Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2004 May;41(5):334–341. doi: 10.1136/jmg.2003.016584

Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes

J McCarthy 1, A Parker 1, R Salem 1, D Moliterno 1, Q Wang 1, E Plow 1, S Rao 1, G Shen 1, W Rogers 1, L Newby 1, R Cannata 1, K Glatt 1, E Topol 1
PMCID: PMC1579684  NIHMSID: NIHMS12086  PMID: 15121769

Abstract

Background: to date, only three groups have reported data from large scale genetic association studies of coronary heart disease using a case control design.

Methods and results: to extend our initial report of 62 genes, we present data for 210 polymorphisms in 111 candidate genes genotyped in 352 white subjects with familial, premature coronary heart disease (onset age for men, 45; for women, 50) and a random sample of 418 population based whites. Multivariate logistic regression analysis was used to compare the distributions of genotypes between cases and the comparison group while controlling for age, sex, body mass, diabetes, and hypertension. Significant associations were found with polymorphisms in thrombospondin-4 (THBS4), thrombospondin-2 (THBS2) and plasminogen activator inhibitor-2 (PAI2), the strongest being with the A387P variant in THBS4 (p = 0.002). The THBS2 and THBS4 associations have since been replicated. We evaluated polymorphisms in 40 genes previously associated with coronary heart disease and found significant (p<0.05) associations with 10: ACE, APOE, F7, FGB, GP1BA, IL1RN, LRP1, MTHFR, SELP, and THPO. For five of these genes, the polymorphism associated in our study was different from that previously reported, suggesting linkage disequilibrium as an explanation for failure to replicate associations consistently across studies. We found strong linkage disequilibrium between polymorphisms within and between genes, especially on chromosome 1q22-q25, a region containing several candidate genes.

Conclusions: despite known caveats of genetic association studies, they can be an effective means of hypothesis generation and complement classic linkage studies for understanding the genetic basis of coronary heart disease.

Full Text

The Full Text of this article is available as a PDF (351.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Behague I., Poirier O., Nicaud V., Evans A., Arveiler D., Luc G., Cambou J. P., Scarabin P. Y., Bara L., Green F. Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l'Infarctus du Myocarde. Circulation. 1996 Feb 1;93(3):440–449. doi: 10.1161/01.cir.93.3.440. [DOI] [PubMed] [Google Scholar]
  2. Broeckel Ulrich, Hengstenberg Christian, Mayer Björn, Holmer Stephan, Martin Lisa J., Comuzzie Anthony G., Blangero John, Nürnberg Peter, Reis André, Riegger Günter A. J. A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet. 2002 Jan 30;30(2):210–214. doi: 10.1038/ng827. [DOI] [PubMed] [Google Scholar]
  3. Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C. R., Lim E. P., Kalyanaraman N. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet. 1999 Jul;22(3):231–238. doi: 10.1038/10290. [DOI] [PubMed] [Google Scholar]
  4. Carter A. M., Ossei-Gerning N., Wilson I. J., Grant P. J. Association of the platelet Pl(A) polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bbeta 448 polymorphism with myocardial infarction and extent of coronary artery disease. Circulation. 1997 Sep 2;96(5):1424–1431. doi: 10.1161/01.cir.96.5.1424. [DOI] [PubMed] [Google Scholar]
  5. Clee S. M., Zwinderman A. H., Engert J. C., Zwarts K. Y., Molhuizen H. O., Roomp K., Jukema J. W., van Wijland M., van Dam M., Hudson T. J. Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease. Circulation. 2001 Mar 6;103(9):1198–1205. doi: 10.1161/01.cir.103.9.1198. [DOI] [PubMed] [Google Scholar]
  6. Colhoun Helen M., McKeigue Paul M., Davey Smith George. Problems of reporting genetic associations with complex outcomes. Lancet. 2003 Mar 8;361(9360):865–872. doi: 10.1016/s0140-6736(03)12715-8. [DOI] [PubMed] [Google Scholar]
  7. Eriksson P., Kallin B., van 't Hooft F. M., Båvenholm P., Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):1851–1855. doi: 10.1073/pnas.92.6.1851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Excoffier L., Slatkin M. Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol. 1995 Sep;12(5):921–927. doi: 10.1093/oxfordjournals.molbev.a040269. [DOI] [PubMed] [Google Scholar]
  9. Francis S. E., Camp N. J., Dewberry R. M., Gunn J., Syrris P., Carter N. D., Jeffery S., Kaski J. C., Cumberland D. C., Duff G. W. Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease. Circulation. 1999 Feb 23;99(7):861–866. doi: 10.1161/01.cir.99.7.861. [DOI] [PubMed] [Google Scholar]
  10. Francke S., Manraj M., Lacquemant C., Lecoeur C., Leprêtre F., Passa P., Hebe A., Corset L., Yan S. L., Lahmidi S. 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 Nov 15;10(24):2751–2765. doi: 10.1093/hmg/10.24.2751. [DOI] [PubMed] [Google Scholar]
  11. Franco R. F., Reitsma P. H. Genetic risk factors of venous thrombosis. Hum Genet. 2001 Oct;109(4):369–384. doi: 10.1007/s004390100593. [DOI] [PubMed] [Google Scholar]
  12. Gonzalez-Conejero R., Lozano M. L., Rivera J., Corral J., Iniesta J. A., Moraleda J. M., Vicente V. Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease. Blood. 1998 Oct 15;92(8):2771–2776. [PubMed] [Google Scholar]
  13. Harrap Stephen B., Zammit Kim S., Wong Zilla Y. H., Williams Fiona M., Bahlo Melanie, Tonkin Andrew M., Anderson Stanley T. Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arterioscler Thromb Vasc Biol. 2002 May 1;22(5):874–878. doi: 10.1161/01.atv.0000016258.40568.f1. [DOI] [PubMed] [Google Scholar]
  14. Herrmann S. M., Ricard S., Nicaud V., Mallet C., Evans A., Ruidavets J. B., Arveiler D., Luc G., Cambien F. The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction. Hum Mol Genet. 1998 Aug;7(8):1277–1284. doi: 10.1093/hmg/7.8.1277. [DOI] [PubMed] [Google Scholar]
  15. Hingorani A. D., Liang C. F., Fatibene J., Lyon A., Monteith S., Parsons A., Haydock S., Hopper R. V., Stephens N. G., O'Shaughnessy K. M. A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. Circulation. 1999 Oct 5;100(14):1515–1520. doi: 10.1161/01.cir.100.14.1515. [DOI] [PubMed] [Google Scholar]
  16. Hirschhorn Joel N., Lohmueller Kirk, Byrne Edward, Hirschhorn Kurt. A comprehensive review of genetic association studies. Genet Med. 2002 Mar-Apr;4(2):45–61. doi: 10.1097/00125817-200203000-00002. [DOI] [PubMed] [Google Scholar]
  17. Hong Seung Ho, Kim Young-Ree, Yoon Yeo Min, Min Won Ki, Chun Sa Il, Kim Jin Q. Association between HaeIII polymorphism of scavenger receptor class B type I gene and plasma HDL-cholesterol concentration. Ann Clin Biochem. 2002 Sep;39(Pt 5):478–481. doi: 10.1258/000456302320314485. [DOI] [PubMed] [Google Scholar]
  18. Humphries S. E., Luong L. A., Ogg M. S., Hawe E., Miller G. J. The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J. 2001 Dec;22(24):2243–2252. doi: 10.1053/euhj.2001.2678. [DOI] [PubMed] [Google Scholar]
  19. Iacoviello L., Di Castelnuovo A., De Knijff P., D'Orazio A., Amore C., Arboretti R., Kluft C., Benedetta Donati M. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med. 1998 Jan 8;338(2):79–85. doi: 10.1056/NEJM199801083380202. [DOI] [PubMed] [Google Scholar]
  20. Inoue N., Kawashima S., Kanazawa K., Yamada S., Akita H., Yokoyama M. Polymorphism of the NADH/NADPH oxidase p22 phox gene in patients with coronary artery disease. Circulation. 1998 Jan 20;97(2):135–137. doi: 10.1161/01.cir.97.2.135. [DOI] [PubMed] [Google Scholar]
  21. Ioannidis John P. A., Trikalinos Thomas A., Ntzani Evangelia E., Contopoulos-Ioannidis Despina G. Genetic associations in large versus small studies: an empirical assessment. Lancet. 2003 Feb 15;361(9357):567–571. doi: 10.1016/S0140-6736(03)12516-0. [DOI] [PubMed] [Google Scholar]
  22. Lewontin R C. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics. 1964 Jan;49(1):49–67. doi: 10.1093/genetics/49.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Livak K. J. Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal. 1999 Feb;14(5-6):143–149. doi: 10.1016/s1050-3862(98)00019-9. [DOI] [PubMed] [Google Scholar]
  24. Lohmueller Kirk E., Pearce Celeste L., Pike Malcolm, Lander Eric S., Hirschhorn Joel N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003 Jan 13;33(2):177–182. doi: 10.1038/ng1071. [DOI] [PubMed] [Google Scholar]
  25. Luc G., Bard J. M., Arveiler D., Evans A., Cambou J. P., Bingham A., Amouyel P., Schaffer P., Ruidavets J. B., Cambien F. Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study. Arterioscler Thromb. 1994 Sep;14(9):1412–1419. doi: 10.1161/01.atv.14.9.1412. [DOI] [PubMed] [Google Scholar]
  26. Morita H., Taguchi J., Kurihara H., Kitaoka M., Kaneda H., Kurihara Y., Maemura K., Shindo T., Minamino T., Ohno M. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation. 1997 Apr 15;95(8):2032–2036. doi: 10.1161/01.cir.95.8.2032. [DOI] [PubMed] [Google Scholar]
  27. Ordovas J. M., Cupples L. A., Corella D., Otvos J. D., Osgood D., Martinez A., Lahoz C., Coltell O., Wilson P. W., Schaefer E. J. Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study. Arterioscler Thromb Vasc Biol. 2000 May;20(5):1323–1329. doi: 10.1161/01.atv.20.5.1323. [DOI] [PubMed] [Google Scholar]
  28. Ozaki Kouichi, Ohnishi Yozo, Iida Aritoshi, Sekine Akihiko, Yamada Ryo, Tsunoda Tatsuhiko, Sato Hiroshi, Sato Hideyuki, Hori Masatsugu, Nakamura Yusuke. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet. 2002 Nov 11;32(4):650–654. doi: 10.1038/ng1047. [DOI] [PubMed] [Google Scholar]
  29. Pajukanta P., Cargill M., Viitanen L., Nuotio I., Kareinen A., Perola M., Terwilliger J. D., Kempas E., Daly M., Lilja H. 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 Nov 13;67(6):1481–1493. doi: 10.1086/316902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Peacock R. E., Hamsten A., Nilsson-Ehle P., Humphries S. E. Associations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden. Atherosclerosis. 1992 Dec;97(2-3):171–185. doi: 10.1016/0021-9150(92)90130-9. [DOI] [PubMed] [Google Scholar]
  31. Pohjola-Sintonen S., Rissanen A., Liskola P., Luomanmäki K. Family history as a risk factor of coronary heart disease in patients under 60 years of age. Eur Heart J. 1998 Feb;19(2):235–239. doi: 10.1053/euhj.1997.0543. [DOI] [PubMed] [Google Scholar]
  32. Rees A., Stocks J., Williams L. G., Caplin J. L., Jowett N. I., Camm A. J., Galton D. J. DNA polymorphisms in the apolipoprotein C-III and insulin genes and atherosclerosis. Atherosclerosis. 1985 Dec;58(1-3):269–275. doi: 10.1016/0021-9150(85)90072-3. [DOI] [PubMed] [Google Scholar]
  33. Reguero J. R., Cubero G. I., Batalla A., Alvarez V., Hevia S., Cortina A., Coto E. Apolipoprotein A1 gene polymorphisms and risk of early coronary disease. Cardiology. 1998 Dec;90(3):231–235. doi: 10.1159/000006849. [DOI] [PubMed] [Google Scholar]
  34. Reich D. E., Goldstein D. B. Detecting association in a case-control study while correcting for population stratification. Genet Epidemiol. 2001 Jan;20(1):4–16. doi: 10.1002/1098-2272(200101)20:1<4::AID-GEPI2>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  35. Rissanen A. M., Nikkilä E. A. Coronary artery disease and its risk factors in families of young men with angina pectoris and in controls. Br Heart J. 1977 Aug;39(8):875–883. doi: 10.1136/hrt.39.8.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rosendaal F. R., Siscovick D. S., Schwartz S. M., Psaty B. M., Raghunathan T. E., Vos H. L. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood. 1997 Sep 1;90(5):1747–1750. [PubMed] [Google Scholar]
  37. Schulz Susanne, Schagdarsurengin Undraga, Greiser Petra, Birkenmeier Gerd, Müller-Werdan Ursula, Hagemann Monika, Riemann Dagmar, Werdan Karl, Gläser Christiane. The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis--novel genomic variants and functional consequences. Hum Mutat. 2002 Nov;20(5):404–404. doi: 10.1002/humu.9070. [DOI] [PubMed] [Google Scholar]
  38. Sen-Banerjee S., Siles X., Campos H. Tobacco smoking modifies association between Gln-Arg192 polymorphism of human paraoxonase gene and risk of myocardial infarction. Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2120–2126. doi: 10.1161/01.atv.20.9.2120. [DOI] [PubMed] [Google Scholar]
  39. Snapir A., Heinonen P., Tuomainen T. P., Alhopuro P., Karvonen M. K., Lakka T. A., Nyyssönen K., Salonen R., Kauhanen J., Valkonen V. P. An insertion/deletion polymorphism in the alpha2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol. 2001 May;37(6):1516–1522. doi: 10.1016/s0735-1097(01)01201-3. [DOI] [PubMed] [Google Scholar]
  40. Stenina Olga I., Desai Shailesh Y., Krukovets Irene, Kight Kelly, Janigro Damir, Topol Eric J., Plow Edward F. Thrombospondin-4 and its variants: expression and differential effects on endothelial cells. Circulation. 2003 Sep 2;108(12):1514–1519. doi: 10.1161/01.CIR.0000089085.76320.4E. [DOI] [PubMed] [Google Scholar]
  41. Topol E. J., McCarthy J., Gabriel S., Moliterno D. J., Rogers W. J., Newby L. K., Freedman M., Metivier J., Cannata R., O'Donnell C. J. Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation. 2001 Nov 27;104(22):2641–2644. doi: 10.1161/hc4701.100910. [DOI] [PubMed] [Google Scholar]
  42. Unkelbach K., Gardemann A., Kostrzewa M., Philipp M., Tillmanns H., Haberbosch W. A new promoter polymorphism in the gene of lipopolysaccharide receptor CD14 is associated with expired myocardial infarction in patients with low atherosclerotic risk profile. Arterioscler Thromb Vasc Biol. 1999 Apr;19(4):932–938. doi: 10.1161/01.atv.19.4.932. [DOI] [PubMed] [Google Scholar]
  43. Waalen Jill, Felitti Vincent, Gelbart Terri, Ho Ngoc J., Beutler Ernest. Prevalence of coronary heart disease associated with HFE mutations in adults attending a health appraisal center. Am J Med. 2002 Oct 15;113(6):472–479. doi: 10.1016/s0002-9343(02)01249-4. [DOI] [PubMed] [Google Scholar]
  44. Wang Lejin, Fan Chun, Topol Sarah E., Topol Eric J., Wang Qing. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science. 2003 Nov 28;302(5650):1578–1581. doi: 10.1126/science.1088477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wang X. L., Oosterhof J., Duarte N. Peroxisome proliferator-activated receptor gamma C161-->T polymorphism and coronary artery disease. Cardiovasc Res. 1999 Dec;44(3):588–594. doi: 10.1016/s0008-6363(99)00256-4. [DOI] [PubMed] [Google Scholar]
  46. Wenzel K., Blackburn A., Ernst M., Affeldt M., Hanke R., Baumann G., Felix S. B., Kleber F. X., Rohde K., Gläser C. Relationship of polymorphisms in the renin-angiotensin system and in E-selectin of patients with early severe coronary heart disease. J Mol Med (Berl) 1997 Jan;75(1):57–61. doi: 10.1007/s001090050087. [DOI] [PubMed] [Google Scholar]
  47. Wenzel K., Felix S., Kleber F. X., Brachold R., Menke T., Schattke S., Schulte K. L., Gläser C., Rohde K., Baumann G. E-selectin polymorphism and atherosclerosis: an association study. Hum Mol Genet. 1994 Nov;3(11):1935–1937. doi: 10.1093/hmg/3.11.1935. [DOI] [PubMed] [Google Scholar]
  48. Xiang K., Zheng T., Sun D., Li J. [The relationship between angiotensin II type 1 receptor gene and coronary heart disease, hypertension and diabetes mellitus in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 1998 Feb 10;15(1):9–12. [PubMed] [Google Scholar]
  49. Yamada Yoshiji, Izawa Hideo, Ichihara Sahoko, Takatsu Fumimaro, Ishihara Hitoshi, Hirayama Haruo, Sone Takahito, Tanaka Masashi, Yokota Mitsuhiro. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002 Dec 12;347(24):1916–1923. doi: 10.1056/NEJMoa021445. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

[Web-only Table]
jmedgene_41_5_334__index.html (1.1KB, html)
jmedgene_41_5_334__1.pdf (243.2KB, pdf)

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES