Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease.

Authors:	Heribert Schunkert, Anika Götz, Peter Braund, Ralph McGinnis, David-Alexandre Tregouet, Massimo Mangino, Patrick Linsel-Nitschke, Francois Cambien, Christian Hengstenberg, Klaus Stark, Stefan Blankenberg, Laurence Tiret, Pierre Ducimetiere, Andrew Keniry, Mohammed J R Ghori, Stefan Schreiber, Nour Eddine El Mokhtari, Alistair S Hall, Richard J Dixon, Alison H Goodall, Henrike Liptau, Helen Pollard, Daniel F Schwarz, Ludwig A Hothorn, H-Erich Wichmann, Inke R König, Marcus Fischer, Christa Meisinger, Willem Ouwehand, Panos Deloukas, John R Thompson, Jeanette Erdmann, Andreas Ziegler, Nilesh J Samani,
Language:	Eng.
Date:	01-04-2008
Journal:	Circulation (1524-4539)
Release:	Circulation. 2008 Apr;117(13):1675-84
Abstract:	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. CONCLUSIONS: This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
Copyright:	Circulation Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany. heribert.schunkert@innere2.uni-luebeck.de
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Terms:	Aged, Case-Control Studies, Chromosomes, Human, Pair 9, Coronary Artery Disease, Female, Genetic Markers, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Repetitive Sequences, Nucleic Acid, Risk Factors, Variation (Genetics)