacaacccta aaagggaact tgtttacaat tctaagaata 167520atattgtcct ttaaaggtga aggctcgctg gaaaacatgc cattcatgtg ataaaaagca 167580ggtagcaggt agtgctaaag acttactaga ctgcatgttt gtgctttctg ctgcattcct 167640ctaatctcaa ggcagtataa ggagataaca tcttcacagc cctttcagcc ctgttgcaat 167700ttctttgacc ctggcctgat ataaaaggca aacttggttt ttcactgttc tagtcatgca 167760gtttctttgt ggttcccttt agaaagactt gaggctatga gtcaaagctt ttacgtcttg 167820ctgatagttc agagttgtga tgtgaagcaa taaataaaat ccctccttcc acatacttgt 167880ctccttgatt agaatcattc tgggcaaatt tagaggctca taaagtccat ttagatattt 167940agtgaaaaaa caccagcact cagaacagaa tgttgataat gtagatggaa tatctttctc 168000tctctgtctc tgtgtgtgtg tgtgtgtgtg tgtgtgtgta tttatatatg tgtgtattta 168060tattatatat gtgtatattt atatatgtgt gtgtatacat ttatatgtgt atatgtattt 168120atagtaaata tatcacatgt atttatatat agtaaaaaag aggggactat aatatatctt 168180tatatgttag catttatttt aaaaagaaaa cacaggaata tctaaaagaa actattactt 168240ataggggtta tgggaaatgc catgggcaag aatttttttt ttttttatca ccatgctttc 168300tgaaacaaca cgatatgtat cacctttata aaaataaaat aaaataaaaa atgaaaaaca 168360aagtccactt gtaaccacat gtcagtagca tgtttgcttt cagggtacat caaatgcatt 168420ctatagcaca ggatgttcca gtcactctaa caaaagatgt cctgtttgga acaccaactc 168480tgtatcagtt acttcagaca ctttctctca ttgagtccct tcagcaagcc cttttaggtt 168540tatgttctta gatgaggaaa ccaagtctta gaaacattaa ctggccaaac taagatcaga 168600gagttagaaa tgtcagagcc cagaactggc atcttctgac ttcagatccc atgtactttc 168660ccctacactg tgctgaccac acctccatta ctacagatgt gttgattaca tctaggggcc 168720aaagtacaca ttcatccaat aaatgcttac tgaatgctta ccgtgttcag ggcactgtgg 168780caatcttttg taatgcaaga aaaataagag tagtgaagac agtcaaggaa acaaagaagc 168840ctaatactag gcaagaagtg cttttgatgg aattaagcac aatgagggtg ttagtacaga 168900aaggacattt aattgaactg ggaaagttca tggcagtttt cccagagatg agtcttgaag 168960gacaaatggt atttagccag gaggaaaggg ggtcaagtgt attccaggga gagggaacaa 169020catgtacaaa agcacagttt tgaaagaaca ctccattttt gaggaatagc caatagctgg 169080gcacgtctag agcatagggt agtagagaga aaggaggccg gaaatgggaa gagacttgaa 169140tgccacattc agttatgtgg acttcatctt gtagcaatgg gagcctacaa aattttaagt 169200agaggaataa aaagattcca tctaaaactt agaaaaatta ctttggcagg ataagagaca 169260atgaattgac ggggagctgg gtttgatagc aagaaactgt ttgggagact gttctaatta 169320catattttct tgtttttaga tgcacatata cgtacttttt tagctggtca tttctttctg 169380aaattggaat gaatcttaca atcaatggca tgttataatt tcattggcag cattatttgt 169440ctcttaaggg cccccaaata atagtgtgtc acataactga tagcatctca aattagatga 169500aatacagtag tccaggcaag aaatactgag atggtggggt ggtaaagagg gaaaagattt 169560gagccacatt tagatcctga tgtggtatta attattaagt aaaaaaaagg aatgtgcagt 169620acatattcag tatgccacaa gttgtggaaa aaaggtgtgc atggatagat gcacatgtat 169680gtattcataa agttaatgtg gatgcataaa gcgtctctag aatgatacac aagaaacaaa 169740taacacccgt ggcttttagt ggggggcatt gggtggctga gggagaacag cggtaggaaa 169800atttttcatt gtgttctatt ttgtacattt gatagtttga actagtcgta ttatgcactt 169860caaatatgta aaaagataaa aagtaagaga tatttagaaa ggagcattga cacatttgtt 169920gacagattgg ttatgggata aaggcgatag tattttattg actatatttt attcttttaa 169980ttattcctct aatttcttaa aacaacttta ttgaggtata acttccacgg tataatttca 170040cccattttaa gtgcatgaat tcagtgattt ttagtagagt cattgagtag tgtaaccatt 170100cctacaatgg ttatagcaca tttttatcat cctaatgaga tccttcatgc tcatttattt 170160aatctccatt cccatctcca tccccaggca accataatct tccatgtttt taaaatagct 170220ttgcctattt ttggatgttt catacaaatg gaatcataca aaaggtggtg ttctgtgtct 170280agcttctttc ccttaggata atgttttctg gtttataaat gttgcaaatg tcagtatgat 170340acttcattcc tttttatttg tgtctacaaa atactctatt ttatgtatat accacctttt 170400gtttttctgt tcatcagttg aagaacattg cagccgtttt tgctttttga cttttatgaa 170460taatgctgtt ataaacgttt atgtttaagt ctttgtgtgg aagtattttt tcatttcctt 170520gggtagacac ctagaagtag gatgttgtat ggaaaattaa tgtttgactt tttaagaaac 170580tgttttccaa agtggctgta acagtttaca cttctactaa caatgtatgg aggttcccac 170640ttctccacat ctttgcttac acttattatt gcctgtcttt ttggcagact taagcctagt 170700ggttgtgaag tggtacttca ttgtgggttt gacttccatt cccctaatga ccaatgattt 170760cggacatctt tcaagtgctt attaaccatt cacgtgtctt ctgtgatgaa atgtctattt 170820gaatattttg cccaatttaa aactgggttg tttacctccc tattcttgac ttgttaggat 170880tctttgtatt tttaacttta atttgactga ggataatgat ccaccagtaa agagatgcat 170940ttatttctgt atttatgaaa atctttaaaa ttcctctacc tttcagagac acccttcaac 171000agactgcgct tcttattttc agagtatgta tttccatgat aacacaagta tcaattataa 171060atattaatta caactttccc tcctcactgc agactcaacc aagagttata aatctgtgta 171120ttactttcaa tgctcataac aatcttctta accaccataa gcagactgaa aaagtcaatc 171180tagttgaatt gttttacttt ataatgcttt tataagatac tcagtctgaa actgaaagat 171240aggtagctct agaaatgtga taaatggcca cagaagtaac aacttttaat aaattaaatt 171300atggatgtta tgtcaatttt aagtaatgtc tcagttttat atcttgttac ctgacctaaa 171360tatcattccc tttagtaaaa tatctattaa agctttgtgg caaaataaga acagaaaaat 171420ggtttttgat tttcagcttt ctctggtgaa taatttgttt tcttttattt ttccttctaa 171480aataatcaca cgtttcattg caaccctaac cctcttcaac acacacacac acacacacac 171540acacacacac acacatggct tctagattct acatgtacaa gagtgcaaat caaactacca 171600tagaaaaact aagaagagag gcctagaagc aagaggctga

tacactatct caggcttcaa 171660caaaatattt atctctgact ataccaagga tgggcagagc ttgcatgtaa gtggcttggg 171720ctagcagact gggttttgaa ggaggacaac atggccatgt tcttggttcg gtcatgaact 171780gtctatggca cataccttaa atactgttgg aaggatccgt tagctccaga gactgcaacc 171840aactgcctat ggtcataact cagctctcag acacattttg ttgtgcccac agagtgctgt 171900ttgcctgttt ggtttttaaa ccaacactta aaatgcaggg aatttaagat aaaaatttga 171960taaaaatggg aagatttggc cgtattgggc tcatggtaac tgagatgcat ctgaatgaca 172020ggcattcctt tgaattgcac atttgctctt gtttttacta taggccactc tcactttctg 172080tttttttccc cggctttgaa acgatcagtt ttagtactga aaaattatct aggatactaa 172140aaccagaatt tctctgctag atggcttgct cattacatta cctacatgat tctgtgtaag 172200ggattgtgta agttttctat ggttgccata actatcacaa acttgatggc tttataacaa 172260cagaaatgta tttacagttt ggaggcagaa ggtctaaaat caagacttct gattttagtc 172320tgtccaagag cctctgctgg tagggccatg ctctcggcag aggctcttgg ggagaatctg 172380ttccttgcct cttccacctt ctggtggctt caggtgtttt gtggcttgtg gctgtatcac 172440tccaatttct gcctctgttt tcgtatggcc ttctactctg ctcctttagt ctctccttta 172500ggctgtttct tataagacac tcacctaaaa cccaaaaaca atctaaaaga ttttgcaaat 172560atgaacattc taattacctt agagttaaga ttttcttttc tgctaagtga gggcatggtg 172620cagagagcag gaaagatgtg aaactagata gcatacaaaa ataggtgttc atagatctgg 172680gcctaacaag ggtgtggcca gcaactctgc cctgctttat cagcattaga aagccagtcc 172740tctcagaaag tgcccagtta gctaaattca tgagattata gactattaag gtggaatgga 172800cctcagagat ggtccttgct ctcatctgag gcttcagttg ggccagtcag aaatgtggga 172860aaattgaggc aggtcaaata accaggagta caaacaaaca caatctatcc agaaaactag 172920aaatcttact agtgactatt cacaggttac tttctgcatt ctggggtttt cattctagaa 172980cagatgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tggtgcgtga 173040agagagggga ggggtgccca gaaaaccata cccactttcc cacatatccc aactatgact 173100gggcaattat gtcattatca ccactgatat atagctggaa gagtttagtg ttgccctgct 173160aagatctgga ttttcttttc tggagcttgg ctattggggc attgagaagt ccagccagga 173220ggttggtcag aggctaaccc aaaaagcttt gcttaactct gggctacagc tgggggttgc 173280cagagagaag tgcctggcat tcctgcatgc tgacatcaag cttcgaagtt gctgccctct 173340ggtgagtcag cagcaaaggc ccacatcgtt cgagaatgct gcccaatcag aagatgtgat 173400gccacacctc agaaatcttt ctaaacctca gcattctgta gacttcaaac aactcctcct 173460gagaaagaat gtagaaataa ttaaatttat aagattaaag ttataaaaag catagagcct 173520ataataataa cagcaataag ataaactcca catttgcttt taaaacaatt tatttgagta 173580gacagccaac cccctgtatt gtactccttt aaaaaatatt ttaggctttt taaatgctga 173640ggcaagggga cataccaaac actaacaggc acattggggt tttctggcta ttgaaataaa 173700aatgtcctta cataacactg atgtactgga atagcactgc gttccagtga cggttattgc 173760aactcagcca gcatatctgt agcttgtgag cttttcttat cagaatttta tctataaata 173820tacatatacg taaattctat tgtgaaataa aaataaaatg tagaatcttc tcatctttct 173880tattagtcaa tattgtgcta ctctttaata atttctctca attttttcat taagcagata 173940ttactaggga aatatacatg aggcagaagg caaattattt gcttagtgca atgcaaactt 174000gcttaacagg taagagcaga gtcccttcca tagcattgcc accatatggc attgccatat 174060cgtggaggcc ataaagagga atgacattgt aaagattaac tggattttac ttggcaaggt 174120caggcaccta gatggcatgc tataaaatgg ttagaagtgc aaaggaaacc tgtagctaga 174180ggccatgtga gattatggaa gtgacttttc ttacaatcct gccatctggt ttggattgtc 174240aggatcaaaa catttcactt gcccaagtga ggatgctctc tacatggttt tggggatgag 174300ggagactcag aaataatgtt tgtggtactg tagcaccact aggaaaagag aaaaattgga 174360cctgacatga agaaaagcat gcagccagcc actaagacta cttcccacag gactggaaat 174420ctctaccacc gtacctctcc tacatgctgg gtataagaag ttaaagggaa gccagattat 174480atttacctac tctttcattc attcattcac tcattcattt attcatccat ttaccatttg 174540tttgtttttt gttcatttac ttatttaata aaaattgtgt tttgcatatt ctaggtgcca 174600ggcattgaag aaccactgtt attgttctca aatgactgac agtttagagg agaaaatgga 174660agaataaata gacacttgtg atgcaatata atagtgctct aataagagca acatatattg 174720aataccactg aatattaaat accagggact ttgctaggag ctataaatta atctccacag 174780tacatctaag atagaagttt tataattact ctctttagga ggaaataggg gtctatagag 174840gttaagtctc acagcctgga aggagtcaac aaaaaaatac tcagccttag gtattctgac 174900tagaagcttg ggtccttaac cacctactca ccaatttgaa gaaagatgat tgaaactgca 174960acagctacac tgactcttga aagcaaagta actcgttaaa tgagggtatg tgtatactgg 175020ctgggatatt gtgggctcat gatgacttgt aggccgaggc agctgcacat atgaagacta 175080tggagggtat atcatcagcg gaaatgaaag tgattagtgt tggaggtttc agtgcatatt 175140ctggttttct attactgcat aacaaatcac cctaaaattt agtgacttaa ataaacatga 175200tcatttattt agctcatgaa tttgcaagtt gtgcagcact tgggtgggat agctcacctt 175260tcttccatgc agtgtctgct gggactgcat gattgcatga agcggggctg ggcagctaga 175320gctcttcatg aatctctatt tttgcatgat attttcacaa ggtctctcaa gcatgggagc 175380ttcaggtagc agaacttctg acagggcagc ttagtccttt gaaagtgtat gtctgaaaag 175440agagactcag gcagatgcta tattgccttt tgtgaccaag ccttggaaat cactagtctc 175500tcttgtgttg aggtggttat aagagcctgt ccaggttcag tagggagcat aaatttcacc 175560tctgaatgga gaagtgccaa tgtcctgaaa aagcatgtgg gcccagaaat actgttgtgg 175620caattttttg aaaatcaagt gtgataaaga cagcatagtg tagtcataaa aaacagatta 175680ggagcatgat gtgctttgat ttcaactatg ggctttatta cttactaact gggttacttt 175740ggttaagttg tttgactctt gttttttgag atggagtcag tctgggagac tccagctctg 175800tcgcccaggc cggagtgcaa tggcacgatc ttggctcact gcaacctctg cctcccggat 175860acaagcgatt ctcatgcctt agcctcccga gtagctggga ttacaggcac ctgccaccac 175920atctggataa tttttgtact ttttttcttt ttcgagaccg tgtctcactc tgtcacccag 175980gctggagtgc agtggcatga actcggctca ctgcaacttc cacctcctgg gttcaagcca 176040ttctcctgcc tcagcctcct gagtagctgg gagtacaggc acacgccacc atgccaggtt 176100aatttttgta ttcttagtaa agatagggtt tcagcatgtt ggccaggttg gtctcaaact 176160cttgacctca tgatccgccc gcctcagcct ctcaaagtgc tgggattaca ggcatgagcc 176220actgtgcccg gcctaatttt tgtattttta gtagagacag gattacacca tgttgaccag 176280gctggtctgg aactcctgac ctcaggtgat ctgcccacct tggcttccca aagtgctcgg 176340attataggca tgcgctaccg tgcccagccc aagttgtctg actcttaatt ctcagctttc 176400ttatttgtaa aatgaaggta ctagtactaa tttggagagt tgttaaagat taaataatat 176460atgtaaatgc cttggcataa gggactggca caaagtaggc acttcatata taaaagctgt 176520gattattgat gaaccagtag tgaggtacat aactggggaa ggagaagggg ccagtttgtg 176580ggaatgcttt tttagttatt aatagtaagg tggtaaaata ataatagtaa taataaccaa 176640aagttactga aaactaaata cagtgctaaa ctctttaaaa ggagtatcta attggatctt 176700aacaacaaag ctatgaagca ggactaatgt tatctcattt tataaatgag gaaatgtaag 176760atcaaacagg ttaagaaact ttcccaagtt gatcagtagc aaagacagga ttcgaaccaa 176820ggtaattgtc ctatcagaaa ctgtactagg atagtctgca tttcatggta aagactatca 176880gatgccacta aaacttttta aaaagggaag tcttgtggtc aaatttgctc tttagaaggc 176940agtatggagt gcagatcaga tgctggcagc agggagatca gttagaagat ggttgctcta 177000attcagttga gaaatactga gacatctgaa atattgaaga catcagtagt gtgggtgatg 177060tgaaagtggt tctaagaaac tagcggcaat catccttcat tactgattgg gcgtggagag 177120aaagagaggt agcattggta gccgttagtc aactctgagt gcaggcactg gcatgtgcat 177180tattacccag ggctctaagt ggagaaagaa aacaacccca gggtgtcttc aaacctaaag 177240catatttcct aagcctttgc actctcagtc tagactaaaa acaaacaaag cagcctcctc 177300tgaaatgctg gaaactttcc ccacttgaaa ctctcagatc tcttaccttg caattctagc 177360tttcaaattc caagctgagc ttcctttccc acaccccgag tccttgtact ggggattaca 177420atgatcattt gtatgtacta ggtgattgtt ccttccacat caggggcctt ggagcggatg 177480acctaaagct gctttctcct gtcctgactt tctccaccca gcactgcaac catacataca 177540attttctggt cttgtagaga atgactgact ggtcattata gtcttccaaa aggataagag 177600attagtgtca tgatgtggcc ttcaggcagc cagggggaat ctccatatga ggtacttgtt 177660gactgtatta cttagtttta ggtgaacttc ctgtggaggg acaatatgtg cttagaagga 177720cagagaagga atgtattagg taaggcattc tacatctcag ataaagaact tcaatgaatt 177780gttgggtcaa ggtctaagaa acaaaccagc cgtcaatggg aaagttaact aaaatgaaga 177840acccaacata caaccccaaa tcctagtttt tctgactatg ttttcttaaa ctgaaataat 177900ttctgagatt aaaaagaagt tgctgtgact ttgtctgata gatgtatttt tttgttatat 177960attagtttgg gccttctatc tctcctactt tgttttcttt ataatagaat taatctctga 178020aaagtaactt tactgtattc tgatgctcca ttttgaataa gtcagttctt ctccgaatgg 178080gctctggaga ttggcatttg attgaacagc ttttgtgtat tgattgtttt aggtagactg 178140ggtactccat ttaacttagt atttctgaca ataaatcagt cgagaaggga gtattactct 178200aacggtttga acacttgtct atgcacattg cttggtcatt caataagtag ttattggtga 178260gatcgggcac gttcagggtg gtatggccat agacaataaa tggttacgac tctgccttca 178320gctgtaccag tatttaagtt ataaggtagt taagttacac cagtgcaaaa tcatacagtt 178380tggtcacagt cctacttgag gatctcaaac ctagctcccc ttaacaaaca tggaggctta 178440atcttggctt tgcacactga attattcctt tagaaaaata cttggtgtac aactcatcct 178500tttcatttac aaagaaacaa atttgagcag tttcacaatt taaaaagtct cccaaatgga 178560ttatatttaa ttgtccattt ccaatgaaac tcactaaatt ggtaaatagc agtgagtgaa 178620taactgatga ggtcatactt tcttgttttg gactactaca aacaccacgg agcaacaaca 178680gattagaata taaaggttaa gcaagggttt agtttttgtt caaaagccgt tttgcttgtt 178740acaaaggcta ccaaaccttt gaacatcaga ccaaaccaaa aacaaaacaa aacaaaataa 178800aaaaaacccc aaaactgaaa gatgaaaaca tagtttgata atctaagctg ctcttccttt 178860atttaacctt gaatttatga gattattttt ttccccagaa gaaaaattct cttagggaca 178920ctttcagcaa tttaacattt tctaagcatt acagcaaata agaggcgatc atcattcttc 178980agtcataaag ataagccaag gaatgaaagt gttttgcagg tcatgtcacc tgacagaaac 179040tttggactgg tcctttcctg gttcaagagt tcagccataa tacctacttt ccctatcagc 179100tggctcaagc tgataaggtc ctgaagcaag caaagcttct ttatgagctt ttatttaatt 179160gtccttgcca cataagggtt gaggggattc gtctgtacag agttacttct tgttggtcta 179220ttttttcttt ggaataaatc gctgtctccc ctgactggat agagtaaata gagtttgttt 179280aaacactttt catcaaattc ctagtgccta gtacagagct tttaacccta atacgtttcc 179340tgcgtgtact tattgaagga ataatgacaa actctgcctt agattggtga ctggctaggg 179400agaaacatgg ttcaagagct gaataagtaa gagcaagtat tttattgtat gcccatcaaa 179460tgtattcgat gctggtgatg gaggtaagag tgtgatagag gctgagttct ctgaaattac 179520atatgagatg tcatctgcca tttagtatta gctgtgtctg tcttttttcc aggaatttgg 179580ccttaaaaga gatcattcaa aagtattacc caaatagtga tttatcaggc tttattgtgg 179640ggaacctaaa gtggattgca actgctatgg tccctttgaa gggagctggt gcaagatttt 179700ccatgcctaa tcacactcat tttcccttgc tctcccaatg acctcccatc tttccttcta 179760tttggtctga taaacaccaa caataggatc ctttctgcag cttccatcct aacttgtatt 179820ctagccttaa cactgcaaca aactcactgt tacctagaag tcaattgact tccctgaatg 179880ttagcttctt tagctgtaaa taagtaattg tatgaggtga tggttaaggt gatttactaa 179940ttttacaatt ctattatttt atgaatagac cctagttagg atagtttgaa atagatactt 180000aatccactat tattctctct tctaagatat agttactagt tgatcatact tttccttaaa 180060ggctgaactg aattctctga tatcagcaac taaacatctc atatttgtca gtatgaacat 180120ccactgggtg cctgttattt aaccaggtag aattcttagc tgtgattgaa aatctaggta 180180tctcttctgg tactatcact tggatgagta aagtttgaaa accattaagt tgacatttct 180240aataggactg tggatttaac atagattccc agaagtcttg gaatacaaca gtgtacacag 180300atgaagatac agtacttttt ggtattttct ttttgcaagt gttacaaata tctgcatgtc 180360ataacatcat cactatggat cccatctttt aatgagagct tagtatatgc tacacactgt 180420cactaaacat gtaggatctt gtttagtttt ctcaaaatgt tgtagttact atgattattt 180480tttgtgtctt gcaatcattg tgtataagtg cgtaaaccat gtatctagag tttatagaag 180540aattaaaatt caaaaaccct atactcatct ctcattttta aaaaatacca ttttacctgt 180600ctttagatgc cctgtatttc ctccccaatc tcatcccgct cctactcttg aaagtgatca 180660ctatccaaat tttgtgccaa acattaactt gttttcttta gctttgccat ctatgtatgt 180720atccctaggt aatacatggc ttagttacac ttgtttttaa atttgatgta aatgtaatcc 180780tatagtatga attttctaag acttgattaa tctatgaaca ttttattttg agattcatca 180840atattgatgt gtgtagctat agtttattca ttgctgttgc tgaaaaatat tctattggat 180900gactttgcta caatttattc taccattgtt ggatatttga gttgttccca ttttatttat 180960ttattttatt tttttgctgt tatgaacaat gtggctttga acattcttat actacctggc 181020gtgtatatgt atgtatctgt ctgtctgttc atcttaagat gcactacaaa actgaggcct 181080agagtcacca agcaacttgt ttaatgtcag agtgagttgg tggtgaggcc aaagtctgaa 181140ttcagcagtc tgttaccata gttttcatcc ttaaccacaa tactctatga atccttattt 181200taaaaaggaa ggtctggaga atttaaaata acttcctaaa gagcagggat tcaacaaagc 181260tcagtctgac taatgccttc catttttaaa aaatcaccca aagcacatat tatgattcta 181320tttgtgaagt attagctaat tacaagagaa tgagttcata cttggcacta ctatctcttt 181380cttacaagtg atcagatgtc aaaatgtgaa aactatacat ttcacattat ccatatatat 181440gtgacatttt tcctttagga atatgagtag aaatagaaag acaggttttt acagtgaaat 181500agattttttt tctctctctt tagcctacca aatctctttc gcaataccta acacttataa 181560atgcatttaa tttcagtgcc aattaaagaa attcgaaagt agataataag tgagacaagc 181620acccagtaaa tgtttatgat gtgacactga caaattatgg gctgctataa tcaagatagc 181680attaaaaatt ttaaagtgtt tgtatgaaca aaccattttg gaaggagtgt ttggtgtggc 181740agtgagcaaa acaacccagt aactatggca gttagtgtta aagctctgat tttgacatga 181800aaggaataaa aatggaagtc cagctaaatc acaagtgtcc tggagaaact tggatgagtt 181860tcttggctag aggtttttcc caccacagta agtattttca aaggaaaaca aagtaaaatt 181920tttctcttgt atgagtcaca tctctgttgg ttgtaagtgg ctgaaactca tcttgaacta 181980ccaaggtaag agaagaaaca tactggttaa tggaattcca gaaaggactg aacaatcaaa 182040ccattttgaa ggacagcata gagctggact ctagaacagc caaaacaagg ggttaaacca 182100ctgcgaggga tctctctcca actcttgctc aggcttttct ccctggcttg actttcttct 182160ctttcactgt agattggctt ctctcacatg gcaagaaaca ttgctgctag cacttcccga 182220gttctacgtt ctacaacatc caccactggt gagagattaa cttatggttt ttctgttgaa 182280aagtcaaaaa ttacctggga aaagtctgat tgtctcagat tggagatgtt gcccatctct 182340ggaccaatac actattatgt gtggctgact atataaaaac atggatattt tcttggaatc 182400acttggtttg actgggagaa gaccattctc aaaacaaagg aagtgcaatt tatagaaggt 182460agtagaatag gcagataaaa caataattct tcactatatt gctcaaataa tccccatgac 182520atttttagta tattataaag agagttctaa agtgtttcca aactattata gcaaaattta 182580atcttataat aatttcttct tgaactatgt ataatttacc tgaaatattt tccaaaaagc 182640aatcaatgtg agaaaatgag agccctgtct tcttaaaaaa atgagtaaaa gtccacaagt 182700tcagaacaaa agaaaatgag gtaaggccta aaataaattg tgctaagaaa gctaaaattc 182760tagacaaagt cacatcggca aaactagaag gttggtactg tgcttcagtt tactgcttgc 182820tgtttggtta agaggagggg tgatgtgata aaaatagtga cgaagtgaga aaactgacgt 182880attagttttc tattgcatta taacaagtca ccacaaactt agaggtttga aataacgccc 182940atgtattatc tcgcagttcc tgtgtgtcag acctccaggc actgcgtggc tcggctgggt 183000tctctgctta gaatctcaca ggtcaaaatc aaagtatcaa tgggagctgc agttctccca 183060agctggagcc tgtgtccctt ttaaactctc aggctgctgg cataatttat ttccttatca 183120agccatccat atgatcccct ccatcttcag gccagcaatg gcctgtcaaa tccttctcat 183180tctttgaaaa tctctgactt ccctttctgt cacagctctg taacttcttt tctcttctgc 183240caccagcaga agaggctttt aagagtttat gggattagat tacatccgtc tggataatct 183300tttacttaaa ggtcaactat gctatataac atagccaatc acattcgcac attgcagaga 183360ctagggtata aaatcttcgg ggtcattcct agaaattctg cctgctgcag cctggtttct 183420tgcttggact ctagtatata tttgctaaat ctcccaagcc tcagtctcac tatttgcaaa 183480agtgagtttt aatgctcttt gccctgcttg cctcacagga tcttaacata gacgtaagat 183540caaatgcaat agcatgtcaa acaatgtgta actccagtta tacaaacatt actgtatctc 183600attggggata cgaagctcta cacacttgaa gatggtgaag gaatataaaa atgtaagtat 183660tgcttttata ataaatgtgt tcctattggc tgaaaatttc aatatctgat acaaatagtc 183720aactttctat tttacttttt ctaattatgc aagaccttgt aatcacaaat gtaaaaattg 183780caagccacat gcccctaagg ccaaataaaa atttgtaaaa ttctcttaaa aagactctat 183840agagtccaaa tgaaaatacg tcgagtcctt ttaaaaggat ccaaccacat atatcaactg 183900atatacatgg taccaaaaac aatggaatct tttcagattc tctaattggc ctttggaact 183960tatgtagcat caggtatgca aatgaacaac ttcagacctt gattactcca acctcctctc 184020ccactgtcac agccacttct gtcatgacct agttgttctc agaaagttcc ctcttatacc 184080tggtcaaact tctcttacaa tcacctgtga ctttccctct tggtcttgga tcaaatcatc 184140ctaaatacat taaaagtcct gattcttcct gtcccttaaa tatatctcta cttgaatcac 184200tgtgttagtt caggtcctct gagagaaaga tgttaagatg aaattagatg tgcaagagat 184260tcgccgaggt aaaccttgtg ggagaaaatg gagaggtaca tagaggagcc tgggcagact 184320gtgtggctac tatgtaagac tcatccccat gaaggagaaa ggagaggaag gcaaagaaga 184380aaaaccttaa gatttcaatt ctaagaacgt tttgacaaag ctgattagga gtatttaagg 184440caaagctgcc caccagaaga gtactgcatc tttcaggaac ggacttgctt tagtacatct 184500gctgtgctta gtaattggct gggagcagcc atagaaagca tggactcagt acaaacttgg 184560tgatgaattt cagaggcagc ggctaagacc atcagtctat tattttcctt gcaatagctg 184620tcataattac tatcagagca aacaattttt tgtgtgtgaa ttcatgagat aatggtcttt 184680tctttcctgc tttcaagagc catgtcattg aaagagctaa tcattcaaat ttatgctgca 184740ttactgacta aatactttca tttatcatac tttattttaa aatactttaa ctcatggccc 184800gatgattttc agttaaccaa attctccctt actatcctgg ttgccccttc tgtcttttcc 184860ttagaaatgt tattgtagta tttgcaagat ggcctgaatc ctgaaccccc catcttcaat 184920gagcaccaaa tggtaattat agattcccag ctgtagagct atgtcagaca aaggaaactt 184980cattagtatg taccaatgtt tggactccaa atgcttttgt gtctgagtca caaggactcc 185040tcttccttgg tggcttaaag ttaggctgaa gaagatttac attatgttgt gcatgacctc 185100tttagtttgg ttctacttat actttcaagg agggaagact ggggaaggtg tcccttagtg 185160agcatatttt gtacaaatga aaacagggta ctaacactta tgccaggacg catgcataaa 185220ctaggatggt tctgagaaaa ctgcgatata tgatcactcc agggtctccc ctctcagaag 185280cgagggagac ttaaaccttt tacatcacca agtacatgga aagaaagaca gcagggaagt 185340gattccgaag agaaacctga aaaaagcaat gtggaaagat agacacttta gccttttctt 185400tcttctcaaa acttcacatt ccttttcact ctgcttcact taagctgccc tagttccaga 185460gtgtttcctc tcttgggtga agatgggaac aagtacatgg ggtagcaagg ggtgggtggg 185520acctgtgctc ccattaaggt tcttccagaa tcatttctat gtgattatca gcttggatca 185580catggacttg gggattattg gtggttttct agggtaaaca gggcatattg tgctggagga 185640catattttat atgtaacaat ttggggaaat tttcttttat attaaataaa actgagatat 185700gtaatgaatt aggatgaaaa attcatattc atctgaattt tataagtgaa tcatgagaac 185760tcaaagatac ttagcccttg ggaccatttt ttactcctgt tcggatccct tcagctaagc 185820atgattattt actattttca gctattagtt atgtcttgtt gaaaaagtat gaaaagagct 185880gcccaataaa ttagagtgta tgctcaacat tctcttagct tctttatctc tttccaaaat 185940tggatcaaat gacattggac atgatcaact tcttactgtt ttgacaaaca tctgaggata 186000cttttataat tgataatttg gactagatta tgcaatgtgt gatgagacac aaggtagtct 186060gtactcccca tgatatgtat atctgtttga tatactcaaa cggtgtatat caaacggata 186120taagtttgag taggtatgga gatgagccag ggtttatttc ttcaactagt atttactgaa 186180tggtcttatg tgccacaact gttctggaaa ctgtgataca ttaattaaca gataaagcct 186240ttccctcaca atgcataaca gacccaacag agtatgaatg tacatacaaa ctagtaaata 186300agaaaacaaa taaaagtatt cagatagtgc tataactact gggatgaaaa tcgagcagga 186360aggaaaatat agcctgcttg atgtggaaga cagggatagc ctctctgagg aggtgacatt 186420tgacccaaga cctaaatgag gagaaggaga cagtgagatg aaaatgaggg aaacagcaat 186480ggcaaataca gagaacttga gacaacttgg cccattggag ggacagagac aaagccaatg 186540tgggaccaca ggggatgaaa gggaggctga ttggagaaat aggcagtgct gaggccataa 186600aaggtcctat aggtcatgga aagacatttg gttaccattc taatgacagt gagatgttac 186660tggggagttt taaactggag aatgtcataa ctgtccagat

gtaaccaaat agtaaaacca 186720ttcttcctga ataacttggc taaaaggaat attatgacta cagatgtaca tgaagattaa 186780gcagaacatg gaagaaaggc ctcaagtaaa cttgacctca cataaatatg ggaggaagat 186840caaatggaag ctgggagtgt tgaaagaatg taaggggaat gacttctaat aatgaacaaa 186900aagctgttat tttattatga agaaaaatgt tatgcatctt atgcatgcag aagaaattcc 186960cattcaaaag acttggaaaa tgtcttgggt gtttactata ataaaccttt taagatatag 187020aaaattcaca tatttagagc ttaatttcta aagagctcag acttctcagt ttattatatg 187080ctatgaaatt ttgtttattt ttaatttaac ctacttgtgt gcaaaatcaa taaggaagct 187140taaggaatat aaacaactat ttaacatggc catttaaata gattcaaagt aaagaatatc 187200agcatagtgt ttctttgata tgacaacccc tcctcccagg gcacttaaat gaagggttgg 187260gggggaatct taacctgaaa ttgaaaaccc tgaaatcatg tttccaagga aggagaagga 187320aaataggaaa aacaaaaaca aaaagcagca actcatttgg aagctcgtgg gagaggagag 187380gaggattcat acatctcgga ctggtttgcc ttagcaagtg aatcatttaa ataggaaaaa 187440acagggggct gactcagctt gagcaaactc ttgctatccc ctgctgaggt ccgcacttgc 187500tgtggcccct gccgctctcc tcggaccttg ctgccctcct cctttgtcac tgtggagaaa 187560caggaaggaa tgtttattag caagactgac tggggtcaca cccaaggcaa tatcaggttt 187620ttacctctcc caggcctggg aagaggttca aggatcaagg acaagctccc ggttagagtg 187680agaggcaagt tcaaaccttt gaaaaataaa ctcacaacca gcatttggca caggcctctg 187740gagtttacag aatgtatctg cctgtgtgtg atttcattag ttcctcctgc caatctaatg 187800agattttacg tcctgtaaca gtgaggcaat tggagtctca gcagggaaag gaacttgcct 187860aaaactgcag gatgggtagc gcttggatcc tgactttctg actcctagga ctgtgctgtc 187920ttcagatgat cacatgcctt cttggcagat gtttctaaca aaggagagag ttgcccaggg 187980tggggctctg ctagctccct tgtcatgagc cattctctcc acattgcctt ttagttgcac 188040cacatagtca ccttcaatta gctgtgcgaa taggctcact cttatgctaa catgtactaa 188100aagtgaaaat ggggagagag agagagagag agaaagagag acacacagag agagagactc 188160atattatggt atgttccctg ccccacccca ctccactccc tctcaacagg gagaaagtac 188220ctgaagaaaa tcattgctat gaagggcata gccagctaaa tgggtgtcac ttagtctgaa 188280aaatctcaaa gatgtcaata agccactcga gacaacaagg aacctgtttt cctgtcatca 188340ttccttctca gtccttggct ttgggaaggg taactttatg gagagagaag aacctctgtg 188400gagttaaaag gtttatgaac ttttttccct gcaacaaatc agtgacagct gttccacagg 188460ctgatggttt tccctttacc tttcgttttt taacagctat gtctcacagt ccagacttgg 188520agtacaagta ataagaagaa taaaacttaa tcccttaagt agattcacca taagttagct 188580cagagcaatt ccagtgcaag tatggtctgt gatccagtag gtgagtgact ctgctgctga 188640aattcacatg tatgtgaatt tcacagtggc ctttgctttg tagcatgctg taatcctttt 188700gtccattttc atcacacgaa ctgctgaata taggattgtt aaatggatgg ggagatatca 188760tgaaaatgat taaagaagaa agttcttatt taggggtgca tacctgccta tctgaccatt 188820gtacttaggc aatcgggatc ttgctttaag aaaaggtagg cattggagtc aggctgctgg 188880agtatgaatc actatgctat catttttcat ttgtttttgc tctgttacat taggaaagtt 188940atgtagaatt ttgtgcctca gtttcctcat tcaatatggg tgtaataact gtgcctgtct 189000tgtaggatta ttgtgaggcc caagtgcaat aatatatagt acactgtgtc tggcatctag 189060taagcattca ttaagatgac atgaagataa cacagatata tcttaacatg taattatgat 189120tttgcttatt caaggccaag cattccaatt taatggagtt aggcaaacac agtaaattca 189180ttgctctttc ctttttatgc tacttccttt gaagaggcag tcaagttcca tttgactgat 189240tcggaacttt ttagcaatgt atattatgct gacttcactc ttatgcgctc ttggggctat 189300aattcatcaa gttaggcgag caaagaagtg tgttggtgaa agagaaatga ggaagaacaa 189360ggaagaaaaa aagggtcatg agcttattca ctgccaatat ttattatatg gaacaatgac 189420catccttcag aagtgtttgt tctctattat actgtaggtg tggaagaatt atcattgctc 189480aatagctgtc tcagtcacta cctgatagac ttgggaggtc tggctatttc agggcgcatt 189540tgacatacag tgacattttt ggattaaagc tttcatgatg agtgccagtc tgggtccaaa 189600agggttgaaa gctgtcgcca tctataggct agttgtttgt agtaaaatac tttccctcac 189660tgcattaggt tcttggtacc atttatctag cagagttctt cagtgggctt gaggcttagc 189720agtcaagtta aaacaataac caacatccca aacccagtgg ctgtcaaatt tcagtgaggt 189780ggcatagaac tttagcatga acttgagctt gggttcagct agactttcat ataaatcctt 189840gtttgaagtt agtagctgtg tgatcttggg cactgatatt aaacctttat gagaaagtta 189900tgtctgaaat atgggaaata aaccttccac ttaggttgtt gtgaagattc aatgagttgt 189960aacgattgta tacactataa tgatctatat tacagttgtt tcataaatat gattgccttc 190020attttattct ttccttgtct cgttcttccc agtatcttac agacagcaag ttgaacattg 190080tgggatgcat gagctattga ggcctttgca gctttctgct acatggaggc tagggccaga 190140gtcaagattt atgctttgca gcacactggt cagctgtttt tgcaaatcag attaaatgat 190200ttttaaatga ggctgagagc atgggagata ctaatgtgtg tttccttgtg agctactgca 190260taagtaagtg ctttgtaaaa tgtcaggggc tccaggatta tatggtatta ctgtcactat 190320tgtaagcact tctacctttt ttttctcctt ttacaggtta ggaaattgaa atacagaaag 190380atgaaaagtg atttgcccaa gcatatagat caaagctgtg gcagaaccag gactggaacc 190440tatatctctc tactaatggt ttttttaaaa aaataacctt gtttcaaaaa tattaaaaag 190500tcacaagaaa ggtaaacatg tggataaaca aaatgaagaa aataaaaatt atccagtaat 190560aacatattgg catatgtctt tctggtatat tttcctgtgt tgtcatcatt atcatctcca 190620tcatcattat atccatcatt atcatcatca tcatcatcat catcatcatt atcatcacca 190680tagtgaacat gtaatgctta cctagtgcca gatgctgtct aggcatttta catgtgttac 190740tggtaactca tgtaatcctc ataacaacct tataaggtgg ttgctattat ccccatgtta 190800catatgaaga gacagaagca taaagaagtt gcaccgctgg taattggctg ggatttgaac 190860ttaagcagtc taaccttaga gtaatgattt taacaactat gctatataca tacaaattta 190920caaaataaaa ctgggctcag acaataaaaa cagctctctt ttcatgttat aatacttttt 190980caccccataa cacataatca ctaatgtttt aaagatcaaa acaatgcaca taaaatgtac 191040tggttttaaa aaaaagagga aatagccact tacctcaacc aaactaactt ggagatagat 191100tagattgata atggcaaggg tgatgggtag atgggtagag gttgctcaaa aagaaacaca 191160aaatatatcc tcttttaagg atcctgatgc tttgctcaaa gtaattttta ttcttttaaa 191220actaaaaaaa aactgtacaa aattcatagg gtacatagtg gcgctttgat atatataatg 191280tatagtgatc agatcagggt aattcgcata cccagtcatc ctatagtggg tatagaacac 191340cagaacttat tctttctatg tagctataat tttgtatcct ttaacaattc tctccctatc 191400cctcccttcc ccctactttt cctagcttct agtatcctct gttctacttt ttacttctat 191460gaaatcaact ttttcagctt ctgtatgtga gtgagaacat gcggtgttta gtaggaaatt 191520tctgttcctg gcttatttca cttaacacag tgtcctccaa gagcatccat ccaggatttt 191580attgcttttt atggcttaat agtatttcat tgtgtatata taccatattt tctttgtcca 191640ttcctttgtt tttggatgcc tggattgatt ctataacttg gctattgtga atagtactgc 191700aataaacatg gtctgtagat gtctctttga tataatgatt ttctttcctt tggataaatt 191760gctagtaatg ggattgctca atcataccat agtactattc gtagtttttt gaggaacctc 191820cattctgtcc tccatagtgg ttgtactagt ttacgttccc accaacagtg tataagaatt 191880cccttttctc caaatccctg ccagcatttg ttattttttt ttttttgtct ctttgacaat 191940agtcatccta actggggtga gatgatacct cattgcagct tcaattcaca tctccctgat 192000gattagggat gttgagcatt ttttcatata tttattggcc atttgtatgt gttcttttga 192060gaaacgtctg ttcagatcat tttcctactc tttaattaga ttgtttttac tgttgagatg 192120tttgagtccc ttatatattc tagatattaa tctcttgtca gatgagtagt ttgcaaatat 192180tttcttccat tctgtagttt gtatattcac tctgttgatt acttcctttg ctgtacaaaa 192240gctatttgga ttgatataat cccatttgtg tattttgttt gtgttaccta tgtttttaag 192300gtattattca gaaaattttt gcccagacca aggtcctgaa gcatttcttc tatgttttct 192360tctagtaatt ctatttttca tgtcttacat ttaggttttt gatccatttt gcaatgatat 192420ttatataggg tgagagacgg gaatctagtt taattcttct gcatatagat atccagtttt 192480cccagcacca ttcgttgagg agactgtcct ttacccactg agtgttcttg atatctttgt 192540taaaaatcag gtggttgtag atatgtggat taatttctgg gttctctatt ctgttctatt 192600gatctatgtg tctgttttta taccagtacc atgctatttt gtttactata gctttgtagt 192660atactttgat gtctggtagt gtgataactc cagctttgtt ctttttgctt aggattgctt 192720tggctgtttg gggtcttttg tggttccata taaattttag aatttttttt tctatttctg 192780tgaagaacgt cattagtatt ttgataggga ttgcattgaa tctataggtt gctttgggca 192840gcagatatct ttccatttgt ttatgtcctt ttccatttct ttcatcagta ttttgtagtt 192900ttagttgcag aggtctttca cctccttggt tacatttatt ccttggtatt ttattgtttt 192960cgtagctatt gtaaatggga ttgccttctt gattgctttt tcagctagtt cattgttcat 193020gtatagaaat actactgatt tttgtatatt gatatcgtat tctgcaactt tacagaattt 193080gttattagct ctgagttttt tggtagagtc attagatttt tctgtatata aaatcatgtc 193140atctgcaaac aggaacaatt tgacttcctc ctttccaatt tggatgtcct ttatttcttt 193200gtcttgccta gttgcttggg ctaggacttc cattactgtg ttgaataaga atgttaagag 193260tgggcatcct tgtcttgttt cagttcttag aggaaatgct agtgtagctg aggagagaaa 193320tgaaaacaga ataaaaactt cagtagaagt tggggagaaa tgtgtttgca ccaaaagagg 193380tgagggatgg aactgaggga ggtctcgagg ggtaagagag gccaaagagc tggcaggtgc 193440tgctattagg atggccaatg atccagaagt aatgatgaat gagaagatgg attaaaaaaa 193500ccctgacatt gtttaactag aagaagaaga cagtcagaga gaagtgaggg cttacttttc 193560atgtttaaag tctgttatgt ggtaaaggga ttagatttat ctgtgttgtt ccaggggaca 193620gaaataggac aaatggatgc aaatagagtg aggaagattt aaaacaaatg gagaagacat 193680tctaaaatca actacaatga gcgtaaacaa tgacaacgga aaggactatt tttgcaatta 193740tgtagctctt gttctctata gatagatgtg taagcagacg ctgaataacc atttactgaa 193800aatataaata aaaacaaagc aaattgcagg caataaatat tgtattagtt ctcattttgt 193860aaaacttata caggtatcat atgcatagac aaatacacca aactgatgaa tatttgcctt 193920gtataatctt tttgtagttt ttttatgaac atatattact caaacaattt agaacatttg 193980gcaatatata tatatttcat ttataaaagg ttaggaagat taattacact ttctgaggtc 194040gcaactaaaa gccaagattt taatccattt ctatttgatg taaagtctgg tcttttttca 194100gcaaaccaca atcccacatt ttaagggcat taagaaaggg atgggtagac aaaatgtaga 194160ggtagtaggt acagaataca aagtttcaag aaattaaaag cttctaaact aacaaacagc 194220caatttgtgg agtgtcactg gaaagtgaca aagaggacag ttaagttagt tggaactgaa 194280ctgaggccag acagggctgt gggacaagtc agggtgtggt cattccggta agcagcgatg 194340cagaatcaag acagagtagt ttctccttct ctctctctct ttaattgtaa cgccttttat 194400aacaaacaaa tattatgctt atttctgtct ttaaattttt tgtagtaatt tctcatcact 194460taacctctat tttttaaaaa actaactttt ctcttgtttt tctagttgag ctatcattca 194520tatttattat gtggaactag aggtagtcct ggctacttgg gaacagcgtg gagtctagcc 194580atgtcagggc cagaagtcgt ctcagctaag ttagaatgtg ataccattgt ttacacaagt 194640gtggcctgcc ttcaagatag ggtgaggtgt tttatgacca caggctttat gagttatagc 194700tataaaacaa tcaatctttt aaagcaaaca caccacaatg tctacacgca aatgagaatt 194760gtccttcagg gctgtgacct tgggaaactc ttcacacata ctagcataaa acatatttaa 194820actcttcact gaaaatatta ttcagaccta gtttctctct cagtctctct ctatgtttct 194880ctctcacatg tacgtgcatg cacgcacacg tgtgcacaca cacatatgct cacatcattt 194940taagatacat ctcattttta accaaaacca ttttatcttg cttgataacc aattttattt 195000gttagatgac ttggctataa atgcctttgg ctatcaggaa aatcaaatca aaattaaaag 195060acactgttac tactgaagaa gtaaaaaaag aatgggctgc tgactctgaa gatcataccc 195120gaagtagagc tgcaaagata tttggaatat tggtaatatc caataaagaa tgaccttcat 195180gctattttga ggagatgttt aaatgtcgaa ttattgaaat atttataaaa tacaaataaa 195240ctaactctgc ttcatattcc aacttgtgta tgacacttct taggctatca tttcattcca 195300aatttatggt cactacccta ctgtcattcc tcatactaac catatgatca acagttgaaa 195360agcagccact cgcagaggta agcaagatat atggtaaata ctgtgttgac aaaagtatgc 195420agaagcagtc acatttatac agtagtgaag gaaatgtaaa ttggacaaac tttttggaag 195480ataagttgag aatgtcaaaa atcaaaacac actttctgtt ttattcagca attatgagcc 195540ctttgtttta cagctatgct cacaaatata tacaaacatg tatgcacaat tatgttcact 195600gtggtattgc gctagaaaaa tactaaaaac aaaccaaatg ttcatcaata gggaaattgt 195660tcaacaaatt acagtatatc taaaaaaaga ataatatata acaactgaaa aaataaaata 195720gttgatataa gcagatattc caagatctgc cagacatatt gttaaacgaa aaatctagat 195780acaaaattgt ttatagttct ctttcatact atagccaaag aaaattcaga aaaaactact 195840tacagttgat ccttgaataa tgcagcaggt aggggcacca gcttcctgcg cagtcaagaa 195900ttgcatataa cttttgactc ccccaaaact ttgctaatag cctactgttg actggaagcc 195960ttatcaacaa catcaacagt tgattaacac tggaaaagga ggggttggtc ttactgtctc 196020aagggtggca aaggcggaag aaaagccacc tataagtgaa cccttgaagt tccaacctat 196080gtttttccag ggcaatcata catccatgtc catattcatg atgaatatgt gaaagggtac 196140ataagaaaat gtgatagtcg tttcctctgg agaataaaat gagaggtcta tcataggtga 196200gaaaataatt ttttattata tattcttttg taggtttatt tttttgtcat gtgtatgtat 196260tcttttcaaa ataataaaaa caataacaac gattaaaata tacaagggga aatgcattgg 196320ccaaggttta gttgagagca aagtttgctt atctttcgaa agaggtgaac taagcttttc 196380ctttttctct ttgggtatac ttgaatgggg atggagtaag tggattcttt tttttttttt 196440ttttttttga gacggagtct cgctcgccca ggccgactgc agtggcgcta tctcggctca 196500ctgcaaactc cgcctccgga gttcacgcca ttctcctgcc tcagcctccc gagtagctgg 196560gactacaggc gcccgccact gcacccggct aattttttgt atttttagta gagacggggt 196620ttcaccatgt tagccaggat ggcctggatc tcctgacctc gtgatcagcc cgcctcggcc 196680tcccaaagtg ctgggattac aggcgtgaga agtgagtgaa ttctaaggag tatcgagaac 196740agtgattaaa acagaaggtg gggaggtgtc ataagcttat ttgtaggtga agtattaaga 196800ctagaagaat gacattatgc atcaaatctt ttacattgtt tgatctcttt tacctaaaaa 196860caaaacaaga tacttttttg ttgtttgaca tatgaccaat tagcagccag ttggagctaa 196920atgttttctt ttttcttttt cttttctttt tttagatgta gtgtcactct gtcgcccagg 196980ctggagtgca gtggcgtgat ctcggctcac tgcaacctct gctacccagg ttcaagcgat 197040tctcctgcct cagcctccca aggagctggg attgcaggca cctgccacca cgcccagcta 197100atttttgtag ttttggtaga gatggtgttt caccattttg gccaggctgg tcttaaactc 197160ctgaccttgt gatccacctg ccttcgcctc ccaaagtgct ggtattacag gcatgagcca 197220ctgtgcccag cctaaatgtt ttctttaaaa gcaaggtaag tatgcctaga tgcactgcct 197280cttagtaatt tttgaggatg gattattcat taaattgctt ccctttctca cagctggtga 197340attagaacga tagtgagctt acaagagctt taacgaggaa aagatggtca ttgtttaaca 197400gagaaggatg gtttgggtga gcatttttgt gtttttggag gggaactttg agggcaatga 197460gtgttgcacc tgtgtccact gaggatctct gggcggggta aaaggaaggc agggatgaga 197520gtgaggaagg gagacaggag ggtcccaaat acgaactttg acttaacgag gatgattact 197580agaagggaaa gattgtggat tcattgatga gatgttgaac catgaaaact ctaattgtag 197640aactcacttc agactgaatt gacttggctt tcagtagcag aagccctttg tctacttctc 197700tagtattgaa gtgaatgcaa atttctcaat gtaagaaaag tagagtggtg aaataagagt 197760gtgggttcca gggtcagaca actgggtgca taaaaagggt aaggatgcta caactggtaa 197820gccctgtgag aattatttaa tccttccatg tctcattccg ctcatctgga aaatgatgat 197880catactaact tatgagatgt gtgtacagac tagatataat attaaaacat ttctgatacc 197940tatgcattat attggatcaa tatatatttg caataaatga tcaacttttt attaatgaag 198000ttagtactta tttcataacg agattgttta cttctaattt actagtattg tcattattac 198060tgttgctgtt atactgctac tgctgttgct actaactctt tatgaagtac ctaatatgct 198120ctaagccttg ctctaggtgt tgtatatgaa gtatttctaa acctgaaaac tatctaagat 198180ggctcagtct agcccatttt atagacgaag actgaagcca agagagttga aataatgagt 198240aaagttgaga tttgactttg tcttccaaac aactagaagc ataaagcaat ggaccaggtt 198300ccaaagtgac agggaggggc attagtttgg cccataggct gcagagcctg tgaccacaga 198360gccctatata ttccagtggt gaattatgtt tgggaatgtg gcagaccata tggctatggc 198420atcgttagac atgaggtgga gagaggcaga tgtgtggtta ctcgattgag ttgagagatg 198480ccatggaaag gaggaagaag agcctgagag agcaacttca ctcatgggga gagaagctta 198540tgtggagata agcttcactt cactaatggg gagataagct tcacttatgg ggagacaagt 198600aaggaagcag ggatctccag aggatgtgga gtatgcctgg tactttcatt gttctttttc 198660cttattcttc tttattcttt tcattatttt acctaggtta gatgttaaac acttcctgtt 198720gtttagtcag gcttcctttt ctaattataa gactaaacac taagatttca tttgtagata 198780taattattag agaattttga taaaatttcc aagcagtgtt ccctctgttt atcatcgtgt 198840tccctgctgt tattagttca cagtttggtc tggaattact ccagttaatc ttggggtttc 198900aggagagaaa ttgtgctcag ggtacatgag aagagaaagt ttagaaagcg aagggcttcc 198960ctgtctagtt tctagctcag aaaagcaaag atattctact ttcatatgta tgataattgg 199020agctgagctg actttaaaaa cagataattt ttctttttta tccctaataa ataatggtgc 199080ttacagcaat gagtgttgct ggtaacagat tccaccaatg ggtgtggtgt gaagtttagc 199140atttgtggat tttgcagctt ctgctattgt ctacagcatt tcctctcttg tctcggaggt 199200tcatactttc tcaggcaagg acacttttaa ctccagataa atgtctgggt tttctcactc 199260caaggataag aaggtggggg tgatggagtg gtggtggtag ttgtggagtt gtcttcctgg 199320cagggatttc attgtggggg aaagtctgtc tttagaaaag aaatgtaaac tgggcaagta 199380gtctcatcag ttaaatgatt tccttgttga cataaggtga ggaaaagaag aacaactttt 199440gggaaaagta actgtgagaa tacaagggaa gaagaaaaat aaggggttga acattgagga 199500agacttatga gacagataaa gtataaaggc aggtaatttg ttctttcaat ttggcatggg 199560gacagtaaaa attttttctt actaaacaaa taaagcccat gtatttcttc tgctctggga 199620gcaccaatta tattgagcct ctaaataaag aaagtcaaca tccacaagtg ttctaaattc 199680catctcgtag tgagagtcct gaaaattgca atagctagag tcaatacttg gagtatatgc 199740ataagacgtg gtgtctcaaa taggattaag gcctactctt ggcatcttct gttattggtg 199800ttgtttctct gtattgattg gtataacgtt agacaaaact gcaggtcatc tttgagaaaa 199860actcagtata aacaatgaaa aaaatgtgta gctgcacatg taatttgcat gtaacaaaac 199920caaaggatgc tttagatagt aacagcagcc tgtactttac tccaacccat tagttttatg 199980ataaatgtgg tctggggaag tgctcgatct aggttgttca ctttgtgttt ttgtttcttt 200040ctatcattcg ggtgttgagt cacctgtttg tctgtgtcag tgtcagagca ctgggtcaca 200100tcctgcattg tccaggtttt attggtccct ttcttaaatt aaagctgatt ttccacttaa 200160agagaattct gtctccttct gcaattgttc aaagtctagc atctcaagtg cagactctaa 200220actgtatgta tatgtattgt gcaggctatc tatcttctta gctttgaatt ctctagaaat 200280attccagagg tgtgattcct ctgttattca agagtgattt ccaaattgcc tcagccaatg 200340tgcctgcaca agttgtttgt aactcagggt gtaatgggaa atgctttaga gccacatttg 200400tggcttttga tgggaaaaaa aaaaaatcag tgtcctccta agacttatac agtccttgaa 200460gccttttagg ctattcctgc atctcatgtt gcatccatac ggactattta gccatattca 200520acaccatcct cttgctattt tgttaagatt tgactgttgt tgttgttgtt tttaaatata 200580aatgtgtgat cacatgcaca tacacagaca atgatgtgta actcataaac atgaaaagta 200640aaaatttgaa ttttaactga agaaaaatca gcattattca taaaaagctg gtaagatatt 200700ctaaaagtgg aaattcatgc agaaaattga ttcttaagca cttactaaat gccaggaata 200760ttttaccagc atattatcat ttaattttta aacaagtttg agagatagag atgtcttatt 200820ttatagaaga ggcaactggg gttctgaaat gtgaaataac ttgcaaaggc tatggttaag 200880ggcagggcca gccacgtgtc tagtgtctct gacacctgag atcacacact gtatgctggg 200940cttcaattaa tttgcagcta cttgttgcat taaattcaca atccttgctt tcatcataat 201000aaaaacaata ataatcatac aacacaacta ttttcagtga gctctggcta aggccatttg 201060attcagagtc aaaaccttct atttgtatag tattttatat tgtcaaaatc taataaggat 201120agttttcata tctgacgtaa accaaactga tctgtctcca tttgatatag tgacatatca 201180aattgttact ttcatatatc ttagtcaacc tctatgttta tcattctcta tgttttagaa 201240agtaaagaat ttaaaattac ttcagaaaga tttcttcttc ataaacataa aatgattaga 201300tgtccctttt aaaggcaaca gcttcttctt tttctttttt cttttctttt tttttttttt 201360tttttttgag aaggagtctg gctctgccgc ccaggctgga gtgcagtggc gccatctcga 201420ctcactgcaa gctccacctc ccgggtttaa gccattctcc tgcctcagcc tcccgagtag 201480ctgggactgc aggcgcctgc cactacgcct ggctaatttt tcgtattttt agtagagacg 201540gcgtttcacc gtgttagcca ggatggtctg gatctcctga cctcgtgatc cgcccgcctt 201600ggcctcccaa agtgctggga taacaggcgt gagccaccgc gcccggccaa ggcaacagtt 201660tcttaatgag agagtagaaa tgagaattca cattcataac aaagagttta ttgtctttcc 201720tagtatactg tactatctag tagctaatct gtctaaagac

atgtttctta tctattaata 201780gtcctattaa taatgtaaag tagctttaga tatgccaagc tgttactggc tggggaacta 201840aaaaagcttc cagagttata tctagaaagt ctttggggtt tcttaatgtt atgtgattag 201900caactaaaac tgtgacagga aggaagtcca catgaattga gcatctacta gtttcaagat 201960ttatcattat gcacattact tataataact ttgtgaagct gatattaact ttacaatgga 202020taaaaagata gatgaattag taatttacct ccagtggtgc agacagcagg atttgaattt 202080agtctgtcca acaccaaagc ctccgtactt ttcattaccc tgcatccatc tagtttaaaa 202140aataaatgta ctaggcatag tggcttgcac ctgcaatccc agctgcttgg gaggttgagg 202200ccagaggatc acttgagccc agaagttcaa ggctgcagtg agttatgagc acacaactgc 202260actccagcct gggtgataga cagaccccat ctcaaaaaaa aaaaaaaaaa aaaaaaaaga 202320gagagagaaa ataaaagaaa aatcgaatgt attgcatttc atgtctggac cacctgtatg 202380agaaaattgg gcactttctc tctgaagtaa ctcatactaa aaacaaacac cttcttcctc 202440ccaggagctt cccaaggttg aagagaggaa ccctgaagct ctaatatgcc taagatgctc 202500tctggtgtta tctaaaatca aaatatatca cctagagcac ttatttattt atttatttat 202560ttttgagatg gagtctagct ctatcaccca ggctggagtg caatggcatg atctcggctc 202620actgcaacct ccgcctccca ggttcaagcc attctcctgc ctcagcctct gggattatag 202680gtgcacgcca ccatggccgg ctaatttttg tatttttagt agagatgggg tttcaccatg 202740ttggtcaggc tggtctcgaa ctcctgacct cgtgatccgc ccaccttggc ctcctgaagt 202800gctgggatta caggcgtgag ccaccacgcc cggccagagc actttttttt cttaattttt 202860tatgatggaa aatttcaagc atacattaag tagagaaaat agtataatga acaactgaat 202920acttaaatct ggcttcaata atttctaatt ttatgttctg tctaatgttg acataaagta 202980tagtttgtat gtatttggtg gtgagtacat aatgggccac atgattttta ccttttaggc 203040tgtagttcta catcagtata agatggttgt ttttttcttc caatacaaaa tctaaagcgt 203100tgtcggcagt gacattttta aaaacacaat atgagacgca acaataaatc agttattaaa 203160ataagataaa gtaggtatat aaatatttca ccttggaaat aaagcaaagt cagtggaaga 203220gtgtgaagac tgtgaagatt aggagcatga aaataaacga ctattgggag ccattctatt 203280cccatgagtg aatgtgtatt ggttccattc aatgtaggga agagcagtaa aagggaataa 203340ccataaggat aagaccactg gattatctga gagccacagt tgtcctttgc cacatggagc 203400atctgcccta ggtattacag ctctgtgaga aacagaggtt caaggaaaga aatttgttat 203460ttttcaatta tctgcataaa ttctttggaa caggggcatg gattataaaa gatgtaagat 203520aataaaaagc atttgtattt gactttggaa tgtattgtac ttacatttgt ctagaggtgt 203580gtctattctg gctattctct ttaaaggagc cattctatcg tgaacagatc ctgttggagc 203640tgttttcttg ttctaccaac cttcagccac ctctctgtct ttcatattac ttattggcag 203700ggtttcaaaa ggttttagtc cttacttaat ataaacaaaa atgtacaata ttgacaaagt 203760ttcagttaag cagatgaaat tctaagagtt aagctgggat tttccaaaat aatcctgtta 203820acagacttga aagcacttat cagttctgtc taatgaagac attagaacac cataaccttt 203880ccggcccatt ttctttgtca ataagcgttc ttgccctgtc agcagctcac ctccagcttt 203940agttttctca tgacagtaag tctattaccc tcctgatctg tcttctggct cctcctaccc 204000aggatgggga aggtttttga ctttactgat attctcagaa caaattttgg gaagtaaata 204060taaggttttc cagtcgggtg cagtggctca cgcctatgat cccagcgctt tgggaaacca 204120aggtgggtgg atcacctgag gtcaggagtt tgagaccagc ttggccaata aggtgaaacc 204180ccatctctac aaaaattagt tgggcgtggt ggcggcacct gtaaatccag ctactcagga 204240ggctgaggca agaggattgc ttgaatctgg gagccggagg ttgaagtgaa ctgagattgg 204300gccactgcat tctagcctgg gcgacaagag tgaagctcca tctcaaaaaa aaaaaaaaag 204360atgaggtttt ccttaagagc actaacctag tatactgcac aggtgcctgt attcatgcat 204420cccacacaga aagagaaaat acttgtctga acttgtccat aaattcagaa tcctgcccct 204480taacttgtat gccaggtttc tggcatactc ttatctgaaa actcactcta ttagaaaagc 204540aaagcacagt gattttccca tcctgattac ctggcactgt tttttatttc agtgcttctg 204600tttctttgcc atgtaaatgc ctgtgatttg ccaggtcatt tgtcctgatt ttagttgaaa 204660cagtgcagtc atcatacttg cagaatgata caaaataata taaaatatat tgcctttgta 204720ctaaacagaa gtgcctctct gttggtgaaa taatacatat aaacaaaaat aataattagt 204780gatacttatt gtgtgttcac tatctactag cactgtattg agtgctttac ctgcattgct 204840tcattttctc ctcacaatat ccctattagg taaattcagt tataattccc attttacaga 204900tgggggcatt gaggcttgat gaggttagtt aacctgcttc atggtagtaa aagcagagct 204960tggatttgag cacagcatga atgactccag aacttacaca cacacaccca ctcacacaca 205020tgcaaagaga gagagagaga gagagagaca actgctgaac atagacccaa ggcaaaatat 205080ccttgagtag aggaacagtg tgagagtgaa gctgtagtgc tggttggggt taatcaggat 205140gggctcactg ggcaagacca ggttgtgggg ggcaaaggag atggaaaatt gtgtgaagag 205200aagaagggtg gactaggtag ataaaggtag tggactaggt aaataaaggt ggtaattcag 205260acatccactt taggcttcaa atcactttag gagaagtggt ggtctattgc tttgcccttt 205320agtagcaaca tgcttattat acaatttaat aagattctat ccaatacact gttttaaggg 205380ctcccatctc ccggattaga gctgagttct aacttccttt tccaatgata atgatctgag 205440aaatttcctt catgttgcac tttttttttc tgaagacttg acattgatgg aaagaagtga 205500aacccaccta tgcttttgat tttggtgact aatattaatt gtcatgtatt actaatagtg 205560aatctgcatt tttaaagtct tgttggaaag cacattaggt gtgtatataa aggtattaac 205620cttgaaagta tgaacgtgtt ttctataatt agtcctatga taatttaaaa tttaacatgt 205680gcttgacaca tttgataaag gctttgtcta ctatggtttt atttatggtt gttaattaag 205740taggagcagc agcatactac ttgaaagtat gaaggtgtcc tctatagtta gtcctatgat 205800aatttaaaat ttaacaggta cttgacacat ttgataaagg ctttgtctac tatggtttta 205860ttggaataga caacttatct tttcttaaag tatattttac cttggtacca ggaaacttga 205920gaccaaggta aaatgtaata ctttaaaaaa tgcctaaata ggaactgtca tatatagtta 205980tatttagggt tgattcatat tttgaaatat attctagaat ataaaaacta ctatatttta 206040caattacttt accaagctct ctaataatac ctgtttacct ttaaaatctt ggtctttccc 206100acagaggaca agttattata tttttaattg ttaagccttc tgatcatatg aattcttttc 206160atatttcatt gaaattatat aaaacatttt acttcaaagg aaaaatgtta tgaatttata 206220atgcttttag aatttaaaaa tctgtttcct attttgttga ttaagacaga gaagcattgc 206280ttgtgaataa atagcatgct atgttgaaaa gaaaattaag gatcctgatg tttctctgcc 206340agataggaca aaaactaagg acgccacagg aatttttcaa catttttaac ctcttgacaa 206400tatgtgggtc gtataaagga caaatgaatg tttggatgga ctgagaatgc caattttaac 206460agattgtcca atcactgtag ataaatattt gtgttcctgg ggattatctg attattatca 206520agcaaattga attggaaaca tagcatgtat taagtcatta ctacttattg tctagttctt 206580tttctcatag aagtgtctat gtactagaag agcactaagt catcagttag acatgatctt 206640tatcatatcc agacaaaaat aaaaaccttt taagaagcta ctttacaaga caactgcata 206700gctttcttca caggaacttg ttaaataaat aatgattatt aaagcaattg ggtcagtctc 206760ttacactaat ttaacaagag cagttccaag atgtctagcc cattccacat tccgtgtgac 206820taaccatggt atccagagct tggaaaatat ccaggcaacc cacagtagct tttcttaaat 206880gcattatgga cactggaatg taaggaaagt gatagaacta ggtgaacaag aagagagtct 206940ttaaggcata cccattgtca gtgtcgtaaa tggcctcaat tgtatgttga acattgttca 207000aaagtaccca tggctgaaac agtgtagatt tagctcctat ctgtattgaa gttgataaat 207060gcataaatct taatcattga catggaggtt tattgtattc aatgagacag atatacttgg 207120agttttccac aaaccaccaa taagagtcta ttgtgaattg gaatgattag cttttaaaga 207180tgtatacatg ttaaccaccc ttttatatta agttggtgca caagtaattg tgctttcaac 207240ggcaaaaacc acaattactt gtgcaccaac ctaatactta cagttatgcc aagatagggg 207300tagaagcaga aggaaaattt agagtgagaa gatagagaca agagataggg aggacaggaa 207360ttgagtcaaa caaagattct ggaaagtctg tgattaattc tgtggttgtt aattaagtag 207420gagcagcaga tattataaaa ctcaatatac aagtggtcaa gttcaggaag agccaaggag 207480gagaccagtt gatattctag gtccatgttt cttgtaagca aagtttggaa accagaactt 207540tggatctgtt tcaagagccc aaggtaagag gctttagaat aaagtctaac ccaggccaag 207600aatctgggta acagaaccag ggatctccta gggcactagc actaactggt ggccaaggca 207660agtacttcta catttcctgc tttgagtcca aacttgtgaa aatttttaga aggcctgagc 207720ccacagattt attttttcat caattcatat ttattaggca cctatatgtg ccaggcactg 207780tattaggagc atggactatt ggtgatctca atggacatat tatccgtttt tataaaggag 207840atgtatcgtg gaccagtaaa taaagaagtg aacaaatagc actagaagga aataaaaagg 207900gcaataaatc agataatcta ggggagggtg ttttagatag aatgatcagg gaaagcctat 207960ccaaagaagt gatgtttgag aatgagaatt aagtttgaga atgagcagat acatgaggag 208020ctggaaggag gacactccaa agtctaggcc aagtggaaag gcttggaggg gagaaaggcc 208080ttggcatgtt caaggcttgg aaggaagtgg atttagacgc tagcaagcag aaaagagagg 208140gtgtgacttg gggcatagag aaattggtaa gagccagatc aagcagtggg aggggaaaag 208200ccacttagct agagtaaggg atggaccaag tactctgtag aacagatatg aaattattca 208260gtgtttttat agctgtaaac tggaaaatag attacaggga cttaaaattc tccctaagta 208320ctccatgcat tgtgaagggt ttactaatga aatcttctta gagatggaaa catgaggcag 208380accattagtg ctagatcatg gtggtcatat tagttctggg gagtccaggg ttaaaaaaag 208440tagcttcagg gcaaagcatt gcagttcaag agagtggtgg taatagccag agagttttgc 208500ctttggatga tgaaactggt tggcaaatga cagtggagca gggtagtgag gcacccaggg 208560tgggctggtt tgaaacagag cataatgtga gtgaacctgg gatgcacatg aataataaga 208620tggaagaaac ataaagcatc atccttctta ggatttcctt tcttccacag agtcagctaa 208680gttataggtg ccctgaggag gtcttccaaa tggttaacag tatattatgc tcttcctttg 208740aatttttagt ttgaaaattt gttaatagcc aaacaatagt aatgatatcc ttaccactct 208800ttggattgaa tgatgtcccc caccaaacca aaacatcagt taagtcctaa tccccagtag 208860ctcagaatgt ggtcttattt ggaaacagag tcattgcaga tgacattagt taaatgaaga 208920tgaggtcata ctggaatagc atgggccatt tatccaacac gactggtgtc tttacaagaa 208980gaggaaattt gaacacagtg ggaagatggc tgtataaaga tacaaagatg gctgcagtga 209040gtcatggtca tgctactgca ctccagactg gacgacagag tgagaatttg tctcaaagga 209100aaagaaaaag aaaaaaaagc taggcatagt ggttcatgcc tgtaacccta gcactttggg 209160aggttaaagt tggaggatca cttgagctta ggagtttgag acaagcatgg gcaacatagc 209220aagaccccgt cttcgcaaaa aataaaacta gccaggtgtt gtggtgcatg cctgtagtcc 209280cagctactga ggtggctgag gtgggaggat tgcctaagcc cagcaggtca aggttgcagt 209340gaccagtgat ctcaccactg caatccagcc tgggcaaaag agcaagaccc tgtcaaaaaa 209400agaaagaaag tagaaagaaa gaaagagaaa aagaaaacaa aaagaaaaaa gacagataca 209460gagctgcaga aggagaatat tatgtgaaga aggagacaaa gattgaagtg atatatctat 209520tatcaaggaa atgctagggc atgatgcctg tcatcacaag ctgggagatg gcatggaaca 209580gattcttcct tagggccttc caaaggaacc accactgcca caccttgacc tcagaatttt 209640agcctccaga actgtgatat aataaatttc tgtttaaagc cacccagtgt gtggtactca 209700ttagggcagc cgtagaaaag gaaaactacc ccttcccatt cctcttgtcg tattcttttc 209760caccgttttg tctcacacac tacaatcgat gaaaaccaaa ttgctttttc taccacttgt 209820actctttcaa cccagaatag cctcctcttt tttttttttt tttttttttg tctccaggga 209880cctattttaa aataagaaaa aagtttttaa gcatagtacc tgatagtttt ttaatcttca 209940cccacaccca ccccttcccc ataacttttt tgattgatta tgaaatattt caagcaaaca 210000cagaaaataa tatgacagta ttcttctaaa atctacattc atcagattac aactttttgc 210060catatttgct tcaaatcact ccttttcacc ctaaaaagaa aatattactg agagagagaa 210120agtctcctct cttcatactt tctttcactt cactgttcgc atccttaatt tttatttatt 210180tatttttaat ttttttttta gagacagggt ctctttttgt tgtccaggct agagtgcagt 210240ggcacaatca tagctcactg cagcctcaaa ctccttggct caagcaatcc tcatgtctca 210300gcctcctgag tagctgggac tacaggtaca tgccaccatg ccccactcca attcttattt 210360atttttaaag tggcatcact ttgttagtaa agccttccca ttatcactca gatttactta 210420actctatcac ctattcccac aatattttat acacaaatta tattacagga atgatcatat 210480tgtattttaa ttgtagtcac tttttctcta taagaaaaaa atgacttggt catttttaat 210540catctagtgc ctatgcaata tctaactctg ggttaaactg aattttaata taatagtgtt 210600tacatcgaac cgtttgacct tcaaaagagc cctaagagtc aggactagaa ttgtcattct 210660ttattccaga aatggcaact ttatgaattt tacgtgttta atgtggtcga ttattgtttg 210720tcactgttgg tgaagtttac ttccttgccc tcctgatgtt gggcttggcc gtgtggtttg 210780cttaggccag tggaaggcag gtggaagtga caacatgtca gttccaaact gaggctgtaa 210840gaagttcaca tatttctgct ttcttctttg tgcttctgac attcaccgtg aaaacattcc 210900ctgagtagct gttggtccca gaatgaagag acagatggag ccaacctgaa cccaacttga 210960aggctgaatg ccaacaaaca tagcaggatc acagcaaacc tgaagtgaat gctcgctgat 211020gtcagttacc aagatttggg gtggtggtta cccagcatta gcatagttga aacctcacta 211080atacacctag atggttgata ataaaggcag aactagaata cacgttatct gattagcaat 211140atagtgtctt tttactaaat tattctgtta ttcatctgca cattcaacaa gtatttaatc 211200atatatttac tgtagaaaac agcacatcat taaacagaca gactgtggtc tctgccccca 211260aggagaatat gtttctagtg agggaaagag atacaaattc ataaatctaa actatagaaa 211320atggcaaact ctatagcaca aatgtctttt gagagagaat aatgggtgag gggaaggaaa 211380ggagatgaat acctttaagg tggcaggggt agagctcttt gagagactgc aaagcagaga 211440agatgcttca agaaaaagaa gtacacattt ctctccctgg aatggtctca gtggtctcag 211500ataatggttt cagttttcca tattccttta tttatgtagt gtcaggccaa cagtgtactt 211560tagctccagg ctaaccagtt gtccttggtt tgcatcccgt gtattcagaa agctattgga 211620ttgttttgta agttcttaaa gaaggactga aaaaggcttc attttccctt tttccaaagg 211680gagcaattac atactgtcac tggaataata aacttaagtc ctaggctgcg aatgaaattt 211740gatttctctc aggtgagagg tattttgtat atggaaagct aaggaaagaa atgcaatgtt 211800tttttttttt tttttttttt ttagcaatcc agtagggaac tgtggccagc attgagctga 211860taaagacctt tgttttccat gttttgattg gcccagtgag aagcctcgag cagtttgcac 211920acccatctgt gtccatactg gtggggcaga aaagtgctga cacaggattg cagattagcc 211980cctgcagctt gccagggtaa acttgtgtaa tgcactgtac accactccta acaacagtgg 212040tccttttgtc acttaaacag aggttattaa gaatatgagt cattaaaaag agctttagaa 212100aagcaggcaa cattttccaa tacagtggct ttaggggatc tttggaaagt atcagaagtt 212160ccggaagaag taaagcatct cattaataac taacaataga cacagaatca aaatctgaat 212220tgatgaaaaa aagtaatatt taaaatgtaa tttttgaatg ttgaaaagag cccatttttg 212280tagagaattg gatgaggatt aacttagata ttttcttgaa tgtgtataaa tattacatat 212340aagaatactt tcaagtctta aattggcccg gggatctcca gcttgctgat aaaaacaaat 212400caaagaaact acctttagga cttctttttc ttatttttga aacattaaaa agttgcaagt 212460gccggaataa tggggaaaaa gtctttattc tattatccag acaaaaagct ggtcaacatt 212520ttaatgctgt ttctgctggc atttttctct acaaatactt tctatgtagt taagatcata 212580tggtatatgt aatcttgttt cattcatttt ctttcacttt tgttattcct tattcagtga 212640ttggaaaact atggtttata ggccaaatct ggactactgc tacacgtgga acacagccac 212700atgcattcat ttacatattg tgtatgactg ctgtctctgt accataatag aattgagggc 212760ggctacagag cttaagtgac tcacaaagcc tgaaatattt gctctctgga cctttataga 212820aacagttttc cagtttgtga gatagattat tagagtcata tgaacacaat agaattttac 212880aaaaatatac caaaagttta tacagccatt gatactttaa ctagcattgt ctgatgaaac 212940tgttttattg cctataacaa tatatatggt aaatatatat ggttatgcat atataaccat 213000atatatgtaa tagccagcta tatatatata tgtataattt tatatgtata cagttttgga 213060ttttaataga catagaatgt tagtgtatct cttttttgct ttaatattta tttctttgag 213120tagcagttag acaaaatgat tttccatttt tttagttctt taattttctt tatcttcaac 213180tgccttctta tgacgtttgc ccctttttaa atagagggtt tttttaaaaa taaatttgta 213240agggctctat atagatgcgg aataccaact cttattgttt ttactttgac tatattttct 213300cagtttttta atcctttaat ttgagagatt tttttgaaac ttgaaagttg tttaatcagt 213360gtaaaatttc ctctgtgatt cctttccaag ctccaatata tcatgctgag gaagtatctt 213420atcattttta attttttaaa aatttataag gattgatatt ttatgaaagg cctcttgagt 213480gtctattttt aaaaacatac tttgttctta gaatagtttt ggacttacag aaaaattgag 213540aagatagtac aaagggttct cataaactcc acagtgattt ttccctgtca ttaacatcat 213600tcattagcat tttgtcatta gtatctttca ttagtattgt atgttcgtta caatcaatta 213660actaagattg atgcattgtc attacctaaa gtccatattt tattagaatt gtttaagttt 213720ttacctaata tactttttgt tctggtatct tgtcctagat accaccattc aaccattcat 213780ttagttgtta tgtctcctta tgtttttctt ggcttgttat attttctcat agttttttgg 213840tttttgatga ccttgacaat tttaaggagt attgactagg cattttgtaa aactcctttc 213900tattagaatt ggtcactgtg agcagtccac attttaggaa taggaagttt tatttcccca 213960tcttgagggt gaagttgttg cataaacttt tggggattct tctgcatggg agattttttc 214020tacttctcct tttatttatt tattcagtca tttagtatga gctcatagat attaatttta 214080tactttgggt tataatctaa tactttttta ttattttgtt gcttacatac ttctagattt 214140ggccactggg agctctttca gttgacttcc gtatttcttt gacatacctt ggcaaatgta 214200ggatttgtgt gtgtgtgtgt ttattagcac atttttcatt tctggcacta caagatcctc 214260caggctcatc ttgtttattt cctgtgccag tcctaggatt agtcatttct acaatgtgcc 214320ctgattcctt tagtcagttt ccttttatta ggaaccaata tctggacact ggttatgctt 214380atttgtacaa gcatgtagtt acttctgggc cctctcagct tacagagcaa ggaaccatac 214440tatgctatgt gtgtgtatgc taagctgtgt atacacacac agaaaaaaat atatatatat 214500atatgcacac acatatattt ctatacatag ccatctgtat caattttgag ctaaacatga 214560gtgttcatac tggtgtctcc aactctaatc cagtatcaca tgtatcattt tagccttatc 214620cccttgttta tctgtacact cccatcccaa cagtgataat cctggctcct gccatctgtc 214680aattccagta tacaggtatt ggaatatcag aatttttaac ttgtactcta gttattttaa 214740ccaagaaata actttgttaa ctagagtaca atgcttatgt actgtcaaac gagattccac 214800tcgtttccaa agttatttag gttcctctcc tgatttttaa ctcttatttc actgcatttt 214860aatccggatt tatttattgt tcctggttgt cagtcctgaa actaaagtgg taataaagga 214920aacaggtggt atacgtgaga ggctttcaaa ttccttgagg tcataaaata tatatgtatg 214980tgcatatatt taaaataaag ccttgaacag gcagaaaaac tgatattgca ttgtagataa 215040caaatggcat aaaacactta tgtagaatta gtcccatcaa aatatgtaaa gaagtaaggt 215100tcgataaaag ttgtgggcat tataataaaa tatttctctc cctttatatt cactccttac 215160ctgttctcag taaaataagt tcaactctgt acaattaatt ttctgccatg tctactgctt 215220gtacttggga acaaatgcta tattataata taaagatatg tgtggaactt ggtttcaaaa 215280gtcaggtaat gcaaatatca aaaaacaggt gatctctcaa acaccttatg ataagtcagt 215340cagataaagt gctctgcaga actccagcca acaaacaggt tgattatcag tgaagtatct 215400catattttca ggtagtcctc acactaagaa agctaatgaa aaagagtttg agctcacata 215460atcatgagaa agtacatttc aaaccacctt cccaaatttc ctgctgcagt ttcttctctt 215520tttactcatt atttttcttt ttacctcagt ttactttctg gttttcttgg ctgagtgcct 215580ttttaactgc tttgaagtaa gatgctatct tctttatcag gtttgcaaac tatttattga 215640atttagcaat taaaattgtc gctgtggttg aactggaaaa tgtccttttg gtacttgaat 215700ttactgaata taatgactga aaaagcattt caaacaaaca aatcaacaaa caaaaaatct 215760caattagttt gttgcataga cacaatagta actcacagca ctggcatatt atttttgatt 215820cacaaaacac atatagagcc tggcatctat tagacatgga agccacttat taagtattta 215880tttaatcaat gaatgcatca aaggattagt aatatcaact tcaacacaat cctgtagtat 215940atgtaatatt cttcctcttc cctaccttta acaatgagga atttgagctc agaaggatta 216000agtgaattac ttgaagttat attattaatt aaactactga agccagaaca cgaatctaga 216060acttaatcat cagaagggca actactacct ccacctacgt tactcatgat agtattaaca 216120tggtagcaca gtggtacata gtagttgctc attgaatatt atttagtaaa agaaatgaaa 216180agagtggtgc tagatacttg gaagaataag aattctaaga aggagaataa aggtgtatat 216240acatattcat ttgataagta ttcaaataat agttaaagag atgcatagga tactgcagag 216300ctctttcaga attgagaagc tgaaattaaa agatgtatta gacttgtttc catcttaaat 216360catcatcata tcaagtgata gacattggta cctgcagtat ttcagtggca tttgattttt 216420ttcctgcaga gttctattaa tacagtattt taaaatttta ttgtatgtca tttaaaaaat 216480acttttaaaa agcaagaaca ccacattttt ctgggcataa gagacaaggt tgctttttgc 216540atgcatgtat gcaattctaa cctttaaatt tcctatgtct ttattttttc ccctgacttt 216600agagcctaat attgactaac agctcatttt gaaagataaa aatccacaaa ataataattt 216660agaaagtgaa aatgaaaaat tacattaatt tctcctctac cattgttttt cgttcaaaac 216720cacagttaac atgagttgat ttattttttt taaatgaatc tactgtgacc ggccttatga 216780tccacccatt cgcctaagtt tgaaaccaca ttgattcagt

caacaaactc tataccacct 216840actaattgat aggtaatgac tagttttgtt aatacttggt tacagcgata gctttgagca 216900aattttcaaa gtgaagcttt tctcaacttt ttcttgttga ttcggtatct gaaatagctt 216960attaattcat tccttccttg tttccactga cactgccaat cagttgtagg tgaaaactct 217020aaactggtct cctgtacttt actatcccat tttctgcctt aattcatctt ctccagtgtc 217080tcaagtgtaa tcttgctaaa atacaaacct aattatgtta ctcctctgtt tacagtcttt 217140aaatgtttta ccaaattaaa tccaaactcc ttgagaagtt catacaaggt tgtatcagag 217200cctctgaaac gctaacccac atcttcacag cttcatctct tgattccagc ctggatgcaa 217260tgggcattct ggatttgact catattacaa caacaaaata atctcaagtg aataccatgc 217320actttttact ttttttccac tgggcttctt cagtgccaca cctgggaatg gggttttact 217380tgttaagctt acctatggag ctccaaaatg caaggaagtt taacttttga gagcaatgtc 217440caaccaatga gggatggaaa cataggaaaa catgctttcc caagttattc ttctaacaaa 217500cagctctaag gtacgttctg tatgcttatt ccccctagat gtcagggttg agttccagtg 217560tcccaaagct atataataaa aatgcacctt ggtatagact ttcccgcctt cccttactct 217620ctttagtctc cttttgtact ccataggatt atctcattga ctgggctttg ctttctagta 217680gaacctaagc tatgacatat agtactagac tctctcacca ggagtgattt aggacgagga 217740ggcgttgaaa actgaagctt tggacatctc agatagttaa agcactcgca atttctggca 217800tttatgtgct cataatgtag tggtgaatgg caattgcggc aaccatggcc tgacaagagc 217860aaggtcatca agagcttaga ttgtttggag ctgaaggtct gagtcacccc attaggctaa 217920aaacctagaa aagtagaagt gctgatggag ggtgaggaaa atctaatatg gattgtggag 217980gaaggagacg atacatataa aacatgactg caggacctgc agttgtagca gtgagggctg 218040taacttattc cattaatatt tgtgtgttaa gtcacatgta gagattgtgg ctaactacca 218100ccttgaagac ttagaggttg ctggaactta ttctagggcg taggtgtatc tgtgtggtac 218160aaaggataga ctgtatgggt tgtttttggc tttctgactc atatcctctt ggcttcatct 218220ctgattacag tgtagatgca gtgggtagtt tggcttacgt caggctgaca tctttcctca 218280agcactggat gttttgcact tttgcccttg ggtttttcca atgccacaat tgccattggg 218340aagccctctg ttcaagcagg catgctcagt cgagaagcca acaggggttt acatccccaa 218400agcaaacctt aactaatgga ggatacaagt tgatggataa aaatagtcaa accttaagta 218460cataattcca aaaggtattc taaacactcc ttagaagatt ccaggcaggg ctgagcacaa 218520gttgcctaca atggtgatat taataatgca tctatatata tgccttttca cattccctcc 218580ctcttctgtc tctcactcct gctccctgtt cataaatttt tgcagcaggc tctgcttttg 218640ggaaaactca agctaaaaca aaagtcctta aattccagta tgcctctgtc ctccactttc 218700tacccaattt tgtgttgttt cttttggttg tttccctgat atatgccaag aaaataaatg 218760gagaaataga agggtgggac tatcaacaaa tactttaata gaatttccag aaggacttaa 218820gctgtcagat tgaaaggatc cactaagtag cccagaaaat agtttaaaag ttggttgttt 218880tgaagttttt ttctccctgg tttgttttaa tctctacatc tggtgtacag ctgtcctcat 218940gagatgcctt gttactatta ttctcttgtg ccaaaacttc tatttcttat ccctgtaatg 219000ttttctttct tggagcacct cctaaatagt cttagaaagg atgcatggga ggtaactttt 219060ttgaggcctc aaacatctaa tgaagtctct attttatttc ctttgacctg attgaatgat 219120tatggattta taggttagaa actatttctt tcaaatacat gaagggagtg tcttattttc 219180tgtgttgcta ttaaaaagtc ctaatgcaac tctttttatc attctgtgta cagtgtatgt 219240gatttttttt cttctctgga agcatgtgga gtcttcttta gtcccctgtg ttctgaaatt 219300tcaacagaaa tacccttatt aaggtctgct gcttggtttc tattctccat gttaaaactt 219360tccacacatg tttggtaatc cttggaagtg tttaaatttt cagttatctt ttaagtaagt 219420taagagaaga aaaaacttta aaaaggcagt ttttatgttt actcatgtat ttcccatttc 219480tgttgctctt cattctttcc tgtaattctt agttcccatt taatgtcatt ttcttcacct 219540gaataacttc ttttactgca tattttctgc ttataaattc tctcagtttc catttatccc 219600ataaagtcta ttttaccttt attttcaaag gatcttttca ctggatatag atttatggtt 219660gacagtattt tgttgttgtt gttgttgtta atttacttca gtacttacat atattctagt 219720ttcttctgtc tccactgttt ctgatgagaa gtcattattg gtatcagtgt tcctttgtat 219780ataatatgtt cttttccctc cagctacttt caagagtttc cccttgtctt tgttttttca 219840gtttgattgt gatgtacttc gttttcttta tgtttatcct gcttcaggtt ccctgaaatt 219900cttggatatg taggttgatg ttttaaataa atttttaaac attagaccat tatttcttca 219960aatattttct tcttctcttc atctaagact tcaatgatat acatggagac tccttgatat 220020tgttccattg tcacaaagcc tttattaatt tctttcaata gttttttctt tttgcagctt 220080gaacttaaaa ttcactgcac tctgcacctc cttttccccc cgtgaagtct ccaatccatt 220140gttaagctca ttcaggattt ctccacttca gatattatac gctgtagttc taaaatttcc 220200atttttctgc tgctatccca tatgcattca ctgattatga ccataatttc tatacatttt 220260tgagcatatt tataataagt gctttaaagt ccttttctac taattataca tctggggcat 220320ttcagagttc agtttctcct gactactttg tctcttgagt atgctttttc ttccagtgtc 220380taataatttt taaattatac acaaagcatt aaagataatt tgttggccag gagcggtggt 220440tcacgcctgt aatcccagca ctttgggagg ccaaggcgga cagatcatga agtcaggaga 220500ttgagatcat cctggctatc actgtgaaac cctgtctcta ctaaaaatac aaaaaaaaga 220560aaaaattagc tgggcatggt ggcgggcgcc tgtagtccca gctacttggg aggctgaggc 220620aggagaatgg cgtgaacctg ggaggcggag cttgtagtga gccgagatcg cgccactaca 220680ctccagcctg ggtgacagag cgagactgtc tcaaaaaaaa taaataactt gtagagattt 220740tggagtctgt tacctttctc tgaagaatgt tgatttttgt tgtagcagca gggcatcagt 220800gaaatctctg ctcggtttac aagtcttttt ttcttttctt ttcttttttt ttgagatgga 220860gtttcgctct tgttgtcttg ttgtccaggc tggagtgcaa tggcgtgatc ttggctcacc 220920gcgacctcca cctcccgggt tcaagagagt ctcttgcctc agcctcctga gtagttggga 220980ttacaggcag gcgccaccac acctggctaa ttttgtattt ttagtagaga cgtggtttct 221040ccatgttggt caggctggtc tcgaactcct gaccttaggt gatcctccca tctcagcctc 221100ccaaactgct gggattacag gcgtgagcca cggcgcccgg cctagtcttt taactattgc 221160tatctgctgg gctttttgga gtctctacca tgcatgcata gtccagtagt tagtcaagga 221220tttgaaggga gttgatacac agattttgtg gcttcctcct ctgtgcgtct ctcctttcag 221280caatttttct gtttaaattc agtcaccctg gaatccctga gctcactctc tgactccaca 221340actcagaaag acaatgactt tctttatgaa ttttagctac cctgcatcac ttgggctgca 221400agatgctctc cagagaaaat ctacattaaa acatgtcact caatgcagtt accttctttc 221460aaaggttgaa tcaccttctt tttgaatccc tgttggttgt tattttgtac cttaaataat 221520tatttttaat actggtccag agtttataat tgttatctat gaggagtgtt agtctaacac 221580aagatatttt gtcatttcta gaacaagact actccactct tatgtagctg tgacattgtc 221640atgcatttct ttaaaacatt ttagtggttc tttattgttt atcaaataga aaatattcct 221700taaactgcat gtactctatt ttttcattgt ttcccataac aaagaaatat tatttcattg 221760aaatattgaa atattgagca tgccttcaaa tattatgttt caccatgttc ttttgctcat 221820accgttttcc atccagaata catttttccc cctacatttg aatgcccaaa tcctgcctat 221880tctttaagat ctagctaaaa tgtcacctcc tccacgaaag ctattcttct ccctccagtt 221940tcagttttga ctaaattatc tgtttctatt tcattgcttt acttatgttt tataaggaca 222000ataagagatt agtgccctta taaaagagac cccacaaagc ttccttgccc cttctactat 222060gtgaggacac agcaagaaga cagccaacta tgagcctgga agcagggcct catcaaacct 222120tgagcatgct ggtacactga tcttggactt tccagtctcc aaaactgtaa gaaataaatt 222180tctgttgttg atggctgggc gtggtggctc acgcctgtat tcccagcact tgggaggccg 222240aggtgggcga atcacgaggt caggagatcg agaccatcct ggctaacatg gtgaaaccct 222300gtctctacta aaaatacaaa aaattagctg ggtgtggtgg caggtgcctg cagtcccagc 222360tactcgggag gctgaggcag gagaatggcg tgaacctgaa aggtggagct tgcagtgagc 222420caagatctca ccagtgcact ccagcctggg tgacagagcg agactccgtc tcaaaaaaaa 222480gaaagaaatt tctgtttttt ataagccacc cagtctatgg tactttgtta tagctgcctg 222540aatggactaa gacacaatgt gaaagtacat tatcttcttt ttgattctca agttaccacc 222600ttttctcaaa cgaccaccaa ctctctctgg acttctgaaa tattcttgta actggtctct 222660ctgcttccat tcttgtacct ttaaacctta gtattccaca gtagcctaag aggtcttagg 222720gtatataaac aaaatgacgt taatttcctg catctaatca ttcaatagct tcccattgca 222780ctaaagtgga accctttctt tagagtcctt gccatgatca ataaggtctc ctctcctaca 222840aggtatgggc actgcctact actctgacct catttattac actcttccct gccttaacat 222900atgccaaaag tattcgacct ttcccccaat tctcaaacac tgcaaaaaac cctccaaagg 222960cctactactt tacagttgct ctatcttctt cctcgaatgc cctccttatc tttatagatg 223020gctccttctt ttaagttctt agtaaaaata tcatctcctt agagggacct tcaccccctc 223080agtcacaacc ttgttttaaa ttcctcagac cctcatgatt atctgaaatt atcttattat 223140atttctttct ttgttgttta atgtttctct ctgtcacaaa gcaatacatt tttttttaaa 223200gcaggaatgg gctatatatt cttcattttg ttgacctcta ggagctgcat cagttggggt 223260cccctgcctc tgccctccag ttgagttcag ttaagtaaag accagaggat aagaaagaag 223320gctactgtgt gtttctactg agggttatag ctcctttcag gcagtcctct tctacagctt 223380ttgggttcca taactatttc ttctccttga tgatctccgg taattcaact tggctccttg 223440ttttctcttt ctgtcctcct cactgttgct agccttaggg tgcttcagtt tcccttaacg 223500cagttcacat cttttaaaaa cagactcttc attaaattct ctttaatgat ttgtttcaag 223560tatgacaaat ctgtctttct gggaccttga attttattct tcaaaatatt accagccctt 223620agcacagaac ctgttacatg gtgacgttca acacatattt gttgaatgaa tggatgaatt 223680aataggctct tttgctcttc attcagaatc tattaagcta tacactccct cagtatttta 223740aacccaaaat tcagttttta aaaactaaac ttcttgagag catagtctat ctatatctct 223800ttaaaattta ggcctaagac aggacactgc cccacattga gtcccacaca acaacctgtg 223860agtctggctc cccaggaggg cccccagaca gctcccaggc acttcatagg caaagcctgt 223920cccccccact caggattccc aaggtctggg gtcccgctca ccccgctttc ctctcatgcc 223980cagcctgacc ccaggtttca gctgggagag gccacttccc ttagccaagg aaaacgagaa 224040cccccagggt acaggaggaa gctgggacag gtccccttgg gtgtcactcc ctcaccccct 224100gcccaggccc actcccactg gtgctggagt acgcactggt ggggggaccc tgctcagccc 224160agcctggagg gccccagtgt caccacaacc aggggcacgg caacatcatt gatgggttct 224220gcagcccagg gcccccgatg cggggtcaga gtgtgtgggg cacagggccc ccgatgcggg 224280gtcagtgtgt gggggtgcag ggcccccgat gtggggtcag tgggggtggg gcgcagggtc 224340cccgatgcgg ggtcagagtg tgtggggcac agggcccccg atgcggggtc agtgtgtggg 224400ggtgcagggc ccccgatgcg gggtcagtgg gggtggggcg cagggtcccc gatgcggggt 224460cagagtgtgt ggggcgcagg gcccccgatg cggggtcagt gggggtgggg cgcagggtcc 224520ccgatgcggg gtcagagtgt gtggggcgca gggcccccga tgcggggtca gattgtgtgg 224580agcgcagggc cccctcgtgt ccagggcact ttggtacact gtcccacaag gcacctgtct 224640cagaggaggg gtcctggcag gcagtgtggc aactcccttc cagagcccag ctccatgcta 224700acctgcccac agcaacccca cagagccaca tcccctgctg cacctggcct gcaggagtgt 224760cccaggacag gcccaagtca gcccagcatg cagctgccct cctaccctga agaagggagt 224820gggctttcca ggggacataa ggatgccagg cctggacctc ctgggcagga aagggagcag 224880gtcctgaggg cctgtgcccc acagccccag caccaggtgg actgcagcgc agtgggtggg 224940ccagtggcag ctggggagaa gccccccgtc agcaggctgg ggtctgccca ccagggcctc 225000cccacgtctg cctttgaggg tgcctgccat gccctggggg atcctggtat ctttactgga 225060ctggaagcag gagacagaac agtgtctgtc ccggggtgac ttcatcagga gaccgcccac 225120atagagctgg accccgcagc tgaagcggaa atgtgagaca ggctggcacc tccggaaaaa 225180ctgcctttca gccttggtgt tccgtgcaag gtgaaaaaaa ataggtcctc caagtttaca 225240gcttgaaatc aggctactgt gtggccctgg agaccacgag gggagaattt aaagtggccc 225300cggctggcag ggtctaggtg gctggcagag gcacatgcag accctacctg gagcccgccc 225360tagggacgct gggcaggtca gtctccgtgc aggatgtgag cagcgtccct gggctctatc 225420cgcgaggtgc cagtagcgtg tgcaggtaca tacacatgcg tgcacactgt tatgacaccc 225480agaaatgtct caggacgtcg aaatgtgtcc ttgggagcag aagtgtcccc ggttgagaat 225540ctgtcccaga ggaacacgac cacgacaggc ctcaggattt tgtgttgatc aagttccaag 225600gaaaaggaac atctcggcca ggcgtggtgg ctcacgcctg gaatcccagc acttgaggcc 225660aggagttcga gaccagcctg ggcaacgcag tgagagaccc ccatctctac aaaaaaaaaa 225720aagaaaaaaa aaagaaagaa agaaagaaaa gaaaatgaga tctccaggtt taaaaattca 225780taaacaccac aaggaaacaa tacactatga gatccagcag aagcaacaga ttgactctgt 225840agacccagat actggaatta tcagagagaa tataaagtaa cagtgtttta tatatctaaa 225900gaaataaaag agatttctgg aaaaaaaaat ttaggcctaa gaattagtga aaatcccaac 225960attaaggaag ggattatatg ttcagttttt gaaaggataa tgtgtcattt ttaatatttg 226020ctatttcctg gaatcttagt tctaggatac accataaatg tctgctttta taggtgaaga 226080aactgagggt gagaactgaa gagggattta tctgaagacg ttatggtagt ggaaccaatt 226140tttactttaa tgttgttgct ctcttgatga tattagatgg tttcatcaat tactaagtaa 226200attcccaaga tttacctcga agtcacatta ccctattaac ttattctcca gttgtaccaa 226260tttgccattt cattctggta acaaagctct cttactacaa ttcagaaaat atttgggagg 226320cagctgccac tgagcccaga ctttgacaaa atatcctccc acagaggccc agttaaacta 226380tggattgcac tgagcattct gtccttaggt gctctggcct cccagtagat agcggatgct 226440gtggtaattt atcacaaccc tctacccctc cgattacctg ccaggtgact cttcactcct 226500ggcttctgca gcctctgctc tccccaagat ccagctctct cagcccccca tctaaggttg 226560cacagtttag gtacatgctg aaatcaccaa tacagaatcg ttttaaaatt cgaattaatt 226620ggctgagtgt tttgttaaga cctgattgtg ggcaagaact atttgttaaa tactctaaat 226680tcttagaacc cagcccagta cttgctagtc atcatttaaa tacattgaat gatagagaaa 226740attcttctga tcacaaacct tataccagcg ttgtcaaaat tataatgata aagtagctca 226800ttttaagcgc gtcctgggtt gggaaactta acaattttaa aacttggaat aaattcaata 226860aaatgacata gtatggttac aatgtctgtc tacagagtca gggcaagaac aaagaaaatt 226920gaaagaagat tgttttagtg tagtaaaatt actggataat tttcatttcc tttgctcttt 226980aaagaattat ttgtaaaggg tatttgaaat gaaaacaaga ttggagaaaa acaacttgga 227040agaaaatcat aggcaaataa caataatgat tgaagagttg tgaataagga gagttaggaa 227100tcaagtggtt ccaggcttgc agaatctgaa aggagcctag agtgaggagg ttgatctgtg 227160aaggatgatg atgatctcca ttaaggacca gacaggaggc aataggctta agctgcagta 227220tgagggattt agataagaga aaaggaaaaa ttttcagaca gtgaggttca tagatactgg 227280aatgtgtaac tgaggaagct tgtggaattt ccttctctag aagtctttta aaaatagggc 227340agtgtctcat ctgcctgaag gatggactct atttgacctc tcaaattgtc tactgaactc 227400agaaggtgaa ccacacctta gataagaaag agagcctgaa tgatcctggg tagcttgagt 227460aataaaagta gggtgaacaa gtcatattta ttttgattta tatatgtcat atatgtaaat 227520tatgtctgct ataattcctt tttttctttc aattgaatgt tttcattttt aaggcctaga 227580gattagagtt caagtaaaga tattatagga aagcaaggaa gaactctttt atcttactgt 227640agaacaaatt tttagaggaa taaaaggaga aaaggatata ttggacatat ttgattttga 227700tttcactccc tattctaaat aaaaaaaaat acactgccct ttctgttagc tttagtattt 227760taagggtaaa tttcaaaaag ttaatttagt gtaagtgttt ctcacggtgt ttttggcaga 227820accggtatcc caaactggaa gaggttctct gtatttaatt tcctctcagg aagtttaccg 227880tcagaagtcc aaatgtgagg tcaagttttg ggttgccgga aatggtaatg tcctttactg 227940tctgaacacc cagacaacac ttaatgaaac attctacttt gtggacattg aaagaaatta 228000aaatgctttg tttcctcctt tttatgattg gtgatttctg tattcagtct tctaaaactc 228060agaaacaaga ctatgtgtaa gtaagagcat ctgcattctc aggatcaagt tataactgca 228120gattttcagt tacaggtgat atccatcttt tttttccttc ctaaaaataa aaatgtactt 228180acttcaggcc aaaggagagg caagctttag aactcattag ccttcaagaa aaacaattcc 228240agagcattct aaacctgatt tctttctaac tctgtttgag ttgacctgag gacttttaca 228300ggttaaagca gtgagtcatt atatctcaca ttcatacagc tctacatatt tgtcaaagtg 228360cttactcatc taatatctaa tatgatctta ataagaacct tgtgaatgtc attatcttat 228420agatgaaaaa atgatatctt cataagatac agtttgctca agatcacaaa actagaaaat 228480gtagtttgaa cacttctgat ttcaaagcca gagtcttctc cactgcccca tgctgtactg 228540tttttgagaa tttgtgattt cctggtgttg tattattttt accattgatg agatttttgc 228600ctgtgattta tcctgaatca aaatagatac tgtgatatga tactaaagta attgttacca 228660aacaaaaagt tgtgctagca ttcttatgaa gtacagcact aaagattttc aaaacatttt 228720gttattttta cataattggt catgtaaatt tctggtagga cactccttat gagattacaa 228780cccattctaa tttatgctag ctatttattg ttaagcagta tgttgttttt attacaaaac 228840ctcctttaat cattgcatca gtctctggca gaatattaaa aacaactccc ataatccctg 228900gcactctgtc ctgggtgtct ttgggggtac agtggcttta tttccttccc taatagttcg 228960gaagtttgtt taatactgac tcagaggaag cattctagct gagtcctcac atggtcttgt 229020ttacagctcc ggagtgtaca taatagataa gctactgact tccacaagac ccccacgctt 229080cctgggtgtg tgggtgtgtg tgcttgtgct tgtgaattaa ggttgtgcaa tctccctgct 229140agctgcatca ggttgcaaag tcatttactt ctctaaaata ttcctctagc cagcctgact 229200tgataaacca aaatcattgt attccatggt ggacatgctg gtaactcatg ataaacacta 229260aaaatcctac gggtttataa caagataaaa cctgatattg gggcagggtg tagagaaatt 229320tgcccaagga aatattgtga aataaagttg caaatggcta tagatgaatg cttttctatc 229380tataggattt cttttcttga ttgtaattat aaattctttt actggttgta aatataatta 229440tgattcttat gttacccagt ctgtaccaag aactttgtta ggccaacaac atcttacttg 229500attgtagtag taaccttaaa agataaatat aggtataatg ctttttcaga agaaaaactg 229560gagaattcaa acatgttctg cattgcacag atggtaaatg agtgatgaat agggtccttt 229620gactccaaag atcaactagg ttctttccac atatctctct ttggttccct tttttgatat 229680gactgtatga aatataattg tatttacata aagtgcagta gagttcatta gaaaaactat 229740ttctgaatct tagggttcag actaaaggtg tttggaggct gatgatagtg ggctgcaaag 229800agcttcatgg tgggctgcga atagcttcat caaacc 2298369523DNAArtificial SequenceSynthetic primer 95ttggtgtcca tgctgtgatg att 239624DNAArtificial SequenceSynthetic primer 96ggttcaagca tcactgttag gtgt 249723DNAArtificial SequenceSynthetic primer 97gctcagagca attccagtgc aag 239823DNAArtificial SequenceSynthetic primer 98tctcattggg gatacgaagc tct 239923DNAArtificial SequenceSynthetic primer 99aactccaaag aaaccatcag agg 2310025DNAArtificial SequenceSynthetic primer 100ctttcccgag tcagtactgc tttct 2510124DNAArtificial SequenceSynthetic primer 101ttccagtgca agtatggtct gtga 2410224DNAArtificial SequenceSynthetic primer 102tcattgggga tacgaagctc taca 2410320DNAArtificial SequenceSynthetic primer 103ggttggggac ccctggtgta 2010418DNAArtificial SequenceSynthetic primer 104gaggcgggcg aatcacga 1810520DNAArtificial SequenceSynthetic primer 105ggttccagtc ctggttctgc 2010620DNAArtificial SequenceSynthetic primer 106tctggcccta gcctccatgt 2010720DNAArtificial SequenceSynthetic primer 107tggggacccc tggtgtagtg 2010818DNAArtificial SequenceSynthetic primer 108cgggcgaatc acgaggtc 1810920DNAArtificial SequenceSynthetic primer 109ccagtcctgg ttctgccaca 2011021DNAArtificial SequenceSynthetic primer 110cagaaagctg caaaggcctc a 2111120DNAArtificial SequenceSynthetic primer 111aaagaagcca gacacggaag 2011218DNAArtificial SequenceSynthetic primer 112ggatgaggca gcgtggac 1811318DNAArtificial SequenceSynthetic primer 113tccggtttgg cagcagtc 1811421DNAArtificial SequenceSynthetic primer 114caacagtgtc agaaacgatg c 2111521DNAArtificial

SequenceSynthetic primer 115cttgatctcc caaagtgaag g 2111618DNAArtificial SequenceSynthetic primer 116agatctcgga acggctct 1811720DNAArtificial SequenceSynthetic primer 117ggaagaaagg aaagcgaggt 2011820DNAArtificial SequenceSynthetic primer 118tcctcgcgta gaatggttgt 2011918DNAArtificial SequenceSynthetic primer 119cctgagcgcg gtctaagc 1812020DNAArtificial SequenceSynthetic primer 120ccccttcaga tcttctcagc 2012118DNAArtificial SequenceSynthetic primer 121cccgcacctc ctctaccc 1812220DNAArtificial SequenceSynthetic primer 122ttggcaagga aggaggactg 2012325DNAArtificial SequenceSynthetic primer 123ggttcactaa gtcagaaacc ctagt 2512420DNAArtificial SequenceSynthetic primer 124agtcttcatt gctccgcagt 2012520DNAArtificial SequenceSynthetic primer 125atctatgcgg gcatggttac 2012622DNAArtificial SequenceSynthetic primer 126caaaatgctt gtcatgaagt cg 2212720DNAArtificial SequenceSynthetic primer 127tttcaatcgg ggatgtctgc 2012820DNAArtificial SequenceSynthetic primer 128attcccaccc aggatattcg 2012918DNAArtificial SequenceSynthetic primer 129ctgcgcacca tgttctcg 1813026DNAArtificial SequenceSynthetic primer 130ccctactgac tattacatat caatgc 2613123DNAArtificial SequenceSynthetic primer 131ttttaaccat ttaaggcata gga 2313222DNAArtificial SequenceSynthetic primer 132ctgctgatga aacagctaaa cc 2213327DNAArtificial SequenceSynthetic primer 133tcttggaatt taagatatag aggtcaa 2713425DNAArtificial SequenceSynthetic primer 134gttagagaaa gaaaagccac cttag 2513526DNAArtificial SequenceSynthetic primer 135aacatatgct ctgattctca actaac 2613622DNAArtificial SequenceSynthetic primer 136caaacattga gagaagggaa cc 2213721DNAArtificial SequenceSynthetic primer 137tctgcaccct gagacactct a 2113821DNAArtificial SequenceSynthetic primer 138taagagcaaa ggccagcatc c 2113922DNAArtificial SequenceSynthetic primer 139taatcactgc cttctcccac tc 2214018DNAArtificial SequenceSynthetic primer 140gggtgggaaa ttgggtaa 1814118DNAArtificial SequenceSynthetic primer 141ggcaggtatg ggagatgc 1814231DNAArtificial SequenceSynthetic primer 142acaatacaac agatttcata tagtagctta g 3114319DNAArtificial SequenceSynthetic primer 143taggttccag ccccgatcc 1914419DNAArtificial SequenceSynthetic primer 144ttcctggcgc tcaagaacc 1914518DNAArtificial SequenceSynthetic primer 145cactgccctc agctccta 1814622DNAArtificial SequenceSynthetic primer 146tgcattatgg atacaaccct ta 2214720DNAArtificial SequenceSynthetic primer 147cggatgctac attggatagg 2014818DNAArtificial SequenceSynthetic primer 148gaagggaacc gggtagca 1814920DNAArtificial SequenceSynthetic primer 149gtaactgaat ccagccaacc 2015019DNAArtificial SequenceSynthetic primer 150aagccgtgtc tcaagatcg 1915119DNAArtificial SequenceSynthetic primer 151ctagcaaatg gcagaacca 1915220DNAArtificial SequenceSynthetic primer 152atcagtcacc gaaggtccta 2015320DNAArtificial SequenceSynthetic primer 153cgactctgga ggacgaagtt 2015418DNAArtificial SequenceSynthetic primer 154gaggcgtgca gcggttta 1815518DNAArtificial SequenceSynthetic primer 155cgggatcaag gggagtcg 1815619DNAArtificial SequenceSynthetic primer 156agcccgcgag gtttaggac 1915722DNAArtificial SequenceSynthetic primer 157cgttttgtct tgggtttgta cc 2215820DNAArtificial SequenceSynthetic primer 158agcaccggag gaagaaagag 2015920DNAArtificial SequenceSynthetic primer 159agtgaacgca ctcaaacacg 2016020DNAArtificial SequenceSynthetic primer 160taccaggcaa tgtacacgtc 2016120DNAArtificial SequenceSynthetic primer 161agcttaggat gtgtggcact 2016218DNAArtificial SequenceSynthetic primer 162gacacgctgg tggtgctg 1816321DNAArtificial SequenceSynthetic primer 163acagtgctct ctgcctgtga c 2116418DNAArtificial SequenceSynthetic primer 164gtgaagccat tgcgagaa 1816529DNAArtificial SequenceSynthetic primer 165ccactgagac tcattatata acactcgtt 2916620DNAArtificial SequenceSynthetic primer 166ggtcccagtc tgcagttaag 2016718DNAArtificial SequenceSynthetic primer 167cgagcagcac cagaatcc 1816829DNAArtificial SequenceSynthetic primer 168cagaaaatta aatatacctg ttaagttcg 2916921DNAArtificial SequenceSynthetic primer 169gcaaacctca aacattattg g 2117023DNAArtificial SequenceSynthetic primer 170gcactcaatc attagaggct aca 2317122DNAArtificial SequenceSynthetic primer 171tgcacaaaga agtgcatcta gt 2217223DNAArtificial SequenceSynthetic primer 172acaagtcatt tgagagtgga gac 2317321DNAArtificial SequenceSynthetic primer 173gggatttaat ttccagggtt g 2117427DNAArtificial SequenceSynthetic primer 174ggaagaacta cagctcttaa atgtagc 2717518DNAArtificial SequenceSynthetic primer 175ggagaccctc gcccaact 1817620DNAArtificial SequenceSynthetic primer 176cactcaccat gaagcgaaac 2017718DNAArtificial SequenceSynthetic primer 177ggagggcttc ctggacac 1817820DNAArtificial SequenceSynthetic primer 178ggaaagtgga ttgcatcagc 2017921DNAArtificial SequenceSynthetic primer 179tctcccctaa accattactc c 2118020DNAArtificial SequenceSynthetic primer 180tagtggagaa ggtgcgacag 2018118DNAArtificial SequenceSynthetic primer 181ggctggctcc ccactctg 1818218DNAArtificial SequenceSynthetic primer 182cacaagggag ccaccaac 1818325DNAArtificial SequenceSynthetic primer 183cctgacaaag tgggtttaaa taggt 2518420DNAArtificial SequenceSynthetic primer 184tcttcctcag cactccgaac 2018518DNAArtificial SequenceSynthetic primer 185ggctcaagaa ttgggtca 1818624DNAArtificial SequenceSynthetic primer 186ccataatgtc ctttctattt gacg 2418721DNAArtificial SequenceSynthetic primer 187ttattacgag cctggtctgg a 2118821DNAArtificial SequenceSynthetic primer 188cccatctaag ggtagagaag c 2118920DNAArtificial SequenceSynthetic primer 189agcaatctag gcgtttgcac 2019024DNAArtificial SequenceSynthetic primer 190tgctaaatga tctatttcca ccat 2419120DNAArtificial SequenceSynthetic primer 191cttcgattgc tgggattatg 2019217DNAArtificial SequenceSynthetic primer 192tgggtatggt tttctgg 1719320DNAArtificial SequenceSynthetic primer 193ctgttcgtgc aggatgaatg 2019424DNAArtificial SequenceSynthetic primer 194aagcaagatt ccaaacagta aaca 2419520DNAArtificial SequenceSynthetic primer 195tgctggcctt tgctcttact 2019620DNAArtificial SequenceSynthetic primer 196cctttgcata gggagaccac 2019720DNAArtificial SequenceSynthetic primer 197gggcctgtga acctactgac 2019818DNAArtificial SequenceSynthetic primer 198ttgaggcagg tcaaataa 18199414DNAHomo sapiens 199ggaagcagcc ctcgccagag ccagcgttgg caaggaagga ggactgggct cctccccacc 60tgccccccac accgccctcc ggcctccctg ctcccagccg cgctcccccg cctgccagca 120aaggcgtgtt tgagtgcgtt cactctgtta aaaagaaatc cgcccccgcc ccgtttcctt 180cctccgcgat acaaccttcc waactgccaa attgaatcgg ggtgtttggt gtcataggga 240aagtatggct tcttctttta atcataagaa aaagcaaaac tattctttcc tagttgtgag 300agccccaccg agaatcgaaa tcacctgtac gactagaaag tgtcccccta ccccctcaac 360ccttgatttt caggagcgcg gggttcacta agtcagaaac cctagttcaa agga 414200425DNAHomo sapiens 200attggaagga cggactccat tctcaaagtc ataattccta gaccagaaaa agtgctcagt 60gttctagaag cagagttgma cagtgatcca aagaccagct tcaaatactg tcctgtctcc 120ttcacacttc tcacatttct ctttcctact gaaaatacct tgcatttttc gtaattataa 180agggggaagg gaatatgagt gccccctgct ttataggggt tgttgtgagt ttaaatgatg 240tattaataca tataagcctt aagaacagtg ccacacatcc taagctaata cctgttagct 300cttgaattat ccgctttgag gactggcttg caatcttgtt ttgaggcata gaaagaaaat 360gctttggagc aggacgcggt ggctcacacc tgtaatccca gcactttggg aagccgaggc 420gggca 425201824DNAHomo sapiens 201tgaatcaaca tttattactt aaaatattta aaacatttca gcggatgcta cattggatag 60gaagagaacc gcaagttatg gatttgttgc ctaaaaactt tggtgaggaa ctgcataagt 120ggacctctcc taaaagtgaa caatttttgt ttacagaatc attttggttc ggagtgctga 180ggaagacaaa gtcttaacag gagggcaatt gcttgtgtat tgcaaaatga gagtcttcac 240atgttttttt taggatacct tagctctgac tcctcatccc ccaaatccct gtagaattaa 300aaaaagctct ttcttttaaa ggcagtggaa gtgccaccac catggaagtg ctggttaggg 360ctgaaaatct actgacagag cctcaacaga gctgaaatcc acctggacag graagggaac 420cgggtagcat taataacaat ttctttttct ttcccatcca acccccattt cctagtcttc 480agtttcttaa tttctctacc ttttactctt atgctcttgt tttgaccttt gagtttctct 540gaaacttatc agaaaagtta ggacaagata gtctgaccca attcttgagc cattttctta 600ggtagtaaat atgtcagaaa aatgaaagct gtttggagtt gataaggaaa tggaagataa 660tgtttttctt tgagggggac ataaagaatg gtgataggga aagaaccaat gactaagtaa 720aatgactgag aatcttgcac gaggcagatg tgtgagcttc gcgaagcaag ttgactgaat 780gaaaaacaac tttgggtagg gaaaacgttg ccgggggcat tcgc 824

Claims

1. A method for determining a susceptibility to arterial disease in a human individual, comprising determining the presence or absence of allele G of polymorphic marker rs10757278 in a nucleic acid sample from the individual, and determining a susceptibility to arterial disease for the human individual from the presence or absence of the G allele of rs10757278 in the nucleic acid sample, wherein the presence of the G allele is indicative of an increased susceptibility to arterial disease, and the absence of the G allele is indicative of a decreased susceptibility to arterial disease.

2. The method according to claim 1, wherein the allele G is determined to be present, and the individual is determined to have an increased susceptibility to arterial disease.

3. The method according to claim 2, wherein the presence of the allele G is indicative of increased susceptibility with a relative risk (RR) or odds ratio (OR) of at least 1.2.

4. The method according to claim 1, further comprising assessing at least one biomarker in a sample from the individual.

5. The method according to claim 4, wherein the biomarker is a cardiac marker or an inflammatory marker.

6. The method according to claim 5, wherein the at least one biomarker is selected from creatine kinase, troponin, glycogen phosphorylase, C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, matrix metalloprotease type-9, serum sCD40L, leukotrienes, leukotriene metabolites, interleukin-6, tissue necrosis factor-alpha, myeloperoxidase (MPO), and N-tyrosine.

7. The method according to claim 6, wherein the at least one biomarker is a leukotriene is selected from LTB4, LTC4, LTD4 and LTE4.

8. The method according to claim 1, wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm.

9. The method according to claim 8, wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, intracranial aneurysm and abdominal aorta aneurysm.

10. The method according to claim 1, wherein the arterial disease is myocardial infarction.

11. The method according to claim 10, wherein the myocardial infarction is an early onset myocardial infarction.

12. The method according to claim 8, wherein the arterial disease is a stroke selected from large artery atherosclerotic stroke or cardiogenic stroke.

13. The method according to claim 1, wherein the arterial disease is myocardial infarction and/or coronary artery disease with an onset before age 50 for males and age 60 for females.

14. The method according to claim 1 comprising contacting nucleic acid from the individual with an oligonucleotide probe, wherein the probe hybridizes to a segment of a nucleic acid whose nucleotide sequence is set forth in SEQ ID NO:94, wherein the probe is 15-500 nucleotides in length.

15. The method of claim 1, wherein the step of determining the presence or absence of allele G of polymorphic marker rs10757278 in a nucleic acid sample obtained from the individual comprises at least one nucleic acid analysis technique selected from: polymerase chain reaction, allele-specific hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5'-exonuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation analysis.

16. The method of claim 1, wherein the step of determining a susceptibility to arterial disease is performed using a computer readable medium on which is stored: an identifier for allele G of polymorphic marker rs10757278; an indicator of the frequency of allele G of polymorphic marker rs10757278 in a plurality of individuals diagnosed with arterial disease; and an indicator of the frequency of allele G of polymorphic marker rs10757278 in a plurality of reference individuals.

17. The method of claim 1, wherein the step of determining a susceptibility to arterial disease is performed using an apparatus that comprises: a computer readable memory, a processor, and a routine stored on the computer readable memory; wherein the routine is adapted to be executed on the processor to analyze marker information for at least one human individual with respect to allele G of polymorphic marker rs10757278, and generate an output based on the marker information, wherein the output comprises an individual risk measure of allele G of polymorphic marker rs10757278 as a genetic indicator of arterial disease for the human individual.

18. A method of genotyping a nucleic acid sample obtained from a human individual at risk for, or diagnosed with, arterial disease, comprising determining the presence or absence of allele G of polymorphic marker rs10757278 in the sample, and diagnosing an increased genetic susceptibility to the arterial disease for the human individual from the presence of the G allele, or diagnosing a decreased genetic susceptibility to the arterial disease for the human individual from the absence of the G allele.

19. The method according to claim 18, wherein the allele G is determined to be present, and the individual is determined to have an increased susceptibility to arterial disease.

20. The method according to claim 18, wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm.

21. A method for determining a susceptibility to arterial disease in a human individual, comprising: analyzing nucleic acid from the individual for evidence in LD block C09 of the presence of allele G of polymorphic marker rs10757278, and determining an increased susceptibility to arterial disease in the human individual from evidence that rs10757278, allele G, is present in the individual, or determining a decreased susceptibility to arterial disease from evidence that rs10757278, allele G, is absent in the individual.

22. The method of claim 21, wherein a susceptibility to arterial disease for the individual is determined using an apparatus that comprises: a computer readable memory, a processor, and a routine stored on the computer readable memory; wherein the routine is adapted to be executed on the processor to analyze marker information for at least one human individual with respect to allele G of polymorphic marker rs10757278, and generate an output based on the nucleic acid sequence information of the individual, wherein the output comprises a determination of an increased susceptibility to breast cancer in the human individual from evidence that allele G of polymorphic marker rs10757278 is present in the nucleic acid sequence of the individual, or a determination of a decreased susceptibility to breast cancer from evidence that allele G of polymorphic marker rs10757278 is absent from the nucleic acid sequence of the individual.

23. The method according to claim 21, wherein the individual is determined to have an increased susceptibility to arterial disease from evidence that the allele G is present in the nucleic acid from the individual.

24. The method according to claim 21 wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm.

25. The method according to claim 21, wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, intracranial aneurysm and abdominal aorta aneurysm.

26. The method of claim 21, wherein the analyzing of the nucleic acid of the individual comprises at least one nucleic acid analysis technique selected from: polymerase chain reaction, allele-specific hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5'-exonuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation analysis.

27. A method of assessing a susceptibility to arterial disease in a human individual, comprising: analyzing a nucleic acid sample from the individual, to determine a presence or an absence of allele G of polymorphic marker rs10757278 in the sample, and assessing susceptibility to arterial disease from the nucleic acid analysis, wherein the presence of the G allele is indicative of an increased susceptibility to arterial disease in humans, and the absence of the G allele is indicative of a decreased susceptibility to the arterial disease.

28. The method according to claim 27, wherein the allele G is determined to be present, and the individual is determined to have an increased susceptibility to arterial disease.

29. The method according to claim 27, wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm.

30. The method according to claim 27, wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, intracranial aneurysm and abdominal aorta aneurysm.

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