Molecular Genetics of Coronary Artery Disease

Abstract

The onset of coronary artery disease (CAD) depends on complex interactions of multiple environmental and genetic factors. CAD including myocardial infarction (MI) is a leading cause of death in the world. Because the genetic portion accounts for approximately half of the CAD pathogenesis, elucidating detailed genetic architecture for CAD would improve to establish a future innovative medicine. Early 2000, we launched a genome‐wide association study (GWAS) using approximately 100 000 single nucleotide polymorphisms (SNP) in Japanese population and found SNPs in LTA associated with the increased risk of MI in Japanese population. As far as we know, this is the first GWAS identified a genetic factor for common disease worldwide. To date, numerous large‐scale GWASs have identified a lot of genetic risk factors for common diseases. Without exception for CAD, recent large‐scale GWASs mainly from Caucasian descent have identified 92 genetic loci for CAD susceptibility.

Key Concept

  • The first GWAS in the world was performed at RIKEN, Japan.
  • BRAP SNP, which is top locus for CAD susceptibility in Japanese, does not exist in Caucasian.
  • An inflammatory cascade associated with increased risk of MI in Japanese.
  • Large‐scale GWAS identified 92 loci associated with increased risk of CAD.
  • Of these, 26 loci associated with lipid traits and blood pressure.
  • Variants on chromosome 9p21.3 are robustly associated with broad ethnic population excluding Africans.
  • The individuals who carry the O allele of the ABO blood group have decreased the risk of CAD.
  • The 92 loci estimate the heritability accounts for only ∼10%.

Keywords: common diseases; coronary artery diseases (CAD); myocardial infarction (MI); genetics; genome‐wide association study (GWAS); heritability; susceptibility; inflammation

Figure 1. BRAP‐IKK signalosome inflammatory cascade for MI pathogenesis. Blue arrows indicate direct interaction for BRAP. TF, transcription factor.
close

References

Abifadel M, Varret M, Rabeè J, et al. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics 34: 154–156.

Aoki A, Ozaki K, Sakata Y, et al. (2011) SNPs on chromosome 5p15.3 associated with myocardial infarction in Japanese population. Journal of Human Genetics 56: 47–51.

Bampali K, Mouzarou A, Lamnisou K and Babalis D (2013) Genetics and coronary artery disease: present and future. Hellenic Journal of Cardiology 55 (2): 156–163.

Braunwald E (1997) Shattuck lecture‐‐cardiovascular medicine at the turn of the millennium: triumphs, concerns and opportunities. New England Journal of Medicine 337: 1360–1369.

Breslow JW (1997) Cardiovascular disease burden increases, NIH funding decreases. Nature Medicine 3: 600–601.

Collins FS, Guyer MS and Charkravarti A (1997) Variations on a theme: cataloging human DNA sequence variation. Science 278: 1580–1581.

Dewey FE, Gusarova V, O'Dushlaine C, et al. (2016) Inactivating variants in ANGPTL4 and risk of coronary artery disease. New England Journal of Medicine 374: 1123–1133.

Dewey FE, Gusarova V, Dunbar RL, et al. (2017) Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. New England Journal of Medicine 377: 211–221.

Do R, Stitziel NO, Won HH, et al. (2015) Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518 (7537): 102–106.

Ebana Y, Ozaki K, Inoue K, et al. (2007) A functional SNP in ITIH3 is associated with susceptibility to myocardial infarction. Journal of Human Genetics 52: 220–229.

Haga H, Yamada R, Ohnishi Y, Nakamura Y and Tanaka T (2002) Gene‐based SNP discovery as part of the Japanese Millennium Genome project: identification of 190,562 genetic variations in the human genome. Journal of Human Genetics 47: 605–610.

Hirokawa M, Morita H, Tajima T, et al. (2014) A genome‐wide association study identifies PLCL2 and AP3D1‐DOT1L‐SF3A2 as new susceptibility loci for myocardial infarction in Japanese. European Journal of Human Genetics 23: 374–380.

Howson JMM, Zhao W, Barnes D, et al. (2017) Fifteen new risk loci for coronary artery disease highlight arterial‐wall‐specific mechanisms. Nature Genetics 49: 1113–1119.

Ishii N, Ozaki K, Sato H, et al. (2006) Identification of a novel non‐coding RNA, MIAT, that confers risk of myocardial infarction. Journal of Human Genetics 51: 1087–1099.

Karin M and Delhase M (2000) The I kappa B kinase (IKK) and NF‐kappa B: key elements of proinflammatory signalling. Seminars in Immunology 12: 85–98.

Konta A, Ozaki K, Sakata Y, et al. (2016) A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population. Journal of Human Genetics 61: 435–441.

Lander ES (1996) The new genomics: global views of biology. Science 274: 536–539.

Lian J, Fang P, Dai D, et al. (2014) Association between LGALS2 3279C>T and coronary artery disease: a case‐control study and a meta‐analysis. Biomedical Reports 2: 879–885.

Liao YC, Wang YS, Guo YC, et al. (2011) BRAP activates the inflammatory cascades and increases the risk for carotid atherosclerosis. Molecular Medicine 17: 1065–1074.

Liu X, Wang X, Shen Y, et al. (2009) The functional variant rs1048990 in PSMA6 is associated with susceptibility to myocardial infarction in a Chinese population. Atherosclerosis 206 (1): 199–203.

McPherson R (2013) Chromosome 9p21.3 locus for coronary artery disease: how little we know. Journal of the American College of Cardiology 62 (15): 1382–1383.

Manolio TA, Collins FS, Cox NJ, et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.

Ohnishi Y, Tanaka T, Ozaki K, et al. (2001) A high‐throughput SNP typing system for genomewide association studies. Journal of Human Genetics 46: 471–477.

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

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

Ozaki K and Tanaka T (2005) Genome‐wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses. Cellular and Molecular Life Sciences 62: 1804–1813.

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: 329–333.

Ozaki K and Tanaka T (2016) Molecular genetics of coronary artery disease. Journal of Human Genetics 61: 71–77.

Peden JF and Farrall M (2011) Thirty‐five common variants for coronary artery disease: the fruits of much collaborative labour. Human Molecular Genetics 20: R198–R205.

PROCARDIS Consortium (2004) A trio family study showing association of the lymphotoxin‐alpha N26 (804A) allele with coronary artery disease. European Journal of Human Genetics 12: 770–774.

Raal FJ, Stein EA, Dufour R, et al. (2015) PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD‐2): a randomised, double‐blind, placebo‐controlled trial. Lancet 385: 331–340.

Reilly MP, Li M, He J, et al. (2011) Identification of ADAMT7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome wide association studies. Lancet 377: 382–392.

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

Roberts R and Stewart AF (2012) Genes and coronary artery disease. Journal of the American College of Cardiology 60 (18): 1715–1721.

Roberts R (2014) Genetics of coronary artery disease: an update. Methodist DeBakey Cardiovascular Journal 10 (1): 7–12.

Stein EA, Mellis S, Yancopoulos GD, et al. (2012) Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. New England Journal of Medicine 366 (12): 1108–1118.

Sudmant PH, Rausch T, Gardner EJ, et al. (2015) An integrated map of structural variation in 2,504 human genomes. Nature 526: 75–81.

Takeuchi F, Yokota M, Yamamoto K, et al. (2012) Genome‐wide association study of coronary artery disease in the Japanese. European Journal of Human Genetics 20: 333–340.

TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute (2014) Loss‐of‐function mutations in APOC3, triglycerides, and coronary disease. New England Journal of Medicine 371 (1): 22–31.

The 1000 Genomes Project Consortium (2015) A global reference for human genetic variation. Nature 526: 68–74.

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.

Verweij N, Eppinga RN, Hagemeijer Y and van der Harst P (2017) Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure. Scientific Reports 7: 2761.

Wang F, Xu CQ, He Q, et al. (2011) Genome‐wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nature Genetics 43: 345–349.

Yamada Y, Nishida T, Ichihara S, et al. (2011) Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations. Atherosclerosis 215: 145–152.

Further Reading

Lander ES (1996) The new genomics: global views of biology. Science 274: 536–539.

Ozaki K and Tanaka T (2005) Genome‐wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses. Cellular and Molecular Life Sciences 62: 1804–1813.

Ozaki K and Tanaka T (2016) Molecular genetics of coronary artery disease. Journal of Human Genetics 61: 71–77.

Roberts R and Stewart AF (2012) Genes and coronary artery disease. Journal of the American College of Cardiology 60 (18): 1715–1721.

Roberts R (2014) Genetics of coronary artery disease: an update. Methodist DeBakey Cardiovascular Journal 10 (1): 7–12.

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

* Required Field

How to Cite close
Ozaki, Kouichi(Nov 2017) Molecular Genetics of Coronary Artery Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027329]