Genetic susceptibility variants associated with cardiovascular disease

Abstract

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

1 . A method for determining a susceptibility to arterial disease in a human individual, comprising
 determining the presence or absence of allele G of polymorphic marker rs10757278 in a nucleic acid sample from the individual, and   determining a susceptibility to arterial disease for the human individual from the presence or absence of the G allele of rs10757278 in the nucleic acid sample, wherein the presence of the G allele is indicative of an increased susceptibility to arterial disease, and the absence of the G allele is indicative of a decreased susceptibility to arterial disease.   
     
     
         2 . The method according to  claim 1 , wherein the allele G is determined to be present, and the individual is determined to have an increased susceptibility to arterial disease. 
     
     
         3 . The method according to  claim 2 , wherein the presence of the allele G is indicative of increased susceptibility with a relative risk (RR) or odds ratio (OR) of at least 1.2. 
     
     
         4 . The method according to  claim 1 , further comprising assessing at least one biomarker in a sample from the individual. 
     
     
         5 . The method according to  claim 4 , wherein the biomarker is a cardiac marker or an inflammatory marker. 
     
     
         6 . The method according to  claim 5 , wherein the at least one biomarker is selected from creatine kinase, troponin, glycogen phosphorylase, C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, matrix metalloprotease type-9, serum sCD40L, leukotrienes, leukotriene metabolites, interleukin-6, tissue necrosis factor-alpha, myeloperoxidase (MPO), and N-tyrosine. 
     
     
         7 . The method according to  claim 6 , wherein the at least one biomarker is a leukotriene is selected from LTB4, LTC4, LTD4 and LTE4. 
     
     
         8 . The method according to  claim 1 , wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm. 
     
     
         9 . The method according to  claim 8 , wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, intracranial aneurysm and abdominal aorta aneurysm. 
     
     
         10 . The method according to  claim 1 , wherein the arterial disease is myocardial infarction. 
     
     
         11 . The method according to  claim 10 , wherein the myocardial infarction is an early onset myocardial infarction. 
     
     
         12 . The method according to  claim 8 , wherein the arterial disease is a stroke selected from large artery atherosclerotic stroke or cardiogenic stroke. 
     
     
         13 . The method according to  claim 1 , wherein the arterial disease is myocardial infarction and/or coronary artery disease with an onset before age 50 for males and age 60 for females. 
     
     
         14 . The method according to  claim 1  comprising contacting nucleic acid from the individual with an oligonucleotide probe, wherein the probe hybridizes to a segment of a nucleic acid whose nucleotide sequence is set forth in SEQ ID NO:94, wherein the probe is 15-500 nucleotides in length. 
     
     
         15 . The method of  claim 1 , wherein the step of determining the presence or absence of allele G of polymorphic marker rs10757278 in a nucleic acid sample obtained from the individual comprises at least one nucleic acid analysis technique selected from: polymerase chain reaction, allele-specific hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5′-exonuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation analysis. 
     
     
         16 . The method of  claim 1 , wherein the step of determining a susceptibility to arterial disease is performed using a computer readable medium on which is stored:
 an identifier for allele G of polymorphic marker rs10757278;   an indicator of the frequency of allele G of polymorphic marker rs10757278 in a plurality of individuals diagnosed with arterial disease; and   an indicator of the frequency of allele G of polymorphic marker rs10757278 in a plurality of reference individuals.   
     
     
         17 . The method of  claim 1 , wherein the step of determining a susceptibility to arterial disease is performed using an apparatus that comprises:
 a computer readable memory, a processor, and a routine stored on the computer readable memory; wherein the routine is adapted to be executed on the processor to analyze marker information for at least one human individual with respect to allele G of polymorphic marker rs10757278, and generate an output based on the marker information, wherein the output comprises an individual risk measure of allele G of polymorphic marker rs10757278 as a genetic indicator of arterial disease for the human individual.   
     
     
         18 . A method of genotyping a nucleic acid sample obtained from a human individual at risk for, or diagnosed with, arterial disease, comprising determining the presence or absence of allele G of polymorphic marker rs10757278 in the sample, and
 diagnosing an increased genetic susceptibility to the arterial disease for the human individual from the presence of the G allele, or diagnosing a decreased genetic susceptibility to the arterial disease for the human individual from the absence of the G allele.   
     
     
         19 . The method according to  claim 18 , wherein the allele G is determined to be present, and the individual is determined to have an increased susceptibility to arterial disease. 
     
     
         20 . The method according to  claim 18 , wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm. 
     
     
         21 . A method for determining a susceptibility to arterial disease in a human individual, comprising:
 analyzing nucleic acid from the individual for evidence in LD block C09 of the presence of allele G of polymorphic marker rs10757278, and determining an increased susceptibility to arterial disease in the human individual from evidence that rs10757278, allele G, is present in the individual, or determining a decreased susceptibility to arterial disease from evidence that rs10757278, allele G, is absent in the individual.   
     
     
         22 . The method of  claim 21 , wherein a susceptibility to arterial disease for the individual is determined using an apparatus that comprises: a computer readable memory, a processor, and a routine stored on the computer readable memory; wherein the routine is adapted to be executed on the processor to analyze marker information for at least one human individual with respect to allele G of polymorphic marker rs10757278, and generate an output based on the nucleic acid sequence information of the individual, wherein the output comprises a determination of an increased susceptibility to breast cancer in the human individual from evidence that allele G of polymorphic marker rs10757278 is present in the nucleic acid sequence of the individual, or a determination of a decreased susceptibility to breast cancer from evidence that allele G of polymorphic marker rs10757278 is absent from the nucleic acid sequence of the individual. 
     
     
         23 . The method according to  claim 21 , wherein the individual is determined to have an increased susceptibility to arterial disease from evidence that the allele G is present in the nucleic acid from the individual. 
     
     
         24 . The method according to  claim 21  wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm. 
     
     
         25 . The method according to  claim 21 , wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, intracranial aneurysm and abdominal aorta aneurysm. 
     
     
         26 . The method of  claim 21 , wherein the analyzing of the nucleic acid of the individual comprises at least one nucleic acid analysis technique selected from: polymerase chain reaction, allele-specific hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5′-exonuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation analysis. 
     
     
         27 . A method of assessing a susceptibility to arterial disease in a human individual, comprising:
 analyzing a nucleic acid sample from the individual, to determine a presence or an absence of allele G of polymorphic marker rs10757278 in the sample, and   assessing susceptibility to arterial disease from the nucleic acid analysis, wherein the presence of the G allele is indicative of an increased susceptibility to arterial disease in humans, and the absence of the G allele is indicative of a decreased susceptibility to the arterial disease.   
     
     
         28 . The method according to  claim 27 , wherein the allele G is determined to be present, and the individual is determined to have an increased susceptibility to arterial disease. 
     
     
         29 . The method according to  claim 27 , wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, peripheral arterial disease, stroke, abdominal aorta aneurysm and intracranial aneurysm. 
     
     
         30 . The method according to  claim 27 , wherein the arterial disease is at least one of myocardial infarction, coronary artery disease, restenosis, intracranial aneurysm and abdominal aorta aneurysm.