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Advances in the genetic basis of coronary artery disease

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Abstract

Exciting advances have been made recently in genetic studies of coronary artery disease (CAD), myocardial infarction (MI), and ischemic stroke. One disease-causing gene for CAD and MI has been identified as MEF2A, which is located on chromosome 15q26.3 and encodes a transcriptional factor with a high level of expression in coronary endothelium. Approximately 1% to 2% of CAD patients may carry an MEF2A mutation. Four new susceptibility genes have been identified using genome-wide association studies or genome-wide linkage studies: LTA (encoding cytokine lymphotoxin-α) on 6p21.3 for MI; LGALS2 (encoding galectin-2, an LTA-interacting protein) on 22q12–q13 for MI; ALOX5AP (encoding 5-lipoxygenase activating protein involved in synthesizing potent proinflammatory leukotrienes) on 13q12–13 for MI and stroke; and PDE4D (encoding phosphodiesterase 4D) on 5q12 for ischemic stroke. These studies identify a new mechanism, the myocyte enhancer factor 2 (MEF2) signaling pathway of vascular endothelium, for the pathogenesis of CAD, and also confirm the role of inflammation in the disease process.

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References and Recommended Reading

  1. Okrainec K, Banerjee DK, Eisenberg MJ: Coronary artery disease in the developing world. Am Heart J 2004, 148:7–15.

    Article  PubMed  Google Scholar 

  2. Wang Q, Bond M, Elston RC, Tian X: Molecular genetics. In Textbook of Cardiovascular Medicine, edn 2. Edited by Topol EJ. Philadelphia: Lippincott Williams & Wilkins; 2001, electronic chapter 97.

    Google Scholar 

  3. Wang L, Fan C, Topol SE, et al.: Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 2003, 302:1578–1581.

    Article  PubMed  CAS  Google Scholar 

  4. Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995, 11:241–247.

    Article  PubMed  CAS  Google Scholar 

  5. Wang Q, Rao S, Shen GQ, Li L, et al.: Premature myocardial infarction novel susceptibility locus on chromosome 1p34–36 identified by genomewide linkage analysis. Am J Hum Genet 2004, 74:262–271.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Helgdottir A, Manolescu A, Thorleifsson G, et al.: The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004, 36:233–239.

    Article  Google Scholar 

  8. Pajukanta P, Cargill M, Viitanen L, et al.: Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of Finland. Am J Hum Genet 2000, 67:1481–1493.

    Article  PubMed  CAS  Google Scholar 

  9. Hauser ER, Crossman DC, Granger CB, et al.: A Genomewide Scan for Early-Onset Coronary Artery Disease in 438 Families: The GENECARD Study. Am J Hum Genet 2004, 75:436–447.

    Article  PubMed  CAS  Google Scholar 

  10. Francke S, Manraj M, Lacquemant C, et al.: A genome-wide scan for coronary heart disease suggests in Indo- Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Genet 2001, 10:2751–2765.

    Article  PubMed  CAS  Google Scholar 

  11. Harrap SB, Zammit KS, Wong ZY, et al.: Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arterioscler Thromb Vasc Biol 2002, 22:874–878.

    Article  PubMed  CAS  Google Scholar 

  12. Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, et al.: Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet 2002, 70:593–603.

    Article  PubMed  CAS  Google Scholar 

  13. Curran ME, Splawski I, Timothy KW, et al.: A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995, 80:795–803.

    Article  PubMed  CAS  Google Scholar 

  14. Wang Q, Shen J, Splawski I, et al.: SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995, 80:805–811.

    Article  PubMed  CAS  Google Scholar 

  15. Chen Q, Kirsch GE, Zhang D, et al.: Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998, 392:293–296.

    Article  PubMed  CAS  Google Scholar 

  16. Bhagavatula MR, Fan C, Shen GQ, et al.: Transcription factor MEF2A mutations in patients with coronary artery disease. Hum Mol Genet 2004, 13:3181–3188.

    Article  PubMed  CAS  Google Scholar 

  17. Helgadottir A, Gretarsdottir S, St Clair D, et al.: Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet 2005, 76:505–509.

    Article  PubMed  CAS  Google Scholar 

  18. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, et al.: The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 2003, 35:131–138.

    Article  PubMed  CAS  Google Scholar 

  19. Shen G, Archacki SR, Wang Q: The molecular genetics of coronary artery disease and myocardial infarction. Acute Coronary Syndrome 2004, 6:129–141.

    CAS  Google Scholar 

  20. Wang Q, Pyeritz RE: Molecular genetics of cardiovascular disease. In Textbook of Cardiovascular Medicine, edn 1. Edited by Topol EJ. New York: Lippincott Williams & Wilkins; 2000:1–12.

    Google Scholar 

  21. Wang Q, Chen Q: Cardiovascular disease and congenital defects. Nature Encyclopedia of Life Sciences 2000, 3:646–657.

    Google Scholar 

  22. Wang Q, Chen Q: Cardiovascular disease and congenital heart defects. Nature Encyclopedia of Human Genome 2003, 1:396–411.

    Google Scholar 

  23. Freimer N, Sabatti C: The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology. Nat Genet 2004, 36:1045–1051.

    Article  PubMed  CAS  Google Scholar 

  24. Ozaki K, Ohnishi Y, Iida A, et al.: Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 2002, 32:650–654.

    Article  PubMed  CAS  Google Scholar 

  25. PROCARDIS Consortium: A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease. Eur J Hum Genet 2004, 12:770–774.

    Article  Google Scholar 

  26. Yamada A, Ichihara S, Murase Y, et al.: Lack of association of polymorphisms of the lymphotoxin alpha gene with myocardial infarction in Japanese. J Mol Med 2004, 82:477–483.

    PubMed  CAS  Google Scholar 

  27. Koch W, Kastrati A, Bottiger C, et al.: Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction. Atherosclerosis 2001, 159:137–144.

    Article  PubMed  CAS  Google Scholar 

  28. Koch W, Tiroch K, Von BN, et al.: Tumor necrosis factor-alpha, lymphotoxin-alpha, and interleukin-10 gene polymorphisms and restenosis after coronary artery stenting. Cytokine 2003, 24:161–171.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Gossett LA, Kelvin DJ, Sternberg EA, Olson EN: A new myocyte-specific enhancer-binding factor that recognizes a conserved element associated with multiple musclespecific genes. Mol Cell Biol 1989, 9:5022–5033.

    PubMed  CAS  Google Scholar 

  31. Pollock R, Treisman R: Human SRF-related proteins: DNA-binding properties and potential regulatory targets. Genes Dev 1991, 5:2327–2341.

    PubMed  CAS  Google Scholar 

  32. Yu YT, Breitbart RE, Smoot LB, et al.: Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors. Genes Dev 1992, 6:1783–1798.

    PubMed  CAS  Google Scholar 

  33. McDermott JC, Cardoso MC, Yu YT, et al.: hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors. Mol Cell Biol 1993, 13:2564–2577.

    PubMed  CAS  Google Scholar 

  34. Breitbart RE, Liang CS, Smoot LB, et al.: A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage. Development 1993, 118:1095–1106.

    PubMed  CAS  Google Scholar 

  35. Black BL, Olson EN: Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol 1998, 14:167–196.

    Article  PubMed  CAS  Google Scholar 

  36. Funk CD, Chen XS, Johnson EN, Zhao L: Lipoxygenase genes and their targeted disruption. Prostaglandins Other Lipid Mediat 2002, 68–69:303–312.

    PubMed  Google Scholar 

  37. Hedi H, Norbert G: 5-lipoxygenase pathway, dendritic cells, and adaptive immunity. J Biomed Biotechnol 2004, 2004:99–105.

    Article  PubMed  Google Scholar 

  38. Mehrabian M, Allayee H, Wong J, et al.: Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res 2002, 91:120–126.

    Article  PubMed  CAS  Google Scholar 

  39. Dwyer JH, Allayee H, Dwyer KM, et al.: Arachidonate 5-lipoxygenase promoter genotype, dietary archidonic acid, and atherosclerosis. N Engl J Med 2004, 350:29–37.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Cardiology, Lerner Research Institute/ND4-38, Cleveland Clinic Foundation, 9500 Euclid Avenue, 44195, Cleveland, OH, USA

    Qing Wang PhD, MBA

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  1. Qing Wang PhD, MBA
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Wang, Q. Advances in the genetic basis of coronary artery disease. Curr Atheroscler Rep 7, 235–241 (2005). https://doi.org/10.1007/s11883-005-0012-6

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  • DOI: https://doi.org/10.1007/s11883-005-0012-6

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