FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 357:443-453 August 2, 2007 Number 5 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Perspective by Hunter, D. J. Editorial by Drazen, J. M. Editorial by Rosenzweig, A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease.

Methods We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix).

Results Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10^–14 and P=3.40x10^–6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10^–5 and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10^–6) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212).

Conclusions We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

Source Information

From the University of Leicester, Leicester (N.J.S., M.M., R.J.D., P.B., S.E.S., H.P., M.D.T., J.R.T.); University of Leeds, Leeds (A.S.H., J.H.B., M.M.I., A.J.B., S.G.B.); University of Cambridge and National Health Service Blood and Transplant, Cambridge (W.O.); and the Wellcome Trust Sanger Institute, Hinxton (P.D.) — all in the United Kingdom; Universität zu Lübeck, Lübeck (J.E., B.M., I.R.K., S.S., F.P., W.L., I.B., A.Z., H.S.); Universität Regensburg, Regensburg (C.H., M.F., A.B.); GSF–Nationales Forschungszentrum für Umwelt und Gesundheit, Neuherberg (T.M., H.-E.W., T.M.S., C.G.); Technische Universität München, Munich (T.M.); Ludwig Maximilians University, Munich (H.-E.W., C.G.); and Johannes Gutenberg University Mainz, Mainz (S.B.) — all in Germany; and INSERM, UMR S525, Université Pierre et Marie Curie, Paris (D.-A.T., F.C.).

This article (10.1056/NEJMoa072366) was published at www.nejm.org on July 18, 2007.

Address reprint requests to Dr. Samani at the Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom, or at njs{at}le.ac.uk or to Dr. Schunkert at Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany, or at heribert.schunkert{at}innere2.uni-luebeck.de.

Full Text of this Article

This article has been cited by other articles:

• Sutton, B. S., Crosslin, D. R., Shah, S. H., Nelson, S. C., Bassil, A., Hale, A. B., Haynes, C., Goldschmidt-Clermont, P. J., Vance, J. M., Seo, D., Kraus, W. E., Gregory, S. G., Hauser, E. R. (2008). Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets. Hum Mol Genet 17: 1318-1328 [Abstract] [Full Text]  
• Malarstig, A., Sigurdsson, S., Eriksson, P., Paulsson-Berne, G., Hedin, U., Wallentin, L., Siegbahn, A., Hamsten, A., Syvanen, A.-C. (2008). Variants of the Interferon Regulatory Factor 5 Gene Regulate Expression of IRF5 mRNA in Atherosclerotic Tissue But Are Not Associated With Myocardial Infarction. Arterioscler. Thromb. Vasc. Bio. 28: 975-982 [Abstract] [Full Text]  
• Liu, X.-Q., Paterson, A. D., He, N., St. George-Hyslop, P., Rauta, V., Gronhagen-Riska, C., Laakso, M., Thibaudin, L., Berthoux, F., Cattran, D., Pei, Y. (2008). IL5RA and TNFRSF6B Gene Variants Are Associated With Sporadic IgA Nephropathy. J. Am. Soc. Nephrol. 19: 1025-1033 [Abstract] [Full Text]  
• Matarin, M., Brown, W. M., Singleton, A., Hardy, J. A., Meschia, J. F., for the ISGS investigators, (2008). Whole Genome Analyses Suggest Ischemic Stroke and Heart Disease Share an Association With Polymorphisms on Chromosome 9p21. Stroke 39: 1586-1589 [Abstract] [Full Text]  
• Trichopoulou, A., Yiannakouris, N., Bamia, C., Benetou, V., Trichopoulos, D., Ordovas, J. M. (2008). Genetic Predisposition, Nongenetic Risk Factors, and Coronary Infarct. Arch Intern Med 168: 891-896 [Abstract] [Full Text]  
• Samuel, J.-L., Schaub, M. C., Zaugg, M., Mamas, M., Dunn, W. B., Swynghedauw, B. (2008). Genomics in cardiac metabolism. Cardiovasc Res 0: cvn061v3-10 [Abstract] [Full Text]  
• Koch, W., Hoppmann, P., Biele, J., Mueller, J. C., Schomig, A., Kastrati, A. (2008). Fibrinogen Genes and Myocardial Infarction: A Haplotype Analysis. Arterioscler. Thromb. Vasc. Bio. 28: 758-763 [Abstract] [Full Text]  
• Yamada, Y, Kato, K, Oguri, M, Fujimaki, T, Yokoi, K, Matsuo, H, Watanabe, S, Metoki, N, Yoshida, H, Satoh, K, Ichihara, S, Aoyagi, Y, Yasunaga, A, Park, H, Tanaka, M, Nozawa, Y (2008). Genetic risk for myocardial infarction determined by polymorphisms of candidate genes in a Japanese population. J. Med. Genet. 45: 216-221 [Abstract] [Full Text]  
• Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M. (2008). Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events. NEJM 358: 1240-1249 [Abstract] [Full Text]  
• Bhattacharyya, T., Nicholls, S. J., Topol, E. J., Zhang, R., Yang, X., Schmitt, D., Fu, X., Shao, M., Brennan, D. M., Ellis, S. G., Brennan, M.-L., Allayee, H., Lusis, A. J., Hazen, S. L. (2008). Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk. JAMA 299: 1265-1276 [Abstract] [Full Text]  
• Pearson, T. A., Manolio, T. A. (2008). How to Interpret a Genome-wide Association Study. JAMA 299: 1335-1344 [Abstract] [Full Text]  
• Sanz, J., Moreno, P. R., Fuster, V. (2008). The year in atherothrombosis.. J Am Coll Cardiol 51: 944-955 [Full Text]  
• Fischer, M., Schunkert, H. (2008). Familial aggregation of left main coronary artery disease and future risk of coronary events in asymptomatic siblings of affected patients: reply. Eur Heart J 29: 827-828 [Full Text]  
• BEYAR, R. (2008). Controlling Ischemic Cardiovascular Disease: From Basic Mechanisms to Clinical Management. Ann. N. Y. Acad. Sci. 1123: 232-236 [Abstract] [Full Text]  
• Emmerich, J., Ridker, P. M (2008). Can Fishing for New Genes Catch Patients at Risk of Coronary Artery Disease?. Clin. Chem. 54: 453-455 [Full Text]  
• Sabatine, M. S., Ploughman, L., Simonsen, K. L., Iakoubova, O. A., Kirchgessner, T. G., Ranade, K., Tsuchihashi, Z., Zerba, K. E., Long, D. U., Tong, C. H., Packard, C. J., Pfeffer, M. A., Devlin, J. J., Shepherd, J., Campos, H., Sacks, F. M., Braunwald, E. (2008). Association Between ADAMTS1 Matrix Metalloproteinase Gene Variation, Coronary Heart Disease, and Benefit of Statin Therapy. Arterioscler. Thromb. Vasc. Bio. 28: 562-567 [Abstract] [Full Text]  
• Talmud, P. J., Cooper, J. A., Palmen, J., Lovering, R., Drenos, F., Hingorani, A. D., Humphries, S. E. (2008). Chromosome 9p21.3 Coronary Heart Disease Locus Genotype and Prospective Risk of CHD in Healthy Middle-Aged Men. Clin. Chem. 54: 467-474 [Abstract] [Full Text]  
• Zhong, H., Prentice, R. L. (2008). Bias-reduced estimators and confidence intervals for odds ratios in genome-wide association studies. Biostatistics 0: kxn001v1-kxn001 [Abstract] [Full Text]  
• Shen, G.-Q., Li, L., Rao, S., Abdullah, K. G., Ban, J. M., Lee, B.-S., Park, J. E., Wang, Q. K. (2008). Four SNPs on Chromosome 9p21 in a South Korean Population Implicate a Genetic Locus That Confers High Cross-Race Risk for Development of Coronary Artery Disease. Arterioscler. Thromb. Vasc. Bio. 28: 360-365 [Abstract] [Full Text]  
• Frayling, T. M (2008). Commentary: Genetic association studies see light at the end of the tunnel. Int J Epidemiol 37: 133-135 [Full Text]  
• Ridker, P. M, Chasman, D. I., Zee, R. Y.L., Parker, A., Rose, L., Cook, N. R., Buring, J. E, for the Women's Genome Health Study Working Group, (2008). Rationale, Design, and Methodology of the Women's Genome Health Study: A Genome-Wide Association Study of More Than 25 000 Initially Healthy American Women. Clin. Chem. 54: 249-255 [Abstract] [Full Text]  
• Hegele, R. A., Dichgans, M. (2008). Update on the Genetics of Stroke and Cerebrovascular Disease 2007. Stroke 39: 252-254 [Full Text]  
• Marian, A. J. (2008). Surprises of the genome and "personalized" medicine.. J Am Coll Cardiol 51: 456-458 [Full Text]  
• Cambien, F., Tiret, L. (2007). Genetics of Cardiovascular Diseases: From Single Mutations to the Whole Genome. Circulation 116: 1714-1724 [Full Text]  
• Rosenzweig, A. (2007). Scanning the Genome for Coronary Risk. NEJM 357: 497-499 [Full Text]  
• Drazen, J. M., Phimister, E. G. (2007). Publishing Genomewide Association Studies. NEJM 357: 496-496 [Full Text]