Single Nucleotide Polymorphisms as Prognostic Tool to Diagnose Adverse Drug Reactions (Adr) and Drug Efficacy

Abstract

The invention provides diagnostic methods and kits including oligo and/or polynucleotides or derivatives, including as well antibodies determining whether a human subject is at risk of getting adverse drug reaction after statin therapy or whether the human subject is a high or low responder or a good a or bad metabolizer of statins. The invention provides further diagnostic methods and kits including antibodies determining whether a human subject is at risk for a cardiovascular disease. Still further the invention provides polymorphic sequences and other genes. The present invention further relates to isolated polynucleotides encoding a phenotype associated (PA) gene polypeptide useful in methods to identify therapeutic agents and useful for preparation of a medicament to treat cardiovascular disease or influence drug response, the polynucleotide is selected from the group comprising: SEQ ID 1-131 with allelic variation as indicated in the sequences section contained in a functional surrounding like full length cDNA for PA gene polypeptide and with or without the PA gene promoter sequence. Sequences: The sequence section contains all phenotype associated (‘PA’) SNPs and adjacent genomic sequences. The position of the polymorphisms that were used for the association studies (‘baySNP’) is indicated. Sometimes additional variations are found in the surrounding genomic sequence, that are marked by it's respective IUPAC code. Although those surrounding SNPs were not explicitly analyzed, they likely exhibit a similar association to a phenotype as the baySNP (due to linkage disequilibrium, Reich D. E. et al. Nature 411, 199-204, 2001).

Description

TECHNICAL FIELD

This invention relates to genetic polymorphisms useful for assessing the response to lipid lowering drug therapy and adverse drug reactions of those medicaments. In addition it relates to genetic polymorphisms useful for assessing cardiovascular risks in humans, including, but not limited to, atherosclerosis, ischemia/reperfusion, hypertension, restenosis, arterial inflammation, myocardial infarction, and stroke. Specifically, the present invention identifies and describes gene variations which are individually present in humans with cardiovascular disease states, relative to humans with normal, or non-cardiovascular disease states, and/or in response to medications relevant to cardiovascular disease. Further, the present invention provides methods for the identification and therapeutic use of compounds as treatments of cardiovascular disease or as prophylactic therapy for cardiovascular diseases. Moreover, the present invention provides methods for the diagnostic monitoring of patients undergoing clinical evaluation for the treatment of cardiovascular disease, and for monitoring the efficacy of compounds in clinical trials. Still further, the present invention provides methods to use gene variations to predict personal medication schemes omitting adverse drug reactions and allowing an adjustment of the drug dose to achieve maximum benefit for the patient. Additionally, the present invention describes methods for the diagnostic evaluation and prognosis of various cardiovascular diseases, and for the identification of subjects exhibiting a predisposition to such conditions.

BACKGROUND OF THE INVENTION

Cardiovascular disease is a major health risk throughout the industrialized world.

Cardiovascular diseases include but are not limited by the following disorders of the heart and the vascular system: congestive heart failure, myocardial infarction, atherosclerosis, ischemic diseases of the heart, coronary heart disease, all kinds of atrial and ventricular arrhythmias, hypertensive vascular diseases and peripheral vascular diseases.

Heart failure is defined as a pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirement of the metabolizing tissue. It includes all forms of pumping failure such as high-output and low-output, acute and chronic, right-sided or left-sided, systolic or diastolic, independent of the underlying cause.

Myocardial infarction (MI) is generally caused by an abrupt decrease in coronary blood flow that follows a thrombotic occlusion of a coronary artery previously narrowed by arteriosclerosis. MI prophylaxis (primary and secondary prevention) is included as well as the acute treatment of MI and the prevention of complications.

Ischemic diseases are conditions in which the coronary flow is restricted resulting in an perfusion which is inadequate to meet the myocardial requirement for oxygen. This group of diseases include stable angina, unstable angina and asymptomatic ischemia.

Arrhythmias include all forms of atrial and ventricular tachyarrhythmias (atrial tachycardia, atrial flutter, atrial fibrillation, atrio-ventricular reentrant tachycardia, preexitation syndrome, ventricular tachycardia, ventricular flutter, ventricular fibrillation) as well as bradycardic forms of arrhythmias.

Hypertensive vascular diseases include primary as well as all kinds of secondary arterial hypertension (renal, endocrine, neurogenic, others).

Peripheral vascular diseases are defined as vascular diseases in which arterial and/or venous flow is reduced resulting in an imbalance between blood supply and tissue oxygen demand. It includes chronic peripheral arterial occlusive disease (PAOD), acute arterial thrombosis and embolism, inflammatory vascular disorders, Raynaud's phenomenon and venous disorders.

Atherosclerosis, the most prevalent of vascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principal cause of death. Atherosclerosis is a complex disease involving many cell types and molecular factors (for a detailed review, see Ross, 1993, Nature 362: 801-809 and Lusis, A. J., Nature 407, 233-241 (2000)). The process, in normal circumstances a protective response to insults to the endothelium and smooth muscle cells (SMCs) of the wall of the artery, consists of the formation of fibrofatty and fibrous lesions or plaques, preceded and accompanied by inflammation. The advanced lesions of atherosclerosis may occlude the artery concerned, and result from an excessive inflammatory-fibroproliferative response to numerous different forms of insult. For example, shear stresses are thought to be responsible for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures.

The first observable event in the formation of an atherosclerotic plaque occurs when blood-borne monocytes adhere to the vascular endothelial layer and transmigrate through to the sub-endothelial space. Adjacent endothelial cells at the same time produce oxidized low density lipoprotein (LDL). These oxidized LDLs are then taken up in large amounts by the monocytes through scavenger receptors expressed on their surfaces. In contrast to the regulated pathway by which native LDL (nLDL) is taken up by nLDL specific receptors, the scavenger pathway of uptake is not regulated by the monocytes.

These lipid-filled monocytes are called foam cells, and are the major constituent of the fatty streak. Interactions between foam cells and the endothelial and SMCs which surround them lead to a state of chronic local inflammation which can eventually lead to smooth muscle cell proliferation and migration, and the formation of a fibrous plaque. Such plaques occlude the blood vessel concerned and thus restrict the flow of blood, resulting in ischemia.

Ischemia is a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion. Such inadequate perfusion can have number of natural causes, including atherosclerotic or restenotic lesions, anemia, or stroke, to name a few. Many medical interventions, such as the interruption of the flow of blood during bypass surgery, for example, also lead to ischemia. In addition to sometimes being caused by diseased cardiovascular tissue, ischemia may sometimes affect cardiovascular tissue, such as in ischemic heart disease. Ischemia may occur in any organ, however, that is suffering a lack of oxygen supply.

The most common cause of ischemia in the heart is atherosclerotic disease of epicardial coronary arteries. By reducing the lumen of these vessels, atherosclerosis causes an absolute decrease in myocardial perfusion in the basal state or limits appropriate increases in perfusion when the demand for flow is augmented. Coronary blood flow can also be limited by arterial thrombi, spasm, and, rarely, coronary emboli, as well as by ostial narrowing due to luetic aortitis. Congenital abnormalities, such as anomalous origin of the left anterior descending coronary artery from the pulmonary artery, may cause myocardial ischemia and infarction in infancy, but this cause is very rare in adults. Myocardial ischemia can also occur if myocardial oxygen demands are abnormally increased, as in severe ventricular hypertrophy due to hypertension or aortic stenosis. The latter can be present with angina that is indistinguishable from that caused by coronary atherosclerosis. A reduction in the oxygen-carrying capacity of the blood, as in extremely severe anemia or in the presence of carboxy-hemoglobin, is a rare cause of myocardial ischemia. Not infrequently, two or more causes of ischemia will coexist, such as an increase in oxygen demand due to left ventricular hypertrophy and a reduction in oxygen supply secondary to coronary atherosclerosis.

The foregoing studies are aimed at defining the role of particular gene variations presumed to be involved in the misleading of normal cellular function leading to cardiovascular disease. However, such approaches cannot identify the full panoply of gene variations that are involved in the disease process.

At present, the only available treatments for cardiovascular disorders are pharmaceutical based medications that are not targeted to an individual's actual defect; examples include angiotensin converting enzyme (ACE) inhibitors and diuretics for hypertension, insulin supplementation for non-insulin dependent diabetes mellitus (NIDDM), cholesterol reduction strategies for dyslipidaemia, anticoagulants, β blockers for cardiovascular disorders and weight reduction strategies for obesity. If targeted treatment strategies were available it might be possible to predict the response to a particular regime of therapy and could markedly increase the effectiveness of such treatment. Although targeted therapy requires accurate diagnostic tests for disease susceptibility, once these tests are developed the opportunity to utilize targeted therapy will become widespread. Such diagnostic tests could initially serve to identify individuals at most risk of hypertension and could allow them to make changes in lifestyle or diet that would serve as preventative measures. The benefits associated by coupling the diagnostic tests with a system of targeted therapy could include the reduction in dosage of administered drugs and thus the amount of unpleasant side effects suffered by an individual. In more severe cases a diagnostic test may suggest that earlier surgical intervention would be useful in preventing a further deterioration in condition.

It is an object of the invention to provide genetic diagnosis of predisposition or susceptibility for cardiovascular diseases. Another related object is to provide treatment to reduce or prevent or delay the onset of disease in those predisposed or susceptible to this disease. A further object is to provide means for carrying out this diagnosis.

Accordingly, a first aspect of the invention provides a method of diagnosis of disease in an individual, said method comprising determining one, various or all genotypes in said individual of the genes listed in the Examples.

In another aspect, the invention provides a method of identifying an individual predisposed or susceptible to a disease, said method comprising determining one, various or all genotypes in said individual of the genes listed in the Examples.

The invention is of advantage in that it enables diagnosis of a disease or of certain disease states via genetic analysis which can yield useable results before onset of disease symptoms, or before onset of severe symptoms. The invention is further of advantage in that it enables diagnosis of predisposition or susceptibility to a disease or of certain disease states via genetic analysis.

The invention may also be of use in confirming or corroborating the results of other diagnostic methods. The diagnosis of the invention may thus suitably be used either as an isolated technique or in combination with other methods and apparatus for diagnosis, in which latter case the invention provides a further test on which a diagnosis may be assessed.

The present invention stems from using allelic association as a method for genotyping individuals; allowing the investigation of the molecular genetic basis for cardiovascular diseases. In a specific embodiment the invention tests for the polymorphisms in the sequences of the listed genes in the Examples. The invention demonstrates a link between this polymorphisms and predispositions to cardiovascular diseases by showing that allele frequencies significantly differ when individuals with “bad” serum lipids are compared to individuals with “good” serum levels. The meaning of “good and bad” serum lipid levels is defined in Table 1a.

Certain disease states would benefit, that is to say the suffering of the patient may be reduced or prevented or delayed, by administration of treatment or therapy in advance of disease appearance; this can be more reliably carried out if advance diagnosis of predisposition or susceptibility to disease can be diagnosed.

Pharmacogenomics and Adverse Drug Reactions

Adverse drug reactions (ADRs) remain a major clinical problem. A recent meta-analysis suggested that in the USA in 1994, ADRs were responsible for 100000 deaths, making them between the fourth and sixth commonest cause of death (Lazarou 1998, J. Am. Med. Assoc. 279:1200). Although these figures have been heavily criticized, they emphasize the importance of ADRs. Indeed, there is good evidence that ADRs account for 5% of all hospital admissions and increase the length of stay in hospital by two days at an increased cost of ˜$2500 per patient. ADRs are also one of the commonest causes of drug withdrawal, which has enormous financial implications for the pharmaceutical industry. ADRs, perhaps fortunately, only affect a minority of those taking a particular drug. Although factors that determine susceptibility are unclear in most cases, there is increasing interest in the role of genetic factors. Indeed, the role of inheritable variations in predisposing patients to ADRs has been appreciated since the late 1950s and early 1960s through the discovery of deficiencies in enzymes such as pseudocholinesterase (butyrylcholinesterase) and glucose-6-phosphate dehydrogenase (G6PD). More recently, with the first draft of the human genome just completed, there has been renewed interest in this area with the introduction of terms such as pharmacogenomics and toxicogenomics. Essentially, the aim of pharmacogenomics and pharmacogenetics is to produce personalized medicines, whereby administration of the drug class and dosage is tailored to an individual genotype. Thus, the term pharmacogenetics embraces both efficacy and toxicity.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) specifically inhibit the enzyme HMG-CoA reductase which catalyzes the rate limiting step in cholesterol biosynthesis. These drugs are effective in reducing the primary and secondary risk of coronary artery disease and coronary events, such as heart attack, in middle-aged and older men and women, in both diabetic and non-diabetic patients, and are often prescribed for patients with hyperlipidemia. Statins used in secondary prevention of coronary artery or heart disease significantly reduce the risk of stroke, total mortality and morbidity and attacks of myocardial ischemia; the use of statins is also associated with improvements in endothelial and fibrinolytic functions and decreased platelet thrombus formation.

The tolerability of these drugs during long term administration is an important issue. Adverse reactions involving skeletal muscle are not uncommon, and sometimes serious adverse reactions involving skeletal muscle such as myopathy and rhabdomyolysis may occur, requiring discontinuation of the drug. In addition an increase in serum creatine kinase (CK) may be a sign of a statin related adverse event. The extend of such adverse events can be read from the extend of the CK level increase (as compared to the upper limit of normal [ULN]).

Occasionally arthralgia, alone or in association with myalgia, has been reported. Also an elevation of liver transaminases has been associated with statin administration.

It was shown that the drug response to statin therapy is a class effects, i.e. all known and presumably also all so far undiscovered statins share the same beneficial and harmful effects (Ucar, M. et al., Drug Safety 2000, 22:441). It follows that the discovery of diagnostic tools to predict the drug response to a single statin will also be of aid to guide therapy with other statins.

The present invention provides diagnostic tests to predict the patient's individual response to statin therapy. Such responses include, but are not limited by the extent of adverse drug reactions, the level of lipid lowering or the drug's influence on disease states. Those diagnostic tests may predict the response to statin therapy either alone or in combination with another diagnostic test or another drug regimen.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based at least in part on the discovery that a specific allele of a polymorphic region of a so called “candidate gene” (as defined below) is associated with CVD or drug response.

For the present invention the following candidate genes were analyzed:

• • Genes found to be expressed in cardiac tissue (Hwang et al., Circulation 1997, 96:4146-4203).
  • Genes from the following metabolic pathways and their regulatory elements:

Lipid Metabolism

Numerous studies have shown a connection between serum lipid levels and cardiovascular diseases. Candidate genes falling into this group include but are not limited by genes of the cholesterol pathway, apolipoproteins and their modifying factors.

Coagulation

Ischemic diseases of the heart and in particular myocardial infarction may be caused by a thrombotic occlusion. Genes falling into this group include all genes of the coagulation cascade and their regulatory elements.

Inflammation

Complications of atherosclerosis are the most common causes of death in Western societies. In broad outline atherosclerosis can be considered to be a form of chronic inflammation resulting from interaction modified lipoproteins, monocyte-derived macrophages, T cells, and the normal cellular elements of the arterial wall. This inflammatory process can ultimately lead to the development of complex lesions, or plaques, that protrude into the arterial lumen. Finally plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction and stroke (Glass et al., Cell 2001, 104:503-516).

It follows that all genes related to inflammatory processes, including but not limited by cytokines, cytokine receptors and cell adhesion molecules are candidate genes for CVD.

Glucose and Energy Metabolism

As glucose and energy metabolism is interdependent with the metabolism of lipids (see above) also the former pathways contain candidate genes. Energy metabolism in general also relates to obesity, which is an independent risk factor for CVD (Melanson et al., Cardiol Rev 2001 9:202-207). In addition high blood glucose levels are associated with many microvascular and macrovascular complications and may therefore affect an individuals disposition to CVD (Duckworth, Curr Atheroscler Rep 2001, 3:383-391).

Hypertension

As hypertension is an independent risk factor for CVD, also genes that are involved in the regulation of systolic and diastolic blood pressure affect an individuals risk for CVD (Safar, Curr Opin Cardiol 2000, 15:258-263). Interestingly hypertension and diabetes (see above) appear to be interdependent, since hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons (Sowers et al., Hypertension 2001, 37:1053-1059).

Genes Related to Drug Response

Those genes include metabolic pathways involved in the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. Prominent members of this group are the cytochrome P450 proteins which catalyze many reactions involved in drug metabolism.

Unclassified Genes

As stated above, the mechanisms that lead to cardiovascular diseases or define the patient's individual response to drugs are not completely elucidated. Hence also candidate genes were analysed, which could not be assigned to the above listed categories. The present invention is based at least in part on the discovery of polymorphisms, that lie in genomic regions of unknown physiological function.

Results

After conducting an association study, we surprisingly found polymorphic sites in a number of candidate genes which show a strong correlation with the following phenotypes of the patients analysed: “Healthy” as used herein refers to individuals that neither suffer from existing CVD, nor exhibit an increased risk for CVD through their serum lipid level profile. “CVD prone” as used herein refers to individuals with existing CVD and/or a serum lipid profile that confers a high risk to get CVD (see Table 1a for definitions of healthy and CVD prone serum lipid levels). “High responder” as used herein refers to patients who benefit from relatively small amounts of a given drug. “Low responder” as used herein refers to patients who need relatively high doses in order to obtain benefit from the medication. “Tolerant patient” refers to individuals who can tolerate high doses of a medicament without exhibiting adverse drug reactions. “ADR patient” as used herein refers to individuals who suffer from ADR or show clinical symptoms (like creatine kinase elevation in blood) even after receiving only minor doses of a medicament (see Table 1b for a detailed definition of drug response phenotypes).

Polymorphic sites in candidate genes that were found to be significantly associated with either of the above mentioned phenotypes will be referred to as “phenotype associated SNPs” (PA SNPs). The respective genomic loci that harbour PA SNPs will be referred to as “phenotype associated genes” (PA genes), irrespective of the actual function of this gene locus.

In particular we surprisingly found PA SNPs associated with CVD, drug efficacy (EFF) or adverse drug reactions (ADR) in the following genes:

ABCA1: ATP-Binding Cassette, Sub-Family A (ABC1), Member 1

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesterol efflux pump in the cellular lipid removal pathway. Mutations in this gene have been associated with Tangier's disease and familial high-density lipoprotein deficiency.

ABCB1: ATP-Binding Cassette, Sub-Family B (MDR/TAP), Member 1

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier.

ACACB: Acetyl-Coenzyme A Carboxylase Beta

Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. There is evidence for the presence of two ACC-beta isoforms.

ADRB3: Adrenergic, Beta-3-, Receptor

The ADRB3 gene product, beta-3-adrenergic receptor, is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis. Beta adrenergic receptors are involved in the epenephrine and norepinephrine-induced activation of adenylate cyclase through the action of G proteins.

AKAP1: A Kinase (PRKA) Anchor Protein 1

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in 2 transcript variants encoding 2 isoforms with different sizes. Both of the isoforms bind to types I and R regulatory subunits of PKA and anchor them to mitochondria. As compared to the longer isoform, the shorter isoform lacks a K-homologous motif, which is an RNA-binding domain typically associated with proteins involved in RNA catalysis, mRNA processing, or translation. The longer isoform is speculated to be involved in the cAMP-dependent signal transduction pathway and in directing RNA to a specific cellular compartment. The function of the shorter isoform has not been determined.

AKAP10: A Kinase (PRKA) Anchor Protein 10

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein interacts with both the type I and type II regulatory subunits of PKA; therefore, it is a dual-specific AKAP. This protein is highly enriched in mitochondria. It contains RGS (regulator of G protein signalling) domains, in addition to a PKA-RII subunit-binding domain. The mitochondrial localization and the presence of RGS domains may have important implications for the function of this protein in PKA and G protein signal transduction.

AKAP13: A Kinase (PRKA) Anchor Protein 13

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in at least 3 transcript variants encoding different isoforms containing a dbI oncogene homology (DH) domain and a pleckstrin homology (PH) domain. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway and, in addition, function as protein kinase A-anchoring proteins.

AMPD1: Adenosine Monophosphate Deaminase 1 (Isoform M)

Adenosine monophosphate deaminase 1 catalyzes the deamination of AMP to IMP in skeletal muscle and plays an important role in the purine nucleotide cycle. Two other genes have been identified, AMPD2 and AMPD3, for the liver- and erythocyte-specific isoforms, respectively. Deficiency of the muscle-specific enzyme is apparently a common cause of exercise-induced myopathy and probably the most common cause of metabolic myopathy in the human.

APOE: Apolipoprotein E

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. Apolipoprotein E, a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells. ApoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. The APOE gene is mapped to chromosome 19 in a cluster with APOC1 and APOC2. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants.

APOM: Apolipoprotein M

The protein encoded by this gene is an apolipoprotein and member of the lipocalin protein family. It is found associated with high density lipoproteins and to a lesser extent with low density lipoproteins and triglyceride-rich lipoproteins. The encoded protein is secreted through the plasma membrane but remains membrane-bound, where it is involved in lipid transport. Two transcript variants encoding two different isoforms have been found for this gene, but only one of them has been fully characterized.

ARHGAP1: Rho GTPase Activating Protein 1

GTPase-activating protein for rho, rac and Cdc42Hs; has an SH3 binding domain

ATP1A2: ATPase, Na+/K+ Transporting, Alpha 2 (+) Polypeptide

ATP2A1: ATPase, Ca++ Transporting, Cardiac Muscle, Fast Twitch 1

This gene encodes one of the SERCA Ca (2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in two transcript variants encoding different isoforms.

BAT3: HLA-B Associated Transcript 3

A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. The protein encoded by this gene is a nuclear protein. It has been implicated in the control of apoptosis and regulating heat shock protein. There are three alternatively spliced transcript variants described for this gene.

BAT4: HLA-B Associated Transcript 4

A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. The protein encoded by this gene is thought to be involved in some aspects of immunity.

BAT5: HLA-B Associated Transcript 5

A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. These genes are all within the human major histocompatibility complex class III region. The protein encoded by this gene is thought to be involved in some aspects of immunity.

BRD3: Bromodomain Containing 3

This gene was identified based on its homology to the gene encoding the RING3 protein, a serine/threonine kinase. The gene localizes to 9q34, a region which contains several major histocompatibility complex (MHC) genes. The function of the encoded protein is not known.

CDC42BPB: CDC42 Binding Protein Kinase Beta (DMPK-Like)

The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein contains a Cdc42/Rac-binding p21 binding domain resembling that of PAK kinase. The kinase domain of this protein is most closely related to that of myotonic dystrophy kinase-related ROK. Studies of the similar gene in rat suggested that this kinase may act as a downstream effector of Cdc42 in cytoskeletal reorganization.

CDC42EP2: CDC42 Effector Protein (Rho GTPase Binding) 2

CDC42, a small Rho GTPase, regulates the formation of F-actin-containing structures through its interaction with the downstream effector proteins. The protein encoded by this gene is a member of the Borg family of CDC42 effector proteins. Borg family proteins contain a CRIB (Cdc42/Rac interactive-binding) domain. They bind to, and negatively regulate the function of, CDC42. Coexpression of this protein with dominant negative mutant CDC42 protein in fibroblast was found to induce pseudopodia formation, which suggested a role of this protein in actin filament assembly and cell shape control.

CDC42EP3: CDC42 Effector Protein (Rho GTPase Binding) 3

CDC42, a small Rho GTPase, regulates the formation of F-actin-containing structures through its interaction with the downstream effector proteins. The protein encoded by this gene is a member of the Borg family of CDC42 effector proteins. Borg family proteins contain a CRIB (Cdc42/Rac interactive-binding) domain. They bind to, and negatively regulate the function of, CDC42. This protein can interact with CDC42, as well as with the ras homolog gene family, member Q (ARHQ/TC10). Expression of this protein in fibroblasts has been shown to induce pseudopodia formation.

CDC42EP4: CDC42 Effector Protein (Rho GTPase Binding) 4

The product of this gene is a member of the CDC42-binding protein family. Members of this family interact with Rho family GTPases and regulate the organization of the actin cytoskeleton. This protein has been shown to bind both CDC42 and TC10 GTPases in a GTP-dependent manner. When overexpressed in fibroblasts, this protein was able to induce pseudopodia formation, which suggested a role in inducing actin filament assembly and cell shape control.

CENPC1: Centromere Protein C 1

Centromere protein C 1 is a centromere autoantigen and a component of the inner kinetochore plate. The protein is required for maintaining proper kinetochore size and a timely transition to anaphase. A putative psuedogene exists on chromosome 12.

CETP: Cholesteryl Ester Transfer Protein, Plasma

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters between lipoproteins. CETP may effect susceptibility to atherosclerosis.

CPB2: Carboxypeptidase B2 (Plasma, Carboxypeptidase U)

Carboxypeptidases are enzymes that hydrolyze C-terminal peptide bonds. The carboxypeptidase family includes metallo-, serine, and cysteine carboxypeptidases. According to their substrate specificity, these enzymes are referred to as carboxypeptidase A (cleaving aliphatic residues) or carboxypeptidase B (cleaving basic amino residues). The protein encoded by this gene is activated by trypsin and acts on carboxypeptidase B substrates. After thrombin activation, the mature protein downregulates fibrinolysis. Polymorphisms have been described for this gene and its promoter region. Available sequence data analyses indicate splice variants that encode different isoforms.

CROT: Carnitine O-Octanoyltransferase

CSF2: Colony Stimulating Factor 2 (Granulocyte-Macrophage) IL3: Interleukin 3 (Colony-Stimulating Factor, Multiple)

The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q-syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13.

DFNA5: Deafness, Autosomal Dominant 5

Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene.

F2: Coagulation Factor II (Thrombin)

Coagulation factor II is proteolytically cleaved to form thrombin in the first step of the coagulation cascade which ultimately results in the stemming of blood loss. F2 also plays a role in maintaining vascular integrity during development and postnatal life. Mutations in F2 leads to various forms of thrombosis and dysprothrombinemia.

FKBP1A: FK506 Binding Protein 1A, 12 kDa

The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin. It interacts with several intracellular signal transduction proteins including type I TGF-beta receptor. It also interacts with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor. In mouse, deletion of this homologous gene causes congenital heart disorder known as noncompaction of left ventricular myocardium. There is evidence of multiple alternatively spliced transcript variants for this gene, but the full length nature of some variants has not been determined.

FYN: FYN Oncogene Related to SRC, FGR, YES

This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist.

GHR: Growth Hormone Receptor

Biologically active growth hormone (MIM 139250) binds its transmembrane receptor (GHR), which dimerizes to activate an intracellular signal transduction pathway leading to synthesis and secretion of insulin-like growth factor I (IGF1; MIM 147440). In plasma, IGF1 binds to the soluble IGF1 receptor (IGF1R; MIM 147370). At target cells, this complex activates signal-transduction pathways that result in the mitogenic and anabolic responses that lead to growth. [supplied by OMIM]

HSPA9B: Heat Shock 70 kDa Protein 9B (Mortalin-2)

The product encoded by this gene belongs to the heat shock protein 70 family which contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate proteins. This gene encodes a heat-shock cognate protein. This protein plays a role in the control of cell proliferation. It may also act as a chaperone.

IQGAP1: IQ Motif Containing GTPase Activating Protein 1

IQGAP2: IQ Motif Containing GTPase Activating Protein 2

LAG3: Lymphocyte-Activation Gene 3

Lymphocyte-activation protein 3 belongs to Ig superfamily and contains 4 extracellular Ig-like domains. The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4.

LCAT: Lecithin-Cholesterol Acyltransferase

This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency.

LCP2: Lymphocyte Cytosolic Protein 2 (SH2 Domain Containing Leukocyte Protein of 76 kDa)

SLP-76 was originally identified as a substrate of the ZAP-70 protein tyrosine kinase following T cell receptor (TCR) ligation in the leukemic T cell line Jurkat. The SLP-76 locus has been localized to human chromosome 5q33 and the gene structure has been partially characterized in mice. The human and murine cDNAs both encode 533 amino acid proteins that are 72% identical and comprised of three modular domains. The NH2-terminus contains an acidic region that includes a PEST domain and several tyrosine residues which are phosphorylated following TCR ligation. SLP-76 also contains a central proline-rich domain and a COOH-terminal SH2 domain. A number of additional proteins have been identified that associate with SLP-76 both constitutively and inducibly following receptor ligation, supporting the notion that SLP-76 functions as an adaptor or scaffold protein. Studies using SLP-76 deficient T cell lines or mice have provided strong evidence that SLP-76 plays a positive role in promoting T cell development and ac

LIF: Leukemia Inhibitory Factor (Cholinergic Differentiation Factor)

Leukaemia inhibitory factor is a cytokine that induces macrophage differentiation. Neurotransmitters and neuropeptides, well known for their role in the communication between neurons, are also capable of activating monocytes and macrophages and inducing chemotaxis in immune cells. LIF signals through different receptors and transcription factors. LIF in conjunction with BMP2 acts in synergy on primary fetal neural progenitor cells to induce astrocytes.

LIMK1: LIM Domain Kinase 1

There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs and a C-terminal protein kinase domain. LIMK1 is likely to be a component of an intracellular signaling pathway and may be involved in brain development. LIMK1 hemizygosity is implicated in the impaired visuospatial constructive cognition of Williams syndrome. Two splice variant have been identified.

LIPA: Lipase A, Lysosomal Acid, Cholesterol Esterase (Wolman Disease)

LIPA encodes lipase A, the lysosomal acid lipase (also known as cholesteryl ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in LIPA can result in Wolman disease and cholesteryl ester storage disease.

LPA: Lipoprotein, Lp(a)

LPL: Lipoprotein Lipase

LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism.

LTA: Lymphotoxin Alpha (TNF Superfamily, Member 1)

Lymphotoxin alpha, a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. LTA is highly inducible, secreted, and exists as homotrimeric molecule. LTA forms heterotrimers with lymphotoxin-beta which anchors lymphotoxin-alpha to the cell surface. LTA mediates a large variety of inflammatory, immunostimulatory, and antiviral responses. LTA is also involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis.

MTND4L: NADH Dehydrogenase 4L

NDUFA6: NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex, 6, 14 kDa

NDUFB10: NADH Dehydrogenase (Ubiquinone) 1 Beta Subcomplex, 10, 22 kDa

Subunit of NADH-ubiquinone oxidoreductase (complex I); transports electrons from NADH to ubiquinone

NDUFB5: NADH Dehydrogenase (Ubiquinone) 1 Beta Subcomplex, 5, 16 kDa

The protein encoded by this gene is a subunit of the multisubunit NADH: ubiquinone oxido-reductase (complex I). Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxido-reductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.

NDUFC2: NADH Dehydrogenase (Ubiquinone) 1, Subcomplex Unknown, 2, 14.5 kDa

Subunit of NADH-ubiquinone oxidoreductase (complex I); transports electrons from NADH to ubiquinone

NF1: Neurofibromin 1 (Neurofibromatosis, Von Recklinghausen Disease, Watson Disease)

Mutations linked to neurofibromatosis type 1 led to the identification of NF1. NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the ras signal transduction pathway. In addition to type 1 neurofibromatosis, mutations in NF1 can also lead to juvenile myelomonocytic leukemia. Alternatively spliced NF1 mRNA transcripts have been isolated, although their functions, if any, remain unclear.

GRAF: GTPase Regulator Associated with Focal Adhesion Kinase Pp125(FAK)

SPC25: AD024-Protein

TOSO: Regulator of Fas-Induced Apoptosis

ZNF202: Zinc Finger Protein 202

PAK2: P21 (CDKN1A)-Activated Kinase 2

The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.

PDCD6IP: Programmed Cell Death 6 Interacting Protein

This gene encodes a protein thought to participate in programmed cell death. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization which may be partly responsible for the protection against cell death.

PDE4D: Phosphodiesterase 4D, cAMP-Specific (Phosphodiesterase E3 Dunce Homolog, Drosophila

CAMP-specific phosphodiesterase 4D; has similarity to Drosophila dnc, which is the affected protein in learning and memory mutant dunce

PDGFRA: Platelet-Derived Growth Factor Receptor, Alpha Polypeptide

This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies in knockout mice, where homozygosity is lethal, indicate that the alpha form of the platelet-derived growth factor receptor is particularly important for kidney development since mice heterozygous for the receptor exhibit defective kidney phenotypes.

PFKM: Phosphofructokinase, Muscle

PLA2G4C: Phospholipase A2, Group IVC (Cytosolic, Calcium-Independent)

PLP1: Proteolipid Protein 1 (Pelizaeus-Merzbacher Disease, Spastic Paraplegia 2, Uncomplicated)

PPP1R12C: Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 12C

Low similarity to MYPT2

PRKAR2B: Protein Kinase, Camp-Dependent, Regulatory, Type II, Beta

PRKCB1: Protein Kinase C, Beta 1

PTK2B: PTK2B Protein Tyrosine Kinase 2 Beta

This gene encodes a cytoplasmic protein tyrosine kinase which is involved in calcium-induced regulation of ion channels and activation of the map kinase signaling pathway. The encoded protein may represent an important signaling intermediate between neuropeptide-activated receptors or neurotransmitters that increase calcium flux and the downstrearm signals that regulate neuronal activity. The encoded protein undergoes rapid tyrosine phosphorylation and activation in response to increases in the intracellular calcium concentration, nicotinic acetylcholine receptor activation, membrane depolarization, or protein kinase C activation. This protein has been shown to bind CRK-associated substrate, nephrocystin, GTPase regulator associated with FAK, and the SH2 domain of GRB2. The encoded protein is a member of the FAK subfamily of protein tyrosine kinases but lacks significant sequence similarity to kinases from other subfamilies. Four transcript variants encoding two different isoforms have been found for this gene

PYGM: Phosphorylase, Glycogen; Muscle (McArdle Syndrome, Glycogen Storage Disease Type V)

RABGGTA: Rab Geranylgeranyltransferase, Alpha Subunit

RYR1: Ryanodine Receptor 1 (Skeletal)

RYR3: Ryanodine Receptor 3

SCARB1: Scavenger Receptor Class B, Member 1

SCO2: SCO Cytochrome Oxidase Deficient Homolog 2 (Yeast)

Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog of the yeast SCO2 gene.

SELE: Selectin E (Endothelial Adhesion Molecule 1)

The endothelial leukocyte adhesion molecule-1 is expressed by cytokine-stimulated endothelial cells. It is thought to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. It exhibits structural features such as the presence of lectin- and EGF-like domains followed by short consensus repeat (SCR) domains that contain 6 conserved cysteine residues. These proteins are part of the selectin family of cell adhesion molecules. This gene is present in single copy in the human genome and contains 14 exons spanning about 13 kb of DNA. Adhesion molecules participate in the interaction between leukocytes and the endothelium and appear to be involved in the pathogenesis of atherosclerosis.

SEPP1: Selenoprotein P, Plasma, 1

Selenoprotein P is an extracellular glycoprotein and is the only selenoprotein known to contain multiple selenocysteine residues. Two isoforms of this protein are Sep51 and Sep61. Sep51 lacks part of the C-terminal sequence. Selenoprotein P binds heparin and associates with endothelial cells. They are implicated as an oxidant defense in the extracellular space and in the transport of selenium.

SERPINA1: Serine (or Cysteine) Proteinase Inhibitor, Clade A (Alpha-1 Antiproteinase, Antitrypsin), Member 1

Alpha-1-antitrypsin is a protease inhibitor, deficiency of which is associated with emphysema and liver disease. The protein is encoded by a gene (PI) located on the distal long arm of chromosome 14. [supplied by OMIM]

SERPINA5: Serine (or Cysteine) Proteinase Inhibitor, Clade A (Alpha-1 Antiproteinase, Antitrypsin), Member 5

SERPINB2: Serine (or Cysteine) Proteinase Inhibitor, Clade B (Ovalbumin), Member 2

SLC6A8: Solute Carrier Family 6 (Neurotransmitter Transporter, Creatine), Member 8

Sodium and chloride-dependent creatine transporter; member of neurotransmitter transporter family

SSA1: Sjogren Syndrome Antigen A1 (52 kDa, Ribonucleoprotein Autoantigen SS-A/Ro)

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This protein is part of the RoSSA ribonucleoprotein which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. RoSSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. The function of the RoSSA particle has not been determined. Two alternatively spliced transcript variants for this gene have been described; however, the full length nature of one variant has not been determined.

STCH: Stress 70 Protein Chaperone, Microsome-Associated, 60 kDa

SULT1A2: Sulfotransferase Family, Cytosolic, 1A, Phenol-Preferring, Member 2

Sulfotransferase enzymes catalyze the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. These cytosolic enzymes are different in their tissue distributions and substrate specificities. The gene structure (number and length of exons) is similar among family members. This gene encodes one of two phenol sulfotransferases with thermostable enzyme activity. Two alternatively spliced variants that encode the same protein have been described.

SYK: Spleen Tyrosine Kinase

TAP1: Transporter 1, ATP-Binding Cassette, Sub-Family B (MDR/TAP)

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease.

TAP2: Transporter 2, ATP-Binding Cassette, Sub-Family B (MDR/TAP)

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. This gene is located 7 kb telomeric to gene family member ABCB2. The protein encoded by this gene is involved in antigen presentation. This protein forms a heterodimer with ABCB2 in order to transport peptides from the cytoplasm to the endoplasmic reticulum. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Alternative splicing of this gene produces two products which differ in peptide selectivity and level of restoration of surface expression of MHC class I molecules.

THBD: Thrombomodulin

TRIM28: Tripartite Motif-Containing 28 LocusID:

TRIP10: Thyroid Hormone Receptor Interactor 10

Similar to the non-kinase domains of FER and Fes/Fps tyrosine kinases; binds to activated Cdc42 and may regulate actin cytoskeleton; contains an SH3 domain

UGT2B15: UDP Glycosyltransferase 2 Family, Polypeptide B15

VEGF: Vascular Endothelial Growth Factor

Many polypeptide mitogens, such as basic fibroblast growth factor (MIM 134920) and platelet-derived growth factors (MIM 173430, MIM 190040), are active on a wide range of different cell types. In contrast, vascular endothelial growth factor is a mitogen primarily for vascular endothelial cells. It is, however, structurally related to platelet-derived growth factor

WASL: Wiskott-Aldrich Syndrome-Like

The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. The WASL gene product is a homolog of WAS protein, however, unlike the latter, it is ubiquitously expressed and shows highest expression in neural tissues. It has been shown to bind Cdc42 directly, and induce formation of long actin microspikes.

CACNA2D2: Calcium Channel, Voltage-Dependent, Alpha 2/Delta Subunit 2

TFAP2B: Transcription Factor AP-2 Beta (Activating Enhancer Binding Protein 2 Beta)

TRIT1: tRNA Isopentenyltransferase 1

This enzyme modifies both cytoplasmic and mitochondrial tRNAs at A(37) to give isopentenyl A(37).

UGT2A1: UDP Glycosyltransferase 2 Family, Polypeptide A1

As PA SNPs are linked to other SNPs in neighboring genes on a chromosome (Linkage Disequilibrium) those SNPs could also be used as marker SNPs. In a recent publication it was shown that SNPs are linked over 100 kb in some cases more than 150 kb (Reich D. E. et al. Nature 411, 199-204, 2001). Hence SNPs lying in regions neighbouring PA SNPs could be linked to the latter and by this being a diagnostic marker. These associations could be performed as described for the gene polymorphism in methods.

Definitions

For convenience, the meaning of certain terms and phrases employed in the specification, examples, and appended claims are provided below. Moreover, the definitions by itself are intended to explain a further background of the invention.

The term “allele”, which is used interchangeably herein with “allelic variant” refers to alternative forms of a gene or portions thereof. Alleles occupy the same locus or position on homologous chromosomes. When a subject has two identical alleles of a gene, the subject is said to be homozygous for the gene or allele. When a subject has two different alleles of a gene, the subject is said to be heterozygous for the gene. Alleles of a specific gene can differ from each other in a single nucleotide, or several nucleotides, and can include substitutions, deletions, and insertions of nucleotides. An allele of a gene can also be a form of a gene containing a mutation.

The term “allelic variant of a polymorphic region of a gene” refers to a region of a gene having one of several nucleotide sequences found in that region of the gene in other individuals.

“Homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An “unrelated” or “non-homologous” sequence shares less than 40% identity, though preferably less than 25% identity, with one of the sequences of the present invention.

The term “a homologue of a nucleic acid” refers to a nucleic acid having a nucleotide sequence having a certain degree of homology with the nucleotide sequence of the nucleic acid or complement thereof. A homologue of a double stranded nucleic acid having SEQ ID NO. X is intended to include nucleic acids having a nucleotide sequence which has a certain degree of homology with SEQ ID NO. X or with the complement thereof. Preferred homologous of nucleic acids are capable of hybridizing to the nucleic acid or complement thereof.

The term “interact” as used herein is meant to include detectable interactions between molecules, such as can be detected using, for example, a hybridization assay.

The term interact is also meant to include “binding” interactions between molecules. Interactions may be, for example, protein-protein, protein-nucleic acid, protein-small molecule or small molecule-nucleic acid in nature.

The term “intronic sequence” or “intronic nucleotide sequence” refers to the nucleotide sequence of an intron or portion thereof.

The term “isolated” as used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively, that are present in the natural source of the macromolecule. The term isolated as used herein also refers to a nucleic acid or peptide that is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.

Moreover, an “isolated nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used herein to refer to polypeptides which are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides.

The term “lipid” shall refer to a fat or fat-like substance that is insoluble in polar solvents such as water. The term “lipid” is intended to include true fats (e.g. esters of fatty acids and glycerol); lipids (phospholipids, cerebrosides, waxes); sterols (cholesterol, ergosterol) and lipoproteins (e.g. HDL, LDL and VLDL).

The term “locus” refers to a specific position in a chromosome. For example, a locus of a gene refers to the chromosomal position of the gene.

The term “modulation” as used herein refers to both up-regulation, (i.e., activation or stimulation), for example by agonizing, and down-regulation (i.e. inhibition or suppression), for example by antagonizing of a bioactivity (e.g. expression of a gene).

The term “molecular structure” of a gene or a portion thereof refers to the structure as defined by the nucleotide content (including deletions, substitutions, additions of one or more nucleotides), the nucleotide sequence, the state of methylation, and/or any other modification of the gene or portion thereof.

The term “mutated gene” refers to an allelic form of a gene, which is capable of altering the phenotype of a subject having the mutated gene relative to a subject which does not have the mutated gene. If a subject must be homozygous for this mutation to have an altered phenotype, the mutation is said to be recessive. If one copy of the mutated gene is sufficient to alter the genotype of the subject, the mutation is said to be dominant. If a subject has one copy of the mutated gene and has a phenotype that is intermediate between that of a homozygous and that of a heterozygous (for that gene) subject, the mutation is said to be co-dominant.

As used herein, the term “nucleic acid” refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to include, as equivalents, derivatives, variants and analogs of either RNA or DNA made from nucleotide analogs, including peptide nucleic acids (PNA), morpholino oligonucleotides (J. Summerton and D. Weller, Antisense and Nucleic Acid Drug Development 7:187 (1997)) and, as applicable to the embodiment being described, single (sense or antisense) and double-stranded polynucleotides. Deoxyribonucleotides include deoxyadenosine, deoxycytidine, deoxyguanosine, and deoxythymidine. For purposes of clarity, when referring herein to a nucleotide of a nucleic acid, which can be DNA or an RNA, the term “adenosine”, “cytidine”, “guanosine”, and “thymidine” are used. It is understood that if the nucleic acid is RNA, a nucleotide having a uracil base is uridine.

The term “nucleotide sequence complementary to the nucleotide sequence set forth in SEQ ID NO. x” refers to the nucleotide sequence of the complementary strand of a nucleic acid strand having SEQ ID NO. x. The term “complementary strand” is used herein interchangeably with the term “complement”. The complement of a nucleic acid strand can be the complement of a coding strand or the complement of a non-coding strand. When referring to double stranded nucleic acids, the complement of a nucleic acid having SEQ ID NO. x refers to the complementary strand of the strand having SEQ ID NO. x or to any nucleic acid having the nucleotide sequence of the complementary strand of SEQ ID NO. x. When referring to a single stranded nucleic acid having the nucleotide sequence SEQ ID NO. x, the complement of this nucleic acid is a nucleic acid having a nucleotide sequence which is complementary to that of SEQ ID NO. x. The nucleotide sequences and complementary sequences thereof are always given in the 5′ to 3′ direction. The term “complement” and “reverse complement” are used interchangeably herein.

The term “operably linked” is intended to mean that the promoter is associated with the nucleic acid in such a manner as to facilitate transcription of the nucleic acid.

The term “polymorphism” refers to the coexistence of more than one form of a gene or portion thereof. A portion of a gene of which there are at least two different forms, i.e., two different nucleotide sequences, is referred to as a “polymorphic region of a gene”. A polymorphic region can be a single nucleotide, the identity of which differs in different alleles. A polymorphic region can also be several nucleotides long.

A “polymorphic gene” refers to a gene having at least one polymorphic region.

To describe a “polymorphic site” in a nucleotide sequence often there is used an “ambiguity code” that stands for the possible variations of nucleotides in one site. The list of ambiguity codes is summarized in the following table:

Ambiguity Codes (IUPAC
Nomenclature)
B c/g/t
D a/g/t
H a/c/t
K g/t
M a/c
N a/c/g/t
R a/g
S c/g
V a/c/g
W a/t
Y c/t

So, for example, a “R” in a nucleotide sequence means that either an “a” or a “g” could be at that position.

The terms “protein”, “polypeptide” and “peptide” are used interchangeably herein when referring to a gene product.

A “regulatory element”, also termed herein “regulatory sequence is intended to include elements which are capable of modulating transcription from a basic promoter and include elements such as enhancers and silencers. The term “enhancer”, also referred to herein as “enhancer element”, is intended to include regulatory elements capable of increasing, stimulating, or enhancing transcription from a basic promoter. The term “silencer”, also referred to herein as “silencer element” is intended to include regulatory elements capable of decreasing, inhibiting, or repressing transcription from a basic promoter. Regulatory elements are typically present in 5′ flanking regions of genes. However, regulatory elements have also been shown to be present in other regions of a gene, in particular in introns. Thus, it is possible that genes have regulatory elements located in introns, exons, coding regions, and 3′ flanking sequences. Such regulatory elements are also intended to be encompassed by the present invention and can be identified by any of the assays that can be used to identify regulatory elements in 5′ flanking regions of genes.

The term “regulatory element” further encompasses “tissue specific” regulatory elements, i.e., regulatory elements which effect expression of the selected DNA sequence preferentially in specific cells (e.g., cells of a specific tissue). gene expression occurs preferentially in a specific cell if expression in this cell type is significantly higher than expression in other cell types. The term “regulatory element” also encompasses non-tissue specific regulatory elements, i.e., regulatory elements which are active in most cell types. Furthermore, a regulatory element can be a constitutive regulatory element, i.e., a regulatory element which constitutively regulates transcription, as opposed to a regulatory element which is inducible, i.e., a regulatory element which is active primarily in response to a stimulus. A stimulus can be, e.g., a molecule, such as a hormone, cytokine, heavy metal, phorbol ester, cyclic AMP (cAMP), or retinoic acid.

Regulatory elements are typically bound by proteins, e.g., transcription factors. The term “transcription factor” is intended to include proteins or modified forms thereof, which interact preferentially with specific nucleic acid sequences, i.e., regulatory elements, and which in appropriate conditions stimulate or repress transcription. Some transcription factors are active when they are in the form of a monomer. Alternatively, other transcription factors are active in the form of a dimer consisting of two identical proteins or different proteins (heterodimer). Modified forms of transcription factors are intended to refer to transcription factors having a post-translational modification, such as the attachment of a phosphate group. The activity of a transcription factor is frequently modulated by a post-translational modification. For example, certain transcription factors are active only if they are phosphorylated on specific residues. Alternatively, transcription factors can be active in the absence of phosphorylated residues and become inactivated by phosphorylation. A list of known transcription factors and their DNA binding site can be found, e.g., in public databases, e.g., TFMATRIX Transcription Factor Binding Site Profile database.

As used herein, the term “specifically hybridizes” or “specifically detects” refers to the ability of a nucleic acid molecule of the invention to hybridize to at least approximately 6, 12, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130 or 140 consecutive nucleotides of either strand of a gene.

The term “wild-type allele” refers to an allele of a gene which, when present in two copies in a subject results in a wild-type phenotype. There can be several different wild-type alleles of a specific gene, since certain nucleotide changes in a gene may not affect the phenotype of a subject having two copies of the gene with the nucleotide changes.

“Adverse drug reaction” (ADR) as used herein refers to an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which

predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product. In it's most severe form an ADR might lead to the death of an individual.

The term “Drug Response” is intended to mean any response that a patient exhibits upon drug administration. Specifically drug response includes beneficial, i.e. desired drug effects, ADR or no detectable reaction at all. More specifically the term drug response could also have a qualitative meaning, i.e. it embraces low or high beneficial effects, respectively and mild or severe ADR, respectively. The term “Statin Response” as used herein refers to drug response after statin administration. An individual drug response includes also a good or bad metabolizing of the drug, meaning that “bad metabolizers” accumulate the drug in the body and by this could show side effects of the drug due to accumulative overdoses.

“Candidate gene” as used herein includes genes that can be assigned to either normal cardiovascular function or to metabolic pathways that are related to onset and/or progression of cardiovascular diseases.

With regard to drug response the term “candidate gene” includes genes that can be assigned to distinct phenotypes regarding the patient's response to drug administration. Those phenotypes may include patients who benefit from relatively small amounts of a given drug (high responders) or patients who need relatively high doses in order to obtain the same benefit (low responders). In addition those phenotypes may include patients who can tolerate high doses of a medicament without exhibiting ADR, or patients who suffer from ADR even after receiving only low doses of a medicament.

As neither the development of cardiovascular diseases nor the patient's response to drug administration is completely understood, the term “candidate gene” may also comprise genes with presently unknown function.

“PA SNP” (phenotype associated SNP) refers to a polymorphic site which shows a significant association with a patients phenotype (healthy, diseased, low or high responder, drug tolerant, ADR prone, etc.)

“PA gene” (phenotype associated gene) refers to a genomic locus harbouring a PA SNP, irrespective of the actual function of this gene locus.

PA gene polypeptide refers to a polypeptide encoded at least in part by a PA gene.

The term “Secondary SNP” is intended to mean a SNP that is in neighborhood to at least one other (“primary”) SNP. Due to linkage disequilibrium both primary and secondary SNP(s) might shown a similar association with a phenotype.

The term “Haplotype” as used herein refers to a group of two or more SNPs that are functionally and/or spatially linked. I.e. haplotypes define groups of SNPs that lie inside genes belonging to identical (or related metabolic) pathways and/or lie on the same chromosome. Haplotypes are expected to give better predictive/diagnostic information than a single SNP

The term “statin” is intended to embrace all inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins specifically inhibit the enzyme HMG-CoA reductase which catalyzes the rate limiting step in cholesterol biosynthesis. Known statins are Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin and Simvastatin.

Methods for Assessing Cardiovascular Status

The present invention provides diagnostic methods for assessing cardiovascular status in a human individual. Cardiovascular status as used herein refers to the physiological status of an individual's cardiovascular system as reflected in one or more markers or indicators. Status markers include without limitation clinical measurements such as, e.g., blood pressure, electrocardiographic profile, and differentiated blood flow analysis as well as measurements of LDL- and HDL-Cholesterol levels, other lipids and other well established clinical parameters that are standard in the art. Status markers according to the invention include diagnoses of one or more cardiovascular syndromes, such as, e.g., hypertension, acute myocardial infarction, silent myocardial infarction, stroke, and atherosclerosis. It will be understood that a diagnosis of a cardiovascular syndrome made by a medical practitioner encompasses clinical measurements and medical judgement. Status markers according to the invention are assessed using conventional methods well known in the art. Also included in the evaluation of cardiovascular status are quantitative or qualitative changes in status markers with time, such as would be used, e.g., in the determination of an individual's response to a particular therapeutic regimen.

The methods are carried out by the steps of:

(i) determining the sequence of one or more polymorphic positions within one, several or all of the genes listed in Examples or other genes mentioned in this file in the individual to establish a polymorphic pattern for the individual; and

(ii) comparing the polymorphic pattern established in (i) with the polymorphic patterns of humans exhibiting different markers of cardiovascular status. The polymorphic pattern of the individual is, preferably, highly similar and, most preferably, identical to the poly-morphic pattern of individuals who exhibit particular status markers, cardiovascular syndromes, and/or particular patterns of response to therapeutic interventions. Poly-morphic patterns may also include polymorphic positions in other genes which are shown, in combination with one or more polymorphic positions in the genes listed in the Examples, to correlate with the presence of particular status markers. In one embodiment, the method involves comparing an individual's polymorphic pattern with polymorphic patterns of individuals who have been shown to respond positively or negatively to a particular therapeutic regimen. Therapeutic regimen as used herein refers to treatments aimed at the elimination or amelioration of symptoms and events associated cardiovascular disease. Such treatments include without limitation one or more of alteration in diet, lifestyle, and exercise regimen; invasive and noninvasive surgical techniques such as atherectomy, angioplasty, and coronary bypass surgery; and pharmaceutical interventions, such as administration of ACE inhibitors, angiotensin II receptor antagonists, diuretics, alpha-adrenoreceptor antagonists, cardiac glycosides, phosphodiesterase inhibitors, beta-adrenoreceptor antagonists, calcium channel blockers, HMG-CoA reductase inhibitors, imidazoline receptor blockers, endothelin receptor blockers, organic nitrites, and modulators of protein function of genes listed in the Examples. Interventions with pharmaceutical agents not yet known whose activity correlates with particular polymorphic patterns associated with cardiovascular disease are also encompassed. It is contemplated, for example, that patients who are candidates for a particular therapeutic regimen will be screened for polymorphic patterns that correlate with responsivity to that particular regimen.

In a preferred embodiment, the method involves comparing an individual's polymorphic pattern with polymorphic patterns of individuals who exhibit or have exhibited one or more markers of cardiovascular disease, such as, e.g., elevated LDL-Cholesterol levels, high blood pressure, abnormal electrocardiographic profile, myocardial infarction, stroke, or atherosclerosis.

In another embodiment, the method involves comparing an individual's polymorphic pattern with polymorphic patterns of individuals who exhibit or have exhibited one or more drug related phenotypes, such as, e.g., low or high drug response, or adverse drug reactions.

In practicing the methods of the invention, an individual's polymorphic pattern can be established by obtaining DNA from the individual and determining the sequence at predetermined polymorphic positions in the genes such as those described in this file.

The DNA may be obtained from any cell source. Non-limiting examples of cell sources available in clinical practice include blood cells, buccal cells, cervicovaginal cells, epithelial cells from urine, fetal cells, or any cells present in tissue obtained by biopsy. Cells may also be obtained from body fluids, including without limitation blood, saliva, sweat, urine, cerebrospinal fluid, feces, and tissue exudates at the site of infection or inflammation. DNA is extracted from the cell source or body fluid using any of the numerous methods that are standard in the art. It will be understood that the particular method used to extract DNA will depend on the nature of the source.

Diagnostic and Prognostic Assays

The present invention provides methods for determining the molecular structure of at least one polymorphic region of a gene, specific allelic variants of said polymorphic region being associated with cardiovascular disease. In one embodiment, determining the molecular structure of a polymorphic region of a gene comprises determining the identity of the allelic variant. A polymorphic region of a gene, of which specific alleles are associated with cardiovascular disease can be located in an exon, an intron, at an intron/exon border, or in the promoter of the gene.

The invention provides methods for determining whether a subject has, or is at risk, of developing a cardiovascular disease. Such disorders can be associated with an aberrant gene activity, e.g., abnormal binding to a form of a lipid, or an aberrant gene protein level. An aberrant gene protein level can result from an aberrant transcription or post-transcriptional regulation. Thus, allelic differences in specific regions of a gene can result in differences of gene protein due to differences in regulation of expression. In particular, some of the identified polymorphisms in the human gene may be associated with differences in the level of transcription, RNA maturation, splicing, or translation of the gene or transcription product.

In preferred embodiments, the methods of the invention can be characterized as comprising detecting, in a sample of cells from the subject, the presence or absence of a specific allelic variant of one or more polymorphic regions of a gene. The allelic differences can be: (i) a difference in the identity of at least one nucleotide or (ii) a difference in the number of nucleotides, which difference can be a single nucleotide or several nucleotides.

A preferred detection method is allele specific hybridization using probes overlapping the polymorphic site and having about 5, 10, 20, 25, or 30 nucleotides around the polymorphic region. Examples of probes for detecting specific allelic variants of the polymorphic region located in intron X are probes comprising a nucleotide sequence set forth in any of SEQ ID NO. X. In a preferred embodiment of the invention, several probes capable of hybridizing specifically to allelic variants are attached to a solid phase support, e.g., a “chip”. Oligonucleotides can be bound to a solid support by a variety of processes, including lithography. For example a chip can hold up to 250,000 oligonucleotides (GeneChip, Affymetrix). Mutation detection analysis using these chips comprising oligonucleotides, also termed “DNA probe arrays” is described e.g., in Cronin et al. (1996) Human Mutation 7:244 and in Kozal et al. (1996) Nature Medicine 2:753. In one embodiment, a chip comprises all the allelic variants of at least one polymorphic region of a gene. The solid phase support is then contacted with a test nucleic acid and hybridization to the specific probes is detected. Accordingly, the identity of numerous allelic variants of one or more genes can be identified in a simple hybridization experiment. For example, the identity of the allelic variant of the nucleotide polymorphism of nucleotide A or G at position 33 of Seq ID 1 (baySNP179) and that of other possible polymorphic regions can be determined in a single hybridization experiment.

In other detection methods, it is necessary to first amplify at least a portion of a gene prior to identifying the allelic variant. Amplification can be performed, e.g., by PCR and/or LCR, according to methods known in the art. In one embodiment, genomic DNA of a cell is exposed to two PCR primers and amplification for a number of cycles sufficient to produce the required amount of amplified DNA. In preferred embodiments, the primers are located between 40 and 350 base pairs apart. Preferred primers for amplifying gene fragments of genes of this file are listed in Table 2 in the Examples.

Alternative amplification methods include: self sustained sequence replication (Guatelli, J. C. et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1173-1177), Q-Beta Replicase (Lizardi, P. M. et al., 1988, Bio/Technology 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

In one embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence at least a portion of a gene and detect allelic variants, e.g., mutations, by comparing the sequence of the sample sequence with the corresponding wild-type (control) sequence. Exemplary sequencing reactions include those based on techniques developed by Maxam and Gilbert (Proc. Natl. Acad Sci USA (1977) 74:560) or Sanger (Sanger et al (1977) Proc. Nat. Acad. Sci 74:5463). It is also contemplated that any of a variety of automated sequencing procedures may be utilized when performing the subject assays (Biotechniques (1995) 19:448), including sequencing by mass spectrometry (see, for example, U.S. Pat. No. 5,547,835 and international patent application Publication Number WO 94/16101, entitled DNA Sequencing by Mass Spectrometry by H. Koster; U.S. Pat. No. 5,547,835 and international patent application Publication Number WO 94/21822 entitled “DNA Sequencing by Mass Spectrometry Via Exonuclease Degradation” by H. Koster), and U.S. Pat. No. 5,605,798 and International Patent Application No. PCT/US96/03651 entitled DNA Diagnostics Based on Mass Spectrometry by H. Koster; Cohen et al. (1996) Adv Chromatogr 36:127-162; and Griffin et al. (1993) Appl Biochem Biotechnol 38:147-159). It will be evident to one skilled in the art that, for certain embodiments, the occurrence of only one, two or three of the nucleic acid bases need be determined in the sequencing reaction. For instance, A-track or the like, e.g., where only one nucleotide is detected, can be carried out.

Yet other sequencing methods are disclosed, e.g., in U.S. Pat. No. 5,580,732 entitled “Method of DNA sequencing employing a mixed DNA-polymer chain probe” and U.S. Pat. No. 5,571,676 entitled “Method for mismatch-directed in vitro DNA sequencing”.

In some cases, the presence of a specific allele of a gene in DNA from a subject can be shown by restriction enzyme analysis. For example, a specific nucleotide polymorphism can result in a nucleotide sequence comprising a restriction site which is absent from the nucleotide sequence of another allelic variant.

In other embodiments, alterations in electrophoretic mobility is used to identify the type of gene allelic variant. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc Natl. Acad. Sci USA 86:2766, see also Cotton (1993) Mutat Res 285:125-144; and Hayashi (1992) Genet Anal Tech Appl 9:73-79). Single-stranded DNA fragments of sample and control nucleic acids are denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using PNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In another preferred embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet 7:5).

In yet another embodiment, the identity of an allelic variant of a polymorphic region is obtained by analyzing the movement of a nucleic acid comprising the polymorphic region in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al (1985) Nature 313:495). When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing agent gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys Chem 265:1275).

Examples of techniques for detecting differences of at least one nucleotide between 2 nucleic acids include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide probes may be prepared in which the known polymorphic nucleotide is placed centrally (allele-specific probes) and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163); Saiki et al (1989) Proc. Natl. Acad. Sci USA 86:6230; and Wallace et al. (1979) Nucl. Acids Res. 6:3543). Such allele specific oligonucleotide hybridization techniques may be used for the simultaneous detection of several nucleotide changes in different polymorphic regions of gene. For example, oligonucleotides having nucleotide sequences of specific allelic variants are attached to a hybridizing membrane and this membrane is then hybridized with labeled sample nucleic acid. Analysis of the hybridization signal will then reveal the identity of the nucleotides of the sample nucleic acid.

Alternatively, allele specific amplification technology which depends on selective PCR amplification may be used. Oligonucleotides used as primers for specific amplification may carry the allelic variant of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3′ end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech 11:238; Newton et al. (1989) Nucl. Acids Res. 17:2503). This technique is also termed “PROBE” for Probe Oligo Base Extension. In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al (1992) Mol. Cell Probes 6:1).

In another embodiment, identification of the allelic variant is carried out using an oligonucleotide ligation assay (OLA), as described, e.g., in U.S. Pat. No. 4,998,617 and in Landegren, U. et al., Science 241:1077-1080 (1988). The OLA protocol uses two oligonucleotides which are designed to be capable of hybridizing to abutting sequences of a single strand of a target. One of the oligonucleotides is linked to a separation marker, e.g., biotinylated, and the other is detectably labeled. If the precise complementary sequence is found in a target molecule, the oligonucleotides will hybridize such that their termini abut, and create a ligation substrate. Ligation then permits the labeled oligonucleotide to be recovered using avidin, or another biotin ligand. Nickerson, D. A. et al. have described a nucleic acid detection assay that combines attributes of PCR and OLA (Nickerson, D. A. et al., Proc. Natl. Acad. Sci. (U.S.A.) 87:8923-8927 (1990). In this method, PCR is used to achieve the exponential amplification of target DNA, which is then detected using OLA.

Several techniques based on this OLA method have been developed and can be used to detect specific allelic variants of a polymorphic region of a gene. For example, U.S. Pat. No. 5,593,826 discloses an OLA using an oligonucleotide having 3′-amino group and a 5′-phosphorylated oligonucleotide to form a conjugate having a phosphoramidate linkage. In another variation of OLA described in Tobe et al. ((1996) Nucleic Acids Res 24: 3728), OLA combined with PCR permits typing of two alleles in a single microtiter well. By marling each of the allele-specific primers with a unique hapten, i.e. digoxigenin and fluorescein, each LA reaction can be detected by using hapten specific antibodies that are labeled with different enzyme reporters, alkaline phosphatase or horseradish peroxidase. This system permits the detection of the two alleles using a high throughput format that leads to the production of two different colors.

The invention further provides methods for detecting single nucleotide polymorphisms in a gene. Because single nucleotide polymorphisms constitute sites of variation flanked by regions of invariant sequence, their analysis requires no more than the determination of the identity of the single nucleotide present at the site of variation and it is unnecessary to determine a complete gene sequence for each patient. Several methods have been developed to facilitate the analysis of such single nucleotide polymorphisms.

In one embodiment, the single base polymorphism can be detected by using a specialized exonuclease-resistant nucleotide, as disclosed, e.g., in Mundy, C. R. (U.S. Pat. No. 4,656,127). According to the method, a primer complementary to the allelic sequence immediately 3′ to the polymorphic site is permitted to hybridize to a target molecule obtained from a particular animal or human. If the polymorphic site on the target molecule contains a nucleotide that is complementary to the particular exonuclease-resistant nucleotide derivative present, then that derivative will be incorporated onto the end of the hybridized primer. Such incorporation renders the primer resistant to exonuclease, and thereby permits its detection. Since the identity of the exonuclease-resistant derivative of the sample is known, a finding that the primer has become resistant to exonucleases reveals that the nucleotide present in the polymorphic site of the target molecule was complementary to that of the nucleotide derivative used in the reaction. This method has the advantage that it does not require the determination of large amounts of extraneous sequence data.

In another embodiment of the invention, a solution-based method is used for determining the identity of the nucleotide of a polymorphic site. Cohen, D. et al. (French Patent 2,650,840; PCT Appln. No. WO91/02087). As in the Mundy method of U.S. Pat. No. 4,656,127, a primer is employed that is complementary to allelic sequences immediately 3′ to a polymorphic site. The method determines the identity of the nucleotide of that site using labeled dideoxynucleotide derivatives, which, if complementary to the nucleotide of the polymorphic site will become incorporated onto the terminus of the primer.

An alternative method, known as Genetic Bit Analysis or GBA TM is described by Goelet, P. et al. (PCT Appln. No. 92/15712). The method of Goelet, P. et al. uses mixtures of labeled terminators and a primer that is complementary to the sequence 3′ to a polymorphic site. The labeled terminator that is incorporated is thus determined by, and complementary to, the nucleotide present in the polymorphic site of the target molecule being evaluated. In contrast to the method of Cohen et al. (French Patent 2,650,840; PCT Appln. No. WO91/02087) the method of Goelet, P. et al. is preferably a heterogeneous phase assay, in which the primer or the target molecule is immobilized to a solid phase.

Recently, several primer-guided nucleotide incorporation procedures for assaying polymorphic sites in DNA have been described (Komher, J. S. et al., Nucl. Acids. Res. 17:7779-7784 (1989); Sokolov, B. P., Nucl. Acids Res. 18:3671 (1990); Syvanen, A.-C., et al., Genomics 8:684-692 (1990), Kuppuswamy, M. N. et al., Proc. Natl. Acad. Sci. (U.S.A.) 88:1143-1147 (1991); Prezant, T. R. et al., Hum. Mutat. 1:159-164 (1992); Ugozzoli, L. et al., GATA 9:107-112 (1992); Nyren, P. et al., Anal. Biochem. 208:171-175 (1993)). These methods differ from GBA TM in that they all rely on the incorporation of labeled deoxynucleotides to discriminate between bases at a polymorphic site. In such a format, since the signal is proportional to the number of deoxynucleotides incorporated, polymorphisms that occur in runs of the same nucleotide can result in signals that are proportional to the length of the run (Syvanen, A.-C., et al., Amer. J. Hum. Genet. 52:46-59 (1993)).

For determining the identity of the allelic variant of a polymorphic region located in the coding region of a gene, yet other methods than those described above can be used. For example, identification of an allelic variant which encodes a mutated gene protein can be performed by using an antibody specifically recognizing the mutant protein in, e.g., immunohistochemistry or immunoprecipitation. Antibodies to wild-type gene protein are described, e.g., in Acton et al. (1999) Science 271:518 (anti-mouse gene antibody cross-reactive with human gene). Other antibodies to wild-type gene or mutated forms of gene proteins can be prepared according to methods known in the art. Alternatively, one can also measure an activity of an gene protein, such as binding to a lipid or lipoprotein. Binding assays are known in the art and involve, e.g., obtaining cells from a subject, and performing binding experiments with a labeled lipid, to determine whether binding to the mutated form of the receptor differs from binding to the wild-type of the receptor.

If a polymorphic region is located in an exon, either in a coding or non-coding region of the gene, the identity of the allelic variant can be determined by determining the molecular structure of the mRNA, pre-mRNA, or cDNA. The molecular structure can be determined using any of the above described methods for determining the molecular structure of the genomic DNA, e.g., sequencing and SSCP.

The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits, such as those described above, comprising at least one probe or primer nucleic acid described herein, which may be conveniently used, e.g., to determine whether a subject has or is at risk of developing a disease associated with a specific gene allelic variant.

Sample nucleic acid for using in the above-described diagnostic and prognostic methods can be obtained from any cell type or tissue of a subject. For example, a subject's bodily fluid (e.g. blood) can be obtained by known techniques (e.g. venipuncture) or from human tissues like heart (biopsies, transplanted organs). Alternatively, nucleic acid tests can be performed on dry samples (e.g. hair or skin). Fetal nucleic acid samples for prenatal diagnostics can be obtained from maternal blood as described in International Patent Application No. WO91/07660 to Bianchi. Alternatively, amniocytes or chorionic villi may be obtained for performing prenatal testing.

Diagnostic procedures may also be performed in situ directly upon tissue sections (fixed and/or frozen) of patient tissue obtained from biopsies or resections, such that no nucleic acid purification is necessary. Nucleic acid reagents may be used as probes and/or primers for such in situ procedures (see, for example, Nuovo, G. J., 1992, PCR in situ hybridization: protocols and applications, Raven Press, New York).

In addition to methods which focus primarily on the detection of one nucleic acid sequence, profiles may also be assessed in such detection schemes. Fingerprint profiles may be generated, for example, by utilizing a differential display procedure, Northern analysis and/or RT-PCR.

In practicing the present invention, the distribution of polymorphic patterns in a large number of individuals exhibiting particular markers of cardiovascular status or drug response is determined by any of the methods described above, and compared with the distribution of polymorphic patterns in patients that have been matched for age, ethnic origin, and/or any other statistically or medically relevant parameters, who exhibit quantitatively or qualitatively different status markers. Correlations are achieved using any method known in the art, including nominal logistic regression, chi square tests or standard least squares regression analysis. In this manner, it is possible to establish statistically significant correlations between particular polymorphic patterns and particular cardiovascular statuses (given in p values). It is further possible to establish statistically significant correlations between particular polymorphic patterns and changes in cardiovascular status or drug response such as, would result, e.g., from particular treatment regimens. In this manner, it is possible to correlate polymorphic patterns with responsivity to particular treatments.

In another embodiment of the present invention two or more polymorphic regions are combined to define so called ‘haplotypes’. Haplotypes are groups of two or more SNPs that are functionally and/or spatially linked. It is possible to combine SNPs that are disclosed in the present invention either with each other or with additional polymorphic regions to form a haplotype. Haplotypes are expected to give better predictive/diagnostic information than a single SNP.

In a preferred embodiment of the present invention a panel of SNPs/haplotypes is defined that predicts the risk for CVD or drug response. This predictive panel is then used for genotyping of patients on a platform that can genotype multiple SNPs at the same time (Multiplexing). Preferred platforms are e.g. gene chips (Affymetrix) or the Luminex LabMAP reader. The subsequent identification and evaluation of a patient's haplotype can then help to guide specific and individualized therapy.

For example the present invention can identify patients exhibiting genetic polymorphisms or haplotypes which indicate an increased risk for adverse drug reactions. In that case the drug dose should be lowered in a way that the risk for ADR is diminished. Also if the patient's response to drug administration is particularly high (or the patient is badly metabolizing the drug), the drug dose should be lowered to avoid the risk of ADR.

In turn if the patient's response to drug administration is low (or the patient is a particularly high metabolizer of the drug), and there is no evident risk of ADR, the drug dose should be raised to an efficacious level.

It is self evident that the ability to predict a patient's individual drug response should affect the formulation of a drug, i.e. drug formulations should be tailored in a way that they suit the different patient classes (low/high responder, poor/good metabolizer, ADR prone patients). Those different drug formulations may encompass different doses of the drug, i.e. the medicinal products contains low or high amounts of the active substance. In another embodiment of the invention the drug formulation may contain additional substances that facilitate the beneficial effects and/or diminish the risk for ADR (Folkers et al. 1991, U.S. Pat. No. 5,316,765).

Isolated Polymorphic Nucleic Acids, Probes, and Vectors

The present invention provides isolated nucleic acids comprising the polymorphic positions described herein for human genes; vectors comprising the nucleic acids; and transformed host cells comprising the vectors. The invention also provides probes which are useful for detecting these polymorphisms.

In practicing the present invention, many conventional techniques in molecular biology, microbiology, and recombinant DNA, are used. Such techniques are well known and are explained fully in, for example, Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; DNA Cloning: A Practical Approach, Volumes I and II, 1985 (D. N. Glover ed.); Oligonucleotide Synthesis, 1984, (M. L. Gait ed.); Nucleic Acid Hybridization, 1985, (Hames and Higgins); Ausubel et al., Current Protocols in Molecular Biology, 1997, (John Wiley and Sons); and Methods in Enzymology Vol. 154 and Vol. 155 (Wu and Grossman, and Wu, eds., respectively).

Insertion of nucleic acids (typically DNAs) comprising the sequences in a functional surrounding like full length cDNA of the present invention into a vector is easily accomplished when the termini of both the DNAs and the vector comprise compatible restriction sites. If this cannot be done, it may be necessary to modify the termini of the DNAs and/or vector by digesting back single-stranded DNA overhangs generated by restriction endonuclease cleavage to produce blunt ends, or to achieve the same result by filling in the single-stranded termini with an appropriate DNA polymerase.

Alternatively, any site desired may be produced, e.g., by ligating nucleotide sequences (linkers) onto the termini. Such linkers may comprise specific oligonucleotide sequences that define desired restriction sites. Restriction sites can also be generated by the use of the polymerase chain reaction (PCR). See, e.g., Saiki et al., 1988, Science 239:48. The cleaved vector and the DNA fragments may also be modified if required by homopolymeric tailing.

The nucleic acids may be isolated directly from cells or may be chemically synthesized using known methods. Alternatively, the polymerase chain reaction (PCR) method can be used to produce the nucleic acids of the invention, using either chemically synthesized strands or genomic material as templates. Primers used for PCR can be synthesized using the sequence information provided herein and can further be designed to introduce appropriate new restriction sites, if desirable, to facilitate incorporation into a given vector for recombinant expression.

The nucleic acids of the present invention may be flanked by native gene sequences, or may be associated with heterologous sequences, including promoters, enhancers, response elements, signal sequences, polyadenylation sequences, introns, 5′- and 3′-noncoding regions, and the like. The nucleic acids may also be modified by many means known in the art. Non-limiting examples of such modifications include methylation, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, morpholines etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.). Nucleic acids may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators. PNAs are also included. The nucleic acid may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the nucleic acid sequences of the present invention may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, biotin, and the like.

The invention also provides nucleic acid vectors comprising the gene sequences or derivatives or fragments thereof of genes described in the Examples. A large number of vectors, including plasmid and fungal vectors, have been described for replication and/or expression in a variety of eukaryotic and prokaryotic hosts, and may be used for gene therapy as well as for simple cloning or protein expression. Non-limiting examples of suitable vectors include without limitation pUC plasmids, pET plasmids (Novagen, Inc., Madison, Wis.), or pRSET or pREP (Invitrogen, San Diego, Calif.), and many appropriate host cells, using methods disclosed or cited herein or otherwise known to those skilled in the relevant art. The particular choice of vector/host is not critical to the practice of the invention.

Suitable host cells may be transformed/transfected/infected as appropriate by any suitable method including electroporation, CaCl₂ mediated DNA uptake, fungal or viral infection, microinjection, microprojectile, or other established methods. Appropriate host cells included bacteria, archebacteria, fungi, especially yeast, and plant and animal cells, especially mammalian cells. A large number of transcription initiation and termination regulatory regions have been isolated and shown to be effective in the transcription and translation of heterologous proteins in the various hosts. Examples of these regions, methods of isolation, manner of manipulation, etc. are known in the art. Under appropriate expression conditions, host cells can be used as a source of recombinantly produced peptides and polypeptides encoded by genes of the Examples. Nucleic acids encoding peptides or polypeptides from gene sequences of the Examples may also be introduced into cells by recombination events. For example, such a sequence can be introduced into a cell and thereby effect homologous recombination at the site of an endogenous gene or a sequence with substantial identity to the gene. Other recombination-based methods such as non-homologous recombinations or deletion of endogenous genes by homologous recombination may also be used.

In case of proteins that form heterodimers or other multimers, both or all subunits have to be expressed in one system or cell.

The nucleic acids of the present invention find use as probes for the detection of genetic polymorphisms and as templates for the recombinant production of normal or variant peptides or polypeptides encoded by genes listed in the Examples.

Probes in accordance with the present invention comprise without limitation isolated nucleic acids of about 10-100 bp, preferably 15-75 bp and most preferably 17-25 bp in length, which hybridize at high stringency to one or more of the polymorphic sequences disclosed herein or to a sequence immediately adjacent to a polymorphic position. Furthermore, in some embodiments a full-length gene sequence may be used as a probe. In one series of embodiments, the probes span the polymorphic positions in genes disclosed herein. In another series of embodiments, the probes correspond to sequences immediately adjacent to the polymorphic positions.

Polymorphic Polypeptides and Polymorphism-Specific Antibodies

The present invention encompasses isolated peptides and polypeptides encoded by genes listed in the Examples comprising polymorphic positions disclosed herein. In one preferred embodiment, the peptides and polypeptides are useful screening targets to identify cardiovascular drugs. In another preferred embodiments, the peptides and polypeptides are capable of eliciting antibodies in a suitable host animal that react specifically with a polypeptide comprising the polymorphic position and distinguish it from other polypeptides having a different sequence at that position.

Polypeptides according to the invention are preferably at least five or more residues in length, preferably at least fifteen residues. Methods for obtaining these polypeptides are described below. Many conventional techniques in protein biochemistry and immunology are used. Such techniques are well known and are explained in Immunochemical Methods in Cell and Molecular Biology, 1987 (Mayer and Waler, eds; Academic Press, London); Scopes, 1987, Protein Purification: Principles and Practice, Second Edition (Springer-Verlag, N.Y.) and Handbook of Experimental immunology, 1986, Volumes I-IV (Weir and Blackwell eds.).

Nucleic acids comprising protein-coding sequences can be used to direct the ITT recombinant expression of polypeptides encoded by genes disclosed herein in intact cells or in cell-free translation systems. The known genetic code, tailored if desired for more efficient expression in a given host organism, can be used to synthesize oligonucleotides encoding the desired amino acid sequences. The polypeptides may be isolated from human cells, or from heterologous organisms or cells (including, but not limited to, bacteria, fungi, insect, plant, and mammalian cells) into which an appropriate protein-coding sequence has been introduced and expressed. Furthermore, the polypeptides may be part of recombinant fusion proteins.

Peptides and polypeptides may be chemically synthesized by commercially available automated procedures, including, without limitation, exclusive solid phase synthesis, partial solid phase methods, fragment condensation or classical solution synthesis. The polypeptides are preferably prepared by solid phase peptide synthesis as described by Merrifield, 1963, J. Am. Chem. Soc. 85:2149.

Methods for polypeptide purification are well-known in the art, including, without limitation, preparative disc-gel electrophoresis, isoelectric focusing, HPLC, reversed-phase HPLC, gel filtration, ion exchange and partition chromatography, and countercurrent distribution. For some purposes, it is preferable to produce the polypeptide in a recombinant system in which the protein contains an additional sequence tag that facilitates purification, such as, but not limited to, a polyhistidine sequence. The polypeptide can then be purified from a crude lysate of the host cell by chromatography on an appropriate solid-phase matrix. Alternatively, antibodies produced against peptides encoded by genes disclosed herein, can be used as purification reagents. Other purification methods are possible.

The present invention also encompasses derivatives and homologues of the polypeptides. For some purposes, nucleic acid sequences encoding the peptides may be altered by substitutions, additions, or deletions that provide for functionally equivalent molecules, i.e., function-conservative variants. For example, one or more amino acid residues within the sequence can be substituted by another amino acid of similar properties, such as, for example, positively charged amino acids (arginine, lysine, and histidine); negatively charged amino acids (aspartate and glutamate); polar neutral amino acids; and non-polar amino acids.

The isolated polypeptides may be modified by, for example, phosphorylation, sulfation, acylation, or other protein modifications. They may also be modified with a label capable of providing a detectable signal, either directly or indirectly, including, but not limited to, radioisotopes and fluorescent compounds.

The present invention also encompasses antibodies that specifically recognize the polymorphic positions of the invention and distinguish a peptide or polypeptide containing a particular polymorphism from one that contains a different sequence at that position. Such polymorphic position-specific antibodies according to the present invention include polyclonal and monoclonal antibodies. The antibodies may be elicited in an animal host by immunization with peptides encoded by genes disclosed herein or may be formed by in vitro immunization of immune cells. The immunogenic components used to elicit the antibodies may be isolated from human cells or produced in recombinant systems. The antibodies may also be produced in recombinant systems programmed with appropriate antibody-encoding DNA. Alternatively, the antibodies may be constructed by biochemical reconstitution of purified heavy and light chains. The antibodies include hybrid antibodies (i.e., containing two sets of heavy chain/light chain combinations, each of which recognizes a different antigen), chimeric antibodies (i.e., in which either the heavy chains, light chains, or both, are fusion proteins), and univalent antibodies (i.e., comprised of a heavy chain/light chain complex bound to the constant region of a second heavy chain). Also included are Fab fragments, including Fab′ and F(ab).sub.2 fragments of antibodies. Methods for the production of all of the above types of antibodies and derivatives are well-known in the art and are discussed in more detail below. For example, techniques for producing and processing polyclonal antisera are disclosed in Mayer and Walker, 1987, Immunochemical Methods in Cell and Molecular Biology, (Academic Press, London). The general methodology for making monoclonal antibodies by hybridomas is well known. Immortal antibody-producing cell lines can be created by cell fusion, and also by other techniques such as direct transformation of B lymphocytes with oncogenic DNA, or transfection with Epstein-Barr virus. See, e.g., Schreier et al., 1980, Hybridoma Techniques; U.S. Pat. Nos. 4,341,761; 4,399,121; 4,427,783; 4,444,887; 4,466,917; 4,472,500; 4,491,632; and 4,493,890. Panels of monoclonal antibodies produced against peptides encoded by genes disclosed herein can be screened for various properties; i.e. for isotype, epitope affinity, etc.

The antibodies of this invention can be purified by standard methods, including but not limited to preparative disc-gel electrophoresis, isoelectric focusing, HPLC, reversed-phase HPLC, gel filtration, ion exchange and partition chromatography, and countercurrent distribution. Purification methods for antibodies are disclosed, e.g., in The Art of Antibody Purification, 1989, Amicon Division, W. R. Grace & Co. General protein purification methods are described in Protein Purification: Principles and Practice, R. K. Scopes, Ed., 1987, Springer-Verlag, New York, N.Y.

Methods for determining the immunogenic capability of the disclosed sequences and the characteristics of the resulting sequence-specific antibodies and immune cells are well-known in the art. For example, antibodies elicited in response to a peptide comprising a particular polymorphic sequence can be tested for their ability to specifically recognize that polymorphic sequence, i.e., to bind differentially to a peptide or polypeptide comprising the polymorphic sequence and thus distinguish it from a similar peptide or polypeptide containing a different sequence at the same position.

Kits

As set forth herein, the invention provides diagnostic methods, e.g., for determining the identity of the allelic variants of polymorphic regions present in the gene loci of genes disclosed herein, wherein specific allelic variants of the polymorphic region are associated with cardiovascular diseases. In a preferred embodiment, the diagnostic kit can be used to determine whether a subject is at risk of developing a cardiovascular disease. This information could then be used, e.g., to optimize treatment of such individuals.

In preferred embodiments, the kit comprises a probe or primer which is capable of hybridizing to a gene and thereby identifying whether the gene contains an allelic variant of a polymorphic region which is associated with a risk for cardiovascular disease. The kit preferably further comprises instructions for use in diagnosing a subject as having, or having a predisposition, towards developing a cardiovascular disease. The probe or primers of the kit can be any of the probes or primers described in this file.

Preferred kits for amplifying a region of a gene comprising a polymorphic region of interest comprise one, two or more primers.

Antibody-Based Diagnostic Methods and Kits:

The invention also provides antibody-based methods for detecting polymorphic patterns in a biological sample. The methods comprise the steps of: (i) contacting a sample with one or more antibody preparations, wherein each of the antibody preparations is specific for a particular polymorphic form of the proteins encoded by genes disclosed herein, under conditions in which a stable antigen-antibody complex can form between the antibody and antigenic components in the sample; and (ii) detecting any antigen-antibody complex formed in step (i) using any suitable means known in the art, wherein the detection of a complex indicates the presence of the particular polymorphic form in the sample.

Typically, immunoassays use either a labelled antibody or a labelled antigenic component (e.g., that competes with the antigen in the sample for binding to the antibody). Suitable labels include without limitation enzyme-based, fluorescent, chemiluminescent, radioactive, or dye molecules. Assays that amplify the signals from the probe are also known, such as, for example, those that utilize biotin and avidin, and enzyme-labelled immunoassays, such as ELISA assays.

The present invention also provides kits suitable for antibody-based diagnostic applications. Diagnostic kits typically include one or more of the following components:

(i) Polymorphism-specific antibodies. The antibodies may be pre-labelled; alternatively, the antibody may be unlabelled and the ingredients for labelling may be included in the kit in separate containers, or a secondary, labelled antibody is provided; and

(ii) Reaction components: The kit may also contain other suitably packaged reagents and materials needed for the particular immunoassay protocol, including solid-phase matrices, if applicable, and standards.

The kits referred to above may include instructions for conducting the test. Furthermore, in preferred embodiments, the diagnostic kits are adaptable to high-throughput and/or automated operation.

Drug Targets and Screening Methods

According to the present invention, nucleotide sequences derived from genes disclosed herein and peptide sequences encoded by genes disclosed herein, particularly those that contain one or more polymorphic sequences, comprise useful targets to identify cardiovascular drugs, i.e., compounds that are effective in treating one or more clinical symptoms of cardiovascular disease. Furthermore, especially when a protein is a multimeric protein that are build of two or more subunits, is a combination of different polymorphic subunits very useful.

Drug targets include without limitation (i) isolated nucleic acids derived from the genes disclosed herein, and (ii) isolated peptides and polypeptides encoded by genes disclosed herein, each of which comprises one or more polymorphic positions.

In Vitro Screening Methods:

In one series of embodiments, an isolated nucleic acid comprising one or more polymorphic positions is tested in vitro for its ability to bind test compounds in a sequence-specific manner. The methods comprise:

(i) providing a first nucleic acid containing a particular sequence at a polymorphic position and a second nucleic acid whose sequence is identical to that of the first nucleic acid except for a different sequence at the same polymorphic position;

(ii) contacting the nucleic acids with a multiplicity of test compounds under conditions appropriate for binding; and

(iii) identifying those compounds that bind selectively to either the first or second nucleic acid sequence.

Selective binding as used herein refers to any measurable difference in any parameter of binding, such as, e.g., binding affinity, binding capacity, etc.

In another series of embodiments, an isolated peptide or polypeptide comprising one or more polymorphic positions is tested in vitro for its ability to bind test compounds in a sequence-specific manner. The screening methods involve:

(i) providing a first peptide or polypeptide containing a particular sequence at a polymorphic position and a second peptide or polypeptide whose sequence is identical to the first peptide or polypeptide except for a different sequence at the same polymorphic position;

(ii) contacting the polypeptides with a multiplicity of test compounds under conditions appropriate for binding; and

(iii) identifying those compounds that bind selectively to one of the nucleic acid sequences.

In preferred embodiments, high-throughput screening protocols are used to survey a large number of test compounds for their ability to bind the genes or peptides disclosed above in a sequence-specific manner.

Test compounds are screened from large libraries of synthetic or natural compounds. Numerous means are currently used for random and directed synthesis of saccharide, peptide, and nucleic acid based compounds. Synthetic compound libraries are commercially available from Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N.J.), Brandon Associates (Merrimack, N.H.), and Microsource (New Milford, Conn.). A rare chemical library is available from Aldrich (Milwaukee, Wis.). Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available from e.g. Pan Laboratories (Bothell, Wash.) or MycoSearch (N.C.), or are readily producible. Additionally, natural and synthetically produced libraries and compounds are readily modified through conventional chemical, physical, and biochemical means.

In Vivo Screening Methods:

Intact cells or whole animals expressing polymorphic variants of genes disclosed herein can be used in screening methods to identify candidate cardiovascular drugs.

In one series of embodiments, a permanent cell line is established from an individual exhibiting a particular polymorphic pattern. Alternatively, cells (including without limitation mammalian, insect, yeast, or bacterial cells) are programmed to express a gene comprising one or more polymorphic sequences by introduction of appropriate DNA. Identification of candidate compounds can be achieved using any suitable assay, including without limitation (i) assays that measure selective binding of test compounds to particular polymorphic variants of proteins encoded by genes disclosed herein; (ii) assays that measure the ability of a test compound to modify (i.e., inhibit or enhance) a measurable activity or function of proteins encoded by genes disclosed herein; and (iii) assays that measure the ability of a compound to modify (i.e., inhibit or enhance) the transcriptional activity of sequences derived from the promoter (i.e., regulatory) regions of genes disclosed herein.

In another series of embodiments, transgenic animals are created in which (i) one or more human genes disclosed herein, having different sequences at particular polymorphic positions are stably inserted into the genome of the transgenic animal; and/or (ii) the endogenous genes disclosed herein are inactivated and replaced with human genes disclosed herein, having different sequences at particular polymorphic positions. See, e.g., Coffman, Semin. Nephrol. 17:404, 1997; Esther et al., Lab. Invest. 74:953, 1996; Murakami et al., Blood Press. Suppl. 2:36, 1996. Such animals can be treated with candidate compounds and monitored for one or more clinical markers of cardiovascular status.

The following are intended as non-limiting examples of the invention.

Material and Methods

Genotyping of patient DNA with the Pyrosequencing™ Method as described in the patent application WO 9813523:

First a PCR is set up to amplify the flanking regions around a SNP. Therefor 2 ng of genomic DNA (patient sample) are mixed with a primerset (20-40 pmol) producing a 75 to 320 bp PCR fragment with 0, 3 to 1 U Qiagens Hot Star Taq Polymerase™ in a total volume of 20 μL. One primer is biotinylated depending on the direction of the sequencing primer. To force the biotinylated primer to be incorporated it is used 0, 8 fold.

For primer design, programms like Oligo 6™ (Molecular Biology Insights) or Primer Select™ (DNAStar) are used. PCR setup is performed by a BioRobot 3000™ from Qiagen. PCR takes place in T1 or Tgradient Thermocyclers™ from Biometra.

The whole PCR reaction is transferred into a PSQ plate™ (Pyrosequencing) and prepared using the Sample Prep Tool™ and SNP Reagent Kit™ from Pyrosequencing according to their instructions.

Preparation of Template for Pyrosequencing™:

Sample Preparation Using PSQ 96 Sample Prep Tool:

1. Mount the PSQ 96 Sample Prep Tool Cover onto the PSQ 96 Sample Prep Tool as follows: Place the cover on the desk, retract the 4 attachment rods by separating the handle from the magnetic rod holder, fit the magnetic rods into the holes of the cover plate, push the handle downward until a click is heard. The PSQ 96 Sample Prep Tool is now ready for use.

2. To transfer beads from one plate to another, place the covered tool into the PSQ 96 Plate containing the samples and lower the magnetic rods by separating the handle from the magnetic rod holder. Move the tool up and down a few times then wait for 30-60 seconds. Transfer the beads into a new PSQ 96 plate containing the solution of choice.

3. Release the beads by lifting the magnetic rod holder, bringing it together with the handle. Move the tool up and down a few times to make sure that the beads are released.

All steps are performed at room temperature unless otherwise stated.

Immobilization of PCR Product:

Biotinylated PCR products are immobilized on streptavidin-coated Dynabeads™ M-280 Streptavidin. Parallel immobilization of several samples are performed in the PSQ 96 Plate.

Mix PCR product, 20 μl of a well optimized PCR, with 25 μL 2× BW-buffer II. Add 60-150 μg Dynabeads. It is also possible to add a mix of Dynabeads and 2× BW-buffer II to the PCR product yielding a final BW-buffer II concentration of approximately 1×.

1. Incubate at 65° C. for 15 min agitation constantly to keep the beads dispersed. For optimal immobilization of fragments longer than 300 bp use 30 min incubation time.

Strand Separation:

4. For strand separation, use the PSQ 96 Sample Prep Tool to transfer the beads with the immobilized sample to a PSQ 96 Plate containing 50 μl 0.50 M NaOH per well. Release the beads.

5. After approximately 1 min, transfer the beads with the immobilized strand to a PSQ 96 Plate containing 99 μl 1× Annealing buffer per well and mix thoroughly.

6. Transfer the beads to a PSQ 96 Plate containing 45 μl of a mix of 1× Annealing buffer and 3-15 pmoles sequencing primer per well.

7. Heat at 80° C. for 2 minutes in the PSQ 96 Sample Prep Thermoplate and move to room temperature.

8. After reaching room temperature, continue with the sequencing reaction.

Sequencing Reaction:

1. Choose the method to be used (“SNP Method”) and enter relevant information in the PSQ 96 Instrument Control software.

2. Place the cartridge and PSQ 96 Plate in the PSQ 96 Instrument.

3. Start the run.

Genotyping Using the ABI 7700/7900 Instrument (TaqMan)

SNP genotypisation using the TaqMan (Applied Biosystems/Perkin Elmer) was performed according to the manufacturer's instructions. The TaqMan assay is discussed by Lee et al., Nucleic Acids Research 1993, 21: 3761-3766.

Genotyping with a Service Contractor:

Qiagen Genomics, formerly Rapigene, is a service contractor for genotyping SNPs in patient samples. Their method is based on a primer extension method where two complementary primers are designed for each genotype that are labeled with different tags. Depending on the genotype only one primer will be elongated together with a certain tag. This tag can be detected with mass spectrometry and is a measure for the respective genotype. The method is described in the following patent: “Detection and identification of nucleic acid molecules—using tags which may be detected by non-fluorescent spectrometry or potentiometry” (WO 9727325).

EXAMPLES

To exemplify the present invention and it's utility (the imaginary) baySNP 28 will be used in the following:

The nucleotide polymorphism found for baySNP 28 (e.g. C to T exchange) and the gene in which it presumably resides can be read from table 3. baySNP 28 was genotyped in various patient cohorts using primers as described in table 2. As a result the following number of patients carrying different genotypes were found (information combined from tables 3 and 5a):

			Geno-	Geno-	Genotype
			type 11	type 12	22
baySNP	Cohort	Total	“CC”	“CT”	“TT”
28	HELD_FEM_HIRESP	12	1	2	9
28	HELD_FEM_LORESP	22	3	12	7

When comparing the number of female patients exhibiting a high response to statin therapy (HELD_FEM_HIRESP) with the control cohort (HELD_FEM_LORESP) it appears that the number of low responders carrying the CT genotype is increased. This points to a lower statin response among female individuals with the CT genotype. Applying statistical tests on those findings the following p-values were obtained (data taken from table 5b):

		GTYPE	GTYPE	GTYPE
BAYSNP	COMPARISON	CPVAL	XPVAL	LRPVAL
28	HELD_FEM_EFF	0.0506	0.0508	0.0442

As at least one of the GTYPE p values is below 0, 05 the association of genotype and statin response phenotype is regarded as statistically significant. I.e. the analysis of a patient's genotype can predict the response to statin therapy. In more detail one can calculate the relative risk to exhibit a certain statin response phenotype when carrying a certain genotype (data taken from table 6a):

BAYSNP	COMPARISON	GTYPE1	GTYPE2	GTYPE3	RR1	RR2	RR3
28	HELD_FEM_EFF	CC	CT	TT	0.68	0.29	3.38

In case of baySNP 28 the risk to exhibit a high responder phenotype is 3, 38 times higher when carrying the TT genotype. This indicates that a TT polymorphism in baySNP 28 is an independent risk factor for high statin response in females. On the other hand carriers of a CT or CC genotype have a reduced risk of being a high responder.

In addition statistical associations can be calculated on the basis on alleles. This calculation would identify risk alleles instead of risk genotypes.

In case of baySNP 28 the following allele counts were obtained (data combined from tables 3 and 5a):

			Allele 1	Allele 2
baySNP	Cohort	Total	“C”	“T”
28	HELD_FEM_HIRESP	12	4	20
28	HELD_FEM_LORESP	22	18	26

When comparing the number of female patients with high statin response (HELD_FEM_HIRESP) with the control cohort (HELD_FEM_LORESP) it appears that the number of high responders carrying the T allele is increased, whereas the number of high responders carrying the C allele is diminished. This points to a higher statin response among female individuals with the T allele. Applying statistical tests on those findings the following p-values were obtained (data taken from table 5b):

		ALLELE	ALLELE	ALLELE
BAYSNP	COMPARISON	CPVAL	XPVAL	LRPVAL
28	HELD_FEM_EFF	0.0411	0.0579	0.0349

As at least one of the ALLELE p values is below 0, 05 the association of allele and statin response phenotype is regarded as statistically significant (in this example significant p values were obtained from two statistical tests). I.e. also the analysis of a patient's alleles from baySNP 28 can predict the extend of statin response. In more detail one can calculate the relative risk to exhibit a certain statin response phenotype when carrying a certain allele (data taken from table 6b):

baySNP	Allele 1	Allele 2	COMPARISON	RR1	RR2
28	C	T	HELD_FEM_EFF	0.42	2.39

In case of baySNP 28 the risk to exhibit a high responder phenotype is 2, 39 times higher when carrying the T allele. This indicates that the T allele of baySNP28 is an independent risk factor for a high statin response in females. In other words those patients should receive lower doses of statins in order to avoid ADR. However due to their ‘high responder’ phenotype they will still benefit from the drug. In turn carriers of the C allele should receive higher drug doses in order to experience a beneficial therapeutic effect.

Another example is (the imaginary) baySNP 29, which is taken to exemplify polymorphisms relevant for adverse drug reactions. baySNP 29 was found significant when comparing male patients with severe ADR to the respective controls (as defined in table 1b).

The relative risk ratios for the genotypes AA, AG and GG were as follows (data taken from table 6a):

BAYSNP	COMPARISON	GTYPE1	GTYPE2	GTYPE3	RR1	RR2	RR3
29	HELD_MAL_ADR5ULN	AA	AG	GG	3.15	0.66	0.32

In this case male patients carrying the AA genotype have a 3, 15 times higher risk to suffer from ADR. In other words those patients should either receive lower doses of statins or switch to an alternative therapy in order to avoid ADR. On the other hand male patients with AG or GG genotypes appear to be more resistant to ADR and hence better tolerate statin therapy.

As can be seen from the following tables some of the associations that are disclosed in the present invention are indicative for more than one phenotype. Some baySNPs can for example be linked to ADR, but also to the risk to suffer from CVD (table 6).

TABLE 1a
Definition of “good” and “bad” serum lipid levels
	“Good”	“Bad”
	LDL-Cholesterol [mg/dL]	125-150	170-200
	Cholesterol [mg/dL]	190-240	265-315
	HDL-Cholesterol [mg/dL]	60-105	30-55
	Triglycerides [mg/dL]	45-115	170-450

TABLE 1b
Definition of drug response phenotypes
Low responder                    Decrease of serum LDL of at least 10% and at most
                                 50% upon administration of 0.8 mg Cerivastatin
                                 (female patients)
High responder                   Decrease of serum LDL of at least 50% upon
                                 administration of 0.4 mg Cerivastatin (female
                                 patients)
Very low responder               Decrease of serum LDL of at least 10% and at most
                                 35% upon administration of 0.8 mg Cerivastatin
                                 (female patients)
Very high responder              Decrease of serum LDL of at least 55% upon
                                 administration of 0.4 mg Cerivastatin (female
                                 patients)
Ultra low responder              Decrease of serum LDL of at least 10% and at most
                                 25% upon administration of 0.8 mg Cerivastatin
                                 (female patients)
Ultra high responder             Decrease of serum LDL of at least 60% upon
                                 administration of 0.4 mg Cerivastatin (female
                                 patients)
Tolerant patient                 No diagnosis of muscle cramps, muscle pain,
                                 muscle weakness, myalgia or myopathy
                                 AND
                                 serum CK levels below 70 U/l in women and below
                                 80 U/l in men.
ADR patient                      Diagnosis of muscle cramps, muscle pain, muscle
(CK increase at least 2 × ULN)   weakness, myalgia or myopathy
                                 OR
                                 serum CK levels higher than 140 U/l in women and
                                 160 U/l in men.
Advanced ADR patient [ADR3]      Serum CK levels higher than 210 U/l in women and
(advanced CK increase, at least 3 × ULN)* 240 U/l in men
Severe ADR patient [ADR5]        Serum CK levels higher than 350 U/l in women and
(severe CK increase, at least 5 × ULN)* 400 U/l in men
*When assembling the cohorts for advanced and severe ADR we focused on the CK serum levels as those provide a more independent measure of statin related ADR.

TABLE 1c
Definition of “high” and “low” serum HDL cholesterol levels
	Male	Female
	individuals	individuals
‘High’ HDL-Cholesterol [mg/dL]	>=80	>=104
‘Low’ HDL-Cholesterol [mg/dL]	<=35	<=37

An informed consent was signed by the patients and control people. Blood was taken by a physician according to medical standard procedures.

Samples were collected anonymous and labeled with a patient number.

DNA was extracted using kits from Qiagen.

TABLE 2
Oligonucleotide primers used for genotyping
Depending on the method used for genotyping different oligonucleotides were utilized.
The table lists the various methods and primer sets that were used for this invention.
Primers were designed using suitable programs like Primer Express ™ (Applied
Biosystems, Darmstadt, Germany) or Oligo ™ (Molecular Biology Insights, Inc.,
Cascade, CO, USA).
	No. of
Method	oligonucleotides	Type of oligonucletides
Mass Spectrometry	4	2 Primers for preamplification of the genomic
		fragment,
		2 allele specific primers with additional tag
		sequences for subsequent allele spec. PCR
Pyrosequencing ™	3	2 Primers for preamplification of the genomic
		fragment (one biotinylated), 1 sequencing primer
TaqMan	4	2 Primers for amplification of the genomic
		fragment, 2 allele specific probes carrying
		different fluorochromes (VIC, FAM) and a
		quencher. Preferably the allele specific probes
		have a minor groove binder (MGB) attached
		(Kutyavin et al., Nucleic Acids Research 2000,
		28: 655-661).

TABLE 3
PA SNPs, SNP classes and putative PA genes
The baySNP number refers to an internal numbering of the PA SNPs. Listed are the different polymorphisms found in our association
study. Also from the association study we defined SNP classes; with ADR being adverse drug reaction related, with EFF being drug
efficacy related and CVD being cardiovascular disease related. ADR3 and ADR5 relate to advanced and severe ADR, whereas VEFF
and UEFF relate to very high/low and ultra high/low drug efficacy (see table 1b). Also accession numbers and descriptions of those
gene loci are given that are most homologous to the PA genes as listed in the sequences section (see below). Homologous genes
and their accession numbers could be found by those skilled in the art in the Genbank database. The term ‘SECONDARY’
marks SNPs that do not reside inside the respective gene, but in it's proximity. Null: not defined.
	SNP
BAYSNP	class	GTYPE11	GTYPE12	GTYPE22	NCBI	DESCRIPTION
160	ADR3	TT	CT	CC	HS34804	Human thermostable phenol sulfotransferase (STP2) gene, partial cds.
194	ADR5	GG	CG	CC	L33075	Homo sapiens ras GTPase-activating-like
						protein (IQGAP1) mRNA, complete cds.
194	EFF	GG	CG	CC	L33075	Homo sapiens ras GTPase-activating-like
						protein (IQGAP1) mRNA, complete cds.
411	ADR5	AA	AT	TT	HS34804	Human thermostable phenol sulfotransferase (STP2) gene, partial cds.
466	ADR	CC	CT	TT	M33519	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
466	ADR5	CC	CT	TT	M33519	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
555	CVD	AA	AG	GG	HS34804	Human thermostable phenol sulfotransferase (STP2) gene, partial cds.
623	ADR3	CC	CT	TT	ABCB3	TAP2: transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)
625	ADR3	CC	CT	TT	U63721	transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
777	CVD	CC	CT	TT	U63721	LIMK1: LIM domain kinase 1
1005	CVD	AA	AG	GG	O60443	CACNA2D2: calcium channel, voltage-dependent, alpha 2/delta subunit 2
1062	CVD	GG	AG	AA	M17262	DFNA5: deafness, autosomal dominant 5
1275	CVD	CC	CG	GG	M17262	Homo sapiens TNFa and gene for tumor
						necrosis factor and TNFb gene for lymphotoxin
1669	CVD	TT	CT	CC	AC004511	F2: coagulation factor II (thrombin)
1755	CVD	AA	AG	GG	AC004511	Human protein C inhibitor gene, complete cds.
1765	CVD	AA	AG	GG	M29932	Human Na,K-ATPase subunit alpha 2 (ATP1A2) gene, complete cds.
2109	CVD	AA	AG	GG	M29932	TFAP2B: transcription factor AP-2 beta
						(activating enhancer binding protein 2 beta)
2150	CVD	TT	CT	CC	M29932	CSF2: colony stimulating factor 2 (granulocyte-macrophage)
						IL3: interleukin 3 (colony-stimulating
						factor, multiple)
2234	CVD	TT	GT	GG	X06562	Homo sapiens PAC clone RP1-102K2
						from 22q12.1-qter, complete sequence.
2321	CVD	GG	GT	TT	X06562	ADRB3: adrenergic, beta-3-, receptor
2354	CVD	CC	CT	TT	X06562	Human endothelial leukocyte adhesion
						molecule 1 (ELAM-1) mRNA, complete cds.
3451	ADR	CC	CT	TT	X62996	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
3451	ADR5	CC	CT	TT	X62996	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
3452	ADR5	AA	AG	GG	BC014081	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
3453	ADR	CC	CT	TT	NM_000927	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
4912	CVD	GG	AG	AA	NM_000927	Human vascular endothelial growth factor gene, exon 1.
5093	CVD	GG	AG	AA	SECONDARY:	BRD3: bromodomain containing 3
					M34551
6333	ADR5	AA	AC	CC	SECONDARY:	GHR: growth hormone receptor
					M95724
6333	ADR	AA	AC	CC	SECONDARY:	GHR: growth hormone receptor
					AB043943
6333	ADR3	AA	AC	CC	SECONDARY:	GHR: growth hormone receptor
					AB043943
6333	CVD	AA	AC	CC	SECONDARY:	GHR: growth hormone receptor
					AB043943
7407	ADR5	GG	AG	AA	SECONDARY:	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
					AB043943
7407	ADR	GG	AG	AA	SECONDARY:	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
					AB043943
7407	ADR3	GG	AG	AA	SECONDARY:	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
					AF065214
10584	ADR	GG	GT	TT	AF129756	Apolipoprotein M
10584	ADR3	GG	GT	TT	AF129756	Apolipoprotein M
11021	CVD	TT	CT	CC	M60092	Human myoadenylate deaminase (AMPD1) mRNA, complete cds.
11062	ADR5	TT	CT	CC	AB055890	Homo sapiens c-lbc mRNA for guanine
						nucleotide exchange factor Lbc, complete cds.
11147	ADR	CC	CT	TT	U51903	Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
11212	CVD	GG	CG	CC	X06290	Human mRNA for apolipoprotein(a)
11371	ADR3	AA	AG		Z82215	Human DNA sequence from clone RP1-68O2 on chromosome
						22 Contains the 5′ end of the APOL2 gene for apolipoprotein L 2,
						the APOL gene for apolipoprotein L, the MYH9 gene for nonmuscle
						type myosin heavy chain 9. ESTs, STSs and GSSs.
11371	ADR	AA	AG		Z82215	Human DNA sequence from clone RP1-68O2 on chromosome
						22 Contains the 5′ end of the APOL2 gene for apolipoprotein L 2,
						the APOL gene for apolipoprotein L, the MYH9 gene for nonmuscle
						type myosin heavy chain 9. ESTs, STSs and GSSs.
11487	UEFF	TT	AT	AA	M75106	Human prepro-plasma carboxypeptidase B mRNA, complete cds.
11585	CVD	GG	GT	TT	AC073593	Homo sapiens 12 BAC RP11-13J12 (Roswell Park Cancer
						Institute Human BAC Library) complete sequence.
11683	UEFF	CC	CG	GG	NM_002575	serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 2
11863	VEFF	GG	AG	AA	NM_000927	ATP-binding cassette, sub-family B (MDR/TAP), member 1
12024	ADR	CC	CT	TT	AF129756	BAT5
12024	ADR3	CC	CT	TT	AF129756	BAT5
12632	ADR5	CC	CT	TT	NM_000593	transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
13994	CVD	GG	AG	AA	X62996	MTND4L: NADH dehydrogenase 4L
13994	ADR	GG	AG	AA	X62996	MTND4L: NADH dehydrogenase 4L
14090	EFF	CC	AC	AA	AF044954	Homo sapiens NADH:ubiquinone oxidoreductase PDSW
						subunit mRNA, nuclear gene encoding mitochondrial
						protein, complete cds.
14159	EFF	TT	CT	CC	AB014521	Homo sapiens mRNA for KIAA0621 protein, partial cds.
14362	UEFF	TT	GT	GG	X66401	TAP1: transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
14410	ADR	GG	AG		AF057557	Homo sapiens P-glycoprotein (MDR1) gene, exon 10 and partial cds.
14488	ADR	AA	AG		AF057557	BAT3
14488	ADR3	AA	AG		AF057557	BAT3
14490	ADR5	CC	CT	TT	NM_013374	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
14490	ADR3	CC	CT	TT	M33519	Human HLA-B-associated transcript 3 (BAT3) mRNA, complete cds.
14493	ADR	AA	AG		AF129756	BAT4
14493	ADR3	AA	AG		AF129756	BAT4
14554	ADR3	CC	AC	AA	U52111	H. sapiens creatine transporter gene
14554	ADR5	CC	AC	AA	U52111	H. sapiens creatine transporter gene
14554	ADR	CC	AC	AA	U52111	H. sapiens creatine transporter gene
14603	CVD	AA	AG		X04981	H. sapiens gene for lecithin-cholesterol acyltransferase (LCAT)
14820	VEFF	AA	AG	GG	BC008915	SERPINA5
14820	UEFF	AA	AG	GG	BC008915	SERPINA5
14876	EFF	CC	CT	TT	NM_005138	Homo sapiens SCO cytochrome oxidase deficient
						homolog 2 (yeast) (SCO2), nuclear gene encoding
						mitochondrial protein, mRNA.
14876	VEFF	CC	CT	TT	NM_005138	Homo sapiens SCO cytochrome oxidase deficient
						homolog 2 (yeast) (SCO2), nuclear gene encoding
						mitochondrial protein, mRNA.
14954	ADR	GG	CG	CC	AF044954	Homo sapiens NADH:ubiquinone oxidoreductase PDSW
						subunit mRNA, nuclear gene encoding mitochondrial
						protein, complete cds.
14957	ADR5	AA	AC	CC	AF047181	Homo sapiens NADH-ubiquinone oxidoreductase
						subunit CI-SGDH mRNA, complete cds.
14957	VEFF	AA	AC	CC	AF047181	Homo sapiens NADH-ubiquinone oxidoreductase
						subunit CI-SGDH mRNA, complete cds.
14977	UEFF	AA	AG	GG	BC003093	Homo sapiens, Rab geranylgeranyltransferase, alpha
						subunit, clone MGC: 1485 IMAGE: 3537388, mRNA, complete cds.
15349	ADR	CC	CT	TT	U51903	Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
15590	ADR5	GG	AG	AA	HSKINAANP	H. sapiens mRNA for kinase A anchor protein
15590	ADR	GG	AG	AA	HSKINAANP	H. sapiens mRNA for kinase A anchor protein
16268	ADR5	CC	CG	GG	U20158	Human 76 kDa tyrosine phosphoprotein SLP-76 mRNA, complete cds.
36078	VEFF	AA	AG		NM_000927	ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1
36078	EFF	AA	AG		NM_000927	ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1
36406	ADR5	TT	CT	CC	J02973	Human thrombomodulin gene, complete cds.
37135	ADR3	CC	CT	TT	AJ276180	Homo sapiens partial ZNF202 gene for zinc finger protein homolog, exon 4
37135	ADR5	CC	CT	TT	AJ276180	Homo sapiens partial ZNF202 gene for zinc finger protein homolog, exon 4
37327	CVD	TT	CT	CC	M27111	Human PLP gene encoding proteolipid protein, upstream region.
37327	VEFF	TT	CT	CC	M27111	Human PLP gene encoding proteolipid protein, upstream region.
37327	UEFF	TT	CT	CC	M27111	Human PLP gene encoding proteolipid protein, upstream region.
37327	ADR	TT	CT	CC	M27111	Human PLP gene encoding proteolipid protein, upstream region.
37404	ADR	TT	CT	CC	M63971	Human vascular endothelial growth factor gene, exon 1.
37413	ADR5	AA	AT	TT	M74775	Human lysosomal acid lipase/cholesteryl esterase mRNA, complete cds.
37413	ADR3	AA	AT	TT	M74775	Human lysosomal acid lipase/cholesteryl esterase mRNA, complete cds.
37939	EFF	CC	CT	TT	V00595	Human mRNA encoding prothrombin.
37939	CVD	CC	CT	TT	V00595	Human mRNA encoding prothrombin.
38009	ADR	TT	GT	GG	AJ000414	Homo sapiens mRNA for Cdc42-interacting protein 4 (CIP4)
40004	CVD	GG	CG	CC	AF070652	Homo sapiens NADH-ubiquinone oxidoreductase
						subunit B14.5B homolog mRNA, complete cds.
40522	ADR	TT	AT	AA	AF058921	Homo sapiens cytosolic phospholipase A2-gamma mRNA, complete cds.
40522	ADR3	TT	AT	AA	AF058921	Homo sapiens cytosolic phospholipase A2-gamma mRNA, complete cds.
40522	ADR5	TT	AT	AA	AF058921	Homo sapiens cytosolic phospholipase A2-gamma mRNA, complete cds.
41847	EFF	TT	GT	GG	L33075	Homo sapiens ras
						GTPase-activating-like protein (IQGAP1) mRNA, complete cds.
42084	ADR5	AA	AC	CC	M21574	Human platelet-derived growth factor
						receptor alpha (PDGFRA) mRNA, complete cds.
42084	ADR3	AA	AC	CC	M21574	Human platelet-derived growth factor
						receptor alpha (PDGFRA) mRNA, complete cds.
42084	ADR	AA	AC	CC	M21574	Human platelet-derived growth factor
						receptor alpha (PDGFRA) mRNA, complete cds.
42677	ADR3	CC	CG	GG	U51903	Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
42677	ADR5	CC	CG	GG	U51903	Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
42677	ADR	CC	CG	GG	U51903	Human RasGAP-related protein (IQGAP2) mRNA, complete cds.
46865	VEFF	TT	CT	CC	L15189	heat shock 70 kDa protein 9B (mortalin-2)
46865	EFF	TT	CT	CC	L15189	heat shock 70 kDa protein 9B (mortalin-2)
46865	ADR5	TT	CT	CC	L15189	heat shock 70 kDa protein 9B (mortalin-2)
47856	ADR5	TT	CT	CC	M14333	Homo sapiens c-syn protooncogene mRNA, complete cds.
47856	VEFF	TT	CT	CC	M14333	Homo sapiens c-syn protooncogene mRNA, complete cds.
48490	CVD	AA	AG	GG	M31158	Human cAMP-dependent protein
						kinase subunit RII-beta mRNA, complete cds.
48490	ADR3	AA	AG	GG	M31158	Human cAMP-dependent protein
						kinase subunit RII-beta mRNA, complete cds.
48490	ADR	AA	AG	GG	M31158	Human cAMP-dependent protein
						kinase subunit RII-beta mRNA, complete cds.
50164	ADR3	GG	AG	AA	U02570	Human CDC42 GTPase-activating protein mRNA, partial cds.
50164	ADR	GG	AG	AA	U02570	Human CDC42 GTPase-activating protein mRNA, partial cds.
50164	ADR5	GG	AG	AA	U02570	Human CDC42 GTPase-activating protein mRNA, partial cds.
54704	ADR	GG	AG	AA	X97548	H. sapiens mRNA for TIF1beta zinc finger protein
54806	CVD	GG	AG	AA	Y00698	Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54806	UEFF	GG	AG	AA	Y00698	Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807	ADR5	GG	AG	AA	Y00698	Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807	ADR	GG	AG	AA	Y00698	Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807	ADR3	GG	AG	AA	Y00698	Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807	EFF	GG	AG	AA	Y00698	Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
54807	UEFF	GG	AG	AA	Y00698	Human mRNA for muscle phosphofructokinase (E.C. 2.7.1.11)
55733	CVD	GG	AG	AA	NM_021151	Homo sapiens carnitine O-octanoyltransferase (CROT), mRNA.
55733	VEFF	GG	AG	AA	NM_021151	Homo sapiens carnitine O-octanoyltransferase (CROT), mRNA.
55733	ADR	GG	AG	AA	NM_021151	Homo sapiens carnitine O-octanoyltransferase (CROT), mRNA.
55846	VEFF	AA	AG	GG	SECONDARY:	SSA1: Sjogren syndrome antigen A1 (52 kDa,
						ribonucleoprotein autoantigen SS-A/Ro) M34551
55846	UEFF	AA	AG	GG	SECONDARY:	SSA1: Sjogren syndrome antigen A1 (52 kDa,
						ribonucleoprotein autoantigen SS-A/Ro) M34551
55906	EFF	GG	GT	TT	SECONDARY:	CENPC1: centromere protein C 1
					M95724
56084	UEFF	CC	CT	TT	SECONDARY:	AD024 protein
					ABCB11
57818	ADR	GG	AG	AA	SECONDARY:	PPP1R12C: protein phosphatase 1, regulatory (inhibitor) subunit 12C
					AB043943
57818	ADR3	GG	AG	AA	SECONDARY:	PPP1R12C: protein phosphatase 1, regulatory (inhibitor) subunit 12C
					AB043943
57818	EFF	GG	AG	AA	SECONDARY:	PPP1R12C: protein phosphatase 1, regulatory (inhibitor) subunit 12C
					AB043943
57819	ADR	TT	CT	CC	SECONDARY:	PPP1R12C: protein phosphatase 1, regulatory
						(inhibitor) subunit 12C Proteome Summary: AB043943
57819	EFF	TT	CT	CC	SECONDARY:	PPP1R12C: protein phosphatase 1, regulatory
						(inhibitor) subunit 12C Proteome Summary: AB043943
57828	VEFF	AA	AG	GG	SECONDARY:	PPP1R12C: protein phosphatase 1, regulatory
						(inhibitor) subunit 12C Proteome Summary: AB043943
57987	ADR5	TT	CT	CC	SECONDARY:	PLA2G4C: phospholipase A2, group IVC (cytosolic, calcium-independent)
					AF065214
59456	ADR3	AA	AC	CC	HS.150207	Homo sapiens UDP
						glycosyltransferase 2 family, polypeptide B15 (UGT2B15), mRNA.
59460	UEFF	TT	CT	CC	AB055890	Homo sapiens c-lbc mRNA for guanine
						nucleotide exchange factor Lbc, complete cds.
59461	ADR5	CC	CT	TT	AB055890	Homo sapiens c-lbc mRNA for guanine
						nucleotide exchange factor Lbc, complete cds.
59461	UEFF	CC	CT	TT	AB055890	Homo sapiens c-lbc mRNA for guanine
						nucleotide exchange factor Lbc, complete cds.
59461	EFF	CC	CT	TT	AB055890	Homo sapiens c-lbc mRNA for guanine
						nucleotide exchange factor Lbc, complete cds.
60900	ADR3	AA	AG	GG	AB042237	Homo sapiens Borg4 mRNA, complete cds.
60900	ADR	AA	AG	GG	AB042237	Homo sapiens Borg4 mRNA, complete cds.
60902	ADR	AA	AT	TT	AB042237	Homo sapiens Borg4 mRNA, complete cds.
60934	CVD	CC	CT	TT	AF037439	Homo sapiens protein kinase A anchoring protein mRNA, complete cds.
60934	ADR	CC	CT	TT	AF037439	Homo sapiens protein kinase A anchoring protein mRNA, complete cds.
60957	ADR5	GG	AG	AA	AF128625	Homo sapiens CDC42-binding
						protein kinase beta (CDC42BPB) mRNA, complete cds.
60957	ADR3	GG	AG	AA	AF128625	Homo sapiens CDC42-binding protein
						kinase beta (CDC42BPB) mRNA, complete cds.
60959	ADR3	TT	CT	CC	AF128625	Homo sapiens CDC42-binding protein
						kinase beta (CDC42BPB) mRNA, complete cds.
60959	ADR5	TT	CT	CC	AF128625	Homo sapiens CDC42-binding protein
						kinase beta (CDC42BPB) mRNA, complete cds.
60959	ADR	TT	CT	CC	AF128625	Homo sapiens CDC42-binding protein
						kinase beta (CDC42BPB) mRNA, complete cds.
60962	ADR5	CC	CT	TT	AF128625	Homo sapiens CDC42-binding protein
						kinase beta (CDC42BPB) mRNA, complete cds.
60962	ADR3	CC	CT	TT	AF128625	Homo sapiens CDC42-binding protein
						kinase beta (CDC42BPB) mRNA, complete cds.
60962	ADR	CC	CT	TT	AF128625	Homo sapiens CDC42-binding protein
						kinase beta (CDC42BPB) mRNA, complete cds.
60974	ADR5	GG	AG	AA	AF130249	Homo sapiens PAC 126N20 derived from
						chromosome 21p11.2, complete sequence, containing
						STCH and an unknown gene.
60978	ADR	GG	CG	CC	AF163840	Homo sapiens CRIB-containing
						BORG1 protein (BORG1) mRNA, complete cds.
60978	EFF	GG	CG	CC	AF163840	Homo sapiens CRIB-containing BORG1
						protein (BORG1) mRNA, complete cds.
60978	VEFF	GG	CG	CC	AF163840	Homo sapiens CRIB-containing BORG1
						protein(BORG1) mRNA, complete cds.
60999	ADR5	GG	GT	TT	AH006714	Human muscle glycogen phosphorylase (PYGM) gene, 5′UTR and exon 1.
61011	CVD	TT	CT	CC	AJ001515	Homo sapiens mRNA for ryanodine receptor 3, complete CDS
61011	EFF	TT	CT	CC	AJ001515	Homo sapiens mRNA for ryanodine receptor 3, complete CDS
61086	ADR	GG	AG	AA	AL136842	Homo sapiens mRNA; cDNA DKFZp434A0530
						(from clone DKFZp434A0530); complete cds
61126	ADR	CC	CT	TT	D88460	Homo sapiens mRNA for N-WASP, complete cds.
61126	VEFF	CC	CT	TT	D88460	Homo sapiens mRNA for N-WASP, complete cds.
61126	UEFF	CC	CT	TT	D88460	Homo sapiens mRNA for N-WASP, complete cds.
61126	EFF	CC	CT	TT	D88460	Homo sapiens mRNA for N-WASP, complete cds.
61137	ADR	TT	CT	CC	L20969	Homo sapiens cyclic AMP phosphodiesterase mRNA, complete cds.
61147	EFF	GG	AG	AA	M13975	Homo sapiens protein kinase C
						beta-II type (PRKCB1) mRNA, complete cds.
61176	ADR5	AA	AG	GG	M82814	Homo sapiens GAP-related protein (NF1) mRNA, complete cds.
61176	ADR	AA	AG	GG	M82814	Homo sapiens GAP-related protein (NF1) mRNA, complete cds.
61176	ADR3	AA	AG	GG	M82814	Homo sapiens GAP-related protein (NF1) mRNA, complete cds.
61184	ADR5	CC	CT	TT	NM_000295	Homo sapiens serine (or cysteine) proteinase inhibitor, clade
						A (alpha-1 antiproteinase, antitrypsin), member 1 (SERPINA1), mRNA.
61184	ADR	CC	CT	TT	NM_000295	Homo sapiens serine (or cysteine) proteinase inhibitor, clade A
						(alpha-1 antiproteinase, antitrypsin), member 1 (SERPINA1), mRNA.
61197	ADR3	AA	AG	GG	NM_001093	Homo sapiens acetyl-Coenzyme A carboxylase beta (ACACB), mRNA.
61270	ADR3	AA	AG	GG	U24153	Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61270	ADR5	AA	AG	GG	U24153	Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61270	CVD	AA	AG	GG	U24153	Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61272	ADR5	AA	AG	GG	U24153	Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61272	ADR	AA	AG	GG	U24153	Homo sapiens p21-activated protein kinase (Pak2) mRNA, complete cds.
61284	EFF	GG	AG	AA	U43522	Human cell adhesion kinase beta (CAKbeta) mRNA, complete cds.
61292	EFF	GG	AG	AA	U43522	Human cell adhesion kinase beta (CAKbeta) mRNA, complete cds.
61292	ADR	GG	AG	AA	U43522	Human cell adhesion kinase beta (CAKbeta) mRNA, complete cds.
61297	CVD	TT	CT	CC	U48449	Human skeletal muscle ryanodine receptor
						gene (RYR1), promoter region and exon 1.
61324	VEFF	GG	AG	AA	X51985	Human LAG-3 mRNA for CD4-related protein
						involved in lymphocyte activation
61328	EFF	AA	AG	GG	X52220	Human FKBP mRNA for FK-506 binding protein
61373	ADR	GG	CG	CC	Z29630	H. sapiens syk mRNA for protein-tyrosine kinase
900066	CVD	CC	CT	TT	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM2
900071	UEFF	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM3
900072	UEFF	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM4
900072	CVD	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM4
900072	VEFF	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM4
900073	ADR	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM15
900073	CVD	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM15
900073	ADR3	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM15
900073	EFF	GG	CG	CC	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM15
900074	CVD	CC	CT	TT	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM18
900074	UEFF	CC	CT	TT	AF275948	ABCA1: ATP-binding cassette, sub-family
						A (ABC1), member 1 - SNP HTM18
900083	EFF	AA	AG	GG	AF047182	Homo sapiens NADH-ubiquinone oxidoreductase
						subunit CI-B14 mRNA, complete cds.
900115	ADR3	AA	AG	GG	U96781	ATP2A1: ATPase, Ca++ transporting, cardiac muscle, fast twitch 1
900115	CVD	AA	AG	GG	U96781	ATP2A1: ATPase, Ca++ transporting, cardiac muscle, fast twitch 1
900115	ADR5	AA	AG	GG	U96781	ATP2A1: ATPase, Ca++ transporting, cardiac muscle, fast twitch 1
900143	ADR5	GG	GT	TT	AC008945	Selenoprotein P genomic region
900143	ADR	GG	GT	TT	AC008945	Selenoprotein P genomic region
900143	ADR3	GG	GT	TT	AC008945	Selenoprotein P genomic region
900173	ADR3	TT	GT	GG	M76722	H. sapiens lipoprotein lipase (LPL) gene, exons
						7, 8, and 9, and an Alu repetative element.
900174	ADR3	AA	AG	GG	U96781	Human Ca2+ ATPase of fast-twitch skeletal muscle
						sarcoplasmic reticulum adult and neonatal isoforms (ATP2A1) gene, exons
						16 to 23 and complete cds.
900174	ADR5	AA	AG	GG	U96781	Human Ca2+ ATPase of fast-twitch skeletal muscle
						sarcoplasmic reticulum adult and neonatal isoforms (ATP2A1) gene, exons
						16 to 23 and complete cds.
900174	CVD	AA	AG	GG	U96781	Human Ca2+ ATPase of fast-twitch skeletal muscle
						sarcoplasmic reticulum adult and neonatal isoforms (ATP2A1) gene, exons
						16 to 23 and complete cds.
900175	EFF	GG	AG	AA	NM_003455	Homo sapiens zinc finger protein 202 (ZNF202)
900180	CVD	GG	AG	AA	NM_005449	TOSO: regulator of Fas-induced apoptosis
900221	ADR	GG	CG	CC	NM_0013374	PDCD6IP: programmed cell death 6 interacting protein
900250	ADR5	CC	CT	TT	AC011254	UGT2A1: UDP glycosyltransferase 2 family, polypeptide A1
900342	ADR	GG	AG	AA	NM_017646	TRIT1: tRNA isopentenyltransferase 1
900344	ADR	AA	AC	CC	NM_017646	TRIT1: tRNA isopentenyltransferase 1
900344	ADR3	AA	AC	CC	NM_017646	TRIT1: tRNA isopentenyltransferase 1
900344	ADR5	AA	AC	CC	NM_017646	TRIT1: tRNA isopentenyltransferase 1
10000001	CVD	GG	AG	AA	M32992	Cholesteryl ester transfer protein (CETP)
10000002	CVD	AA	AG	GG	M32992	Cholesteryl ester transfer protein (CETP)
10000017	CVD	TT	CT	CC	M10065	Human apolipoprotein E (epsilon-4 allele) gene, complete cds.

TABLE 4
Cohorts
Given are names (as used in table 5) and formations of the various cohorts that were used for
genotyping
COHORT               Definition
HELD_ALL_GOOD/BAD    Healthy elderly individuals of both genders with good or bad serum lipid
                     profiles (as defined in table 1a)
HELD_FEM_GOOD/BAD    Healthy elderly individuals (female) with good or bad serum lipid
                     profiles (as defined in table 1a)
HELD_MAL_GOOD/BAD    Healthy elderly individuals (male) with good or bad serum lipid profiles
                     (as defined in table 1a)
CVD_ALL_CASE/CTRL    Individuals with diagnosis of cardiovascular disease and healthy controls
                     (both genders)
CVD_FEM_CASE/CTRL    Individuals with diagnosis of cardiovascular disease and healthy controls
                     (female)
CVD_MAL_CASE/CTRL    Individuals with diagnosis of cardiovascular disease and healthy controls
                     (male)
HELD_FEM_ADRCTRL     Female individuals that tolerate adminstration of cerivastatin without
                     exhibiting signs of ADR (as defined in table 1b)
HELD_FEM_ADRCASE     Female individuals that exhibited ADR (as defined in table 1b) upon
                     administration of cerivastatin
HELD_MAL_ADRCTRL     Male individuals that tolerate adminstration of cerivastatin without
                     exhibiting signs of ADR (as defined in table 1b)
HELD_MAL_ADRCASE     Male individuals that exhibited ADR (as defined in table 1b) upon
                     administration of cerivastatin
HELD_ALL_ADRCTRL     Individuals of both genders that tolerate adminstration of cerivastatin
                     without exhibiting signs of ADR (as defined in table 1b)
HELD_ALL_ADRCASE     Individuals of both genders that exhibited ADR (as defined in table 1b)
                     upon administration of cerivastatin
HELD_FEM_LORESP      Female individuals with a minor response to cerivastatin administration
                     (as defined in table 1b)
HELD_FEM_HIRESP      Female individuals with a high response to to cerivastatin administration
                     (as defined in table 1b)
HELD_FEM_HIHDL/LOHDL Healthy elderly individuals (female) with high or low serum HDL
                     cholesterol levels (as defined in table 1c)
HELD_MAL_HIHDL/LOHDL Healthy elderly individuals (male) with high or low serum HDL
                     cholesterol levels (as defined in table 1c)
HELD_ALL_HIHDL/LOHDL Healthy elderly individuals of both genders with high or low serum HDL
                     cholesterol levels (as defined in table 1c)
HELD_FEM_ADR3CASE    Female individuals that exhibited advanced ADR (as defined in table
                     1b) upon administration of cerivastatin
HELD_MAL_ADR3CASE    Male individuals that exhibited advanced ADR (as defined in table 1b)
                     upon administration of cerivastatin
HELD_ALL_ADR3CASE    Individuals of both genders that exhibited advanced ADR (as defined in
                     table 1b) upon administration of cerivastatin
HELD_FEM_VLORESP     Female individuals with a very low response to cerivastatin
                     administration (as defined in table 1b)
HELD_FEM_VHIRESP     Female individuals with a very high response to cerivastatin
                     administration (as defined in table 1b)
HELD_FEM_ADR5CASE    Female individuals that exhibited severe ADR (as defined in table 1b)
                     upon administration of cerivastatin
HELD_MAL_ADR5CASE    Male individuals that exhibited severe ADR (as defined in table 1b)
                     upon administration of cerivastatin
HELD_ALL_ADR5CASE    Individuals of both genders that exhibited severe ADR (as defined in
                     table 1b) upon administration of cerivastatin
HELD_FEM_ULORESP     Female individuals with a ultra low response to cerivastatin
                     administration (as defined in table 1b)
HELD_FEM_UHIRESP     Female individuals with a ultra high response to to cerivastatin
                     administration (as defined in table 1b)

Table 5a and 5b Cohort Sizes and p-Values of PA SNPs

The baySNP number refers to an internal numbering of the PA SNPs. Cpval denotes the classical Pearson chi-squared test, Xpval denotes the exact version of Pearson's chi-squared test, LRpval denotes the likelihood-ratio chi-squared test. Cpvalue, Xpvalue, and LRpvalue are calculated as described in (SAS/STAT User's Guide of the SAS OnlineDoc, Version 8), (L. D. Fisher and G. van Belle, Biostatistics, Wiley Interscience 1993), and (A. Agresti, Statistical Science 7, 131 (92)). The GTYPE and Allele p values were obtained through the respective chi square tests when comparing COHORTs A and B. For GTYPE p value the number of patients in cohort A carrying genotypes 11, 12 or 22 (FQ11 A, FQ 12 A, FQ 22 A; genotypes as defined in table 3) were compared with the respective patients in cohort B (FQ11 B, FQ 12 B, FQ 22 B; genotypes as defined in table 3) resulting in the respective chi square test with a 3×2 matrix. For Allele p values we compared the allele count of alleles 1 and 2 (A1 and A2) in cohorts A and B, respectively (chi square test with a 2×2 matrix). SIZE A and B: Number of patients in cohorts A and B, respectively. See table 4 for definition of COHORTs A and B.

TABLE 5a
Cohort sizes and frequency of alleles and genotypes
baySNP	A1	A2	COHORT_A	SIZE_A	FQ1 A	FQ2 A	FQ11 A	FQ12 A	FQ22 A	COHORT_B	SIZE_B	FQ1 B	FQ2 B	FQ11 B	FQ12 B	FQ22 B
29	A	G	HELD_FEM_BAD	80	100	60	32	36	12	HELD_FEM_GOOD	78	80	76	19	42	17
160	T	C	HELD_MAL_ADRCASE3ULN	16	13	19	3	7	6	HELD_MAL_ADRCTRL	59	72	46	22	28	9
194	G	C	HELD_FEM_ADRCASE5ULN	14	10	18	3	4	7	HELD_FEM_ADRCTRL	64	75	53	21	33	10
194	G	C	HELD_ALL_ADRCASE5ULN	20	18	22	6	6	8	HELD_ALL_ADRCTRL	123	145	101	40	65	18
194	G	C	HELD_FEM_HIRESP	249	290	208	81	128	40	HELD_FEM_LORESP	261	274	248	80	114	67
411	A	T	HELD_ALL_ADRCASE5ULN	26	25	27	6	13	7	HELD_ALL_ADRCTRL	126	158	94	49	60	17
466	C	T	HELD_FEM_ADRCASE	71	61	81	10	41	20	HELD_FEM_ADRCTRL	69	75	63	24	27	18
466	C	T	HELD_MAL_ADRCASE5ULN	9	14	4	5	4	0	HELD_MAL_ADRCTRL	56	58	54	17	24	15
555	A	G	HELD_ALL_BAD	97	129	65	45	39	13	HELD_ALL_GOOD	115	135	95	35	65	15
623	C	T	HELD_MAL_ADRCASE3ULN	16	32	0	16	0	0	HELD_MAL_ADRCTRL	59	110	8	52	6	1
625	C	T	HELD_FEM_ADRCASE3ULN	31	29	33	6	17	8	HELD_FEM_ADRCTRL	63	82	44	27	28	8
777	C	T	HELD_ALL_BAD	102	162	42	65	32	5	HELD_ALL_GOOD	110	194	26	86	22	2
777	C	T	HELD_ALL_LOHDL	24	37	11	14	9	1	HELD_ALL_HIHDL	32	59	5	27	5	0
777	C	T	HELD_ALL_CASE2	73	128	18	56	16	1	HELD_ALL_CTRL2	53	82	24	34	14	5
777	C	T	HELD_FEM_CASE2	37	66	8	29	8	0	HELD_FEM_CTRL2	30	45	15	18	9	3
777	C	T	HELD_FEM_BAD	84	133	35	53	27	4	HELD_FEM_GOOD	75	132	18	58	16	1
777	C	T	HELD_ALL_BAD	98	157	39	64	29	5	HELD_ALL_GOOD	114	199	29	87	25	2
1005	A	G	HELD_FEM_BAD	84	142	26	59	24	1	HELD_FEM_GOOD	74	136	12	64	8	2
1062	G	A	HELD_ALL_BAD2	625	1084	166	474	136	15	HELD_ALL_GOOD2	714	1209	219	507	195	12
1275	C	G	CVD_FEM_CASE	30	19	41	6	7	17	CVD_FEM_CTRL	14	20	8	7	6	1
1275	C	G	HELD_MAL_CASE2	41	58	24	18	22	1	HELD_MAL_CTRL2	28	28	28	6	16	6
1275	C	G	HELD_MAL_LOHDL	18	24	12	8	8	2	HELD_MAL_HIHDL	24	20	28	4	12	8
1275	C	G	CVD_MAL_CASE	51	58	44	21	16	14	CVD_MAL_CTRL	20	30	10	14	2	4
1669	T	C	HELD_MAL_CASE2	41	78	4	37	4	0	HELD_MAL_CTRL2	28	45	11	18	9	1
1669	T	C	HELD_ALL_CASE2	97	172	22	76	20	1	HELD_ALL_CTRL2	67	104	30	40	24	3
1669	T	C	CVD_ALL_CASE	96	162	30	72	18	6	CVD_ALL_CTRL	74	120	28	47	26	1
1669	T	C	HELD_MAL_CASE	14	27	1	13	1	0	HELD_MAL_CTRL	18	29	7	12	5	1
1755	A	G	HELD_MAL_BAD2	306	387	225	143	101	62	HELD_MAL_GOOD2	345	413	277	134	145	66
1765	A	G	HELD_FEM_BAD	86	21	151	4	13	69	HELD_FEM_GOOD	70	27	113	2	23	45
2109	A	G	HELD_FEM_BAD2	316	521	111	217	87	12	HELD_FEM_GOOD2	359	561	157	222	117	20
2150	T	C	HELD_ALL_BAD	98	156	40	65	26	7	HELD_ALL_GOOD	115	191	39	76	39	0
2150	T	C	HELD_ALL_BAD	102	162	42	67	28	7	HELD_ALL_GOOD	111	185	37	74	37	0
2150	T	C	HELD_MAL_BAD	19	29	9	13	3	3	HELD_MAL_GOOD	36	62	10	26	10	0
2150	T	C	HELD_MAL_BAD	19	29	9	13	3	3	HELD_MAL_GOOD	36	62	10	26	10	0
2150	T	C	HELD_FEM_BAD	79	127	31	52	23	4	HELD_FEM_GOOD	79	129	29	50	29	0
2234	T	G	HELD_ALL_BAD	100	136	64	42	52	6	HELD_ALL_GOOD	109	141	77	49	43	17
2321	G	T	HELD_MAL_BAD	18	30	6	12	6	0	HELD_MAL_GOOD	35	67	3	32	3	0
2321	G	T	HELD_MAL_BAD	18	30	6	12	6	0	HELD_MAL_GOOD	35	67	3	32	3	0
2321	G	T	HELD_FEM_BAD	80	154	6	74	6	0	HELD_FEM_GOOD	79	143	15	65	13	1
2354	C	T	CVD_FEM_CASE	35	57	13	22	13	0	CVD_FEM_CTRL	40	76	4	36	4	0
3451	C	T	HELD_FEM_ADRCASE	73	64	82	11	42	20	HELD_FEM_ADRCTRL	69	74	64	23	28	18
3451	C	T	HELD_MAL_ADRCASE5ULN	9	14	4	5	4	0	HELD_MAL_ADRCTRL	60	62	58	18	26	16
3452	A	G	HELD_MAL_ADRCASE5ULN	9	17	1	8	1	0	HELD_MAL_ADRCTRL	60	83	37	29	25	6
3453	C	T	HELD_FEM_ADRCASE	71	103	39	36	31	4	HELD_FEM_ADRCTRL	69	84	54	26	32	11
4912	G	A	HELD_FEM_BAD	70	78	62	34	10	26	HELD_FEM_GOOD	60	51	69	23	5	32
5093	G	A	CVD_FEM_CASE	32	30	34	9	12	11	CVD_FEM_CTRL	39	52	26	18	16	5
5093	G	A	HELD_MAL_CASE	11	16	6	6	4	1	HELD_MAL_CTRL	17	14	20	3	8	6
6333	A	C	HELD_MAL_ADRCASE5ULN	8	8	8	0	8	0	HELD_MAL_ADRCTRL	54	61	47	19	23	12
6333	A	C	HELD_ALL_ADRCASE	124	114	134	25	64	35	HELD_ALL_ADRCTRL	117	136	98	44	48	25
6333	A	C	HELD_ALL_ADRCASE3ULN	44	37	51	6	25	13	HELD_ALL_ADRCTRL	117	136	98	44	48	25
6333	A	C	HELD_FEM_ADRCASE3ULN	28	22	34	4	14	10	HELD_FEM_ADRCTRL	63	75	51	25	25	13
6333	A	C	HELD_ALL_ADRCASE5ULN	24	22	26	3	16	5	HELD_ALL_ADRCTRL	117	136	98	44	48	25
6333	A	C	HELD_MAL_ADRCASE	57	49	65	8	33	16	HELD_MAL_ADRCTRL	54	61	47	19	23	12
6333	A	C	CVD_MAL_CASE	32	37	27	8	21	3	CVD_MAL_CTRL	32	29	35	8	13	11
7407	G	A	HELD_ALL_ADRCASE5ULN	8	7	9	2	3	3	HELD_ALL_ADRCTRL	50	32	68	1	30	19
7407	G	A	HELD_FEM_ADRCASE5ULN	7	7	7	2	3	2	HELD_FEM_ADRCTRL	23	14	32	0	14	9
7407	G	A	HELD_FEM_ADRCASE	27	26	28	4	18	5	HELD_FEM_ADRCTRL	23	14	32	0	14	9
7407	G	A	HELD_FEM_ADRCASE3ULN	13	13	13	3	7	3	HELD_FEM_ADRCTRL	23	14	32	0	14	9
10584	G	T	HELD_ALL_ADRCASE	133	254	12	121	12	0	HELD_ALL_ADRCTRL	130	257	3	127	3	0
10584	G	T	HELD_FEM_ADRCASE	70	133	7	63	7	0	HELD_FEM_ADRCTRL	70	139	1	69	1	0
10584	G	T	HELD_FEM_ADRCASE3ULN	29	55	3	26	3	0	HELD_FEM_ADRCTRL	70	139	1	69	1	0
11021	T	C	HELD_FEM_BAD	80	133	27	55	23	2	HELD_FEM_GOOD	71	129	13	59	11	1
11062	T	C	HELD_MAL_ADRCASE5ULN	8	14	2	6	2	0	HELD_MAL_ADRCTRL	58	75	41	22	31	5
11147	C	T	HELD_FEM_ADRCASE	60	75	45	19	37	4	HELD_FEM_ADRCTRL	56	59	53	16	27	13
11212	G	C	HELD_ALL_LOHDL	10	14	6	5	4	1	HELD_ALL_HIHDL	15	12	18	2	8	5
11371	A	G	HELD_ALL_ADRCASE3ULN	48	89	7	41	7	0	HELD_ALL_ADRCTRL	129	252	6	123	6	0
11371	A	G	HELD_FEM_ADRCASE	73	138	8	65	8	0	HELD_FEM_ADRCTRL	71	140	2	69	2	0
11487	T	A	HELD_FEM_UHIRESP	52	74	30	27	20	5	HELD_FEM_ULORESP	72	116	28	44	28	0
11585	G	T	HELD_ALL_BAD	104	117	91	28	61	15	HELD_ALL_GOOD	110	104	116	25	54	31
11683	C	G	HELD_FEM_UHIRESP	56	81	31	28	25	3	HELD_FEM_ULORESP	78	128	28	55	18	5
11863	G	A	HELD_FEM_VHIRESP	154	288	20	134	20	0	HELD_FEM_VLORESP	150	264	36	115	34	1
12024	C	T	HELD_ALL_ADRCASE	134	255	13	121	13	0	HELD_ALL_ADRCTRL	131	259	3	128	3	0
12024	C	T	HELD_FEM_ADRCASE3ULN	29	54	4	25	4	0	HELD_FEM_ADRCTRL	71	141	1	70	1	0
12024	C	T	HELD_FEM_ADRCASE	71	134	8	63	8	0	HELD_FEM_ADRCTRL	71	141	1	70	1	0
12024	C	T	HELD_ALL_ADRCASE3ULN	46	87	5	41	5	0	HELD_ALL_ADRCTRL	131	259	3	128	3	0
12632	C	T	HELD_MAL_ADRCASE5ULN	9	17	1	8	1	0	HELD_MAL_ADRCTRL	64	128	0	64	0	0
13994	G	A	CVD_FEM_CASE	30	56	4	28	0	2	CVD_FEM_CTRL	37	74	0	37	0	0
13994	G	A	HELD_MAL_ADRCASE	52	104	0	52	0	0	HELD_MAL_ADRCTRL	50	97	3	48	1	1
14090	C	A	HELD_FEM_HIRESP	269	455	83	191	73	5	HELD_FEM_LORESP	275	487	63	219	49	7
14159	T	C	HELD_FEM_HIRESP	292	365	219	120	125	47	HELD_FEM_LORESP	293	343	243	94	155	44
14362	T	G	HELD_FEM_UHIRESP	57	109	5	52	5	0	HELD_FEM_ULORESP	79	140	18	63	14	2
14410	G	A	HELD_MAL_ADRCASE	61	120	2	59	2	0	HELD_MAL_ADRCTRL	63	118	8	55	8	0
14488	A	G	HELD_ALL_ADRCASE	132	252	12	120	12	0	HELD_ALL_ADRCTRL	131	259	3	128	3	0
14488	A	G	HELD_FEM_ADRCASE	71	135	7	64	7	0	HELD_FEM_ADRCTRL	71	141	1	70	1	0
14488	A	G	HELD_FEM_ADRCASE3ULN	30	57	3	27	3	0	HELD_FEM_ADRCTRL	71	141	1	70	1	0
14490	C	T	HELD_MAL_ADRCASE5ULN	9	18	0	9	0	0	HELD_MAL_ADRCTRL	58	91	25	36	19	3
14490	C	T	HELD_FEM_ADRCASE5ULN	17	23	11	7	9	1	HELD_FEM_ADRCTRL	71	121	21	51	19	1
14490	C	T	HELD_FEM_ADRCASE3ULN	31	45	17	15	15	1	HELD_FEM_ADRCTRL	71	121	21	51	19	1
14493	A	G	HELD_ALL_ADRCASE	135	257	13	122	13	0	HELD_ALL_ADRCTRL	128	253	3	125	3	0
14493	A	G	HELD_FEM_ADRCASE	73	138	8	65	8	0	HELD_FEM_ADRCTRL	69	137	1	68	1	0
14493	A	G	HELD_FEM_ADRCASE3ULN	31	58	4	27	4	0	HELD_FEM_ADRCTRL	69	137	1	68	1	0
14493	A	G	HELD_ALL_ADRCASE3ULN	48	91	5	43	5	0	HELD_ALL_ADRCTRL	128	253	3	125	3	0
14554	C	A	HELD_MAL_ADRCASE3ULN	16	32	0	16	0	0	HELD_MAL_ADRCTRL	61	99	23	49	1	11
14554	C	A	HELD_MAL_ADRCASE5ULN	8	16	0	8	0	0	HELD_MAL_ADRCTRL	61	99	23	49	1	11
14554	C	A	HELD_MAL_ADRCASE	61	110	12	55	0	6	HELD_MAL_ADRCTRL	61	99	23	49	1	11
14603	A	G	CVD_MAL_CASE	39	69	9	30	9	0	CVD_MAL_CTRL	12	24	0	12	0	0
14820	A	G	HELD_FEM_VHIRESP	147	197	97	65	67	15	HELD_FEM_VLORESP	142	187	97	71	45	26
14820	A	G	HELD_FEM_UHIRESP	55	74	36	24	26	5	HELD_FEM_ULORESP	76	96	56	37	22	17
14876	C	T	HELD_FEM_HIRESP	280	340	220	111	118	51	HELD_FEM_LORESP	285	344	226	96	152	37
14876	C	T	HELD_FEM_VHIRESP	147	179	115	60	59	28	HELD_FEM_VLORESP	145	166	124	43	80	22
14954	G	C	HELD_MAL_ADRCASE	59	118	0	59	0	0	HELD_MAL_ADRCTRL	65	127	3	63	1	1
14957	A	C	HELD_FEM_ADRCASE5ULN	17	34	0	17	0	0	HELD_FEM_ADRCTRL	78	145	11	67	11	0
14957	A	C	HELD_FEM_VHIRESP	148	265	31	118	29	1	HELD_FEM_VLORESP	143	269	17	127	15	1
14977	A	G	HELD_FEM_UHIRESP	56	76	36	29	18	9	HELD_FEM_ULORESP	75	118	32	45	28	2
15349	C	T	HELD_MAL_ADRCASE	59	81	37	27	27	5	HELD_MAL_ADRCTRL	65	72	58	20	32	13
15590	G	A	HELD_ALL_ADRCASE5ULN	25	33	17	9	15	1	HELD_ALL_ADRCTRL	140	149	131	44	61	35
15590	G	A	HELD_ALL_ADRCASE	130	149	111	37	75	18	HELD_ALL_ADRCTRL	140	149	131	44	61	35
15590	G	A	HELD_FEM_ADRCASE	71	81	61	20	41	10	HELD_FEM_ADRCTRL	76	78	74	24	30	22
16268	C	G	HELD_MAL_ADRCASE5ULN	9	18	0	9	0	0	HELD_MAL_ADRCTRL	65	112	18	48	16	1
36078	A	G	HELD_FEM_VHIRESP	22	41	3	19	3	0	HELD_FEM_VLORESP	17	26	8	9	8	0
36078	A	G	HELD_FEM_HIRESP	32	59	5	27	5	0	HELD_FEM_LORESP	26	42	10	16	10	0
36406	T	C	HELD_FEM_ADRCASE5ULN	17	27	7	10	7	0	HELD_FEM_ADRCTRL	74	83	65	23	37	14
37135	C	T	HELD_ALL_ADRCASE3ULN	44	50	38	19	12	13	HELD_ALL_ADRCTRL	117	135	99	37	61	19
37135	C	T	HELD_FEM_ADRCASE3ULN	29	32	26	13	6	10	HELD_FEM_ADRCTRL	61	67	55	18	31	12
37135	C	T	HELD_FEM_ADRCASE5ULN	17	21	13	9	3	5	HELD_FEM_ADRCTRL	61	67	55	18	31	12
37135	C	T	HELD_ALL_ADRCASE5ULN	24	30	18	12	6	6	HELD_ALL_ADRCTRL	117	135	99	37	61	19
37327	T	C	HELD_ALL_CASE2	17	20	14	7	6	4	HELD_ALL_CTRL2	3	6	0	3	0	0
37327	T	C	HELD_FEM_VHIRESP	143	206	80	80	46	17	HELD_FEM_VLORESP	127	163	91	51	61	15
37327	T	C	HELD_FEM_UHIRESP	53	83	23	33	17	3	HELD_FEM_ULORESP	69	90	48	28	34	7
37327	T	C	HELD_MAL_ADRCASE	55	87	23	43	1	11	HELD_MAL_ADRCTRL	49	64	34	31	2	16
37404	T	C	HELD_MAL_ADRCASE	49	94	4	46	2	1	HELD_MAL_ADRCTRL	49	98	0	49	0	0
37413	A	T	HELD_FEM_ADRCASE5ULN	17	23	11	7	9	1	HELD_FEM_ADRCTRL	61	107	15	46	15	0
37413	A	T	HELD_FEM_ADRCASE3ULN	30	43	17	14	15	1	HELD_FEM_ADRCTRL	61	107	15	46	15	0
37413	A	T	HELD_ALL_ADRCASE5ULN	24	36	12	13	10	1	HELD_ALL_ADRCTRL	117	206	28	90	26	1
37413	A	T	HELD_ALL_ADRCASE3ULN	45	70	20	26	18	1	HELD_ALL_ADRCTRL	117	206	28	90	26	1
37939	C	T	HELD_FEM_HIRESP	295	544	46	254	36	5	HELD_FEM_LORESP	298	551	45	253	45	0
37939	C	T	CVD_MAL_CASE	36	60	12	25	10	1	CVD_MAL_CTRL	13	24	2	12	0	1
38009	T	G	HELD_ALL_ADRCASE	126	220	32	96	28	2	HELD_ALL_ADRCTRL	116	184	48	75	34	7
38009	T	G	HELD_MAL_ADRCASE	57	101	13	44	13	0	HELD_MAL_ADRCTRL	55	88	22	37	14	4
40004	G	C	CVD_FEM_CASE	17	23	11	8	7	2	CVD_FEM_CTRL	16	29	3	13	3	0
40522	T	A	HELD_FEM_ADRCASE	73	112	34	45	22	6	HELD_FEM_ADRCTRL	78	100	56	34	32	12
40522	T	A	HELD_FEM_ADRCASE3ULN	31	49	13	19	11	1	HELD_FEM_ADRCTRL	78	100	56	34	32	12
40522	T	A	HELD_FEM_ADRCASE5ULN	17	28	6	11	6	0	HELD_FEM_ADRCTRL	78	100	56	34	32	12
41847	T	G	HELD_FEM_HIRESP	222	266	178	79	108	35	HELD_FEM_LORESP	223	229	217	67	95	61
42084	A	C	HELD_MAL_ADRCASE5ULN	7	11	3	5	1	1	HELD_MAL_ADRCTRL	56	100	12	44	12	0
42084	A	C	HELD_FEM_ADRCASE3ULN	31	48	14	17	14	0	HELD_FEM_ADRCTRL	62	108	16	48	12	2
42084	A	C	HELD_FEM_ADRCASE	71	116	26	45	26	0	HELD_FEM_ADRCTRL	62	108	16	48	12	2
42084	A	C	HELD_ALL_ADRCASE5ULN	25	38	12	14	10	1	HELD_ALL_ADRCTRL	118	208	28	92	24	2
42084	A	C	HELD_FEM_ADRCASE5ULN	18	27	9	9	9	0	HELD_FEM_ADRCTRL	62	108	16	48	12	2
42084	A	C	HELD_ALL_ADRCASE3ULN	46	73	19	28	17	1	HELD_ALL_ADRCTRL	118	208	28	92	24	2
42677	C	G	HELD_FEM_ADRCASE3ULN	30	41	19	13	15	2	HELD_FEM_ADRCTRL	59	61	57	15	31	13
42677	C	G	HELD_FEM_ADRCASE5ULN	17	24	10	8	8	1	HELD_FEM_ADRCTRL	59	61	57	15	31	13
42677	C	G	HELD_FEM_ADRCASE	68	87	49	25	37	6	HELD_FEM_ADRCTRL	59	61	57	15	31	13
46865	T	C	HELD_FEM_VHIRESP	151	248	54	101	46	4	HELD_FEM_VLORESP	143	206	80	72	62	9
46865	T	C	HELD_FEM_HIRESP	272	439	105	176	87	9	HELD_FEM_LORESP	276	416	136	155	106	15
46865	T	C	HELD_ALL_ADRCASE5ULN	26	37	15	11	15	0	HELD_ALL_ADRCTRL	136	203	69	77	49	10
47856	T	C	HELD_ALL_ADRCASE5ULN	26	43	9	20	3	3	HELD_ALL_ADRCTRL	143	214	72	81	52	10
47856	T	C	HELD_MAL_ADRCASE5ULN	9	17	1	8	1	0	HELD_MAL_ADRCTRL	65	98	32	36	26	3
47856	T	C	HELD_FEM_VHIRESP	153	222	84	80	62	11	HELD_FEM_VLORESP	151	240	62	97	46	8
48490	A	G	CVD_ALL_CASE	46	53	39	16	21	9	CVD_ALL_CTRL	35	23	47	4	15	16
48490	A	G	CVD_MAL_CASE	30	37	23	12	13	5	CVD_MAL_CTRL	17	12	22	2	8	7
48490	A	G	HELD_ALL_ADRCASE3ULN	47	41	53	6	29	12	HELD_ALL_ADRCTRL	135	151	119	44	63	28
48490	A	G	HELD_FEM_ADRCASE3ULN	30	25	35	3	19	8	HELD_FEM_ADRCTRL	72	83	61	25	33	14
48490	A	G	HELD_FEM_ADRCASE	70	63	77	13	37	20	HELD_FEM_ADRCTRL	72	83	61	25	33	14
50164	G	A	HELD_FEM_ADRCASE3ULN	31	50	12	20	10	1	HELD_FEM_ADRCTRL	77	143	11	67	9	1
50164	G	A	HELD_FEM_ADRCASE	75	127	23	53	21	1	HELD_FEM_ADRCTRL	77	143	11	67	9	1
50164	G	A	HELD_ALL_ADRCASE5ULN	26	41	11	17	7	2	HELD_ALL_ADRCTRL	142	252	32	112	28	2
54704	G	A	HELD_FEM_ADRCASE	68	125	11	57	11	0	HELD_FEM_ADRCTRL	60	118	2	58	2	0
54806	G	A	CVD_ALL_CASE	34	64	4	30	4	0	CVD_ALL_CTRL	31	62	0	31	0	0
54806	G	A	HELD_FEM_UHIRESP	53	99	7	47	5	1	HELD_FEM_ULORESP	73	128	18	55	18	0
54807	G	A	HELD_FEM_ADRCASE5ULN	17	22	12	7	8	2	HELD_FEM_ADRCTRL	70	124	16	56	12	2
54807	G	A	HELD_ALL_ADRCASE5ULN	26	35	17	12	11	3	HELD_ALL_ADRCTRL	129	218	40	93	32	4
54807	G	A	HELD_FEM_ADRCASE	71	107	35	40	27	4	HELD_FEM_ADRCTRL	70	124	16	56	12	2
54807	G	A	HELD_ALL_ADRCASE	134	205	63	77	51	6	HELD_ALL_ADRCTRL	129	218	40	93	32	4
54807	G	A	HELD_FEM_ADRCASE3ULN	31	47	15	18	11	2	HELD_FEM_ADRCTRL	70	124	16	56	12	2
54807	G	A	HELD_FEM_HIRESP	281	461	101	189	83	9	HELD_FEM_LORESP	267	411	123	160	91	16
54807	G	A	HELD_ALL_ADRCASE3ULN	48	72	24	27	18	3	HELD_ALL_ADRCTRL	129	218	40	93	32	4
54807	G	A	HELD_FEM_UHIRESP	53	94	12	41	12	0	HELD_FEM_ULORESP	69	109	29	43	23	3
55733	G	A	CVD_MAL_CASE	34	58	10	25	8	1	CVD_MAL_CTRL	13	26	0	13	0	0
55733	G	A	CVD_FEM_CASE	15	30	0	15	0	0	CVD_FEM_CTRL	16	28	4	12	4	0
55733	G	A	HELD_FEM_VHIRESP	155	289	21	134	21	0	HELD_FEM_VLORESP	150	265	35	116	33	1
55733	G	A	HELD_ALL_ADRCASE	136	252	20	117	18	1	HELD_ALL_ADRCTRL	140	245	35	107	31	2
55846	A	G	HELD_FEM_VHIRESP	136	169	103	55	59	22	HELD_FEM_VLORESP	144	207	81	76	55	13
55846	A	G	HELD_FEM_UHIRESP	52	62	42	21	20	11	HELD_FEM_ULORESP	76	111	41	42	27	7
55906	G	T	HELD_FEM_HIRESP	26	41	11	15	11	0	HELD_FEM_LORESP	51	57	45	17	23	11
56084	C	T	HELD_FEM_UHIRESP	8	8	8	1	6	1	HELD_FEM_ULORESP	22	36	8	16	4	2
57818	G	A	HELD_MAL_ADRCASE	63	100	26	40	20	3	HELD_MAL_ADRCTRL	65	123	7	59	5	1
57818	G	A	HELD_ALL_ADRCASE	138	229	47	96	37	5	HELD_ALL_ADRCTRL	142	262	22	121	20	1
57818	G	A	HELD_MAL_ADRCASE3ULN	17	27	7	12	3	2	HELD_MAL_ADRCTRL	65	123	7	59	5	1
57818	G	A	HELD_ALL_ADRCASE3ULN	48	80	16	35	10	3	HELD_ALL_ADRCTRL	142	262	22	121	20	1
57818	G	A	HELD_FEM_HIRESP	291	509	73	223	63	5	HELD_FEM_LORESP	293	535	51	245	45	3
57819	T	C	HELD_MAL_ADRCASE	61	93	29	35	23	3	HELD_MAL_ADRCTRL	65	116	14	53	10	2
57819	T	C	HELD_ALL_ADRCASE	136	215	57	86	43	7	HELD_ALL_ADRCTRL	143	249	37	111	27	5
57819	T	C	HELD_FEM_HIRESP	289	484	94	200	84	5	HELD_FEM_LORESP	289	506	72	224	58	7
57828	A	G	HELD_FEM_VHIRESP	149	175	123	55	65	29	HELD_FEM_VLORESP	148	179	117	46	87	15
57987	T	C	HELD_MAL_ADRCASE5ULN	9	10	8	1	8	0	HELD_MAL_ADRCTRL	65	71	59	19	33	13
59456	A	C	HELD_MAL_ADRCASE3ULN	15	23	7	9	5	1	HELD_MAL_ADRCTRL	56	64	48	17	30	9
59460	T	C	HELD_FEM_UHIRESP	53	77	29	24	29	0	HELD_FEM_ULORESP	77	100	54	30	40	7
59461	C	T	HELD_MAL_ADRCASE5ULN	9	16	2	8	0	1	HELD_MAL_ADRCTRL	64	83	45	30	23	11
59461	C	T	HELD_FEM_UHIRESP	53	80	26	27	26	0	HELD_FEM_ULORESP	77	104	50	34	36	7
59461	C	T	HELD_FEM_HIRESP	280	406	154	147	112	21	HELD_FEM_LORESP	282	378	186	129	120	33
60900	A	G	HELD_FEM_ADRCASE3ULN	30	37	23	8	21	1	HELD_FEM_ADRCTRL	56	75	37	26	23	7
60900	A	G	HELD_MAL_ADRCASE	51	64	38	19	26	6	HELD_MAL_ADRCTRL	47	72	22	28	16	3
60900	A	G	HELD_ALL_ADRCASE3ULN	43	56	30	15	26	2	HELD_ALL_ADRCTRL	103	147	59	54	39	10
60902	A	T	HELD_MAL_ADRCASE	53	87	19	36	15	2	HELD_MAL_ADRCTRL	53	72	34	25	22	6
60902	A	T	HELD_ALL_ADRCASE	114	181	47	72	37	5	HELD_ALL_ADRCTRL	112	159	65	58	43	11
60934	C	T	CVD_ALL_CASE	52	75	29	29	17	6	CVD_ALL_CTRL	32	30	34	8	14	10
60934	C	T	CVD_MAL_CASE	36	52	20	20	12	4	CVD_MAL_CTRL	13	12	14	3	6	4
60934	C	T	HELD_MAL_ADRCASE	62	75	49	26	23	13	HELD_MAL_ADRCTRL	63	89	37	29	31	3
60934	C	T	CVD_FEM_CASE	16	23	9	9	5	2	CVD_FEM_CTRL	19	18	20	5	8	6
60957	G	A	HELD_MAL_ADRCASE5ULN	8	16	0	8	0	0	HELD_MAL_ADRCTRL	56	89	23	35	19	2
60957	G	A	HELD_MAL_ADRCASE3ULN	16	30	2	14	2	0	HELD_MAL_ADRCTRL	56	89	23	35	19	2
60959	T	C	HELD_MAL_ADRCASE3ULN	15	11	19	1	9	5	HELD_MAL_ADRCTRL	55	72	38	22	28	5
60959	T	C	HELD_MAL_ADRCASE5ULN	8	6	10	0	6	2	HELD_MAL_ADRCTRL	55	72	38	22	28	5
60959	T	C	HELD_ALL_ADRCASE3ULN	45	42	48	9	24	12	HELD_ALL_ADRCTRL	115	140	90	42	56	17
60959	T	C	HELD_ALL_ADRCASE	126	130	122	35	60	31	HELD_ALL_ADRCTRL	115	140	90	42	56	17
60959	T	C	HELD_MAL_ADRCASE	58	61	55	18	25	15	HELD_MAL_ADRCTRL	55	72	38	22	28	5
60962	C	T	HELD_MAL_ADRCASE5ULN	4	3	5	1	1	2	HELD_MAL_ADRCTRL	40	65	15	27	11	2
60962	C	T	HELD_MAL_ADRCASE3ULN	9	9	9	2	5	2	HELD_MAL_ADRCTRL	40	65	15	27	11	2
60962	C	T	HELD_MAL_ADRCASE	36	48	24	17	14	5	HELD_MAL_ADRCTRL	40	65	15	27	11	2
60974	G	A	HELD_FEM_ADRCASE5ULN	17	27	7	12	3	2	HELD_FEM_ADRCTRL	75	121	29	47	27	1
60978	G	C	HELD_MAL_ADRCASE	63	123	3	60	3	0	HELD_MAL_ADRCTRL	65	117	13	53	11	1
60978	G	C	HELD_FEM_HIRESP	294	546	42	255	36	3	HELD_FEM_LORESP	297	544	50	247	50	0
60978	G	C	HELD_FEM_VHIRESP	159	294	24	137	20	2	HELD_FEM_VLORESP	151	271	31	120	31	0
60999	G	T	HELD_MAL_ADRCASE5ULN	9	18	0	9	0	0	HELD_MAL_ADRCTRL	64	114	14	50	14	0
61011	T	C	CVD_MAL_CASE	38	62	14	24	14	0	CVD_MAL_CTRL	13	24	2	12	0	1
61011	T	C	HELD_FEM_HIRESP	289	472	106	196	80	13	HELD_FEM_LORESP	284	477	91	196	85	3
61086	G	A	HELD_MAL_ADRCASE	39	71	7	32	7	0	HELD_MAL_ADRCTRL	36	56	16	22	12	2
61126	C	T	HELD_MAL_ADRCASE	59	68	50	23	22	14	HELD_MAL_ADRCTRL	56	67	45	16	35	5
61126	C	T	HELD_FEM_VHIRESP	152	152	152	33	86	33	HELD_FEM_VLORESP	137	165	109	51	63	23
61126	C	T	HELD_FEM_UHIRESP	54	54	54	10	34	10	HELD_FEM_ULORESP	72	88	56	29	30	13
61126	C	T	HELD_FEM_HIRESP	274	292	256	76	140	58	HELD_FEM_LORESP	266	317	215	98	121	47
61137	T	C	HELD_ALL_ADRCASE	133	211	55	81	49	3	HELD_ALL_ADRCTRL	140	241	39	103	35	2
61147	G	A	HELD_FEM_HIRESP	293	335	251	101	133	59	HELD_FEM_LORESP	296	363	229	105	153	38
61176	A	G	HELD_MAL_ADRCASE5ULN	8	14	2	6	2	0	HELD_MAL_ADRCTRL	55	63	47	16	31	8
61176	A	G	HELD_MAL_ADRCASE	56	80	32	30	20	6	HELD_MAL_ADRCTRL	55	63	47	16	31	8
61176	A	G	HELD_MAL_ADRCASE3ULN	16	24	8	10	4	2	HELD_MAL_ADRCTRL	55	63	47	16	31	8
61176	A	G	HELD_ALL_ADRCASE5ULN	26	38	14	16	6	4	HELD_ALL_ADRCTRL	117	150	84	46	58	13
61184	C	T	HELD_MAL_ADRCASE5ULN	9	16	2	8	0	1	HELD_MAL_ADRCTRL	61	96	26	38	20	3
61184	C	T	HELD_MAL_ADRCASE	61	108	14	49	10	2	HELD_MAL_ADRCTRL	61	96	26	38	20	3
61197	A	G	HELD_MAL_ADRCASE3ULN	17	24	10	10	4	3	HELD_MAL_ADRCTRL	63	109	17	47	15	1
61270	A	G	HELD_MAL_ADRCASE3ULN	16	23	9	7	9	0	HELD_MAL_ADRCTRL	55	101	9	46	9	0
61270	A	G	HELD_MAL_ADRCASE5ULN	8	11	5	3	5	0	HELD_MAL_ADRCTRL	55	101	9	46	9	0
61270	A	G	HELD_ALL_CASE2	17	32	2	15	2	0	HELD_ALL_CTRL2	3	4	2	1	2	0
61272	A	G	HELD_MAL_ADRCASE5ULN	8	10	6	3	4	1	HELD_MAL_ADRCTRL	56	89	23	33	23	0
61272	A	G	HELD_FEM_ADRCASE	69	116	22	50	16	3	HELD_FEM_ADRCTRL	62	91	33	32	27	3
61284	G	A	HELD_FEM_HIRESP	290	329	251	104	121	65	HELD_FEM_LORESP	295	358	232	103	152	40
61292	G	A	HELD_FEM_HIRESP	288	333	243	100	133	55	HELD_FEM_LORESP	294	381	207	118	145	31
61292	G	A	HELD_MAL_ADRCASE	62	78	46	21	36	5	HELD_MAL_ADRCTRL	64	83	45	30	23	11
61297	T	C	CVD_ALL_CASE	92	134	50	53	28	11	CVD_ALL_CTRL	64	106	22	46	14	4
61324	G	A	HELD_FEM_VHIRESP	21	29	13	12	5	4	HELD_FEM_VLORESP	17	15	19	5	5	7
61328	A	G	HELD_FEM_HIRESP	277	551	3	275	1	1	HELD_FEM_LORESP	276	552	0	276	0	0
61373	G	C	HELD_FEM_ADRCASE	75	136	14	61	14	0	HELD_FEM_ADRCTRL	76	122	30	50	22	4
61373	G	C	HELD_ALL_ADRCASE	136	244	28	110	24	2	HELD_ALL_ADRCTRL	141	236	46	100	36	5
900066	C	T	HELD_MAL_BAD	17	30	4	15	0	2	HELD_MAL_GOOD	32	53	11	23	7	2
900071	G	C	HELD_FEM_UHIRESP	52	57	47	13	31	8	HELD_FEM_ULORESP	77	66	88	17	32	28
900072	G	C	HELD_FEM_UHIRESP	41	50	32	16	18	7	HELD_FEM_ULORESP	62	53	71	14	25	23
900072	G	C	HELD_FEM_LOHDL	25	20	30	2	16	7	HELD_FEM_HIHDL	27	28	26	9	10	8
900072	G	C	HELD_FEM_VHIRESP	123	141	105	44	53	26	HELD_FEM_VLORESP	115	111	119	30	51	34
900073	G	C	HELD_ALL_ADRCASE	125	158	92	45	68	12	HELD_ALL_ADRCTRL	121	178	64	64	50	7
900073	G	C	HELD_MAL_ADRCASE	59	71	47	17	37	5	HELD_MAL_ADRCTRL	55	82	28	30	22	3
900073	G	C	HELD_ALL_CASE2	26	45	7	19	7	0	HELD_ALL_CTRL2	2	2	2	0	2	0
900073	G	C	HELD_MAL_ADRCASE3ULN	17	19	15	5	9	3	HELD_MAL_ADRCTRL	55	82	28	30	22	3
900073	G	C	HELD_FEM_HIRESP	295	398	192	132	134	29	HELD_FEM_LORESP	299	435	163	158	119	22
900074	C	T	HELD_FEM_BAD	76	85	67	19	47	10	HELD_FEM_GOOD	69	93	45	29	35	5
900074	C	T	HELD_FEM_UHIRESP	52	70	34	23	24	5	HELD_FEM_ULORESP	79	87	71	25	37	17
900083	A	G	HELD_FEM_HIRESP	281	296	266	81	134	66	HELD_FEM_LORESP	280	329	231	100	129	51
900115	A	G	HELD_MAL_ADRCASE3ULN	16	13	19	4	5	7	HELD_MAL_ADRCTRL	59	74	44	22	30	7
900115	A	G	HELD_ALL_CASE	45	54	36	15	24	6	HELD_ALL_CTRL	40	61	19	24	13	3
900115	A	G	HELD_ALL_ADRCASE5ULN	25	25	25	7	11	7	HELD_ALL_ADRCTRL	130	169	91	53	63	14
900143	G	T	HELD_MAL_ADRCASE5ULN	7	7	7	0	7	0	HELD_MAL_ADRCTRL	53	59	47	18	23	12
900143	G	T	HELD_ALL_ADRCASE	122	112	132	25	62	35	HELD_ALL_ADRCTRL	117	137	97	43	51	23
900143	G	T	HELD_FEM_ADRCASE3ULN	29	23	35	4	15	10	HELD_FEM_ADRCTRL	64	78	50	25	28	11
900143	G	T	HELD_ALL_ADRCASE3ULN	43	36	50	6	24	13	HELD_ALL_ADRCTRL	117	137	97	43	51	23
900143	G	T	HELD_ALL_ADRCASE5ULN	24	22	26	3	16	5	HELD_ALL_ADRCTRL	117	137	97	43	51	23
900143	G	T	HELD_FEM_ADRCASE	67	65	69	17	31	19	HELD_FEM_ADRCTRL	64	78	50	25	28	11
900173	T	G	HELD_MAL_ADRCASE3ULN	16	30	2	14	2	0	HELD_MAL_ADRCTRL	55	83	27	31	21	3
900174	A	G	HELD_MAL_ADRCASE3ULN	16	12	20	3	6	7	HELD_MAL_ADRCTRL	54	71	37	22	27	5
900174	A	G	HELD_MAL_ADRCASE5ULN	8	5	11	1	3	4	HELD_MAL_ADRCTRL	54	71	37	22	27	5
900174	A	G	HELD_ALL_ADRCASE5ULN	22	21	23	6	9	7	HELD_ALL_ADRCTRL	113	148	78	48	52	13
900174	A	G	HELD_FEM_CASE	28	31	25	7	17	4	HELD_FEM_CTRL	21	32	10	13	6	2
900174	A	G	HELD_ALL_CASE	42	49	35	13	23	6	HELD_ALL_CTRL	37	55	19	21	13	3
900175	G	A	HELD_FEM_HIRESP	12	21	3	9	3	0	HELD_FEM_LORESP	22	29	15	9	11	2
900180	G	A	CVD_ALL_CASE	102	69	135	12	45	45	CVD_ALL_CTRL	73	76	70	21	34	18
900180	G	A	CVD_FEM_CASE	33	18	48	2	14	17	CVD_FEM_CTRL	40	44	36	14	16	10
900180	G	A	HELD_MAL_CASE	14	10	18	2	6	6	HELD_MAL_CTRL	18	26	10	9	8	1
900180	G	A	HELD_ALL_CASE	44	33	55	7	19	18	HELD_ALL_CTRL	40	48	32	13	22	5
900221	G	C	HELD_MAL_ADRCASE	54	68	40	20	28	6	HELD_MAL_ADRCTRL	52	51	53	14	23	15
900250	C	T	HELD_MAL_ADRCASE5ULN	9	12	6	5	2	2	HELD_MAL_ADRCTRL	59	103	15	45	13	1
900342	G	A	HELD_ALL_ADRCASE	113	180	46	71	38	4	HELD_ALL_ADRCTRL	113	199	27	89	21	3
900342	G	A	HELD_FEM_ADRCASE	62	96	28	37	22	3	HELD_FEM_ADRCTRL	61	108	14	49	10	2
900344	A	C	HELD_FEM_ADRCASE	70	62	78	15	32	23	HELD_FEM_ADRCTRL	72	93	51	32	29	11
900344	A	C	HELD_FEM_ADRCASE3ULN	34	30	38	8	14	12	HELD_FEM_ADR3CTRL	72	93	51	32	29	11
900344	A	C	HELD_ALL_ADRCASE	128	127	129	34	59	35	HELD_ALL_ADRCTRL	127	155	99	49	57	21
900344	A	C	HELD_FEM_ADRCASE5ULN	19	17	21	4	9	6	HELD_FEM_ADR5CTRL	72	93	51	32	29	11
10000001	G	A	HELD_MAL_BAD	17	24	10	9	6	2	HELD_MAL_GOOD	36	37	35	5	27	4
10000001	G	A	HELD_ALL_BAD	100	126	74	36	54	10	HELD_ALL_GOOD	110	110	110	24	62	24
10000002	A	G	HELD_ALL_BAD	102	158	46	64	30	8	HELD_ALL_GOOD	109	146	72	50	46	13
10000017	T	C	HELD_ALL_BAD	102	177	27	76	25	1	HELD_ALL_GOOD	110	201	19	94	13	3

TABLE 5b
p-values of PA SNPs.
A SNP is considered as associated to cardiovascular disease, adverse statin response or to efficacy
of statin treatment, respectively, when one of the p values is equal or below 0.05.
		GTYPE	GTYPE	GTYPE	ALLELE	ALLELE	ALLELE
BAYSNP	COMPARISON	CPVAL	XPVAL	LRPVAL	CPVAL	XPVAL	LRPVAL
160	HELD_MAL_ADR3ULN	0.1081	0.1125	0.1233	0.039	0.0457	0.0396
194	HELD_FEM_ADR5ULN	0.0184	0.0197	0.031	0.0277	0.036	0.0275
194	HELD_ALL_ADR5ULN	0.019	0.0203	0.0318	0.0985	0.1212	0.1003
194	HELD_FEM_EFF	0.0253	0.0254	0.0245	0.0652	0.068	0.0651
411	HELD_ALL_ADR5ULN	0.1369	0.1383	0.1483	0.0499	0.0616	0.052
466	HELD_FEM_ADR	0.0127	0.0122	0.0116	0.0566	0.0727	0.0563
466	HELD_MAL_ADR5ULN	0.1444	0.1343	0.0569	0.0395	0.0443	0.0336
555	HELD_ALL_LIP	0.0405	0.0404	0.04	0.0988	0.1081	0.0982
623	HELD_MAL_ADR3ULN	0.351	0.4725	0.1695	0.1301	0.2031	0.0466
625	HELD_FEM_ADR3ULN	0.0541	0.0571	0.0484	0.0164	0.0186	0.0168
777	HELD_ALL_LIP	0.056	0.0527	0.0545	0.0139	0.0169	0.0137
777	HELD_ALL_HDL	0.0732	0.043	0.061	0.0238	0.0302	0.0239
777	HELD_ALL_CC2	0.0768	0.0815	0.071	0.0301	0.0394	0.0312
777	HELD_FEM_CC2	0.0839	0.0747	0.0477	0.0303	0.0385	0.0302
777	HELD_FEM_LIP	0.114	0.1237	0.106	0.0349	0.0494	0.0332
777	HELD_ALL_LIP	0.1423	0.1381	0.1399	0.0446	0.0474	0.0448
1005	HELD_FEM_LIP	0.0189	0.0124	0.0159	0.0445	0.0561	0.0418
1062	HELD_ALL_LIP2	0.048	0.05	0.0474	0.1303	0.1363	0.1296
1275	CVD_FEM	0.0072	0.0055	0.0033	0.0005	0.0006	0.0004
1275	HELD_MAL_CC2	0.0152	0.0104	0.0127	0.0136	0.0197	0.0138
1275	HELD_MAL_HDL	0.083	0.0959	0.0758	0.0232	0.0286	0.0222
1275	CVD_MAL	0.0698	0.0784	0.0582	0.0452	0.0552	0.0411
1669	HELD_MAL_CC2	0.026	0.0164	0.0224	0.0062	0.0103	0.0064
1669	HELD_ALL_CC2	0.0261	0.0203	0.0266	0.0071	0.0088	0.0076
1669	CVD_ALL	0.0229	0.0218	0.0196	0.4234	0.4683	0.4246
1669	HELD_MAL_CC	0.1962	0.1959	0.1469	0.0568	0.1236	0.0421
1755	HELD_MAL_LIP2	0.0505	0.0494	0.05	0.211	0.231	0.2108
1765	HELD_FEM_LIP	0.0313	0.0271	0.0311	0.0849	0.114	0.0857
2109	HELD_FEM_LIP2	0.1538	0.1543	0.1522	0.048	0.0554	0.0474
2150	HELD_ALL_LIP	0.0103	0.0077	0.0027	0.3609	0.383	0.3616
2150	HELD_ALL_LIP	0.0163	0.0137	0.0043	0.2982	0.3198	0.2984
2150	HELD_MAL_LIP	0.0394	0.0461	0.0272	0.1962	0.2882	0.204
2150	HELD_MAL_LIP	0.0394	0.0461	0.0272	0.1962	0.2882	0.204
2150	HELD_FEM_LIP	0.0939	0.1007	0.0433	0.7742	0.8861	0.7742
2234	HELD_ALL_LIP	0.0434	0.0425	0.039	0.4731	0.5345	0.4729
2321	HELD_MAL_LIP	0.023	0.048	0.0268	0.0303	0.0591	0.036
2321	HELD_MAL_LIP	0.023	0.048	0.0268	0.0303	0.0591	0.036
2321	HELD_FEM_LIP	0.1252	0.0691	0.1001	0.0392	0.0439	0.0364
2354	CVD_FEM	0.0051	0.0063	0.0044	0.0089	0.0103	0.0078
3451	HELD_FEM_ADR	0.0297	0.03	0.0282	0.0991	0.1225	0.0988
3451	HELD_MAL_ADR5ULN	0.1398	0.1353	0.0553	0.0378	0.0441	0.0321
3452	HELD_MAL_ADR5ULN	0.0728	0.0666	0.0423	0.0252	0.0436	0.0111
3453	HELD_FEM_ADR	0.0877	0.0885	0.0819	0.0383	0.0428	0.038
4912	HELD_FEM_LIP	0.1602	0.156	0.1583	0.0336	0.0354	0.0334
5093	CVD_FEM	0.075	0.0792	0.0726	0.0175	0.0261	0.0173
5093	HELD_MAL_CC	0.0889	0.0959	0.0802	0.0208	0.029	0.0191
6333	HELD_MAL_ADR5ULN	0.0101	0.0098	0.0022	0.6262	0.7884	0.6272
6333	HELD_ALL_ADR	0.0112	0.0115	0.0108	0.0076	0.0083	0.0075
6333	HELD_ALL_ADR3ULN	0.0137	0.0127	0.0086	0.0099	0.0121	0.0099
6333	HELD_FEM_ADR3ULN	0.0462	0.0459	0.0359	0.0115	0.0155	0.0114
6333	HELD_ALL_ADR5ULN	0.0359	0.0339	0.0256	0.1182	0.1505	0.1196
6333	HELD_MAL_ADR	0.034	0.0361	0.0317	0.0444	0.0599	0.044
6333	CVD_MAL	0.0397	0.0422	0.034	0.1571	0.2156	0.1566
7407	HELD_ALL_ADR5ULN	0.0216	0.0358	0.0786	0.3556	0.3987	0.3637
7407	HELD_FEM_ADR5ULN	0.0296	0.0527	0.0424	0.179	0.2111	0.1857
7407	HELD_FEM_ADR	0.0687	0.0847	0.032	0.0715	0.1011	0.07
7407	HELD_FEM_ADR3ULN	0.0493	0.0682	0.0323	0.0995	0.1303	0.1012
10584	HELD_ALL_ADR	0.0189	0.0304	0.0152	0.0207	0.0328	0.0167
10584	HELD_FEM_ADR	0.0289	0.0625	0.0209	0.0314	0.0664	0.0227
10584	HELD_FEM_ADR3ULN	0.0403	0.0743	0.0533	0.0424	0.0764	0.0562
11021	HELD_FEM_LIP	0.1232	0.1185	0.1182	0.0482	0.0609	0.0457
11062	HELD_MAL_ADR5ULN	0.1284	0.1572	0.102	0.0676	0.0888	0.0493
11147	HELD_FEM_ADR	0.0397	0.0379	0.035	0.1302	0.1447	0.13
11212	HELD_ALL_HDL	0.1073	0.1139	0.1007	0.0375	0.0475	0.0355
11371	HELD_ALL_ADR3ULN	0.0243	0.0455	0.0339	0.0272	0.0496	0.0381
11371	HELD_FEM_ADR	0.0547	0.0974	0.047	0.0592	0.1036	0.0508
11487	HELD_FEM_UEFF	0.0251	0.022	0.0104	0.0843	0.0955	0.0859
11585	HELD_ALL_LIP	0.0498	0.053	0.0471	0.0632	0.0667	0.063
11683	HELD_FEM_UEFF	0.0302	0.031	0.0307	0.058	0.0726	0.0593
11863	HELD_FEM_VEFF	0.0491	0.0295	0.0396	0.0189	0.0242	0.0182
12024	HELD_ALL_ADR	0.0113	0.0177	0.0086	0.0127	0.0195	0.0096
12024	HELD_FEM_ADR3ULN	0.0099	0.024	0.0149	0.0109	0.0256	0.0165
12024	HELD_FEM_ADR	0.0159	0.0332	0.0104	0.0177	0.0361	0.0116
12024	HELD_ALL_ADR3ULN	0.016	0.0289	0.0259	0.0172	0.0305	0.0281
12632	HELD_MAL_ADR5ULN	0.0073	0.1233	0.0384	0.0075	0.1233	0.0396
13994	CVD_FEM	0.1108	0.1967	0.0697	0.0241	0.038	0.0103
13994	HELD_MAL_ADR	0.3462	0.2378	0.2353	0.0752	0.116	0.0376
14090	HELD_FEM_EFF	0.0317	0.0293	0.0312	0.0546	0.0617	0.0543
14159	HELD_FEM_EFF	0.0394	0.04	0.0391	0.1651	0.1694	0.165
14362	HELD_FEM_UEFF	0.1453	0.1401	0.0958	0.0404	0.0472	0.0335
14410	HELD_MAL_ADR	0.0541	0.0956	0.0465	0.0594	0.1027	0.051
14488	HELD_ALL_ADR	0.0174	0.0302	0.014	0.0191	0.0327	0.0154
14488	HELD_FEM_ADR	0.029	0.0626	0.021	0.0314	0.0665	0.0227
14488	HELD_FEM_ADR3ULN	0.0431	0.0773	0.0559	0.0452	0.0794	0.0588
14490	HELD_MAL_ADR5ULN	0.0788	0.0899	0.0199	0.029	0.0444	0.0045
14490	HELD_FEM_ADR5ULN	0.0469	0.0595	0.0572	0.0171	0.025	0.0241
14490	HELD_FEM_ADR3ULN	0.0734	0.0809	0.0779	0.0331	0.0492	0.0377
14493	HELD_ALL_ADR	0.0135	0.0183	0.0103	0.015	0.0201	0.0114
14493	HELD_FEM_ADR	0.0201	0.0339	0.0131	0.0222	0.0368	0.0145
14493	HELD_FEM_ADR3ULN	0.0151	0.0311	0.02	0.0164	0.0329	0.0219
14493	HELD_ALL_ADR3ULN	0.022	0.0357	0.0327	0.0236	0.0375	0.0352
14554	HELD_MAL_ADR3ULN	0.155	0.2923	0.0462	0.0077	0.0094	0.0006
14554	HELD_MAL_ADR5ULN	0.3858	0.4135	0.1949	0.0571	0.0733	0.0125
14554	HELD_MAL_ADR	0.2445	0.201	0.1994	0.0445	0.0667	0.043
14603	CVD_MAL	0.0667	0.094	0.0202	0.0814	0.111	0.024
14820	HELD_FEM_VEFF	0.0241	0.024	0.0233	0.7675	0.7919	0.7675
14820	HELD_FEM_UEFF	0.0398	0.0404	0.0358	0.491	0.5144	0.4903
14876	HELD_FEM_EFF	0.0229	0.0221	0.0227	0.9006	0.9033	0.9006
14876	HELD_FEM_VEFF	0.0353	0.0359	0.0349	0.3707	0.4003	0.3706
14954	HELD_MAL_ADR	0.3975	1	0.2707	0.0969	0.2487	0.048
14957	HELD_FEM_ADR5ULN	0.0996	0.2042	0.0312	0.1107	0.2185	0.0342
14957	HELD_FEM_VEFF	0.0953	0.0675	0.0917	0.0471	0.0509	0.0455
14977	HELD_FEM_UEFF	0.0236	0.0241	0.021	0.0483	0.0637	0.0492
15349	HELD_MAL_ADR	0.0934	0.0992	0.0879	0.0319	0.0367	0.0314
15590	HELD_ALL_ADR5ULN	0.0588	0.069	0.0244	0.094	0.1222	0.0908
15590	HELD_ALL_ADR	0.0282	0.0276	0.0269	0.3392	0.3425	0.3391
15590	HELD_FEM_ADR	0.0407	0.0409	0.0384	0.3248	0.35	0.3246
16268	HELD_MAL_ADR5ULN	0.217	0.2899	0.0797	0.0921	0.1295	0.0253
36078	HELD_FEM_VEFF	0.0214	0.0329	0.0205	0.0355	0.0499	0.0347
36078	HELD_FEM_EFF	0.0482	0.071	0.0476	0.0683	0.095	0.068
36406	HELD_FEM_ADR5ULN	0.0413	0.0481	0.0136	0.0121	0.0186	0.0093
37135	HELD_ALL_ADR3ULN	0.0147	0.0138	0.0133	0.8876	0.8999	0.8876
37135	HELD_FEM_ADR3ULN	0.0242	0.0256	0.0197	0.9744	1	0.9744
37135	HELD_FEM_ADR5ULN	0.0487	0.0489	0.0382	0.4765	0.5592	0.4746
37135	HELD_ALL_ADR5ULN	0.0528	0.054	0.0463	0.538	0.6302	0.5363
37327	HELD_ALL_CC2	0.1712	0.2632	0.0958	0.0512	0.0743	0.0167
37327	HELD_FEM_VEFF	0.021	0.0209	0.0207	0.0502	0.0522	0.0503
37327	HELD_FEM_UEFF	0.0585	0.0643	0.057	0.0257	0.0327	0.0244
37327	HELD_MAL_ADR	0.2383	0.3282	0.237	0.0261	0.0298	0.0259
37404	HELD_MAL_ADR	0.2128	0.2423	0.1192	0.0433	0.1212	0.0177
37413	HELD_FEM_ADR5ULN	0.0093	0.0059	0.0132	0.0055	0.0091	0.009
37413	HELD_FEM_ADR3ULN	0.0143	0.011	0.0136	0.0075	0.0121	0.0092
37413	HELD_ALL_ADR5ULN	0.0523	0.0541	0.0727	0.0184	0.0241	0.027
37413	HELD_ALL_ADR3ULN	0.0514	0.0528	0.0584	0.0199	0.0238	0.0243
37939	HELD_FEM_EFF	0.0501	0.0443	0.0191	0.8734	0.9133	0.8734
37939	CVD_MAL	0.089	0.1075	0.026	0.2623	0.3419	0.2367
38009	HELD_ALL_ADR	0.0629	0.0623	0.058	0.0181	0.02	0.0179
38009	HELD_MAL_ADR	0.0999	0.1083	0.0461	0.0765	0.0974	0.0753
40004	CVD_FEM	0.0923	0.0899	0.0611	0.0225	0.034	0.0191
40522	HELD_FEM_ADR	0.0734	0.0767	0.0716	0.0167	0.0173	0.0162
40522	HELD_FEM_ADR3ULN	0.1135	0.1317	0.0806	0.0325	0.0363	0.0285
40522	HELD_FEM_ADR5ULN	0.1324	0.1359	0.0483	0.0397	0.0444	0.0317
41847	HELD_FEM_EFF	0.0119	0.0125	0.0114	0.0101	0.0104	0.0101
42084	HELD_MAL_ADR5ULN	0.0166	0.114	0.0999	0.2432	0.3726	0.2803
42084	HELD_FEM_ADR3ULN	0.0243	0.0187	0.0203	0.0907	0.1374	0.0973
42084	HELD_FEM_ADR	0.0355	0.0268	0.023	0.2277	0.2429	0.2252
42084	HELD_ALL_ADR5ULN	0.0736	0.0884	0.0912	0.0246	0.0287	0.0344
42084	HELD_FEM_ADR5ULN	0.0295	0.0628	0.0317	0.0784	0.1146	0.0924
42084	HELD_ALL_ADR3ULN	0.0813	0.0683	0.0908	0.0413	0.053	0.0476
42677	HELD_FEM_ADR3ULN	0.089	0.0995	0.0737	0.0339	0.0381	0.0323
42677	HELD_FEM_ADR5ULN	0.1362	0.1584	0.1172	0.0506	0.0767	0.0472
42677	HELD_FEM_ADR	0.0823	0.0825	0.0797	0.0478	0.0559	0.0477
46865	HELD_FEM_VEFF	0.0114	0.0113	0.011	0.0035	0.0043	0.0035
46865	HELD_FEM_EFF	0.0966	0.095	0.0957	0.033	0.0346	0.0327
46865	HELD_ALL_ADR5ULN	0.0697	0.0622	0.0349	0.6	0.6068	0.6033
47856	HELD_ALL_ADR5ULN	0.0435	0.0457	0.0266	0.2215	0.2892	0.2077
47856	HELD_MAL_ADR5ULN	0.156	0.1446	0.1053	0.0686	0.0765	0.0393
47856	HELD_FEM_VEFF	0.1073	0.1127	0.1066	0.0458	0.0469	0.0454
48490	CVD_ALL	0.0121	0.0134	0.01	0.0018	0.0024	0.0016
48490	CVD_MAL	0.0642	0.074	0.0545	0.0139	0.0183	0.0134
48490	HELD_ALL_ADR3ULN	0.0316	0.0339	0.0214	0.0395	0.0422	0.0395
48490	HELD_FEM_ADR3ULN	0.0388	0.0388	0.0247	0.0373	0.0455	0.0372
48490	HELD_FEM_ADR	0.0801	0.0814	0.0773	0.0331	0.0434	0.0329
50164	HELD_FEM_ADR3ULN	0.0281	0.0235	0.0366	0.0085	0.0135	0.012
50164	HELD_FEM_ADR	0.0406	0.0229	0.0379	0.0235	0.0286	0.0223
50164	HELD_ALL_ADR5ULN	0.0948	0.0832	0.1617	0.0498	0.0682	0.0647
54704	HELD_FEM_ADR	0.0164	0.0192	0.0116	0.0195	0.0224	0.0138
54806	CVD_ALL	0.0487	0.115	0.0199	0.0524	0.1208	0.0213
54806	HELD_FEM_UEFF	0.051	0.0266	0.0364	0.1334	0.1428	0.1254
54807	HELD_FEM_ADR5ULN	0.0052	0.0081	0.0085	0.0007	0.0016	0.0017
54807	HELD_ALL_ADR5ULN	0.0188	0.0259	0.0285	0.0035	0.0057	0.0059
54807	HELD_FEM_ADR	0.0106	0.0081	0.0097	0.0039	0.0051	0.0036
54807	HELD_ALL_ADR	0.0459	0.0491	0.045	0.0208	0.0214	0.0203
54807	HELD_FEM_ADR3ULN	0.0712	0.066	0.0796	0.0203	0.0326	0.0244
54807	HELD_FEM_EFF	0.1118	0.1163	0.1103	0.0378	0.0429	0.0377
54807	HELD_ALL_ADR3ULN	0.1244	0.1133	0.1334	0.039	0.0442	0.0442
54807	HELD_FEM_UEFF	0.1063	0.1112	0.0602	0.0447	0.057	0.0412
55733	CVD_MAL	0.1191	0.1098	0.0367	0.0386	0.057	0.0085
55733	CVD_FEM	0.038	0.1012	0.0156	0.0453	0.1136	0.0185
55733	HELD_FEM_VEFF	0.0871	0.0522	0.071	0.0364	0.0488	0.0357
55733	HELD_ALL_ADR	0.1242	0.1043	0.1213	0.0435	0.0472	0.0422
55846	HELD_FEM_VEFF	0.0609	0.0598	0.0598	0.0142	0.0152	0.0141
55846	HELD_FEM_UEFF	0.1006	0.1045	0.1027	0.0244	0.0296	0.0249
55906	HELD_FEM_EFF	0.0174	0.0168	0.0033	0.0051	0.0075	0.0041
56084	HELD_FEM_UEFF	0.0086	0.0109	0.0071	0.0137	0.0214	0.0171
57818	HELD_MAL_ADR	0.0011	0.0006	0.0008	0.0003	0.0003	0.0002
57818	HELD_ALL_ADR	0.0051	0.0037	0.0043	0.0008	0.0012	0.0007
57818	HELD_MAL_ADR3ULN	0.0535	0.0495	0.0914	0.0047	0.0105	0.0103
57818	HELD_ALL_ADR3ULN	0.0312	0.0285	0.05	0.0118	0.0173	0.0164
57818	HELD_FEM_EFF	0.104	0.1252	0.1029	0.0332	0.0366	0.0328
57819	HELD_MAL_ADR	0.0118	0.0082	0.0109	0.0061	0.0072	0.0058
57819	HELD_ALL_ADR	0.0303	0.0285	0.0297	0.0114	0.0128	0.0112
57819	HELD_FEM_EFF	0.0397	0.0343	0.0391	0.065	0.078	0.0647
57828	HELD_FEM_VEFF	0.0147	0.0149	0.0141	0.6642	0.6766	0.6642
57987	HELD_MAL_ADR5ULN	0.0892	0.1114	0.0414	0.9401	1	0.9401
59456	HELD_MAL_ADR3ULN	0.102	0.1048	0.1071	0.0512	0.0593	0.0452
59460	HELD_FEM_UEFF	0.0756	0.0735	0.0215	0.1902	0.2235	0.188
59461	HELD_MAL_ADR5ULN	0.0477	0.0497	0.0141	0.0409	0.0572	0.0266
59461	HELD_FEM_UEFF	0.0757	0.0854	0.0216	0.1666	0.2116	0.164
59461	HELD_FEM_EFF	0.1281	0.13	0.1267	0.0456	0.0513	0.0454
60900	HELD_FEM_ADR3ULN	0.0319	0.0263	0.0273	0.4872	0.5058	0.4886
60900	HELD_MAL_ADR	0.0842	0.0937	0.0823	0.0356	0.0438	0.0346
60900	HELD_ALL_ADR3ULN	0.0408	0.0353	0.04	0.2908	0.3294	0.2942
60902	HELD_MAL_ADR	0.0704	0.0681	0.0665	0.0174	0.0258	0.0168
60902	HELD_ALL_ADR	0.1231	0.1376	0.1195	0.0385	0.0496	0.0382
60934	CVD_ALL	0.0114	0.01	0.0103	0.001	0.0017	0.0011
60934	CVD_MAL	0.0892	0.0853	0.0872	0.0167	0.0291	0.0184
60934	HELD_MAL_ADR	0.0225	0.0225	0.0176	0.0912	0.1102	0.0908
60934	CVD_FEM	0.1649	0.1946	0.1578	0.0381	0.0521	0.0365
60957	HELD_MAL_ADR5ULN	0.1073	0.1266	0.0316	0.0454	0.0743	0.009
60957	HELD_MAL_ADR3ULN	0.1593	0.1386	0.1087	0.0599	0.0673	0.0396
60959	HELD_MAL_ADR3ULN	0.011	0.0119	0.0082	0.0044	0.0062	0.0047
60959	HELD_MAL_ADR5ULN	0.0626	0.0725	0.0193	0.0314	0.0512	0.0343
60959	HELD_ALL_ADR3ULN	0.0662	0.0652	0.0634	0.0211	0.024	0.0215
60959	HELD_ALL_ADR	0.1128	0.1139	0.1099	0.0403	0.0436	0.0401
60959	HELD_MAL_ADR	0.0641	0.0684	0.0572	0.0494	0.0586	0.049
60962	HELD_MAL_ADR5ULN	0.0104	0.0393	0.0564	0.0049	0.0135	0.0106
60962	HELD_MAL_ADR3ULN	0.0304	0.0303	0.034	0.0053	0.0087	0.0084
60962	HELD_MAL_ADR	0.1558	0.1758	0.1517	0.0398	0.0432	0.0394
60974	HELD_FEM_ADR5ULN	0.0452	0.044	0.0767	0.8677	1	0.8684
60978	HELD_MAL_ADR	0.0504	0.0339	0.036	0.0118	0.0177	0.009
60978	HELD_FEM_EFF	0.0675	0.0521	0.0376	0.4134	0.448	0.4131
60978	HELD_FEM_VEFF	0.0709	0.0498	0.0478	0.2342	0.2597	0.2339
60999	HELD_MAL_ADR5ULN	0.1186	0.1915	0.0423	0.14	0.2179	0.0487
61011	CVD_MAL	0.0118	0.0084	0.0024	0.1941	0.2316	0.1671
61011	HELD_FEM_EFF	0.0416	0.0427	0.0326	0.2984	0.3095	0.2982
61086	HELD_MAL_ADR	0.0798	0.0625	0.0538	0.0245	0.0396	0.0232
61126	HELD_MAL_ADR	0.0149	0.0144	0.0135	0.7355	0.7893	0.7355
61126	HELD_FEM_VEFF	0.0147	0.0148	0.0145	0.0137	0.0152	0.0136
61126	HELD_FEM_UEFF	0.0238	0.0242	0.021	0.0784	0.0952	0.0785
61126	HELD_FEM_EFF	0.0743	0.0748	0.0739	0.0368	0.0372	0.0367
61137	HELD_ALL_ADR	0.0826	0.0925	0.082	0.0368	0.0413	0.0366
61147	HELD_FEM_EFF	0.0496	0.0508	0.0487	0.1472	0.1549	0.1471
61176	HELD_MAL_ADR5ULN	0.0353	0.0351	0.0289	0.0205	0.0266	0.0129
61176	HELD_MAL_ADR	0.0316	0.0312	0.0302	0.0276	0.0353	0.0273
61176	HELD_MAL_ADR3ULN	0.0431	0.0347	0.0442	0.07	0.0984	0.0639
61176	HELD_ALL_ADR5ULN	0.0477	0.0456	0.0403	0.2174	0.2593	0.2102
61184	HELD_MAL_ADR5ULN	0.1153	0.1381	0.035	0.3125	0.3706	0.2837
61184	HELD_MAL_ADR	0.0853	0.1075	0.0823	0.038	0.0562	0.0367
61197	HELD_MAL_ADR3ULN	0.025	0.0356	0.0561	0.0278	0.0385	0.0369
61270	HELD_MAL_ADR3ULN	0.0012	0.0027	0.0021	0.0028	0.0058	0.0057
61270	HELD_MAL_ADR5ULN	0.0034	0.0105	0.0076	0.0061	0.0174	0.0167
61270	HELD_ALL_CC2	0.0284	0.0877	0.0488	0.0388	0.0997	0.0757
61272	HELD_MAL_ADR5ULN	0.0212	0.0938	0.0853	0.1294	0.197	0.1493
61272	HELD_FEM_ADR	0.0406	0.0382	0.0397	0.0342	0.0477	0.034
61284	HELD_FEM_EFF	0.0089	0.0089	0.0087	0.1696	0.1725	0.1696
61292	HELD_FEM_EFF	0.0133	0.0133	0.0127	0.0144	0.016	0.0144
61292	HELD_MAL_ADR	0.0356	0.0382	0.0341	0.7485	0.7937	0.7485
61297	CVD_ALL	0.1724	0.1719	0.1656	0.0395	0.0415	0.037
61324	HELD_FEM_VEFF	0.1905	0.2208	0.1848	0.0286	0.0368	0.0281
61328	HELD_FEM_EFF	0.3679	1	0.25	0.0834	0.2493	0.0415
61373	HELD_FEM_ADR	0.0324	0.0277	0.0148	0.0104	0.0138	0.0096
61373	HELD_ALL_ADR	0.1305	0.1304	0.1268	0.0374	0.0453	0.0365
900066	HELD_MAL_LIP	0.1046	0.1002	0.0345	0.4779	0.5666	0.47
900071	HELD_FEM_UEFF	0.029	0.0293	0.0242	0.0594	0.0751	0.0592
900072	HELD_FEM_UEFF	0.056	0.0592	0.0508	0.0104	0.0153	0.0102
900072	HELD_FEM_HDL	0.054	0.0619	0.0449	0.2258	0.244	0.2251
900072	HELD_FEM_VEFF	0.1747	0.1778	0.1734	0.0479	0.0538	0.0478
900073	HELD_ALL_ADR	0.0259	0.0264	0.0253	0.0136	0.0154	0.0134
900073	HELD_MAL_ADR	0.0205	0.0218	0.0196	0.021	0.0242	0.0204
900073	HELD_ALL_CC2	0.033	0.0952	0.0272	0.0552	0.117	0.0977
900073	HELD_MAL_ADR3ULN	0.1049	0.0985	0.1149	0.0377	0.0528	0.0422
900073	HELD_FEM_EFF	0.1253	0.1256	0.1249	0.0466	0.0495	0.0465
900074	HELD_FEM_LIP	0.075	0.0758	0.0735	0.0451	0.0534	0.0446
900074	HELD_FEM_UEFF	0.135	0.1403	0.1233	0.0478	0.0538	0.0467
900083	HELD_FEM_EFF	0.1346	0.135	0.134	0.0403	0.0412	0.0403
900115	HELD_MAL_ADR3ULN	0.0147	0.0152	0.0259	0.0248	0.028	0.0255
900115	HELD_ALL_CC	0.048	0.0451	0.0464	0.0238	0.0324	0.0229
900115	HELD_ALL_ADR5ULN	0.0619	0.0567	0.0914	0.0447	0.0553	0.0475
900143	HELD_MAL_ADR5ULN	0.019	0.0193	0.0049	0.6891	0.7784	0.6897
900143	HELD_ALL_ADR	0.0164	0.0168	0.0158	0.0057	0.0061	0.0056
900143	HELD_FEM_ADR3ULN	0.0301	0.0273	0.0239	0.007	0.0107	0.0069
900143	HELD_ALL_ADR3ULN	0.0192	0.0192	0.013	0.0079	0.0111	0.0079
900143	HELD_ALL_ADR5ULN	0.054	0.0621	0.038	0.1057	0.1128	0.1071
900143	HELD_FEM_ADR	0.1539	0.1646	0.1513	0.0434	0.0477	0.0431
900173	HELD_MAL_ADR3ULN	0.0709	0.0762	0.0411	0.0238	0.0249	0.0128
900174	HELD_MAL_ADR3ULN	0.0049	0.0046	0.0095	0.0043	0.0071	0.0045
900174	HELD_MAL_ADR5ULN	0.0079	0.0124	0.0225	0.0082	0.0123	0.009
900174	HELD_ALL_ADR5ULN	0.0429	0.041	0.0669	0.0259	0.0283	0.0281
900174	HELD_FEM_CC	0.0323	0.033	0.0304	0.0332	0.0544	0.031
900174	HELD_ALL_CC	0.0684	0.073	0.0666	0.0345	0.0437	0.0334
900175	HELD_FEM_EFF	0.1371	0.2067	0.0979	0.0538	0.0835	0.0442
900180	CVD_ALL	0.004	0.0038	0.0038	0.0006	0.0007	0.0006
900180	CVD_FEM	0.0056	0.0051	0.0033	0.0007	0.0008	0.0007
900180	HELD_MAL_CC	0.0189	0.0212	0.0138	0.0035	0.0052	0.0032
900180	HELD_ALL_CC	0.0101	0.0077	0.008	0.0036	0.0053	0.0034
900221	HELD_MAL_ADR	0.0682	0.0749	0.0638	0.0411	0.0525	0.0408
900342	HELD_ALL_ADR	0.0292	0.0339	0.0281	0.0152	0.021	0.0147
900342	HELD_FEM_ADR	0.0414	0.0373	0.0391	0.0206	0.027	0.0196
900344	HELD_FEM_ADR	0.0052	0.0053	0.0047	0.0006	0.0008	0.0006
900344	HELD_FEM_ADR3ULN	0.031	0.0322	0.0321	0.0048	0.0071	0.005
900344	HELD_ALL_ADR	0.0441	0.0447	0.043	0.0095	0.01	0.0095
900344	HELD_FEM_ADR5ULN	0.1109	0.1222	0.1078	0.026	0.0393	0.0275
900250	HELD_MAL_ADR5ULN	0.0191	0.0502	0.0802	0.0241	0.0356	0.0395
10000001	HELD_MAL_LIP	0.0083	0.006	0.0094	0.0619	0.0915	0.0588
10000001	HELD_ALL_LIP	0.0161	0.0166	0.0148	0.0073	0.0079	0.0072
10000002	HELD_ALL_LIP	0.0485	0.0489	0.0477	0.0165	0.0173	0.0162
10000017	HELD_ALL_LIP	0.0407	0.0298	0.0386	0.1282	0.1594	0.1278

TABLE 6a
Correlation of genotypes of PA SNPs to relative risk
For diagnostic conclusions to be drawn from genotyping a particular
patient we calculated the relative risk RR1, RR2, RR3 for the three
possible genotypes of each SNP. Given the genotype frequencies as
	gtype1	gtype2	gtype3
	case	N11	N12	N13
	control	N21	N22	N23

we calculate $\mathrm{RR}1=\frac{N11}{N21}/\frac{N12+N13}{N22+N23}$$\mathrm{RR}2=\frac{N12}{N22}/\frac{N11+N13}{N21+N23}$$\mathrm{RR}3=\frac{N13}{N23}/\frac{N11+N12}{N21+N22}$

Here, the case and control populations represent any case-control-group pair, or bad (case)-good (control)-group pair, respectively (due to their increased response to statins, ‘high responders’ are treated as a case cohort, whereas ‘low responders’ are treated as the respective control cohort). A value RR1>1, RR2>1, and RR3>1 indicates an increased risk for individuals carrying genotype 1, genotype 2, and genotype 3, respectively. For example, RR1=3 indicates a 3-fold risk of an individual carrying genotype 1 as compared to individuals carrying genotype 2 or 3 (a detailed description of relative risk calculation and statistics can be found in (Biostatistics, L. D. Fisher and G. van Belle, Wiley Interscience 1993)). The baySNP number refers to an internal numbering of the PA SNPs and can be found in the sequence listing. null: not defined.

In cases where a relative risk is not given in the table (three times zero or null) the informative genotype can be drawn from the right part of the table where the frequencies of genotypes are given in the cases and control cohorts. For example BaySNP 3360 gave the following results:

BAYSNP	COMPARISON	GTYPE1	GTYPE2	GTYPE3	RR1	RR2	RR3
3360	HELD_MAL_ADR5ULN	GG	GT	TT	null	0	0

	FQ1_A	FQ2_A	FQ3_A	FQ1_B	FQ2_B	FQ3_B
	10	0	0	50	22	1

It can be concluded that a GT or TT genotype is only present in the control cohort; these genotypes are somehow protective against ADR. An analogous proceeding can be used to determine protective alleles if no relative risk is given (table 6b).

BAYSNP	COMPARISON	GTYPE1	GTYPE2	GTYPE3	RR1	RR2
160	HELD_MAL_ADR3ULN	TT	CT	CC	0.46	0.89
194	HELD_FEM_ADR5ULN	GG	CG	CC	0.61	0.44
194	HELD_ALL_ADR5ULN	GG	CG	CC	0.9	0.43
194	HELD_FEM_EFF	GG	CG	CC	1.05	1.17
411	HELD_ALL_ADR5ULN	AA	AT	TT	0.53	1.08
466	HELD_FEM_ADR	CC	CT	TT	0.51	1.45
466	HELD_MAL_ADR5ULN	CC	CT	TT	2.44	1.06
555	HELD_ALL_LIP	AA	AG	GG	1.43	0.7
623	HELD_MAL_ADR3ULN	CC	CT	TT	null	0
625	HELD_FEM_ADR3ULN	CC	CT	TT	0.44	1.32
777	HELD_ALL_LIP	CC	CT	TT	0.71	1.34
777	HELD_ALL_HDL	CC	CT	TT	0.51	1.8
777	HELD_ALL_CC2	CC	CT	TT	1.32	0.9
777	HELD_FEM_CC2	CC	CT	TT	1.54	0.81
777	HELD_FEM_LIP	CC	CT	TT	0.74	1.28
777	HELD_ALL_LIP	CC	CT	TT	0.76	1.23
1005	HELD_FEM_LIP	AA	AG	GG	0.67	1.58
1062	HELD_ALL_LIP2	GG	AG	AA	1.15	0.85
1275	CVD_FEM	CC	CG	GG	0.6	0.73
1275	HELD_MAL_CC2	CC	CG	GG	1.47	0.94
1275	HELD_MAL_HDL	CC	CG	GG	2	0.88
1275	CVD_MAL	CC	CG	GG	0.72	1.35
1669	HELD_MAL_CC2	TT	CT	CC	2.35	0.47
1669	HELD_ALL_CC2	TT	CT	CC	1.5	0.71
1669	CVD_ALL	TT	CT	CC	1.29	0.66
1669	HELD_MAL_CC	TT	CT	CC	3.64	0.33
1755	HELD_MAL_LIP2	AA	AG	GG	1.18	0.81
1765	HELD_FEM_LIP	AA	AG	GG	1.22	0.59
2109	HELD_FEM_LIP2	AA	AG	GG	1.18	0.88
2150	HELD_ALL_LIP	TT	CT	CC	1.01	0.82
2150	HELD_ALL_LIP	TT	CT	CC	0.98	0.86
2150	HELD_MAL_LIP	TT	CT	CC	0.89	0.61
2150	HELD_MAL_LIP	TT	CT	CC	0.89	0.61
2150	HELD_FEM_LIP	TT	CT	CC	1.06	0.84
2234	HELD_ALL_LIP	TT	GT	GG	0.94	1.3
2321	HELD_MAL_LIP	GG	GT	TT	0.41	2.44
2321	HELD_MAL_LIP	GG	GT	TT	0.41	2.44
2321	HELD_FEM_LIP	GG	GT	TT	1.77	0.6
2354	CVD_FEM	CC	CT	TT	0.5	2.02
3451	HELD_FEM_ADR	CC	CT	TT	0.56	1.39
3451	HELD_MAL_ADR5ULN	CC	CT	TT	2.5	1.04
3452	HELD_MAL_ADR5ULN	AA	AG	GG	6.92	0.21
3453	HELD_FEM_ADR	CC	CT	TT	1.29	0.95
4912	HELD_FEM_LIP	GG	AG	AA	1.21	1.28
5093	CVD_FEM	GG	AG	AA	0.64	0.92
5093	HELD_MAL_CC	GG	AG	AA	2.53	0.76
6333	HELD_MAL_ADR5ULN	AA	AC	CC	0	null
6333	HELD_ALL_ADR	AA	AC	CC	0.63	1.23
6333	HELD_ALL_ADR3ULN	AA	AC	CC	0.35	1.59
6333	HELD_FEM_ADR3ULN	AA	AC	CC	0.36	1.33
6333	HELD_ALL_ADR5ULN	AA	AC	CC	0.29	2.41
6333	HELD_MAL_ADR	AA	AC	CC	0.51	1.35
6333	CVD_MAL	AA	AC	CC	1	1.68
7407	HELD_ALL_ADR5ULN	GG	AG	AA	6.11	0.45
7407	HELD_FEM_ADR5ULN	GG	AG	AA	5.6	0.57
7407	HELD_FEM_ADR	GG	AG	AA	2	1.13
7407	HELD_FEM_ADR3ULN	GG	AG	AA	3.3	0.83
10584	HELD_ALL_ADR	GG	GT	TT	0.61	1.64
10584	HELD_FEM_ADR	GG	GT	TT	0.55	1.83
10584	HELD_FEM_ADR3ULN	GG	GT	TT	0.36	2.74
11021	HELD_FEM_LIP	TT	CT	CC	0.71	1.39
11062	HELD_MAL_ADR5ULN	TT	CT	CC	4.07	0.33
11147	HELD_FEM_ADR	CC	CT	TT	1.07	1.31
11212	HELD_ALL_HDL	GG	CG	CC	2.57	0.72
11371	HELD_ALL_ADR3ULN	AA	AG		0.46	2.15
11371	HELD_FEM_ADR	AA	AG		0.61	1.65
11487	HELD_FEM_UEFF	TT	AT	AA	0.81	0.99
11585	HELD_ALL_LIP	GG	GT	TT	1.12	1.22
11683	HELD_FEM_UEFF	CC	CG	GG	0.61	1.71
11863	HELD_FEM_VEFF	GG	AG	AA	1.48	0.69
12024	HELD_ALL_ADR	CC	CT	TT	0.6	1.67
12024	HELD_FEM_ADR3ULN	CC	CT	TT	0.33	3.04
12024	HELD_FEM_ADR	CC	CT	TT	0.53	1.88
12024	HELD_ALL_ADR3ULN	CC	CT	TT	0.39	2.58
12632	HELD_MAL_ADR5ULN	CC	CT	TT	0.11	9
13994	CVD_FEM	GG	AG	AA	0.43	null
13994	HELD_MAL_ADR	GG	AG	AA	null	0
14090	HELD_FEM_EFF	CC	AC	AA	0.8	1.29
14159	HELD_FEM_EFF	TT	CT	CC	1.21	0.82
14362	HELD_FEM_UEFF	TT	GT	GG	1.9	0.59
14410	HELD_MAL_ADR	GG	AG		2.59	0.39
14488	HELD_ALL_ADR	AA	AG		0.6	1.65
14488	HELD_FEM_ADR	AA	AG		0.55	1.83
14488	HELD_FEM_ADR3ULN	AA	AG		0.37	2.69
14490	HELD_MAL_ADR5ULN	CC	CT	TT	null	0
14490	HELD_FEM_ADR5ULN	CC	CT	TT	0.36	2.41
14490	HELD_FEM_ADR3ULN	CC	CT	TT	0.51	1.88
14493	HELD_ALL_ADR	AA	AG		0.61	1.64
14493	HELD_FEM_ADR	AA	AG		0.55	1.82
14493	HELD_FEM_ADR3ULN	AA	AG		0.36	2.81
14493	HELD_ALL_ADR3ULN	AA	AG		0.41	2.44
14554	HELD_MAL_ADR3ULN	CC	AC	AA	null	0
14554	HELD_MAL_ADR5ULN	CC	AC	AA	null	0
14554	HELD_MAL_ADR	CC	AC	AA	1.59	0
14603	CVD_MAL	AA	AG		0.71	1.4
14820	HELD_FEM_VEFF	AA	AG	GG	0.89	1.32
14820	HELD_FEM_UEFF	AA	AG	GG	0.89	1.55
14876	HELD_FEM_EFF	CC	CT	TT	1.14	0.8
14876	HELD_FEM_VEFF	CC	CT	TT	1.27	0.74
14954	HELD_MAL_ADR	GG	CG	CC	null	0
14957	HELD_FEM_ADR5ULN	AA	AC	CC	null	0
14957	HELD_FEM_VEFF	AA	AC	CC	0.74	1.37
14977	HELD_FEM_UEFF	AA	AG	GG	0.83	0.88
15349	HELD_MAL_ADR	CC	CT	TT	1.38	0.93
15590	HELD_ALL_ADR5ULN	GG	AG	AA	1.19	1.76
15590	HELD_ALL_ADR	GG	AG	AA	0.93	1.34
15590	HELD_FEM_ADR	GG	AG	AA	0.92	1.46
16268	HELD_MAL_ADR5ULN	CC	CG	GG	null	0
36078	HELD_FEM_VEFF	AA	AG		2.49	0.4
36078	HELD_FEM_EFF	AA	AG		1.88	0.53
36406	HELD_FEM_ADR5ULN	TT	CT	CC	2.51	0.75
37135	HELD_ALL_ADR3ULN	CC	CT	TT	1.43	0.45
37135	HELD_FEM_ADR3ULN	CC	CT	TT	1.55	0.37
37135	HELD_FEM_ADR5ULN	CC	CT	TT	2.13	0.28
37135	HELD_ALL_ADR5ULN	CC	CT	TT	1.88	0.37
37327	HELD_ALL_CC2	TT	CT	CC	0.7	1.27
37327	HELD_FEM_VEFF	TT	CT	CC	1.35	0.72
37327	HELD_FEM_UEFF	TT	CT	CC	1.65	0.66
37327	HELD_MAL_ADR	TT	CT	CC	1.45	0.62
37404	HELD_MAL_ADR	TT	CT	CC	0.48	2.04
37413	HELD_FEM_ADR5ULN	AA	AT	TT	0.33	2.53
37413	HELD_FEM_ADR3ULN	AA	AT	TT	0.45	2.03
37413	HELD_ALL_ADR5ULN	AA	AT	TT	0.44	2.08
37413	HELD_ALL_ADR3ULN	AA	AT	TT	0.54	1.79
37939	HELD_FEM_EFF	CC	CT	TT	1.05	0.88
37939	CVD_MAL	CC	CT	TT	0.74	1.5
38009	HELD_ALL_ADR	TT	GT	GG	1.33	0.83
38009	HELD_MAL_ADR	TT	GT	GG	1.3	0.93
40004	CVD_FEM	GG	CG	CC	0.51	1.61
40522	HELD_FEM_ADR	TT	AT	AA	1.46	0.77
40522	HELD_FEM_ADR3ULN	TT	AT	AA	1.67	0.84
40522	HELD_FEM_ADR5ULN	TT	AT	AA	2.04	0.82
41847	HELD_FEM_EFF	TT	GT	GG	1.13	1.13
42084	HELD_MAL_ADR5ULN	AA	AC	CC	0.71	0.64
42084	HELD_FEM_ADR3ULN	AA	AC	CC	0.52	2.12
42084	HELD_FEM_ADR	AA	AC	CC	0.74	1.44
42084	HELD_ALL_ADR5ULN	AA	AC	CC	0.44	2.14
42084	HELD_FEM_ADR5ULN	AA	AC	CC	0.4	2.81
42084	HELD_ALL_ADR3ULN	AA	AC	CC	0.57	1.76
42677	HELD_FEM_ADR3ULN	CC	CG	GG	1.67	0.93
42677	HELD_FEM_ADR5ULN	CC	CG	GG	2.05	0.84
42677	HELD_FEM_ADR	CC	CG	GG	1.26	1.04
46865	HELD_FEM_VEFF	TT	CT	CC	1.41	0.75
46865	HELD_FEM_EFF	TT	CT	CC	1.2	0.87
46865	HELD_ALL_ADR5ULN	TT	CT	CC	0.62	2.09
47856	HELD_ALL_ADR5ULN	TT	CT	CC	2.24	0.27
47856	HELD_MAL_ADR5ULN	TT	CT	CC	5.45	0.22
47856	HELD_FEM_VEFF	TT	CT	CC	0.79	1.24
48490	CVD_ALL	AA	AG	GG	1.63	1.05
48490	CVD_MAL	AA	AG	GG	1.57	0.95
48490	HELD_ALL_ADR3ULN	AA	AG	GG	0.39	1.58
48490	HELD_FEM_ADR3ULN	AA	AG	GG	0.29	1.66
48490	HELD_FEM_ADR	AA	AG	GG	0.62	1.15
50164	HELD_FEM_ADR3ULN	GG	AG	AA	0.44	2.23
50164	HELD_FEM_ADR	GG	AG	AA	0.64	1.58
50164	HELD_ALL_ADR5ULN	GG	AG	AA	0.57	1.4
54704	HELD_FEM_ADR	GG	AG	AA	0.59	1.71
54806	CVD_ALL	GG	AG	AA	0.49	2.03
54806	HELD_FEM_UEFF	GG	AG	AA	1.84	0.47
54807	HELD_FEM_ADR5ULN	GG	AG	AA	0.27	2.98
54807	HELD_ALL_ADR5ULN	GG	AG	AA	0.41	1.91
54807	HELD_FEM_ADR	GG	AG	AA	0.6	1.6
54807	HELD_ALL_ADR	GG	AG	AA	0.74	1.33
54807	HELD_FEM_ADR3ULN	GG	AG	AA	0.51	1.87
54807	HELD_FEM_EFF	GG	AG	AA	1.17	0.9
54807	HELD_ALL_ADR3ULN	GG	AG	AA	0.61	1.52
54807	HELD_FEM_UEFF	GG	AG	AA	1.55	0.73
55733	CVD_MAL	GG	AG	AA	0.66	1.5
55733	CVD_FEM	GG	AG	AA	null	0
55733	HELD_FEM_VEFF	GG	AG	AA	1.4	0.73
55733	HELD_ALL_ADR	GG	AG	AA	1.43	0.71
55846	HELD_FEM_VEFF	AA	AG	GG	0.77	1.12
55846	HELD_FEM_UEFF	AA	AG	GG	0.7	1.08
55906	HELD_FEM_EFF	GG	GT	TT	1.92	0.93
56084	HELD_FEM_UEFF	CC	CT	TT	0.11	6
57818	HELD_MAL_ADR	GG	AG	AA	0.51	1.92
57818	HELD_ALL_ADR	GG	AG	AA	0.66	1.43
57818	HELD_MAL_ADR3ULN	GG	AG	AA	0.37	1.98
57818	HELD_ALL_ADR3ULN	GG	AG	AA	0.59	1.4
57818	HELD_FEM_EFF	GG	AG	AA	0.81	1.22
57819	HELD_MAL_ADR	TT	CT	CC	0.58	1.71
57819	HELD_ALL_ADR	TT	CT	CC	0.72	1.38
57819	HELD_FEM_EFF	TT	CT	CC	0.82	1.26
57828	HELD_FEM_VEFF	AA	AG	GG	1.14	0.74
57987	HELD_MAL_ADR5ULN	TT	CT	CC	0.34	6.44
59456	HELD_MAL_ADR3ULN	AA	AC	CC	2.6	0.51
59460	HELD_FEM_UEFF	TT	CT	CC	1.16	1.07
59461	HELD_MAL_ADR5ULN	CC	CT	TT	7.37	0
59461	HELD_FEM_UEFF	CC	CT	TT	1.17	1.06
59461	HELD_FEM_EFF	CC	CT	TT	1.15	0.95
60900	HELD_FEM_ADR3ULN	AA	AG	GG	0.56	2.23
60900	HELD_MAL_ADR	AA	AG	GG	0.64	1.39
60900	HELD_ALL_ADR3ULN	AA	AG	GG	0.6	1.91
60902	HELD_MAL_ADR	AA	AT	TT	1.56	0.74
60902	HELD_ALL_ADR	AA	AT	TT	1.27	0.88
60934	CVD_ALL	CC	CT	TT	1.6	0.83
60934	CVD_MAL	CC	CT	TT	1.41	0.86
60934	HELD_MAL_ADR	CC	CT	TT	0.92	0.78
60934	CVD_FEM	CC	CT	TT	1.93	0.77
60957	HELD_MAL_ADR5ULN	GG	AG	AA	null	0
60957	HELD_MAL_ADR3ULN	GG	AG	AA	3.29	0.35
60959	HELD_MAL_ADR3ULN	TT	CT	CC	0.15	1.34
60959	HELD_MAL_ADR5ULN	TT	CT	CC	0	2.56
60959	HELD_ALL_ADR3ULN	TT	CT	CC	0.53	1.14
60959	HELD_ALL_ADR	TT	CT	CC	0.82	0.98
60959	HELD_MAL_ADR	TT	CT	CC	0.82	0.86
60962	HELD_MAL_ADR5ULN	CC	CT	TT	0.19	0.89
60962	HELD_MAL_ADR3ULN	CC	CT	TT	0.2	2.58
60962	HELD_MAL_ADR	CC	CT	TT	0.65	1.3
60974	HELD_FEM_ADR5ULN	GG	AG	AA	1.34	0.44
60978	HELD_MAL_ADR	GG	CG	CC	2.65	0.41
60978	HELD_FEM_EFF	GG	CG	CC	1.16	0.82
60978	HELD_FEM_VEFF	GG	CG	CC	1.28	0.73
60999	HELD_MAL_ADR5ULN	GG	GT	TT	null	0
61011	CVD_MAL	TT	CT	CC	0.71	1.54
61011	HELD_FEM_EFF	TT	CT	CC	0.97	0.95
61086	HELD_MAL_ADR	GG	AG	AA	1.78	0.64
61126	HELD_MAL_ADR	CC	CT	TT	1.25	0.61
61126	HELD_FEM_VEFF	CC	CT	TT	0.68	1.22
61126	HELD_FEM_UEFF	CC	CT	TT	0.51	1.65
61126	HELD_FEM_EFF	CC	CT	TT	0.81	1.12
61137	HELD_ALL_ADR	TT	CT	CC	0.75	1.31
61147	HELD_FEM_EFF	GG	AG	AA	0.98	0.88
61176	HELD_MAL_ADR5ULN	AA	AG	GG	5.59	0.3
61176	HELD_MAL_ADR	AA	AG	GG	1.63	0.65
61176	HELD_MAL_ADR3ULN	AA	AG	GG	2.88	0.34
61176	HELD_ALL_ADR5ULN	AA	AG	GG	2.09	0.37
61184	HELD_MAL_ADR5ULN	CC	CT	TT	4.17	0
61184	HELD_MAL_ADR	CC	CT	TT	1.64	0.6
61197	HELD_MAL_ADR3ULN	AA	AG	GG	0.58	0.99
61270	HELD_MAL_ADR3ULN	AA	AG	GG	0.26	3.79
61270	HELD_MAL_ADR5ULN	AA	AG	GG	0.17	5.83
61270	HELD_ALL_CC2	AA	AG	GG	1.88	0.53
61272	HELD_MAL_ADR5ULN	AA	AG	GG	0.47	1.37
61272	HELD_FEM_ADR	AA	AG	GG	1.57	0.62
61284	HELD_FEM_EFF	GG	AG	AA	1.02	0.82
61292	HELD_FEM_EFF	GG	AG	AA	0.89	0.94
61292	HELD_MAL_ADR	GG	AG	AA	0.75	1.57
61297	CVD_ALL	TT	CT	CC	0.78	1.19
61324	HELD_FEM_VEFF	GG	AG	AA	1.65	0.88
61328	HELD_FEM_EFF	AA	AG	GG	0.5	2
61373	HELD_FEM_ADR	GG	CG	CC	1.57	0.73
61373	HELD_ALL_ADR	GG	CG	CC	1.35	0.78
900066	HELD_MAL_LIP	CC	CT	TT	2.17	0
900071	HELD_FEM_UEFF	GG	CG	CC	1.1	1.55
900072	HELD_FEM_UEFF	GG	CG	CC	1.56	1.09
900072	HELD_FEM_HDL	GG	CG	CC	0.32	1.78
900072	HELD_FEM_VEFF	GG	CG	CC	1.23	0.98
900073	HELD_ALL_ADR	GG	CG	CC	0.71	1.29
900073	HELD_MAL_ADR	GG	CG	CC	0.58	1.57
900073	HELD_ALL_CC2	GG	CG	CC	1.29	0.78
900073	HELD_MAL_ADR3ULN	GG	CG	CC	0.44	1.49
900073	HELD_FEM_EFF	GG	CG	CC	0.85	1.12
900074	HELD_FEM_LIP	CC	CT	TT	0.67	1.25
900074	HELD_FEM_UEFF	CC	CT	TT	1.37	0.98
900083	HELD_FEM_EFF	AA	AG	GG	0.85	1.03
900115	HELD_MAL_ADR3ULN	AA	AG	GG	0.63	0.52
900115	HELD_ALL_CC	AA	AG	GG	0.59	1.48
900115	HELD_ALL_ADR5ULN	AA	AG	GG	0.62	0.86
900143	HELD_MAL_ADR5ULN	GG	GT	TT	0	null
900143	HELD_ALL_ADR	GG	GT	TT	0.65	1.15
900143	HELD_FEM_ADR3ULN	GG	GT	TT	0.35	1.25
900143	HELD_ALL_ADR3ULN	GG	GT	TT	0.37	1.43
900143	HELD_ALL_ADR5ULN	GG	GT	TT	0.3	2.21
900143	HELD_FEM_ADR	GG	GT	TT	0.72	1.05
900173	HELD_MAL_ADR3ULN	TT	GT	GG	4.04	0.3
900174	HELD_MAL_ADR3ULN	AA	AG	GG	0.42	0.67
900174	HELD_MAL_ADR5ULN	AA	AG	GG	0.24	0.64
900174	HELD_ALL_ADR5ULN	AA	AG	GG	0.56	0.84
900174	HELD_FEM_CC	AA	AG	GG	0.48	1.75
900174	HELD_ALL_CC	AA	AG	GG	0.59	1.45
900175	HELD_FEM_EFF	GG	AG	AA	2.67	0.48
900180	CVD_ALL	GG	AG	AA	0.57	0.96
900180	CVD_FEM	GG	AG	AA	0.23	1.06
900180	HELD_MAL_CC	GG	AG	AA	0.32	0.96
900180	HELD_ALL_CC	GG	AG	AA	0.61	0.8
900221	HELD_MAL_ADR	GG	CG	CC	1.25	1.16
900250	HELD_MAL_ADR5ULN	CC	CT	TT	0.45	1.01
900342	HELD_ALL_ADR	GG	AG	AA	0.7	1.43
900342	HELD_FEM_ADR	GG	AG	AA	0.64	1.56
900344	HELD_FEM_ADR	AA	AC	CC	0.55	1.12
900344	HELD_FEM_ADR3ULN	AA	AC	CC	0.51	1.03
900344	HELD_ALL_ADR	AA	AC	CC	0.75	1.02
900344	HELD_FEM_ADR5ULN	AA	AC	CC	0.41	1.26
10000001	HELD_MAL_LIP	GG	AG	AA	3.13	0.33
10000001	HELD_ALL_LIP	GG	AG	AA	1.41	0.95
10000002	HELD_ALL_LIP	AA	AG	GG	1.43	0.74
10000017	HELD_ALL_LIP	TT	CT	CC	0.72	1.49
	BAYSNP	RR3	FQ1_A	FQ2_A	FQ3_A	FQ1_B	FQ2_B	FQ3_B
	160	2.4	3	7	6	22	28	9
	194	3.59	3	4	7	21	33	10
	194	3	6	6	8	40	65	18
	194	0.72	81	128	40	80	114	67
	411	1.96	6	13	7	49	60	17
	466	1.05	10	41	20	24	27	18
	466	0	5	4	0	17	24	15
	555	1.02	45	39	13	35	65	15
	623	0	16	0	0	52	6	1
	625	1.7	6	17	8	27	28	8
	777	1.51	65	32	5	86	22	2
	777	2.39	14	9	1	27	5	0
	777	0.28	56	16	1	34	14	5
	777	0	29	8	0	18	9	3
	777	1.54	53	27	4	58	16	1
	777	1.57	64	29	5	87	25	2
	1005	0.62	59	24	1	64	8	2
	1062	1.19	474	136	15	507	195	12
	1275	1.89	6	7	17	7	6	1
	1275	0.22	18	22	1	6	16	6
	1275	0.4	8	8	2	4	12	8
	1275	1.11	21	16	14	14	2	4
	1669	0	37	4	0	18	9	1
	1669	0.42	76	20	1	40	24	3
	1669	1.55	72	18	6	47	26	1
	1669	0	13	1	0	12	5	1
	1755	1.04	143	101	62	134	145	66
	1765	1.5	4	13	69	2	23	45
	2109	0.79	217	87	12	222	117	20
	2150	2.26	65	26	7	76	39	0
	2150	2.17	67	28	7	74	37	0
	2150	3.25	13	3	3	26	10	0
	2150	3.25	13	3	3	26	10	0
	2150	2.05	52	23	4	50	29	0
	2234	0.52	42	52	6	49	43	17
	2321	null	12	6	0	32	3	0
	2321	null	12	6	0	32	3	0
	2321	0	74	6	0	65	13	1
	2354	null	22	13	0	36	4	0
	3451	1.03	11	42	20	23	28	18
	3451	0	5	4	0	18	26	16
	3452	0	8	1	0	29	25	6
	3453	0.5	36	31	4	26	32	11
	4912	0.73	34	10	26	23	5	32
	5093	1.8	9	12	11	18	16	5
	5093	0.3	6	4	1	3	8	6
	6333	0	0	8	0	19	23	12
	6333	1.19	25	64	35	44	48	25
	6333	1.36	6	25	13	44	48	25
	6333	1.64	4	14	10	25	25	13
	6333	0.97	3	16	5	44	48	25
	6333	1.16	8	33	16	19	23	12
	6333	0.37	8	21	3	8	13	11
	7407	0.98	2	3	3	1	30	19
	7407	0.69	2	3	2	0	14	9
	7407	0.58	4	18	5	0	14	9
	7407	0.6	3	7	3	0	14	9
	10584	null	121	12	0	127	3	0
	10584	null	63	7	0	69	1	0
	10584	null	26	3	0	69	1	0
	11021	1.26	55	23	2	59	11	1
	11062	0	6	2	0	22	31	5
	11147	0.42	19	37	4	16	27	13
	11212	0.35	5	4	1	2	8	5
	11371	null	41	7	0	123	6	0
	11371	null	65	8	0	69	2	0
	11487	2.53	27	20	5	44	28	0
	11585	0.62	28	61	15	25	54	31
	11683	0.89	28	25	3	55	18	5
	11863	0	134	20	0	115	34	1
	12024	null	121	13	0	128	3	0
	12024	null	25	4	0	70	1	0
	12024	null	63	8	0	70	1	0
	12024	null	41	5	0	128	3	0
	12632	null	8	1	0	64	0	0
	13994	2.32	28	0	2	37	0	0
	13994	0	52	0	0	48	1	1
	14090	0.84	191	73	5	219	49	7
	14159	1.04	120	125	47	94	155	44
	14362	0	52	5	0	63	14	2
	14410	null	59	2	0	55	8	0
	14488	null	120	12	0	128	3	0
	14488	null	64	7	0	70	1	0
	14488	null	27	3	0	70	1	0
	14490	0	9	0	0	36	19	3
	14490	2.69	7	9	1	51	19	1
	14490	1.67	15	15	1	51	19	1
	14493	null	122	13	0	125	3	0
	14493	null	65	8	0	68	1	0
	14493	null	27	4	0	68	1	0
	14493	null	43	5	0	125	3	0
	14554	0	16	0	0	49	1	11
	14554	0	8	0	0	49	1	11
	14554	0.67	55	0	6	49	1	11
	14603	null	30	9	0	12	0	0
	14820	0.69	65	67	15	71	45	26
	14820	0.5	24	26	5	37	22	17
	14876	1.21	111	118	51	96	152	37
	14876	1.14	60	59	28	43	80	22
	14954	0	59	0	0	63	1	1
	14957	null	17	0	0	67	11	0
	14957	0.98	118	29	1	127	15	1
	14977	2.09	29	18	9	45	28	2
	15349	0.55	27	27	5	20	32	13
	15590	0.15	9	15	1	44	61	35
	15590	0.66	37	75	18	44	61	35
	15590	0.59	20	41	10	24	30	22
	16268	0	9	0	0	48	16	1
	36078	null	19	3	0	9	8	0
	36078	null	27	5	0	16	10	0
	36406	0	10	7	0	23	37	14
	37135	1.69	19	12	13	37	61	19
	37135	1.63	13	6	10	18	31	12
	37135	1.5	9	3	5	18	31	12
	37135	1.55	12	6	6	37	61	19
	37327	1.23	7	6	4	3	0	0
	37327	1	80	46	17	51	61	15
	37327	0.67	33	17	3	28	34	7
	37327	0.71	43	1	11	31	2	16
	37404	2.02	46	2	1	49	0	0
	37413	4.81	7	9	1	46	15	0
	37413	3.1	14	15	1	46	15	0
	37413	3.02	13	10	1	90	26	1
	37413	1.82	26	18	1	90	26	1
	37939	2.03	254	36	5	253	45	0
	37939	0.67	25	10	1	12	0	1
	38009	0.42	96	28	2	75	34	7
	38009	0	44	13	0	37	14	4
	40004	2.07	8	7	2	13	3	0
	40522	0.66	45	22	6	34	32	12
	40522	0.25	19	11	1	34	32	12
	40522	0	11	6	0	34	32	12
	41847	0.68	79	108	35	67	95	61
	42084	10.33	5	1	1	44	12	0
	42084	0	17	14	0	48	12	2
	42084	0	45	26	0	48	12	2
	42084	1.94	14	10	1	92	24	2
	42084	0	9	9	0	48	12	2
	42084	1.19	28	17	1	92	24	2
	42677	0.35	13	15	2	15	31	13
	42677	0.28	8	8	1	15	31	13
	42677	0.55	25	37	6	15	31	13
	46865	0.59	101	46	4	72	62	9
	46865	0.75	176	87	9	155	106	15
	46865	0	11	15	0	77	49	10
	47856	1.57	20	3	3	81	52	10
	47856	0	8	1	0	36	26	3
	47856	1.16	80	62	11	97	46	8
	48490	0.54	16	21	9	4	15	16
	48490	0.58	12	13	5	2	8	7
	48490	1.22	6	29	12	44	63	28
	48490	1.32	3	19	8	25	33	14
	48490	1.27	13	37	20	25	33	14
	50164	1.77	20	10	1	67	9	1
	50164	1.01	53	21	1	67	9	1
	50164	3.42	17	7	2	112	28	2
	54704	null	57	11	0	58	2	0
	54806	null	30	4	0	31	0	0
	54806	2.4	47	5	1	55	18	0
	54807	2.77	7	8	2	56	12	2
	54807	2.76	12	11	3	93	32	4
	54807	1.34	40	27	4	56	12	2
	54807	1.19	77	51	6	93	32	4
	54807	1.67	18	11	2	56	12	2
	54807	0.69	189	83	9	160	91	16
	54807	1.62	27	18	3	93	32	4
	54807	0	41	12	0	43	23	3
	55733	1.39	25	8	1	13	0	0
	55733	null	15	0	0	12	4	0
	55733	0	134	21	0	116	33	1
	55733	0.67	117	18	1	107	31	2
	55846	1.35	55	59	22	76	55	13
	55846	1.64	21	20	11	42	27	7
	55906	0	15	11	0	17	23	11
	56084	1.29	1	6	1	16	4	2
	57818	1.55	40	20	3	59	5	1
	57818	1.72	96	37	5	121	20	1
	57818	3.51	12	3	2	59	5	1
	57818	3.1	35	10	3	121	20	1
	57818	1.26	223	63	5	245	45	3
	57819	1.25	35	23	3	53	10	2
	57819	1.21	86	43	7	111	27	5
	57819	0.83	200	84	5	224	58	7
	57828	1.39	55	65	29	46	87	15
	57987	0	1	8	0	19	33	13
	59456	0.44	9	5	1	17	30	9
	59460	0	24	29	0	30	40	7
	59461	0.64	8	0	1	30	23	11
	59461	0	27	26	0	34	36	7
	59461	0.76	147	112	21	129	120	33
	60900	0.34	8	21	1	26	23	7
	60900	1.32	19	26	6	28	16	3
	60900	0.54	15	26	2	54	39	10
	60902	0.48	36	15	2	25	22	6
	60902	0.6	72	37	5	58	43	11
	60934	0.55	29	17	6	8	14	10
	60934	0.64	20	12	4	3	6	4
	60934	1.81	26	23	13	29	31	3
	60934	0.48	9	5	2	5	8	6
	60957	0	8	0	0	35	19	2
	60957	0	14	2	0	35	19	2
	60959	3	1	9	5	22	28	5
	60959	2.67	0	6	2	22	28	5
	60959	1.64	9	24	12	42	56	17
	60959	1.31	35	60	31	42	56	17
	60959	1.62	18	25	15	22	28	5
	60962	10	1	1	2	27	11	2
	60962	3.21	2	5	2	27	11	2
	60962	1.59	17	14	5	27	11	2
	60974	3.96	12	3	2	47	27	1
	60978	0	60	3	0	53	11	1
	60978	2.02	255	36	3	247	50	0
	60978	1.96	137	20	2	120	31	0
	60999	null	9	0	0	50	14	0
	61011	0	24	14	0	12	0	1
	61011	1.64	196	80	13	196	85	3
	61086	0	32	7	0	22	12	2
	61126	1.57	23	22	14	16	35	5
	61126	1.15	33	86	33	51	63	23
	61126	1.02	10	34	10	29	30	13
	61126	1.11	76	140	58	98	121	47
	61137	1.24	81	49	3	103	35	2
	61147	1.28	101	133	59	105	153	38
	61176	0	6	2	0	16	31	8
	61176	0.83	30	20	6	16	31	8
	61176	0.87	10	4	2	16	31	8
	61176	1.35	16	6	4	46	58	13
	61184	2.06	8	0	1	38	20	3
	61184	0.79	49	10	2	38	20	3
	61197	4.07	10	4	3	47	15	1
	61270	null	7	9	0	46	9	0
	61270	null	3	5	0	46	9	0
	61270	null	15	2	0	1	2	0
	61272	9	3	4	1	33	23	0
	61272	0.95	50	16	3	32	27	3
	61284	1.32	104	121	65	103	152	40
	61292	1.36	100	133	55	118	145	31
	61292	0.6	21	36	5	30	23	11
	61297	1.28	53	28	11	46	14	4
	61324	0.58	12	5	4	5	5	7
	61328	2	275	1	1	276	0	0
	61373	0	61	14	0	50	22	4
	61373	0.58	110	24	2	100	36	5
	900066	1.5	15	0	2	23	7	2
	900071	0.47	13	31	8	17	32	28
	900072	0.5	16	18	7	14	25	23
	900072	0.96	2	16	7	9	10	8
	900072	0.8	44	53	26	30	51	34
	900073	1.27	45	68	12	64	50	7
	900073	1.23	17	37	5	30	22	3
	900073	null	19	7	0	0	2	0
	900073	2.36	5	9	3	30	22	3
	900073	1.16	132	134	29	158	119	22
	900074	1.31	19	47	10	29	35	5
	900074	0.53	23	24	5	25	37	17
	900083	1.16	81	134	66	100	129	51
	900115	3.39	4	5	7	22	30	7
	900115	1.3	15	24	6	24	13	3
	900115	2.48	7	11	7	53	63	14
	900143	0	0	7	0	18	23	12
	900143	1.26	25	62	35	43	51	23
	900143	1.8	4	15	10	25	28	11
	900143	1.49	6	24	13	43	51	23
	900143	1.06	3	16	5	43	51	23
	900143	1.33	17	31	19	25	28	11
	900173	0	14	2	0	31	21	3
	900174	3.76	3	6	7	22	27	5
	900174	5.89	1	3	4	22	27	5
	900174	2.68	6	9	7	48	52	13
	900174	1.19	7	17	4	13	6	2
	900174	1.3	13	23	6	21	13	3
	900175	0	9	3	0	9	11	2
	900180	1.4	12	45	45	21	34	18
	900180	1.81	2	14	17	14	16	10
	900180	2.68	2	6	6	9	8	1
	900180	1.84	7	19	18	13	22	5
	900221	0.51	20	28	6	14	23	15
	900250	6.19	5	2	2	45	13	1
	900342	1.15	71	38	4	89	21	3
	900342	1.2	37	22	3	49	10	2
	900344	1.55	15	32	23	32	29	11
	900344	1.97	8	14	12	32	29	11
	900344	1.34	34	59	35	49	57	21
	900344	2.01	4	9	6	32	29	11
	10000001	1.04	9	6	2	5	27	4
	10000001	0.58	36	54	10	24	62	24
	10000002	0.77	64	30	8	50	46	13
	10000017	0.51	76	25	1	94	13	3

TABLE 6b
Correlation of PA SNP alleles to relative risk
For diagnostic conclusions to be drawn from genotyping a particular
patient we calculated the relative risks RR1, and RR2 for the two
possible alleles of each SNP. Given the allele frequencies as
	allele1	allele2
	case	N11	N12
	control	N21	N22

we calculate $\mathrm{RR}1=\frac{N11}{N21}/\frac{N12}{N22}$$\mathrm{RR}2=\frac{N12}{N22}/\frac{N11}{N21}$

Here, the case and control populations represent any case-control-group pair, or bad (case)-good (control)-group pair, respectively (due to their increased response to statins, ‘high responders’ are treated as a case cohort, whereas ‘low responders’ are treated as the respective control cohort). A value RR1>1, and RR2>1 indicates an increased risk for individuals carrying allele 1, and allele2, respectively. For example, RR1=3 indicates a 3-fold risk of an individual carrying allele 1 as compared to individuals not carrying allele 1 (a detailed description of relative risk calculation and statistics can be found in (Biostatistics, L. D. Fisher and G. van Belle, Wiley Interscience 1993)). The baySNP number refers to an internal numbering of the PA SNPs and can be found in the sequence listing. null: not defined.

BAYSNP	ALLELE1	ALLELE2	COMPARISON	RR1	RR2	SIZE_A
160	T	C	HELD_MAL_ADR3ULN	0.52	1.91	16
194	G	C	HELD_FEM_ADR5ULN	0.46	2.15	14
194	G	C	HELD_ALL_ADR5ULN	0.62	1.62	20
194	G	C	HELD_FEM_EFF	1.13	0.89	249
411	A	T	HELD_ALL_ADR5ULN	0.61	1.63	26
466	C	T	HELD_FEM_ADR	0.8	1.25	71
466	C	T	HELD_MAL_ADR5ULN	2.82	0.35	9
555	A	G	HELD_ALL_LIP	1.2	0.83	97
623	C	T	HELD_MAL_ADR3ULN	null	0	16
625	C	T	HELD_FEM_ADR3ULN	0.61	1.64	31
777	C	T	HELD_ALL_LIP	0.74	1.36	102
777	C	T	HELD_ALL_HDL	0.56	1.78	24
777	C	T	HELD_ALL_CC2	1.42	0.7	73
777	C	T	HELD_FEM_CC2	1.71	0.58	37
777	C	T	HELD_FEM_LIP	0.76	1.32	84
777	C	T	HELD_ALL_LIP	0.77	1.3	98
1005	A	G	HELD_FEM_LIP	0.75	1.34	84
1062	G	A	HELD_ALL_LIP2	1.1	0.91	625
1275	C	G	CVD_FEM	0.58	1.72	30
1275	C	G	HELD_MAL_CC2	1.46	0.68	41
1275	C	G	HELD_MAL_HDL	1.82	0.55	18
1275	C	G	CVD_MAL	0.81	1.24	51
1669	T	C	HELD_MAL_CC2	2.38	0.42	41
1669	T	C	HELD_ALL_CC2	1.47	0.68	97
1669	T	C	CVD_ALL	1.11	0.9	96
1669	T	C	HELD_MAL_CC	3.86	0.26	14
1755	A	G	HELD_MAL_LIP2	1.08	0.93	306
1765	A	G	HELD_FEM_LIP	0.76	1.31	86
2109	A	G	HELD_FEM_LIP2	1.16	0.86	316
2150	T	C	HELD_ALL_LIP	0.89	1.13	98
2150	T	C	HELD_ALL_LIP	0.88	1.14	102
2150	T	C	HELD_MAL_LIP	0.67	1.49	19
2150	T	C	HELD_MAL_LIP	0.67	1.49	19
2150	T	C	HELD_FEM_LIP	0.96	1.04	79
2234	T	G	HELD_ALL_LIP	1.08	0.92	100
2321	G	T	HELD_MAL_LIP	0.46	2.16	18
2321	G	T	HELD_MAL_LIP	0.46	2.16	18
2321	G	T	HELD_FEM_LIP	1.81	0.55	80
2354	C	T	CVD_FEM	0.56	1.78	35
3451	C	T	HELD_FEM_ADR	0.83	1.21	73
3451	C	T	HELD_MAL_ADR5ULN	2.86	0.35	9
3452	A	G	HELD_MAL_ADR5ULN	6.46	0.15	9
3453	C	T	HELD_FEM_ADR	1.31	0.76	71
4912	G	A	HELD_FEM_LIP	1.28	0.78	70
5093	G	A	CVD_FEM	0.65	1.55	32
5093	G	A	HELD_MAL_CC	2.31	0.43	11
6333	A	C	HELD_MAL_ADR5ULN	0.8	1.25	8
6333	A	C	HELD_ALL_ADR	0.79	1.27	124
6333	A	C	HELD_ALL_ADR3ULN	0.62	1.6	44
6333	A	C	HELD_FEM_ADR3ULN	0.57	1.76	28
6333	A	C	HELD_ALL_ADR5ULN	0.66	1.51	24
6333	A	C	HELD_MAL_ADR	0.77	1.3	57
6333	A	C	CVD_MAL	1.29	0.78	32
7407	G	A	HELD_ALL_ADR5ULN	1.54	0.65	8
7407	G	A	HELD_FEM_ADR5ULN	1.86	0.54	7
7407	G	A	HELD_FEM_ADR	1.39	0.72	27
7407	G	A	HELD_FEM_ADR3ULN	1.67	0.6	13
10584	G	T	HELD_ALL_ADR	0.62	1.61	133
10584	G	T	HELD_FEM_ADR	0.56	1.79	70
10584	G	T	HELD_FEM_ADR3ULN	0.38	2.65	29
11021	T	C	HELD_FEM_LIP	0.75	1.33	80
11062	T	C	HELD_MAL_ADR5ULN	3.38	0.3	8
11147	C	T	HELD_FEM_ADR	1.22	0.82	60
11212	G	C	HELD_ALL_HDL	2.15	0.46	10
11371	A	G	HELD_ALL_ADR3ULN	0.48	2.06	48
11371	A	G	HELD_FEM_ADR	0.62	1.61	73
11487	T	A	HELD_FEM_UEFF	0.75	1.33	52
11585	G	T	HELD_ALL_LIP	1.2	0.83	104
11683	C	G	HELD_FEM_UEFF	0.74	1.36	56
11863	G	A	HELD_FEM_VEFF	1.46	0.68	154
12024	C	T	HELD_ALL_ADR	0.61	1.64	134
12024	C	T	HELD_FEM_ADR3ULN	0.35	2.89	29
12024	C	T	HELD_FEM_ADR	0.55	1.82	71
12024	C	T	HELD_ALL_ADR3ULN	0.4	2.49	46
12632	C	T	HELD_MAL_ADR5ULN	0.12	8.53	9
13994	G	A	CVD_FEM	0.43	2.32	30
13994	G	A	HELD_MAL_ADR	null	0	52
14090	C	A	HELD_FEM_EFF	0.85	1.18	269
14159	T	C	HELD_FEM_EFF	1.09	0.92	292
14362	T	G	HELD_FEM_UEFF	2.01	0.5	57
14410	G	A	HELD_MAL_ADR	2.52	0.4	61
14488	A	G	HELD_ALL_ADR	0.62	1.62	132
14488	A	G	HELD_FEM_ADR	0.56	1.79	71
14488	A	G	HELD_FEM_ADR3ULN	0.38	2.61	30
14490	C	T	HELD_MAL_ADR5ULN	null	0	9
14490	C	T	HELD_FEM_ADR5ULN	0.46	2.15	17
14490	C	T	HELD_FEM_ADR3ULN	0.61	1.65	31
14493	A	G	HELD_ALL_ADR	0.62	1.61	135
14493	A	G	HELD_FEM_ADR	0.56	1.77	73
14493	A	G	HELD_FEM_ADR3ULN	0.37	2.69	31
14493	A	G	HELD_ALL_ADR3ULN	0.42	2.36	48
14554	C	A	HELD_MAL_ADR3ULN	null	0	16
14554	C	A	HELD_MAL_ADR5ULN	null	0	8
14554	C	A	HELD_MAL_ADR	1.54	0.65	61
14603	A	G	CVD_MAL	0.74	1.35	39
14820	A	G	HELD_FEM_VEFF	1.03	0.97	147
14820	A	G	HELD_FEM_UEFF	1.11	0.9	55
14876	C	T	HELD_FEM_EFF	1.01	0.99	280
14876	C	T	HELD_FEM_VEFF	1.08	0.93	147
14954	G	C	HELD_MAL_ADR	null	0	59
14957	A	C	HELD_FEM_ADR5ULN	null	0	17
14957	A	C	HELD_FEM_VEFF	0.77	1.3	148
14977	A	G	HELD_FEM_UEFF	0.74	1.35	56
15349	C	T	HELD_MAL_ADR	1.36	0.74	59
15590	G	A	HELD_ALL_ADR5ULN	1.58	0.63	25
15590	G	A	HELD_ALL_ADR	1.09	0.92	130
15590	G	A	HELD_FEM_ADR	1.13	0.89	71
16268	C	G	HELD_MAL_ADR5ULN	null	0	9
36078	A	G	HELD_FEM_VEFF	2.24	0.45	22
36078	A	G	HELD_FEM_EFF	1.75	0.57	32
36406	T	C	HELD_FEM_ADR5ULN	2.52	0.4	17
37135	C	T	HELD_ALL_ADR3ULN	0.97	1.03	44
37135	C	T	HELD_FEM_ADR3ULN	1.01	0.99	29
37135	C	T	HELD_FEM_ADR5ULN	1.25	0.8	17
37135	C	T	HELD_ALL_ADR5ULN	1.18	0.85	24
37327	T	C	HELD_ALL_CC2	0.77	1.3	17
37327	T	C	HELD_FEM_VEFF	1.19	0.84	143
37327	T	C	HELD_FEM_UEFF	1.48	0.68	53
37327	T	C	HELD_MAL_ADR	1.43	0.7	55
37404	T	C	HELD_MAL_ADR	0.49	2.04	49
37413	A	T	HELD_FEM_ADR5ULN	0.42	2.39	17
37413	A	T	HELD_FEM_ADR3ULN	0.54	1.85	30
37413	A	T	HELD_ALL_ADR5ULN	0.5	2.02	24
37413	A	T	HELD_ALL_ADR3ULN	0.61	1.64	45
37939	C	T	HELD_FEM_EFF	0.98	1.02	295
37939	C	T	CVD_MAL	0.83	1.2	36
38009	T	G	HELD_ALL_ADR	1.36	0.73	126
38009	T	G	HELD_MAL_ADR	1.44	0.7	57
40004	G	C	CVD_FEM	0.56	1.78	17
40522	T	A	HELD_FEM_ADR	1.4	0.72	73
40522	T	A	HELD_FEM_ADR3ULN	1.75	0.57	31
40522	T	A	HELD_FEM_ADR5ULN	2.26	0.44	17
41847	T	G	HELD_FEM_EFF	1.19	0.84	222
42084	A	C	HELD_MAL_ADR5ULN	0.5	2.02	7
42084	A	C	HELD_FEM_ADR3ULN	0.66	1.52	31
42084	A	C	HELD_FEM_ADR	0.84	1.2	71
42084	A	C	HELD_ALL_ADR5ULN	0.51	1.94	25
42084	A	C	HELD_FEM_ADR5ULN	0.56	1.8	18
42084	A	C	HELD_ALL_ADR3ULN	0.64	1.56	46
42677	C	G	HELD_FEM_ADR3ULN	1.61	0.62	30
42677	C	G	HELD_FEM_ADR5ULN	1.89	0.53	17
42677	C	G	HELD_FEM_ADR	1.27	0.79	68
46865	T	C	HELD_FEM_VEFF	1.36	0.74	151
46865	T	C	HELD_FEM_EFF	1.18	0.85	272
46865	T	C	HELD_ALL_ADR5ULN	0.86	1.16	26
47856	T	C	HELD_ALL_ADR5ULN	1.51	0.66	26
47856	T	C	HELD_MAL_ADR5ULN	4.88	0.2	9
47856	T	C	HELD_FEM_VEFF	0.84	1.2	153
48490	A	G	CVD_ALL	1.54	0.65	46
48490	A	G	CVD_MAL	1.48	0.68	30
48490	A	G	HELD_ALL_ADR3ULN	0.69	1.44	47
48490	A	G	HELD_FEM_ADR3ULN	0.63	1.58	30
48490	A	G	HELD_FEM_ADR	0.77	1.29	70
50164	G	A	HELD_FEM_ADR3ULN	0.5	2.01	31
50164	G	A	HELD_FEM_ADR	0.7	1.44	75
50164	G	A	HELD_ALL_ADR5ULN	0.55	1.83	26
54704	G	A	HELD_FEM_ADR	0.61	1.64	68
54806	G	A	CVD_ALL	0.51	1.97	34
54806	G	A	HELD_FEM_UEFF	1.56	0.64	53
54807	G	A	HELD_FEM_ADR5ULN	0.35	2.84	17
54807	G	A	HELD_ALL_ADR5ULN	0.46	2.16	26
54807	G	A	HELD_FEM_ADR	0.67	1.48	71
54807	G	A	HELD_ALL_ADR	0.79	1.26	134
54807	G	A	HELD_FEM_ADR3ULN	0.57	1.76	31
54807	G	A	HELD_FEM_EFF	1.17	0.85	281
54807	G	A	HELD_ALL_ADR3ULN	0.66	1.51	48
54807	G	A	HELD_FEM_UEFF	1.58	0.63	53
55733	G	A	CVD_MAL	0.69	1.45	34
55733	G	A	CVD_FEM	null	0	15
55733	G	A	HELD_FEM_VEFF	1.39	0.72	155
55733	G	A	HELD_ALL_ADR	1.39	0.72	136
55846	A	G	HELD_FEM_VEFF	0.8	1.25	136
55846	A	G	HELD_FEM_UEFF	0.71	1.41	52
55906	G	T	HELD_FEM_EFF	2.13	0.47	26
56084	C	T	HELD_FEM_UEFF	0.36	2.75	8
57818	G	A	HELD_MAL_ADR	0.57	1.76	63
57818	G	A	HELD_ALL_ADR	0.68	1.46	138
57818	G	A	HELD_MAL_ADR3ULN	0.36	2.78	17
57818	G	A	HELD_ALL_ADR3ULN	0.56	1.8	48
57818	G	A	HELD_FEM_EFF	0.83	1.21	291
57819	T	C	HELD_MAL_ADR	0.66	1.52	61
57819	T	C	HELD_ALL_ADR	0.76	1.31	136
57819	T	C	HELD_FEM_EFF	0.86	1.16	289
57828	A	G	HELD_FEM_VEFF	0.96	1.04	149
57987	T	C	HELD_MAL_ADR5ULN	1.03	0.97	9
59456	A	C	HELD_MAL_ADR3ULN	2.08	0.48	15
59460	T	C	HELD_FEM_UEFF	1.25	0.8	53
59461	C	T	HELD_MAL_ADR5ULN	3.8	0.26	9
59461	C	T	HELD_FEM_UEFF	1.27	0.79	53
59461	C	T	HELD_FEM_EFF	1.14	0.87	280
60900	A	G	HELD_FEM_ADR3ULN	0.86	1.16	30
60900	A	G	HELD_MAL_ADR	0.74	1.35	51
60900	A	G	HELD_ALL_ADR3ULN	0.82	1.22	43
60902	A	T	HELD_MAL_ADR	1.53	0.66	53
60902	A	T	HELD_ALL_ADR	1.27	0.79	114
60934	C	T	CVD_ALL	1.55	0.64	52
60934	C	T	CVD_MAL	1.38	0.72	36
60934	C	T	HELD_MAL_ADR	0.8	1.25	62
60934	C	T	CVD_FEM	1.81	0.55	16
60957	G	A	HELD_MAL_ADR5ULN	null	0	8
60957	G	A	HELD_MAL_ADR3ULN	3.15	0.32	16
60959	T	C	HELD_MAL_ADR3ULN	0.4	2.52	15
60959	T	C	HELD_MAL_ADR5ULN	0.37	2.71	8
60959	T	C	HELD_ALL_ADR3ULN	0.66	1.51	45
60959	T	C	HELD_ALL_ADR	0.84	1.2	126
60959	T	C	HELD_MAL_ADR	0.78	1.29	58
60962	C	T	HELD_MAL_ADR5ULN	0.18	5.67	4
60962	C	T	HELD_MAL_ADR3ULN	0.32	3.08	9
60962	C	T	HELD_MAL_ADR	0.69	1.45	36
60974	G	A	HELD_FEM_ADR5ULN	0.94	1.07	17
60978	G	C	HELD_MAL_ADR	2.73	0.37	63
60978	G	C	HELD_FEM_EFF	1.1	0.91	294
60978	G	C	HELD_FEM_VEFF	1.19	0.84	159
60999	G	T	HELD_MAL_ADR5ULN	null	0	9
61011	T	C	CVD_MAL	0.82	1.21	38
61011	T	C	HELD_FEM_EFF	0.92	1.08	289
61086	G	A	HELD_MAL_ADR	1.84	0.54	39
61126	C	T	HELD_MAL_ADR	0.96	1.04	59
61126	C	T	HELD_FEM_VEFF	0.82	1.21	152
61126	C	T	HELD_FEM_UEFF	0.77	1.29	54
61126	C	T	HELD_FEM_EFF	0.88	1.13	274
61137	T	C	HELD_ALL_ADR	0.8	1.25	133
61147	G	A	HELD_FEM_EFF	0.92	1.09	293
61176	A	G	HELD_MAL_ADR5ULN	4.45	0.22	8
61176	A	G	HELD_MAL_ADR	1.38	0.72	56
61176	A	G	HELD_MAL_ADR3ULN	1.9	0.53	16
61176	A	G	HELD_ALL_ADR5ULN	1.41	0.71	26
61184	C	T	HELD_MAL_ADR5ULN	2	0.5	9
61184	C	T	HELD_MAL_ADR	1.51	0.66	61
61197	A	G	HELD_MAL_ADR3ULN	0.49	2.05	17
61270	A	G	HELD_MAL_ADR3ULN	0.37	2.7	16
61270	A	G	HELD_MAL_ADR5ULN	0.28	3.64	8
61270	A	G	HELD_ALL_CC2	1.78	0.56	17
61272	A	G	HELD_MAL_ADR5ULN	0.49	2.05	8
61272	A	G	HELD_FEM_ADR	1.4	0.71	69
61284	G	A	HELD_FEM_EFF	0.92	1.09	290
61292	G	A	HELD_FEM_EFF	0.86	1.16	288
61292	G	A	HELD_MAL_ADR	0.96	1.04	62
61297	T	C	CVD_ALL	0.8	1.24	92
61324	G	A	HELD_FEM_VEFF	1.62	0.62	21
61328	A	G	HELD_FEM_EFF	0.5	2	277
61373	G	C	HELD_FEM_ADR	1.66	0.6	75
61373	G	C	HELD_ALL_ADR	1.34	0.74	136
900066	C	T	HELD_MAL_LIP	1.36	0.74	17
900071	G	C	HELD_FEM_UEFF	1.33	0.75	52
900072	G	C	HELD_FEM_UEFF	1.56	0.64	41
900072	G	C	HELD_FEM_HDL	0.78	1.29	25
900072	G	C	HELD_FEM_VEFF	1.19	0.84	123
900073	G	C	HELD_ALL_ADR	0.8	1.25	125
900073	G	C	HELD_MAL_ADR	0.74	1.35	59
900073	G	C	HELD_ALL_CC2	1.23	0.81	26
900073	G	C	HELD_MAL_ADR3ULN	0.54	1.85	17
900073	G	C	HELD_FEM_EFF	0.88	1.13	295
900074	C	T	HELD_FEM_LIP	0.8	1.25	76
900074	C	T	HELD_FEM_UEFF	1.38	0.73	52
900083	A	G	HELD_FEM_EFF	0.88	1.13	281
900115	A	G	HELD_MAL_ADR3ULN	0.5	2.02	16
900115	A	G	HELD_ALL_CC	0.72	1.39	45
900115	A	G	HELD_ALL_ADR5ULN	0.6	1.67	25
900143	G	T	HELD_MAL_ADR5ULN	0.82	1.22	7
900143	G	T	HELD_ALL_ADR	0.78	1.28	122
900143	G	T	HELD_FEM_ADR3ULN	0.55	1.81	29
900143	G	T	HELD_ALL_ADR3ULN	0.61	1.63	43
900143	G	T	HELD_ALL_ADR5ULN	0.65	1.53	24
900143	G	T	HELD_FEM_ADR	0.78	1.28	67
900173	T	G	HELD_MAL_ADR3ULN	3.85	0.26	16
900174	A	G	HELD_MAL_ADR3ULN	0.41	2.43	16
900174	A	G	HELD_MAL_ADR5ULN	0.29	3.48	8
900174	A	G	HELD_ALL_ADR5ULN	0.55	1.83	22
900174	A	G	HELD_FEM_CC	0.69	1.45	28
900174	A	G	HELD_ALL_CC	0.73	1.38	42
900175	G	A	HELD_FEM_EFF	2.52	0.4	12
900180	G	A	CVD_ALL	0.72	1.38	102
900180	G	A	CVD_FEM	0.51	1.97	33
900180	G	A	HELD_MAL_CC	0.43	2.31	14
900180	G	A	HELD_ALL_CC	0.64	1.55	44
900221	G	C	HELD_MAL_ADR	1.33	0.75	54
900250	C	T	HELD_MAL_ADR5ULN	0.37	2.74	9
900342	G	A	HELD_ALL_ADR	0.75	1.33	113
900342	G	A	HELD_FEM_ADR	0.71	1.42	62
900344	A	C	HELD_FEM_ADR	0.66	1.51	70
900344	A	C	HELD_FEM_ADR3ULN	0.57	1.75	34
900344	A	C	HELD_ALL_ADR	0.8	1.26	128
900344	A	C	HELD_FEM_ADR5ULN	0.53	1.89	19
10000001	G	A	HELD_MAL_LIP	1.77	0.56	17
10000001	G	A	HELD_ALL_LIP	1.33	0.75	100
10000002	A	G	HELD_ALL_LIP	1.33	0.75	102
10000017	T	C	HELD_ALL_LIP	0.8	1.25	102
	BAYSNP	FREQ1_A	FREQ2_A	SIZE_B	FREQ1_B	FREQ2_B
	160	13	19	59	72	46
	194	10	18	64	75	53
	194	18	22	123	145	101
	194	290	208	261	274	248
	411	25	27	126	158	94
	466	61	81	69	75	63
	466	14	4	56	58	54
	555	129	65	115	135	95
	623	32	0	59	110	8
	625	29	33	63	82	44
	777	162	42	110	194	26
	777	37	11	32	59	5
	777	128	18	53	82	24
	777	66	8	30	45	15
	777	133	35	75	132	18
	777	157	39	114	199	29
	1005	142	26	74	136	12
	1062	1084	166	714	1209	219
	1275	19	41	14	20	8
	1275	58	24	28	28	28
	1275	24	12	24	20	28
	1275	58	44	20	30	10
	1669	78	4	28	45	11
	1669	172	22	67	104	30
	1669	162	30	74	120	28
	1669	27	1	18	29	7
	1755	387	225	345	413	277
	1765	21	151	70	27	113
	2109	521	111	359	561	157
	2150	156	40	115	191	39
	2150	162	42	111	185	37
	2150	29	9	36	62	10
	2150	29	9	36	62	10
	2150	127	31	79	129	29
	2234	136	64	109	141	77
	2321	30	6	35	67	3
	2321	30	6	35	67	3
	2321	154	6	79	143	15
	2354	57	13	40	76	4
	3451	64	82	69	74	64
	3451	14	4	60	62	58
	3452	17	1	60	83	37
	3453	103	39	69	84	54
	4912	78	62	60	51	69
	5093	30	34	39	52	26
	5093	16	6	17	14	20
	6333	8	8	54	61	47
	6333	114	134	117	136	98
	6333	37	51	117	136	98
	6333	22	34	63	75	51
	6333	22	26	117	136	98
	6333	49	65	54	61	47
	6333	37	27	32	29	35
	7407	7	9	50	32	68
	7407	7	7	23	14	32
	7407	26	28	23	14	32
	7407	13	13	23	14	32
	10584	254	12	130	257	3
	10584	133	7	70	139	1
	10584	55	3	70	139	1
	11021	133	27	71	129	13
	11062	14	2	58	75	41
	11147	75	45	56	59	53
	11212	14	6	15	12	18
	11371	89	7	129	252	6
	11371	138	8	71	140	2
	11487	74	30	72	116	28
	11585	117	91	110	104	116
	11683	81	31	78	128	28
	11863	288	20	150	264	36
	12024	255	13	131	259	3
	12024	54	4	71	141	1
	12024	134	8	71	141	1
	12024	87	5	131	259	3
	12632	17	1	64	128	0
	13994	56	4	37	74	0
	13994	104	0	50	97	3
	14090	455	83	275	487	63
	14159	365	219	293	343	243
	14362	109	5	79	140	18
	14410	120	2	63	118	8
	14488	252	12	131	259	3
	14488	135	7	71	141	1
	14488	57	3	71	141	1
	14490	18	0	58	91	25
	14490	23	11	71	121	21
	14490	45	17	71	121	21
	14493	257	13	128	253	3
	14493	138	8	69	137	1
	14493	58	4	69	137	1
	14493	91	5	128	253	3
	14554	32	0	61	99	23
	14554	16	0	61	99	23
	14554	110	12	61	99	23
	14603	69	9	12	24	0
	14820	197	97	142	187	97
	14820	74	36	76	96	56
	14876	340	220	285	344	226
	14876	179	115	145	166	124
	14954	118	0	65	127	3
	14957	34	0	78	145	11
	14957	265	31	143	269	17
	14977	76	36	75	118	32
	15349	81	37	65	72	58
	15590	33	17	140	149	131
	15590	149	111	140	149	131
	15590	81	61	76	78	74
	16268	18	0	65	112	18
	36078	41	3	17	26	8
	36078	59	5	26	42	10
	36406	27	7	74	83	65
	37135	50	38	117	135	99
	37135	32	26	61	67	55
	37135	21	13	61	67	55
	37135	30	18	117	135	99
	37327	20	14	3	6	0
	37327	206	80	127	163	91
	37327	83	23	69	90	48
	37327	87	23	49	64	34
	37404	94	4	49	98	0
	37413	23	11	61	107	15
	37413	43	17	61	107	15
	37413	36	12	117	206	28
	37413	70	20	117	206	28
	37939	544	46	298	551	45
	37939	60	12	13	24	2
	38009	220	32	116	184	48
	38009	101	13	55	88	22
	40004	23	11	16	29	3
	40522	112	34	78	100	56
	40522	49	13	78	100	56
	40522	28	6	78	100	56
	41847	266	178	223	229	217
	42084	11	3	56	100	12
	42084	48	14	62	108	16
	42084	116	26	62	108	16
	42084	38	12	118	208	28
	42084	27	9	62	108	16
	42084	73	19	118	208	28
	42677	41	19	59	61	57
	42677	24	10	59	61	57
	42677	87	49	59	61	57
	46865	248	54	143	206	80
	46865	439	105	276	416	136
	46865	37	15	136	203	69
	47856	43	9	143	214	72
	47856	17	1	65	98	32
	47856	222	84	151	240	62
	48490	53	39	35	23	47
	48490	37	23	17	12	22
	48490	41	53	135	151	119
	48490	25	35	72	83	61
	48490	63	77	72	83	61
	50164	50	12	77	143	11
	50164	127	23	77	143	11
	50164	41	11	142	252	32
	54704	125	11	60	118	2
	54806	64	4	31	62	0
	54806	99	7	73	128	18
	54807	22	12	70	124	16
	54807	35	17	129	218	40
	54807	107	35	70	124	16
	54807	205	63	129	218	40
	54807	47	15	70	124	16
	54807	461	101	267	411	123
	54807	72	24	129	218	40
	54807	94	12	69	109	29
	55733	58	10	13	26	0
	55733	30	0	16	28	4
	55733	289	21	150	265	35
	55733	252	20	140	245	35
	55846	169	103	144	207	81
	55846	62	42	76	111	41
	55906	41	11	51	57	45
	56084	8	8	22	36	8
	57818	100	26	65	123	7
	57818	229	47	142	262	22
	57818	27	7	65	123	7
	57818	80	16	142	262	22
	57818	509	73	293	535	51
	57819	93	29	65	116	14
	57819	215	57	143	249	37
	57819	484	94	289	506	72
	57828	175	123	148	179	117
	57987	10	8	65	71	59
	59456	23	7	56	64	48
	59460	77	29	77	100	54
	59461	16	2	64	83	45
	59461	80	26	77	104	50
	59461	406	154	282	378	186
	60900	37	23	56	75	37
	60900	64	38	47	72	22
	60900	56	30	103	147	59
	60902	87	19	53	72	34
	60902	181	47	112	159	65
	60934	75	29	32	30	34
	60934	52	20	13	12	14
	60934	75	49	63	89	37
	60934	23	9	19	18	20
	60957	16	0	56	89	23
	60957	30	2	56	89	23
	60959	11	19	55	72	38
	60959	6	10	55	72	38
	60959	42	48	115	140	90
	60959	130	122	115	140	90
	60959	61	55	55	72	38
	60962	3	5	40	65	15
	60962	9	9	40	65	15
	60962	48	24	40	65	15
	60974	27	7	75	121	29
	60978	123	3	65	117	13
	60978	546	42	297	544	50
	60978	294	24	151	271	31
	60999	18	0	64	114	14
	61011	62	14	13	24	2
	61011	472	106	284	477	91
	61086	71	7	36	56	16
	61126	68	50	56	67	45
	61126	152	152	137	165	109
	61126	54	54	72	88	56
	61126	292	256	266	317	215
	61137	211	55	140	241	39
	61147	335	251	296	363	229
	61176	14	2	55	63	47
	61176	80	32	55	63	47
	61176	24	8	55	63	47
	61176	38	14	117	150	84
	61184	16	2	61	96	26
	61184	108	14	61	96	26
	61197	24	10	63	109	17
	61270	23	9	55	101	9
	61270	11	5	55	101	9
	61270	32	2	3	4	2
	61272	10	6	56	89	23
	61272	116	22	62	91	33
	61284	329	251	295	358	232
	61292	333	243	294	381	207
	61292	78	46	64	83	45
	61297	134	50	64	106	22
	61324	29	13	17	15	19
	61328	551	3	276	552	0
	61373	136	14	76	122	30
	61373	244	28	141	236	46
	900066	30	4	32	53	11
	900071	57	47	77	66	88
	900072	50	32	62	53	71
	900072	20	30	27	28	26
	900072	141	105	115	111	119
	900073	158	92	121	178	64
	900073	71	47	55	82	28
	900073	45	7	2	2	2
	900073	19	15	55	82	28
	900073	398	192	299	435	163
	900074	85	67	69	93	45
	900074	70	34	79	87	71
	900083	296	266	280	329	231
	900115	13	19	59	74	44
	900115	54	36	40	61	19
	900115	25	25	130	169	91
	900143	7	7	53	59	47
	900143	112	132	117	137	97
	900143	23	35	64	78	50
	900143	36	50	117	137	97
	900143	22	26	117	137	97
	900143	65	69	64	78	50
	900173	30	2	55	83	27
	900174	12	20	54	71	37
	900174	5	11	54	71	37
	900174	21	23	113	148	78
	900174	31	25	21	32	10
	900174	49	35	37	55	19
	900175	21	3	22	29	15
	900180	69	135	73	76	70
	900180	18	48	40	44	36
	900180	10	18	18	26	10
	900180	33	55	40	48	32
	900221	68	40	52	51	53
	900250	12	6	59	103	15
	900342	180	46	113	199	27
	900342	96	28	61	108	14
	900344	62	78	72	93	51
	900344	30	38	72	93	51
	900344	127	129	127	155	99
	900344	17	21	72	93	51
	10000001	24	10	36	37	35
	10000001	126	74	110	110	110
	10000002	158	46	109	146	72
	10000017	177	27	110	201	19

Claims

1. An isolated polynucleotide encoded by a phenotype associated (PA) gene; the polynucleotide is selected from the group comprising SEQ ID 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 with allelic variation as indicated in the sequences section contained in a functional surrounding like full length cDNA for PA gene polypeptide and with or without the PA gene promoter sequence.

2. An expression vector containing one or more of the polynucleotides of claim 1.

3. A host cell containing the expression vector of claim 2.

4. A substantially purified PA gene polypeptide encoded by a polynucleotide of claim 1.

5. A method for producing a PA gene polypeptide, wherein the method comprises the following steps: a) culturing the host cell of claim 3 under conditions suitable for the expression of the PA gene polypeptide; and b) recovering the PA gene polypeptide from the host cell culture.

6. A method for the detection of a polynucleotide of claim 1 or a PA gene polypeptide of claim 4 comprising the steps of: contacting a biological sample with a reagent which specifically interacts with the polynucleotide or the PA gene polypeptide.

7. A method of screening for agents which regulate the activity of a PA gene comprising the steps of: contacting a test compound with a PA gene polypeptide encoded by any polynucleotide of claim 1; and detecting PA gene activity of the polypeptide, wherein a test compound which increases the PA gene polypeptide activity is identified as a potential therapeutic agent for increasing the activity of the PA gene polypeptide and wherein a test compound which decreases the PA activity of the polypeptide is identified as a potential therapeutic agent for decreasing the activity of the PA gene polypeptide.

8. A reagent that modulates the activity of a PA polypeptide or a polynucleotide wherein said reagent is identified by the method of the claim 7.

9. A pharmaceutical composition, comprising: the expression vector of claim 2 or the reagent of claim 8 and a pharmaceutically acceptable carrier.

10. Use of the reagent according to claim 8 for the preparation of a medicament.

11. A method for determining whether a human subject has, or is at risk of developing a cardiovascular disease, comprising determining the identity of nucleotide variations as indicated in the sequences section of SEQ ID 1-131 of the PA gene locus of the subject and where the SNP class of the SNP is “CVD” as can be seen from table 3; whereas a “risk” genotype has a risk ratio of greater than 1 as can be seen from table 6.

12. A method for determining a patient's individual response to statin therapy, including drug efficacy and adverse drug reactions, comprising determining the identity of nucleotide variations as indicated in the sequences section of SEQ ID 1-131 of the PA gene locus of the subject and where the SNP class of the SNP is “ADR”, “EFF” or both as can be seen from table 3; whereas the probability for such response can be seen from table 6.

13. Use of the method according to claim 12 for the preparation of a medicament tailored to suit a patient's individual response to statin therapy.

14. A kit for assessing cardiovascular status or statin response, said kit comprising a) sequence determination primers and b) sequence determination reagents, wherein said primers are selected from the group comprising primers that hybridize to polymorphic positions in human PA genes according to claim 1; and primers that hybridize immediately adjacent to polymorphic positions in human PA genes according to claim 1.

15. A kit as defined in claim 12 detecting a combination of two or more, up to all, poly-morphic sites selected from the groups of sequences as defined in claim 1.

16. A kit for assessing cardiovascular status or statin response, said kit comprising one or more antibodies specific for a polymorphic position defined in claim 1 within the human PA gene polypeptides and combinations of any of the foregoing.