Molecular Genetics of Susceptibility to Coronary Heart Disease


Coronary heart disease (CHD) is a leading cause of mortality and morbidity worldwide and delineating the molecular genetics of susceptibility to CHD is an urgent task. Traditional approaches such as genome‐wide linkage scans and candidate‐gene‐based association studies, yielded frustratingly little progress in identifying genetic determinants of ‘complex’ diseases. However, the completion of the Human Genome Project and the International HapMap Project set the stage for genome‐wide association (GWA) studies, resulting in significant advances in ‘complex disease’ genetics. In this review, we provide an update on the molecular genetics of CHD and its risk factors, most of which are heritable and also significantly influenced by genetic factors. We also summarize recent advances including GWA studies for CHD and its risk factors. Increased knowledge of the molecular genetics of CHD susceptibility will enable more accurate cardiovascular risk stratification and the development of new therapies.

Keywords: complex diseases; coronary heart disease; genetics; linkage; association; genome‐wide association (GWA)

Figure 1.

Multipoint linkage–analysis results for plasma homocysteine levels on chromosomes 1, 14 and 19 in African Americans. Genetic distance (in cM) is plotted on the X‐axis against the LOD score. Candidate‐genes for homocysteine metabolism under the linkage peaks are shown close to their approximate location. MTR, 5‐methyltetrahdrofolate‐homocysteine methyltransferase; CARM, Coactivator‐associated arginine methyltransferase 1; DNMT1, DNA (cytosine‐5)‐methyltransferase 1; GAMT, Guanidinoacetate N‐methyltransferase. Adapted from Kullo et al. , with permission from Wolters Kluwer. © Wolters Kluwer.

Figure 2.

Linkage disequilibrium pattern at the chromosome 9p21 locus in persons of European ancestry (HapMap Data). The two variants (rs10757278 and rs10811661) were associated with coronary heart disease and type 2 diabetes, respectively. There is a recombination hotspot between these two variants.



Almasy L and Blangero J (2001) Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. American Journal of Medical Genetics 105: 42–44.

Altshuler D, Hirschhorn JN, Klannemark M et al. (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genetics 26: 76–80.

Antonarakis SE and Beckmann JS (2006) Mendelian disorders deserve more attention. Nature Reviews: Genetics 7: 277–282.

Ardlie KG, Kruglyak L and Seielstad M (2002) Patterns of linkage disequilibrium in the human genome. Nature Reviews: Genetics 3: 299–309.

Bamshad M and Wooding SP (2003) Signatures of natural selection in the human genome. Nature Reviews: Genetics 4: 99–111.

Bodmer W and Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nature Genetics 40: 695–701.

Boffelli D, McAuliffe J, Ovcharenko D et al. (2003) Phylogenetic shadowing of primate sequences to find functional regions of the human genome. Science 299: 1391–1394.

Cardon LR and Abecasis GR (2003) Using haplotype blocks to map human complex trait loci. Trends in Genetics 19: 135–140.

Chambers JC, Elliott P, Zabaneh D et al. (2008) Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nature Genetics 40: 716–718.

Cohen J, Pertsemlidis A, Kotowski I et al. (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics 37: 161–165.

Cohen JC, Kiss RS, Pertsemlidis A et al. (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305: 869–872.

Colhoun HM, McKeigue PM and Davey Smith G (2003) Problems of reporting genetic associations with complex outcomes. Lancet 361: 865–872.

Connelly JJ, Wang T, Cox JE et al. (2006) GATA2 is associated with familial early onset coronary artery disease. PLoS Genetics 2: 1265–1273.

Corbo RM and Scacchi R (1999) Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele? Annals of Human genetics 63(part 4): 301–310.

Cortese DA (2007) A vision of individualized medicine in the context of global health. Clinical Pharmacology and Therapeutics 82: 491–493.

Dahlman I, Eaves IA, Kosoy R et al. (2002) Parameters for reliable results in genetic association studies in common disease. Nature Genetics 30: 149–150.

Danziger RS, You M and Akil H (2005) Discovering the genetics of complex disorders through integration of genomic mapping and transcriptional profiling. Current Hypertension Reviews 1: 21–34.

Darvasi A and Shifman S (2005) The beauty of admixture. Nature Genetics 37: 118–119.

Devlin B and Roeder K (1999) Genomic control for association studies. Biometrics 55: 997–1004.

Di Rienzo A and Hudson RR (2005) An evolutionary framework for common diseases: the ancestral‐susceptibility model. Trends in Genetics 21: 596–601.

Dina C, Meyre D, Gallina S et al. (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genetics 39: 724–726.

Ding K and Kullo IJ (2006) Molecular evolution of 5′ flanking regions of 87 candidate genes for atherosclerotic cardiovascular disease. Genetic Epidemiology 30: 557–569.

Farrall M, Green FR, Peden JF et al. (2006) Genome‐wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17. PLoS Genetics 2: e72.

Fox CS, Cupples LA, Chazaro I et al. (2004) Genomewide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12. American Journal of Human Genetics 74: 253–261.

Frayling TM (2007) Genome‐wide association studies provide new insights into type 2 diabetes aetiology. Nature Reviews: Genetics 8: 657–662.

Frayling TM, Timpson NJ, Weedon MN et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: 889–894.

Freedman ML, Pearce CL, Penney KL et al. (2005) Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study. American Journal of Human Genetics 76: 82–90.

Friedlander Y, Siscovick DS, Weinmann S et al. (1998) Family history as a risk factor for primary cardiac arrest. Circulation 97: 155–160.

Frikke‐Schmidt R, Nordestgaard BG, Jensen GB and Tybjaerg‐Hansen A (2004) Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population. Journal of Clinical Investigation 114: 1343–1353.

Fullerton SM, Bartoszewicz A, Ybazeta G et al. (2002) Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain‐10 locus. American Journal of Human Genetics 70: 1096–1106.

Fuster V, Badimon L, Badimon JJ and Chesebro JH (1992) The pathogenesis of coronary artery disease and the acute coronary syndromes (1). New England Journal of Medicine 326: 242–250.

Genest J and Pedersen TR (2003) Prevention of cardiovascular ischemic events: high‐risk and secondary prevention. Circulation 107: 2059–2065.

Goldstein JL and Brown MS (1973) Familial hypercholesterolemia: identification of a defect in the regulation of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proceedings of the National Academy of Sciences of the USA 70: 2804–2808.

Hahn MW, Rockman MV, Soranzo N, Goldstein DB and Wray GA (2004) Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans. Genetics 167: 867–877.

Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. New England Journal of Medicine 352: 1685–1695.

Helgadottir A, Gretarsdottir S, St Clair D et al. (2005) Association between the gene encoding 5‐lipoxygenase‐activating protein and stroke replicated in a Scottish population. American Journal of Human Genetics 76: 505–509.

Helgadottir A, Manolescu A, Thorleifsson G et al. (2004) The gene encoding 5‐lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nature Genetics 36: 233–239.

Helgadottir A, Thorleifsson G, Manolescu A et al. (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316: 1491–1493.

Hirschhorn JN and Daly MJ (2005) Genome‐wide association studies for common diseases and complex traits. Nature Reviews: Genetics 6: 95–108.

Hunter DJ, Khoury MJ and Drazen JM (2008) Letting the genome out of the bottle – will we get our wish? New England Journal of Medicine 358: 105–107.

Ioannidis JP, Ntzani EE, Trikalinos TA and Contopoulos‐Ioannidis DG (2001) Replication validity of genetic association studies. Nature Genetics 29: 306–309.

Ji W, Foo JN, O'Roak BJ et al. (2008) Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nature Genetics 40: 592–599.

Jorde LB, Watkins WS and Bamshad MJ (2001) Population genomics: a bridge from evolutionary history to genetic medicine. Human Molecular Genetics 10: 2199–2207.

Kaikkonen KS, Kortelainen ML, Linna E and Huikuri HV (2006) Family history and the risk of sudden cardiac death as a manifestation of an acute coronary event. Circulation 114: 1462–1467.

Kao JT, Wen HC, Chien KL, Hsu HC and Lin SW (2003) A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia. Human Molecular Genetics 12: 2533–2539.

Kathiresan S, Melander O, Guiducci C et al. (2008) Six new loci associated with blood low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol or triglycerides in humans. Nature Genetics 40: 189–197.

Khoury MJ, Little J, Gwinn M and Ioannidis JP (2006) On the synthesis and interpretation of consistent but weak gene‐disease associations in the era of genome‐wide association studies. International Journal of Epidemiology 36: 439–445

Kooner JS, Chambers JC, Aguilar‐Salinas CA et al. (2008) Genome‐wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nature Genetics 40: 149–151.

Kullo IJ and Ding K (2007) Mechanisms of disease: The genetic basis of coronary heart disease. Nature Clinical Practice: Cardiovascular Medicine 4: 558–569.

Kullo IJ, Ding K, Boerwinkle E et al. (2006a) Novel genomic loci influencing plasma homocysteine levels. Stroke 37: 1703–1709.

Kullo IJ, Turner ST, Kardia SL et al. (2006b) A genome‐wide linkage scan for ankle‐brachial index in African American and non‐Hispanic white subjects participating in the GENOA study. Atherosclerosis 187: 433–438.

Lander ES, Linton LM, Birren B et al. (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921.

Lange LA, Lange EM, Bielak LF et al. (2002) Autosomal genome‐wide scan for coronary artery calcification loci in sibships at high risk for hypertension. Arteriosclerosis, Thrombosis, and Vascular Biology 22: 418–423.

Li R, Bensen JT, Hutchinson RG et al. (2000) Family risk score of coronary heart disease (CHD) as a predictor of CHD: the Atherosclerosis Risk in Communities (ARIC) study and the NHLBI family heart study. Genetic Epidemiology 18: 236–250.

Liu PY, Zhang YY, Lu Y et al. (2005) A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases. Journal of Medical Genetics 42: 221–227.

Lloyd‐Jones DM, Nam BH, D'Agostino RB et al. (2004) Parental cardiovascular disease as a risk factor for cardiovascular disease in middle‐aged adults: a prospective study of parents and offspring. Journal of the American Medical Association 291: 2204–2211.

Loos RJ, Lindgren CM, Li S et al. (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics 40: 768–775.

Manly KF (2005) Reliability of statistical associations between genes and disease. Immunogenetics 57: 549–558.

Marcais C, Verges B, Charriere S et al. (2005) Apoa5 Q139X truncation predisposes to late‐onset hyperchylomicronemia due to lipoprotein lipase impairment. Journal of Clinical Investigation 115: 2862–2869.

Marchini J, Donnelly P and Cardon LR (2005) Genome‐wide strategies for detecting multiple loci that influence complex diseases. Nature Genetics 37: 413–417.

Marenberg ME, Risch N, Berkman LF, Floderus B and de Faire U (1994) Genetic susceptibility to death from coronary heart disease in a study of twins. New England Journal of Medicine 330: 1041–1046.

McPherson R, Pertsemlidis A, Kavaslar N et al. (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316: 1488–1491.

Miller W, Makova KD, Nekrutenko A and Hardison RC (2004) Comparative genomics. Annual Review of Genomics and Human Genetics 5: 15–56.

Morrison AC, Bare LA, Chambless LE et al. (2007) Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. American Journal of Epidemiology 166: 28–35.

Murabito JM, Pencina MJ, Nam BH et al. (2005) Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle‐aged adults. Journal of the American Medical Association 294: 3117–3123.

Myers RH, Kiely DK, Cupples LA and Kannel WB (1990) Parental history is an independent risk factor for coronary artery disease: the Framingham Study. American Heart Journal 120: 963–969.

Nakajima T, Wooding S, Sakagami T et al. (2004) Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world. American Journal of Human Genetics 74: 898–916.

Nasir K, Michos ED, Rumberger JA et al. (2004) Coronary artery calcification and family history of premature coronary heart disease: sibling history is more strongly associated than parental history. Circulation 110: 2150–2156.

Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? American Journal of Human Genetics 14: 353–362.

Ozaki K, Sato H, Iida A et al. (2006) A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population. Nature Genetics 38: 921–925.

Patterson N, Hattangadi N, Lane B et al. (2004) Methods for high‐density admixture mapping of disease genes. American Journal of Human Genetics 74: 979–1000.

Pennacchio LA, Olivier M, Hubacek JA et al. (2001) An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 294: 169–173.

Pennacchio LA and Rubin EM (2003) Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice. Arteriosclerosis, Thrombosis, and Vascular Biology 23: 529–534.

Pritchard JK (2001) Are rare variants responsible for susceptibility to complex diseases? American Journal of Human Genetics 69: 124–137.

Pritchard JK and Cox NJ (2002) The allelic architecture of human disease genes: common disease‐common variantor not? Human Molecular Genetics 11: 2417–2423.

Pritchard JK and Rosenberg NA (1999) Use of unlinked genetic markers to detect population stratification in association studies. American Journal of Human Genetics 65: 220–228.

Reich D and Patterson N (2005) Will admixture mapping work to find disease genes? Philosophical Transactions of the Royal Society of London: Series B, Biological Sciences 360: 1605–1607.

Risch N and Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273: 1516–1517.

Rockman MV, Hahn MW, Soranzo N et al. (2004) Positive selection on MMP3 regulation has shaped heart disease risk. Current Biology 14: 1531–1539.

Romero R, Kuivaniemi H, Tromp G and Olson J (2002) The design, execution, and interpretation of genetic association studies to decipher complex diseases. American Journal of Obstetrics and Gynecology 187: 1299–1312.

Roncaglioni MC, Santoro L, D'Avanzo B et al. (1992) Role of family history in patients with myocardial infarction: An Italian case‐control study. GISSI‐EFRIM Investigators. Circulation 85: 2065–2072.

Samani NJ, Erdmann J, Hall AS et al. (2007) Genomewide association analysis of coronary artery disease. New England Journal of Medicine 357: 443–453.

Sandhu MS, Waterworth DM, Debenham SL et al. (2008) LDL‐cholesterol concentrations: a genome‐wide association study. Lancet 371: 483–491.

Saxena R, Voight BF, Lyssenko V et al. (2007) Genome‐wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316: 1331–1336.

Scheuner MT (2003) Genetic evaluation for coronary artery disease. Genetics in Medicine 5: 269–285.

Scott LJ, Mohlke KL, Bonnycastle LL et al. (2007) A genome‐wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341–1345.

Seo D, Ginsburg GS and Goldschmidt‐Clermont PJ (2006) Gene expression analysis of cardiovascular diseases: novel insights into biology and clinical applications. Journal of the American College of Cardiology 48: 227–235.

Seo D, Wang T, Dressman H et al. (2004) Gene expression phenotypes of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 24: 1922–1927.

Sing CF, Stengard JH and Kardia SL (2003) Genes, environment, and cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 23: 1190–1196.

Sladek R, Rocheleau G, Rung J et al. (2007) A genome‐wide association study identifies novel risk loci for type 2 diabetes. Nature 445: 881–885.

Smith MW and O'Brien SJ (2005) Mapping by admixture linkage disequilibrium: advances, limitations and guidelines. Nature Reviews: Genetics 6: 623–632.

Talmud PJ, Hawe E, Martin S et al. (2002) Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Human Molecular Genetics 11: 3039–3046.

The International Hapmap Consortium (2005) A haplotype map of the human genome. Nature 437: 1299–1320.

The Wellcome Trust Case Control Consortium (2007) Genome‐wide association study of 14 000 cases of seven common diseases and 3 000 shared controls. Nature 447: 661–678.

Thom T, Haase N, Rosamond W et al. (2006) Heart disease and stroke statistics–2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113: e85–151.

Thompson EE, Kuttab‐Boulos H, Witonsky D et al. (2004) CYP3A variation and the evolution of salt‐sensitivity variants. American Journal of Human Genetics 75: 1059–1069.

Thorgeirsson TE, Geller F, Sulem P et al. (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452: 638–642.

Todd JA, Walker NM, Cooper JD et al. (2007) Robust associations of four new chromosome regions from genome‐wide analyses of type 1 diabetes. Nature Genetics 39: 857–864.

Vaisse C, Clement K, Durand E et al. (2000) Melanocortin‐4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. Journal of Clinical Investigation 106: 253–262.

Wang D, Yang H, Quinones MJ et al. (2005) A genome‐wide scan for carotid artery intima‐media thickness: the Mexican‐American Coronary Artery Disease family study. Stroke 36: 540–545.

Willer CJ, Sanna S, Jackson AU et al. (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nature Genetics 40: 161–169.

Williams JT and Blangero J (1999) Power of variance component linkage analysis to detect quantitative trait loci. Annals of Human genetics 63: 545–563.

Williams RR, Hunt SC, Heiss G et al. (2001) Usefulness of cardiovascular family history data for population‐based preventive medicine and medical research (the Health Family Tree Study and the NHLBI Family Heart Study). American Journal of Cardiology 87: 129–135.

Yagil C, Hubner N, Monti J et al. (2005) Identification of hypertension‐related genes through an integrated genomic‐transcriptomic approach. Circulation Research 96: 617–625.

Young JH, Chang YP, Kim JD et al. (2005) Differential susceptibility to hypertension is due to selection during the out‐of‐Africa expansion. PLoS Genetics 1: e82.

Yusuf S, Hawken S, Ounpuu S et al. (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case‐control study. Lancet 364: 937–952.

Zeggini E, Weedon MN, Lindgren CM et al. (2007) Replication of genome‐wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336–1341.

Zhu X, Fejerman L, Luke A, Adeyemo A and Cooper RS (2005) Haplotypes produced from rare variants in the promoter and coding regions of angiotensinogen contribute to variation in angiotensinogen levels. Human Molecular Genetics 14: 639–643.

Further Reading

Kullo IJ and Ding K (2007) Mechanisms of disease: the genetic basis of coronary heart disease. Nature Clinical Practice: Cardiovascular Medicine 4: 558–569.

Lusis AJ (2000) Atherosclerosis. Nature 407: 233–241.

Lusis AJ, Mar R and Pajukanta P (2004) Genetics of atherosclerosis. Annual Review of Genomics and Human Genetics 5: 189–218.

McCarthy MI, Abecasis GR, Cardon LR et al. (2008) Genome‐wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews: Genetics 9: 356–369.

Topol EJ, Smith J, Plow EF and Wang QK (2006) Genetic susceptibility to myocardial infarction and coronary artery disease. Human Molecular Genetics 15(Spec No 2): R117–R123.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kullo, Iftikhar J, and Ding, Keyue(Mar 2009) Molecular Genetics of Susceptibility to Coronary Heart Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021453]