Genetic Architecture of Coronary Artery Disease in the Genome-Wide Era: Implications for the Emerging “Golden Dozen” Loci

ABSTRACT

Clinicians are well aware of family history as a risk factor for coronary artery disease (CAD) and myocardial infarction (MI). The underlying genetic architecture of CAD/MI is extremely complex and still poorly understood. Overall, the genetic heritability of CAD/MI is estimated to be near 40 to 60%. This proportion includes mainly genes that regulate known risk factors (e.g., lipid metabolism) but also genes involved in as yet unknown metabolic pathways. In the last 2 years, the systematic application of genome-wide association studies in the setting of large collaborative consortia including thousands of patients and controls has led to the identification of several new loci associated with CAD/MI. Here we review current knowledge on the emerging “top” 12 loci, that is, those showing the most consistent associations with clinical phenotypes. Although these genetic variants have little or no current predictive value of at the level of individual patients, they have the potential to disclose novel biological mechanisms involved in the pathophysiology of CAD/MI.

KEYWORDS

Coronary artery disease - myocardial infarction - single nucleotide polymorphisms - genome-wide association - locus 9p21

REFERENCES

• 1 Rosamond W, Flegal K, Furie K for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee et al,. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.  Circulation. 2008;  117(4) e25-e146
• 2 Reddy K S. Cardiovascular disease in non-Western countries.  N Engl J Med. 2004;  350(24) 2438-2440
• 3 Rosenzweig A. Scanning the genome for coronary risk.  N Engl J Med. 2007;  357(5) 497-499
• 4 Hawe E, Talmud P J, Miller G J, Humphries S E. Second Northwick Park Heart Study . Family history is a coronary heart disease risk factor in the Second Northwick Park Heart Study.  Ann Hum Genet. 2003;  67(Pt 2) 97-106
• 5 Lloyd-Jones D M, Nam B H, D'Agostino Sr R B et al.. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring.  JAMA. 2004;  291(18) 2204-2211
• 6 Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Münster (PROCAM) study.  Circulation. 2002;  105(3) 310-315
• 7 Yusuf S, Hawken S, Ounpuu S INTERHEART Study Investigators et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.  Lancet. 2004;  364(9438) 937-952
• 8 Martin N, Boomsma D, Machin G. A twin-pronged attack on complex traits.  Nat Genet. 1997;  17(4) 387-392
• 9 Marenberg M E, Risch N, Berkman L F, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins.  N Engl J Med. 1994;  330(15) 1041-1046
• 10 Zdravkovic S, Wienke A, Pedersen N L, Marenberg M E, Yashin A I, De Faire U. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins.  J Intern Med. 2002;  252(3) 247-254
• 11 Kaluza G, Abukhalil J M, Raizner A E. Identical atheroscler-zotic lesions in identical twins.  Circulation. 2000;  101(4) E63-E64
• 12 Motulsky A G, Brunzell J D. Genetics of coronary artery disease. In: King RA, Rotter JI, Motulsky AG The Genetic Basis of Common Disease. 2nd ed. New York, NY; Oxford University Press 2002: 105-125
• 13 Watkins H, Farrall M. Genetic susceptibility to coronary artery disease: from promise to progress.  Nat Rev Genet. 2006;  7(3) 163-173
• 14 Girelli D, Martinelli N. Genetic scoring and cardiovascular risk. Building a cathedral.  Available at: http://www.athero.org/commentaries/comm768.asp Accessed October 6, 2009; 
• 15 Lusis A J. Atherosclerosis.  Nature. 2000;  407(6801) 233-241
• 16 Roy H, Bhardwaj S, Yla-Herttuala S. Molecular genetics of atherosclerosis.  Hum Genet. 2009;  125(5-6) 467-491
• 17 Manolio T A, Brooks L D, Collins F S. A HapMap harvest of insights into the genetics of common disease.  J Clin Invest. 2008;  118(5) 1590-1605
• 18 Lohmueller K E, Pearce C L, Pike M, Lander E S, Hirschhorn J N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.  Nat Genet. 2003;  33(2) 177-182
• 19 Kullo I J, Ding K. Mechanisms of disease: the genetic basis of coronary heart disease.  Nat Clin Pract Cardiovasc Med. 2007;  4(10) 558-569
• 20 Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group . No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age.  Circulation. 2003;  107(8) 1117-1122
• 21 Girelli D, Friso S, Trabetti E et al.. Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction.  Blood. 1998;  91(11) 4158-4163
• 22 Girelli D, Russo C, Ferraresi P et al.. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease.  N Engl J Med. 2000;  343(11) 774-780
• 23 Murata M, Kawano K, Matsubara Y, Ishikawa K, Watanabe K, Ikeda Y. Genetic polymorphisms and risk of coronary artery disease.  Semin Thromb Hemost. 1998;  24(3) 245-250
• 24 Pare G, Serre D, Brisson D et al.. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol.  Am J Hum Genet. 2007;  80 673-682
• 25 Morgan T M, Krumholz H M, Lifton R P, Spertus J A. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study.  JAMA. 2007;  297(14) 1551-1561
• 26 Bennet A M, Di Angelantonio E, Ye Z et al.. Association of apolipoprotein E genotypes with lipid levels and coronary risk.  JAMA. 2007;  298(11) 1300-1311
• 27 Song Y, Stampfer M J, Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease.  Ann Intern Med. 2004;  141(2) 137-147
• 28 Ye Z, Liu E HC, Higgins J PT et al.. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls.  Lancet. 2006;  367(9511) 651-658
• 29 Arnett D K, Baird A E, Barkley R A American Heart Association Council on Epidemiology and Prevention et al. Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group.  Circulation. 2007;  115(22) 2878-2901
• 30 Boekholdt S M, Kramer M HH. Arterial thrombosis and the role of thrombophilia.  Semin Thromb Hemost. 2007;  33(6) 588-596
• 31 Ward H, Mitrou P N, Bowman R et al.. APOE genotype, lipids, and coronary heart disease risk: a prospective population study.  Arch Intern Med. 2009;  169(15) 1424-1429
• 32 Reitsma P H. No praise for folly: genomics will never be useful in arterial thrombosis.  J Thromb Haemost. 2007;  5(3) 454-457
• 33 International Human Genome Sequencing Consortium . Finishing the euchromatic sequence of the human genome.  Nature. 2004;  431(7011) 931-945
• 34 International HapMap Consortium . A haplotype map of the human genome.  Nature. 2005;  437(7063) 1299-1320
• 35 Frazer K A, Ballinger D G, Cox D R International HapMap Consortium et al. A second generation human haplotype map of over 3.1 million SNPs.  Nature. 2007;  449(7164) 851-861
• 36 Gunderson K L, Steemers F J, Lee G, Mendoza L G, Chee M S. A genome-wide scalable SNP genotyping assay using microarray technology.  Nat Genet. 2005;  37(5) 549-554
• 37 Steemers F J, Chang W, Lee G, Barker D L, Shen R, Gunderson K L. Whole-genome genotyping with the single-base extension assay.  Nat Methods. 2006;  3(1) 31-33
• 38 Gresham D, Dunham M J, Botstein D. Comparing whole genomes using DNA microarrays.  Nat Rev Genet. 2008;  9(4) 291-302
• 39 Hardy J, Singleton A. Genomewide association studies and human disease.  N Engl J Med. 2009;  360(17) 1759-1768
• 40 Wellcome Trust Case Control Consortium . Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.  Nature. 2007;  447(7145) 661-678
• 41 McPherson R, Pertsemlidis A, Kavaslar N et al.. A common allele on chromosome 9 associated with coronary heart disease.  Science. 2007;  316(5830) 1488-1491
• 42 Helgadottir A, Thorleifsson G, Manolescu A et al.. A common variant on chromosome 9p21 affects the risk of myocardial infarction.  Science. 2007;  316(5830) 1491-1493
• 43 Samani N J, Erdmann J, Hall A S WTCCC and the Cardiogenics Consortium et al. Genomewide association analysis of coronary artery disease.  N Engl J Med. 2007;  357(5) 443-453
• 44 Tousoulis D, Briasoulis A, Papageorgiou N, Antoniades C, Stefanadis C. Candidate gene polymorphisms and the 9p21 locus in acute coronary syndromes.  Trends Mol Med. 2008;  14(10) 441-449
• 45 Schunkert H, Götz A, Braund P Cardiogenics Consortium et al. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease.  Circulation. 2008;  117(13) 1675-1684
• 46 Helgadottir A, Thorleifsson G, Magnusson K P et al.. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.  Nat Genet. 2008;  40(2) 217-224
• 47 Hannon G J, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.  Nature. 1994;  371(6494) 257-261
• 48 Kalinina N, Agrotis A, Antropova Y et al.. Smad expression in human atherosclerotic lesions: evidence for impaired TGF-beta/Smad signaling in smooth muscle cells of fibrofatty lesions.  Arterioscler Thromb Vasc Biol. 2004;  24(8) 1391-1396
• 49 Schmid M, Sen M, Rosenbach M D, Carrera C J, Friedman H, Carson D A. A methylthioadenosine phosphorylase (MTAP) fusion transcript identifies a new gene on chromosome 9p21 that is frequently deleted in cancer.  Oncogene. 2000;  19(50) 5747-5754
• 50 Broadbent H M, Peden J F, Lorkowski S PROCARDIS consortium et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p.  Hum Mol Genet. 2008;  17(6) 806-814
• 51 Lander E S, Linton L M, Birren B et al.. Initial sequencing and analysis of the human genome.  Nature. 2001;  409(6822) 860-921
• 52 Biémont C, Vieira C. Genetics: junk DNA as an evolutionary force.  Nature. 2006;  443(7111) 521-524
• 53 Nowacki M, Higgins B P, Maquilan G M, Swart E C, Doak T G, Landweber L F. A functional role for transposases in a large eukaryotic genome.  Science. 2009;  324(5929) 935-938
• 54 Transcriptomics: rethinking junk DNA.  Nature. 2009;  458(7235) 240-241
• 55 van Rooij E, Olson E N. MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets.  J Clin Invest. 2007;  117(9) 2369-2376
• 56 Mercer T R, Dinger M E, Mattick J S. Long non-coding RNAs: insights into functions.  Nat Rev Genet. 2009;  10(3) 155-159
• 57 Ponting C P, Oliver P L, Reik W. Evolution and functions of long noncoding RNAs.  Cell. 2009;  136(4) 629-641
• 58 Amaral P P, Dinger M E, Mercer T R, Mattick J S. The eukaryotic genome as an RNA machine.  Science. 2008;  319(5871) 1787-1789
• 59 Jarinova O, Stewart A FR, Roberts R et al.. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus.  Arterioscler Thromb Vasc Biol. 2009;  29 1671-1677
• 60 Pasmant E, Laurendeau I, Héron D, Vidaud M, Vidaud D, Bièche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF.  Cancer Res. 2007;  67(8) 3963-3969
• 61 Saxena R, Voight B F, Lyssenko V Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.  Science. 2007;  316(5829) 1331-1336
• 62 Zeggini E, Weedon M N, Lindgren C M Wellcome Trust Case Control Consortium (WTCCC) et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.  Science. 2007;  316(5829) 1336-1341
• 63 Liu Y, Sanoff H K, Cho H et al.. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis.  PLoS One. 2009;  4(4) e5027
• 64 Brautbar A, Ballantyne C, Lawson K et al.. Impact of adding a single allele in the 9p21 locus to traditional risk factors on risk classification for coronary heart disease and implications for lipid-modifying therapy in the white population of the Atherosclerosis Risk in Communities (ARIC) study.  Circ Cardiovasc Genet. 2009 April 21 (Epub ahead of print); 
• 65 Talmud P J, Cooper J A, Palmen J et al.. Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men.  Clin Chem. 2008;  54(3) 467-474
• 66 Paynter N P, Chasman D I, Buring J E, Shiffman D, Cook N R, Ridker P M. Cardiovascular disease risk prediction with and without knowledge of genetic variation at chromosome 9p21.3  Ann Intern Med. 2009;  150(2) 65-72
• 67 Gulcher J, Stefansson K. Questions about genetic variation in 9p21 as a predictor of cardiovascular risk.  Ann Intern Med. 2009;  150(10) 736
• 68 The Myocardial Infarction Genetics Consortium . Genome-wide association of early-onset myocardial infarction with common single nucleotide polymorphisms, common copy number variants, and rare copy number variants.  Nat Genet. 2009;  41 334-341
• 69 Gudbjartsson D F, Bjornsdottir U S, Halapi E et al.. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.  Nat Genet. 2009;  41(3) 342-347
• 70 Erdmann J, Grosshennig A, Braund P S et al.. New susceptibility locus for coronary artery disease on chromosome 3q22.3  Nat Genet. 2009;  41(3) 280-282
• 71 Trégouët D A, König I R, Erdmann J et al.. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.  Nat Genet. 2009;  41(3) 283-285
• 72 Ozaki K, Sato H, Inoue K et al.. SNPs in BRAP associated with risk of myocardial infarction in Asian populations.  Nat Genet. 2009;  41(3) 329-333
• 73 Samani N J, Deloukas P, Erdmann J Coronary Artery Disease Consortium et al. Large scale association analysis of novel genetic loci for coronary artery disease.  Arterioscler Thromb Vasc Biol. 2009;  29(5) 774-780
• 74 Kathiresan S, Melander O, Guiducci C et al.. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.  Nat Genet. 2008;  40(2) 189-197
• 75 Willer C J, Sanna S, Jackson A U et al.. Newly identified loci that influence lipid concentrations and risk of coronary artery disease.  Nat Genet. 2008;  40(2) 161-169
• 76 Sandhu M S, Waterworth D M, Debenham S L et al.. LDL-cholesterol concentrations: a genome-wide association study.  Lancet. 2008;  371(9611) 483-491
• 77 Wallace C, Newhouse S J, Braund P et al.. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.  Am J Hum Genet. 2008;  82(1) 139-149
• 78 Samani N J, Braund P S, Erdmann J et al.. The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol.  J Mol Med. 2008;  86(11) 1233-1241
• 79 Shima Y, Copeland N G, Gilbert D J et al.. Differential expression of the seven-pass transmembrane cadherin genes Celsr1-3 and distribution of the Celsr2 protein during mouse development.  Dev Dyn. 2002;  223(3) 321-332
• 80 Lo P K, Chen J Y, Lo W C et al.. Identification of a novel mouse p53 target gene DDA3.  Oncogene. 1999;  18(54) 7765-7774
• 81 Nielsen M S, Jacobsen C, Olivecrona G, Gliemann J, Petersen C M. Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase.  J Biol Chem. 1999;  274(13) 8832-8836
• 82 Linsel-Nitschke P, Heerenb J, Aherrahroua Z et al.. Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease.  Atherosclerosis. 2009 July 8 (Epub ahead of print); 
• 83 Gretarsdottir S, Thorleifsson G, Holm H et al.. The LDL cholesterol and coronary artery disease associated sequence variant on 1p13 also confers risk of abdominal aortic aneurysm and large artery atherosclerotic stroke.  Am J Hum Genet. 2009;  , In press
• 84 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.  JAMA. 1998;  279(18) 1477-1482
• 85 Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn P F. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men.  Circulation. 1991;  84(2) 613-617
• 86 Velazquez L, Cheng A M, Fleming H E et al.. Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice.  J Exp Med. 2002;  195(12) 1599-1611
• 87 Seita J, Ema H, Ooehara J et al.. Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction.  Proc Natl Acad Sci U S A. 2007;  104(7) 2349-2354
• 88 Smyth D J, Plagnol V, Walker N M et al.. Shared and distinct genetic variants in type 1 diabetes and celiac disease.  N Engl J Med. 2008;  359(26) 2767-2777
• 89 Hunt K A, Zhernakova A, Turner G et al.. Newly identified genetic risk variants for celiac disease related to the immune response.  Nat Genet. 2008;  40(4) 395-402
• 90 Todd J A, Walker N M, Cooper J D et al.. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.  Nat Genet. 2007;  39(7) 857-864
• 91 Aiuti A, Webb I J, Bleul C, Springer T, Gutierrez-Ramos J C. The chemokine SDF-1 is a chemoattractant for human CD34+hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+progenitors to peripheral blood.  J Exp Med. 1997;  185(1) 111-120
• 92 Askari A T, Unzek S, Popovic Z B et al.. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.  Lancet. 2003;  362(9385) 697-703
• 93 Stellos K, Langer H, Daub K et al.. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+cells to endothelial progenitor cells.  Circulation. 2008;  117(2) 206-215
• 94 Tillmanns J, Rota M, Hosoda T et al.. Formation of large coronary arteries by cardiac progenitor cells.  Proc Natl Acad Sci U S A. 2008;  105(5) 1668-1673
• 95 Yoshikawa Y, Satoh T, Tamura T et al.. The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-α dependent regulation of integrin activation in splenocytes.  Mol Biol Cell. 2007;  18(8) 2949-2959
• 96 Kamstrup P R, Tybjaerg-Hansen A, Steffensen R, Nordestgaard B G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.  JAMA. 2009;  301(22) 2331-2339
• 97 Hardy J, Singleton A. Genomewide association studies and human disease.  N Engl J Med. 2009;  360(17) 1759-1768
• 98 Costet P, Krempf M, Cariou B. PCSK9 and LDL cholesterol: unravelling the target to design the bullet.  Trends Biochem Sci. 2008;  33 426-434
• 99 Kathiresan S, Willer C J, Peloso G M et al.. Common variants at 30 loci contribute to polygenic dyslipidemia.  Nat Genet. 2009;  41(1) 56-65
• 100 Willer C J, Speliotes E K, Loos R J et al.. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.  Nat Genet. 2009;  41(1) 25-34
• 101 Newton-Cheh C, Johnson T, Gateva T et al.. Genome-wide association study identifies eight loci associated with blood pressure.  Nat Genet. 2009 May 10 (Epub ahead of print); 
• 102 Kathiresan S, Melander O, Anevski D et al.. Polymorphisms associated with cholesterol and risk of cardiovascular events.  N Engl J Med. 2008;  358(12) 1240-1249
• 103 Martinelli N, Trabetti E, Pinotti M et al.. Combined effect of hemostatic gene polymorphisms and the risk of myocardial infarction in patients with advanced coronary atherosclerosis.  PLoS One. 2008;  6(3) e1523
• 104 Cardon L R, Bell J I. Association study designs for complex diseases.  Nat Rev Genet. 2001;  2(2) 91-99
• 105 Redon R, Ishikawa S, Fitch K R et al.. Global variation in copy number in the human genome.  Nature. 2006;  444(7118) 444-454
• 106 International Schizophrenia Consortium . Rare chromosomal deletions and duplications increase risk of schizophrenia.  Nature. 2008;  455(7210) 237-241
• 107 Chiang D Y, Getz G, Jaffe D B et al.. High-resolution mapping of copy-number alterations with massively parallel sequencing.  Nat Methods. 2009;  6(1) 99-103
• 108 Ouwehand W H. Bloodomics and Cardiogenics Consortia . The discovery of genes implicated in myocardial infarction.  J Thromb Haemost. 2009;  7(Suppl 1) 305-307
• 109 Cohen J C, Kiss R S, Pertsemlidis A, Marcel Y L, McPherson R, Hobbs H H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.  Science. 2004;  305(5685) 869-872
• 110 Biesecker L G, Mulliking J C, Facio F M. The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine.  Genome Res. 2009 August 5 (Epub ahead of print); 
• 111 Eisenstein M. Sequencing in a flash.  Nat Methods. 2009;  6 114-115
• 112 Hirschhorn J N. Genomewide association studies—illuminating biologic pathways.  N Engl J Med. 2009;  360(17) 1699-1701
• 113 Goldstein D B. Common genetic variation and human traits.  N Engl J Med. 2009;  360(17) 1696-1698
• 114 Hamsten A, Eriksson P. Identifying the susceptibility genes for coronary artery disease: from hyperbole through doubt to cautious optimism.  J Intern Med. 2008;  263(5) 538-552