Skip to main content
SpringerLink
Log in

Nonconventional genetic risk factors for cardiovascular disease

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Despite numerous advances made in identifying the genes for rare mendelian forms of cardiovascular disease (CVD), relatively little is known about the common, complex forms at the genetic level. Moreover, most genes that have been associated with CVD, whether they are single gene forms or more common forms of the disease, have primarily been involved in biochemical pathways related to what are considered “conventional” risk factors. However, recent genetic studies have begun to identify genes and pathways associated with CVD that would not be considered to underlie conventional risk factors. In this review, we discuss the evidence for this latter notion based on recent linkage and association studies in humans. As an example, we also illustrate how a combination of mouse and human genetics led to identification of the 5-lipoxygenase pathway for CVD, with potentially important implications for its treatment and diagnosis. We conclude with a discussion of the prospects for identifying CVD genes in the future and for potentially developing more effective therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Lusis AJ: Atherosclerosis. Nature 2000, 407:233–241.

    Article  PubMed  CAS  Google Scholar 

  2. Lusis AJ, Weinreb A, Drake TA, Allayee H: Genetics of Atherosclerosis. In Textbook of Cardiovascular Disease. Edited by Topol EJ. Philadelphia: Lippincott-Raven; 2002:Chapter 98.

    Google Scholar 

  3. Wang Q, Rao S, Shen GQ, 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 

  4. Yamada Y, Izawa H, Ichihara S, et al.: Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 2002, 347:1916–1923.

    Article  PubMed  CAS  Google Scholar 

  5. Hauser ER, Crossman DC, Granger CB, et al.: A genome-wide 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 

  6. 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 

  7. 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 

  8. Weng L, Kavaslar N, Ustaszewska A, et al.: Lack of MEF2A mutations in coronary artery disease. J Clin Invest 2005, 115:1016–1020.

    Article  PubMed  CAS  Google Scholar 

  9. Fox CS, Cupples LA, Chazaro I, et al.: Genomewide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12. Am J Hum Genet 2004, 74:253–261.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Lange LA, Lange EM, Bielak LF, et al.: Autosomal genome-wide scan for coronary artery calcification loci in sibships at high risk for hypertension. Arterioscler Thromb Vasc Biol 2002, 22:418–423.

    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. 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 

  14. 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 

  15. Iwanaga Y, Ono K, Takagi S, et al.: Association analysis between polymorphisms of the lymphotoxin-alpha gene and myocardial infarction in a Japanese population. Atherosclerosis 2004, 172:197–198.

    Article  PubMed  CAS  Google Scholar 

  16. Laxton R, Pearce E, Kyriakou T, Ye S: Association of the lymphotoxin-alpha gene Thr26Asn polymorphism with severity of coronary atherosclerosis. Genes Immunol 2005, 6:539–541.

    Article  CAS  Google Scholar 

  17. Szolnoki Z, Havasi V, Talian G, et al.: Lymphotoxin-alpha gene 252G allelic variant is a risk factor for large-vessel-associated ischemic stroke. J Mol Neurosci 2005, 27:205–211.

    Article  PubMed  CAS  Google Scholar 

  18. 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 

  19. 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 

  20. Kiechl S, Lorenz E, Reindl M, et al.: Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002, 347:185–192.

    Article  PubMed  CAS  Google Scholar 

  21. Ameziane N, Beillat T, Verpillat P, et al.: Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler Thromb Vasc Biol 2003, 23:e61-e64.

    Article  PubMed  CAS  Google Scholar 

  22. Holloway JW, Yang IA, Ye S: Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction. Pharmacogenet Genom 2005, 15:15–21.

    Article  CAS  Google Scholar 

  23. Balistreri CR, Candore G, Colonna-Romano G, et al.: Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA 2004, 292:2339–2340.

    Article  PubMed  CAS  Google Scholar 

  24. Topol EJ, McCarthy J, Gabriel S, et al.: Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation 2001, 104:2641–2644.

    PubMed  CAS  Google Scholar 

  25. McCarthy JJ, Parker A, Salem R, et al.: Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes. J Med Genet 2004, 41:334–341.

    Article  PubMed  CAS  Google Scholar 

  26. Wessel J, Topol EJ, Ji M, et al.: Replication of the association between the thrombospondin-4 A387P polymorphism and myocardial infarction. Am Heart J 2004, 147:905–909.

    Article  PubMed  CAS  Google Scholar 

  27. Yamada Y, Ichihara S, Izawa H, et al.: Genetic risk for coronary artery disease in individuals with or without type 2 diabetes. Mol Genet Metab 2004, 81:282–290.

    Article  PubMed  CAS  Google Scholar 

  28. Listi F, Candore G, Lio D, et al.: Association between C1019T polymorphism of connexin37 and acute myocardial infarction: a study in patients from Sicily. Int J Cardiol 2005, 102:269–271.

    Article  PubMed  Google Scholar 

  29. Newby AC, Johnson JL: Genetic strategies to elucidate the roles of matrix metalloproteinases in atherosclerotic plaque growth and stability. Circ Res 2005, 97:958–960.

    Article  PubMed  CAS  Google Scholar 

  30. Pollanen PJ, Lehtimaki T, Mikkelsson J, et al.: Matrix metalloproteinase3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques. Atherosclerosis 2005, 180:73–78.

    Article  PubMed  CAS  Google Scholar 

  31. Pearce E, Tregouet DA, Samnegard A, et al.: Haplotype effect of the matrix metalloproteinase-1 gene on risk of myocardial infarction. Circ Res 2005, 97:1070–1076.

    Article  PubMed  CAS  Google Scholar 

  32. Shiffman D, Ellis SG, Rowland CM, et al.: Identification of four gene variants associated with myocardial infarction. Am J Hum Genet 2005, 77:596–605.

    Article  PubMed  CAS  Google Scholar 

  33. Ohashi R, Mu H, Yao Q, Chen C: Cellular and molecular mechanisms of atherosclerosis with mouse models. Trends Cardiovasc Med 2004, 14:187–190.

    Article  PubMed  CAS  Google Scholar 

  34. Allayee H, Ghazalpour A, Lusis AJ: Using mice to dissect genetic factors in atherosclerosis. Arterioscler Thromb Vasc Biol 2003, 23:1501–1509.

    Article  PubMed  CAS  Google Scholar 

  35. Wang X, Ishimori N, Korstanje R, et al.: Identifying novel genes for atherosclerosis through mouse-human comparative genetics. Am J Hum Genet 2005, 77:1–15.

    Article  PubMed  CAS  Google Scholar 

  36. Mehrabian M, Allayee H: 5-lipoxygenase and atherosclerosis. Curr Opin Lipidol 2003, 14:447–457.

    Article  PubMed  CAS  Google Scholar 

  37. 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 

  38. Zhao L, Moos MP, Grabner R, et al.: The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med 2004, 10:966–973.

    Article  PubMed  CAS  Google Scholar 

  39. Mehrabian M, Allayee H, Stockton J, et al.: Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits. Nat Genet 2005, 37:1224–1233.

    Article  PubMed  CAS  Google Scholar 

  40. Aiello RJ, Bourassa PA, Lindsey S, et al.: Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol 2002, 22:443–449.

    Article  PubMed  CAS  Google Scholar 

  41. Subbarao K, Jala VR, Mathis S, et al.: Role of leukotriene B4 leceptors in the development of atherosclerosis: potential mechanisms. Arterioscler Thromb Vasc Biol 2004, 24:369–375.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. Helgadottir 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  PubMed  CAS  Google Scholar 

  44. Lohmussaar E, Gschwendtner A, Mueller JC, et al.: ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke 2005, 36:731–736.

    Article  PubMed  CAS  Google Scholar 

  45. 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 

  46. Helgadottir A, Manolescu A, Helgason A, et al.: A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet 2005, In press.

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

    Article  PubMed  CAS  Google Scholar 

  48. 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 

  49. 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 

  50. 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 

Download references

Author information

Authors and Affiliations

  1. Institute for Genetic Medicine, USC Keck School of Medicine, 2250 Alcazar Street, IGM 240, 90089-9075, Los Angeles, CA, USA

    Hooman Allayee PhD

Authors
  1. Christopher N. Tymchuk MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaana Hartiala MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pragna I. Patel PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margarete Mehrabian PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hooman Allayee PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hooman Allayee PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tymchuk, C.N., Hartiala, J., Patel, P.I. et al. Nonconventional genetic risk factors for cardiovascular disease. Curr Atheroscler Rep 8, 184–192 (2006). https://doi.org/10.1007/s11883-006-0072-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-006-0072-2

Keywords

Search

Navigation