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on March 24, 2008

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Submitted on July 27, 2007
Accepted on January 29, 2008

Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease

Heribert Schunkert MD^*, Anika Götz MSc, Peter Braund MSc, Ralph McGinnis PhD, David-Alexandre Tregouet PhD, Massimo Mangino PhD, Patrick Linsel-Nitschke MD, Francois Cambien MD, Christian Hengstenberg MD, Klaus Stark PhD, Stefan Blankenberg MD, Laurence Tiret PhD, Pierre Ducimetiere MD, Andrew Keniry PhD, Mohammed J.R. Ghori PhD, Stefan Schreiber MD, Nour Eddine El Mokhtari MD, Alistair S. Hall FRCP, Richard J. Dixon PhD, Alison H. Goodall PhD, Henrike Liptau MD, Helen Pollard MSc, Daniel F. Schwarz MSc, Ludwig A. Hothorn PhD, H.-Erich Wichmann MD, Inke R. König PhD, Marcus Fischer MD, Christa Meisinger MD, Willem Ouwehand FRCPath, Panos Deloukas PhD, John R. Thompson PhD, Jeanette Erdmann PhD, Andreas Ziegler PhD, Nilesh J. Samani FMedSci^*, for the Cardiogenics Consortium

From Medizinische Klinik II (H.S., A.G., P.L.-N., H.L., J.E.), and Institut für Medizinische Biometrie und Statistik (A.G., D.F.S., I.R.K., A.Z.), Universität zu Lübeck, Lübeck, Germany; Department of Cardiovascular Sciences (P.B., M.M., R.J.D., A.H.G., H.P., N.J.S.), and Department of Health Sciences and Genetics (J.R.T.), Glenfield Hospital, University of Leicester, Leicester, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (R.M., A.K., M.J.R.G., P.D.), and Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge Centre (W.O.), Cambridge, UK; INSERM and Université Pierre et Marie Curie-Paris 6, Paris, France (D.-A.T., F.C., L.T.); Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany (C.H., K.S., M.F.); II. Medizinische Klinik, Johannes Gutenberg University, Mainz, Germany (S.B.); Unité INSERM 780–Université Paris Sud XI, Villejuif, France (P.D.); Institut für Klinische Molekularbiologie, UK-SH, Campus Kiel, Kiel, Germany (S.S., N.E.E.M.); C-NET Group, Leeds Institute for Genetics and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds, UK (A.S.H.); Institut für Biostatistik, Leibniz Universität Hannover, Hannover, Germany (L.A.H.); Institut für Epidemiologie, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, Neuherberg, Germany (H.-E.W., C.M.); Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig Maximilians University, Munich, Germany (H.-E.W.).

^* To whom correspondence should be addressed. E-mail: heribert.schunkert{at}innere2.uni-luebeck.de or njs{at}le.ac.uk.

Background—Recently, genome-wide association studies identified variants on chromosome 9p21.3 as affecting the risk of coronary artery disease (CAD). We investigated the association of this locus with CAD in 7 case-control studies and undertook a meta-analysis.

Methods and Results—A single-nucleotide polymorphism (SNP), rs1333049, representing the 9p21.3 locus, was genotyped in 7 case-control studies involving a total of 4645 patients with myocardial infarction or CAD and 5177 controls. The mode of inheritance was determined. In addition, in 5 of the 7 studies, we genotyped 3 additional SNPs to assess a risk-associated haplotype (ACAC). Finally, a meta-analysis of the present data and previously published samples was conducted. A limited fine mapping of the locus was performed. The risk allele (C) of the lead SNP, rs1333049, was uniformly associated with CAD in each study (P<0.05). In a pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% confidence interval, 1.22 to 1.37; P=0.0001). Haplotype analysis further suggested that this effect was not homogeneous across the haplotypic background (test for interaction, P=0.0079). An autosomal-additive mode of inheritance best explained the underlying association. The meta-analysis of the rs1333049 SNP in 12 004 cases and 28 949 controls increased the overall level of evidence for association with CAD to P=6.04x10^-10 (odds ratio, 1.24; 95% confidence interval, 1.20 to 1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP.

Conclusion—This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.

Key words: chromosomes • coronary disease • genetics • meta-analysis • myocardial infarction • risk factors

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