Molecular Genetics of Myocardial Infarction


Myocardial infarction (MI) is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for MI include hypertension, dyslipidaemia, diabetes mellitus, chronic kidney disease and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Genetic linkage analyses of families and sib‐pairs as well as candidate gene association studies have implicated several loci and many candidate genes in predisposition to coronary heart disease (CHD) or MI. Recent genome‐wide association studies demonstrated that single nucleotide polymorphisms (SNPs) at chromosome 9p21.3 or other loci were associated with CHD or MI. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of CHD and MI.

Key concepts

  • Twin and family studies have established that CHD aggregates in families, with a family history of early onset CHD being considered a risk factor for the disease.

  • Genes responsible for familial hypercholesterolaemia and Tangier disease are the prototypical examples of causal genes for Mendelian disorders associated with CHD and MI.

  • Several genome‐wide linkage analyses of families or sib‐pairs have identified chromosomal loci linked, or genetic variations that confer susceptibility, to MI, acute coronary syndrome (ACS) or CHD.

  • Various association studies of unrelated individuals have identified genetic variations that confer susceptibility to MI or CHD. Numerous candidate genes have been implicated, but those that show reproducible associations between risk alleles and CHD or MI in replication studies are few.

  • A genome‐wide association study (GWAS) and subsequent analysis have suggested that the lymphotoxin alpha gene is important in the pathogenesis of coronary atherosclerosis and thrombosis.

  • Four independent GWAS have identified SNPs at chromosome 9p21.3 that were associated with CHD or MI in several white cohorts.

  • In addition, several GWAS identified SNPs associated with CHD or MI at various chromosomal loci.

  • Identification of susceptibility genes for CHD and MI and clarification of the functional relevance of genetic variants to these conditions will contribute to the prevention, early diagnosis and treatment of CHD and MI.

Keywords: myocardial infarction; coronary heart disease; genetics; polymorphism; linkage analysis; genome‐wide association study

Figure 1.

Pathogenesis of myocardial infarction. The main causal and treatable risk factors for MI include hypertension, diabetes mellitus, dyslipidaemia, chronic kidney disease and smoking. In addition to these risk factors, genetic factors and interactions between multiple genes and environmental factors are important in the development of myocardial infarction.



Arnett DK, Baird AE, Barkley RA et al. (2007) 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 115: 2878–2901.

Bodzioch M, Orso E, Klucken J et al. (1999) The gene encoding ATP‐binding cassette transporter 1 is mutated in Tangier disease. Nature Genetics 22: 347–351.

Broadbent HM, Peden JF, Lorkowski S et al. (2008) Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Human Molecular Genetics 17: 806–814.

Brooks‐Wilson A, Marcil M, Clee SM et al. (1999) Mutations in ABC1 in Tangier disease and familial high‐density lipoprotein deficiency. Nature Genetics 22: 336–345.

Clarke R, Xu P, Bennett D et al. (2006) Lymphotoxin‐alpha gene and risk of myocardial infarction in 6928 cases and 2712 controls in the ISIS case‐control study. PLoS Genetics 2: e107.

Clee SM, Kastelein JJ, van Dam M et al. (2000) Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. Journal of Clinical Investigation 106: 1263–1270.

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

Dwyer JH, Allayee H, Dwyer KM et al. (2004) Arachidonate 5‐lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. New England Journal of Medicine 350: 29–37.

Erdmann J, Grosshennig A, Braund PS et al. (2009) New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nature Genetics 41: 280–282.

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.

Gudbjartsson DF, Bjornsdottir US, Halapi E et al. (2009) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nature Genetics 41: 342–347.

Hakonarson H, Thorvaldsson S, Helgadottir A et al. (2005) Effects of a 5‐lipoxygenase‐activating protein inhibitor on biomarkers associated with risk of myocardial infarction. JAMA 293: 2245–2256.

Helgadottir A, Manolescu A, Helgason A et al. (2006) A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity‐specific risk of myocardial infarction. Nature Genetics 38: 68–74.

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, Magnusson KP et al. (2008) The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nature Genetics 40: 217–224.

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.

Hinohara K, Nakajima T, Yasunami M et al. (2009) Megakaryoblastic leukemia factor‐1 gene in the susceptibility to coronary artery disease. Human Genetics 126: 539–547.

International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431: 931–945.

Jarinova O, Stewart AF, Roberts R et al. (2009) Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arteriosclerosis, Thrombosis, and Vascular Biology 29: 1671–1677.

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

Lloyd‐Jones D, Adams R, Carnethon M et al. (2009) Heart disease and stroke statistics – 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119: e21–e181.

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

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

Mehrabian M, Allayee H, Wong J et al. (2002) Identification of 5‐lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circulation Research 91: 120–126.

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

Myocardial Infarction Genetics Consortium (2009) Genome‐wide association of early onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nature Genetics 4: 334–341.

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.

Oram JF and Heinecke JW (2005) ATP‐binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiological Review 85: 1343–1372.

Ozaki K, Inoue K, Sato H et al. (2004) Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin‐α secretion in vitro. Nature 429: 72–75.

Ozaki K, Ohnishi Y, Iida A et al. (2002) Functional SNPs in the lymphotoxin‐α gene that are associated with susceptibility to myocardial infarction. Nature Genetics 32: 650–654.

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.

Ozaki K, Sato H, Inoue K et al. (2009) SNPs in BRAP associated with risk of myocardial infarction in Asian populations. Nature Genetics 41: 329–933.

Rader DJ, Cohen J and Hobbs HH (2003) Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. Journal of Clinical Investigation 111: 1795–1803.

Rust S, Rosier M, Funke H et al. (1999) Tangier disease is caused by mutations in the gene encoding ATP‐binding cassette transporter 1. Nature Genetics 22: 352–355.

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

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.

Schunkert H, Götz A, Braund P et al. (2008) Repeated replication and a prospective meta‐analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation 117: 1675–1684.

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.

Soutar AK and Naoumova RP (2007) Mechanism of disease: genetic causes of familial hypercholesterolemia. Nature Clinical Practice. Cardiovascular Medicine 4: 214–225.

Spanbroek R, Grabner R, Lotzer K et al. (2003) Expanding expression of the 5‐lipoxygenase pathway within the arterial wall during human atherogenesis. Proceedings of the National Academy of Sciences of the USA 100: 1238–1243.

The International HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449: 851–861.

Topol EJ, Smith J, Plow EF and Wang QK (2006) Genetic susceptibility to myocardial infarction and coronary artery disease. Human Molecular Genetics 15: R117–R123.

Trégouët DA, König IR, Erdmann J et al. (2009) Genome‐wide haplotype association study identifies the SLC22A3‐LPAL2‐LPA gene cluster as a risk locus for coronary artery disease. Nature Genetics 41: 283–285.

van Dam MJ, de Groot GE, Clee SM et al. (2002) Association between increased arterial‐wall thickness and impairment in ABCA1‐driven cholesterol efflux: an observational study. Lancet 359: 37–42.

Wellcome Trust Case Control Consortium (2007) Genome‐wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 447: 661–678.

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 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.

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.

Further Reading

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

Broeckel U, Hengstenberg C, Mayer B et al. (2002) A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nature Genetics 30: 210–214.

Cohen JC, Boerwinkle E, Mosley TH Jr and Hobbs HH (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New England Journal of Medicine 354: 1264–1272.

Coronary Artery Disease Consortium, Samani NJ, Deloukas P et al. (2009) Large scale association analysis of novel genetic loci for coronary artery disease. Arteriosclerosis, Thrombosis, and Vascular Biology 29: 774–780.

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.

Shen GQ, Li L, Girelli D et al. (2007) An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction. American Journal of Human Genetics 81: 780–791.

Swanberg M, Lidman O, Padyukov L et al. (2005) MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nature Genetics 37: 486–494.

Wang L, Fan C, Topol SE, Topol EJ and Wang Q (2003) Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302: 1578–1581.

Wang X, Ria M, Kelmenson PM et al. (2005) Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics 37: 365–372.

Yamada Y, Izawa H, Ichihara S et al. (2002) Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. New England Journal of Medicine 347: 1916–1923.

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Yamada, Yoshiji(Feb 2010) Molecular Genetics of Myocardial Infarction. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022412]