title: Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease.
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.
  
  
  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.
authors: Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany. heribert.schunkert@innere2.uni-luebeck.de
authors: Heribert
authors: H
authors: Schunkert
authors: Anika
authors: A
authors: Götz
authors: Peter
authors: P
authors: Braund
authors: Ralph
authors: R
authors: McGinnis
authors: David-Alexandre
authors: DA
authors: Tregouet
authors: Massimo
authors: M
authors: Mangino
authors: Patrick
authors: P
authors: Linsel-Nitschke
authors: Francois
authors: F
authors: Cambien
authors: Christian
authors: C
authors: Hengstenberg
authors: Klaus
authors: K
authors: Stark
authors: Stefan
authors: S
authors: Blankenberg
authors: Laurence
authors: L
authors: Tiret
authors: Pierre
authors: P
authors: Ducimetiere
authors: Andrew
authors: A
authors: Keniry
authors: Mohammed J R
authors: MJ
authors: Ghori
authors: Stefan
authors: S
authors: Schreiber
authors: Nour Eddine
authors: NE
authors: El Mokhtari
authors: Alistair S
authors: AS
authors: Hall
authors: Richard J
authors: RJ
authors: Dixon
authors: Alison H
authors: AH
authors: Goodall
authors: Henrike
authors: H
authors: Liptau
authors: Helen
authors: H
authors: Pollard
authors: Daniel F
authors: DF
authors: Schwarz
authors: Ludwig A
authors: LA
authors: Hothorn
authors: H-Erich
authors: HE
authors: Wichmann
authors: Inke R
authors: IR
authors: König
authors: Marcus
authors: M
authors: Fischer
authors: Christa
authors: C
authors: Meisinger
authors: Willem
authors: W
authors: Ouwehand
authors: Panos
authors: P
authors: Deloukas
authors: John R
authors: JR
authors: Thompson
authors: Jeanette
authors: J
authors: Erdmann
authors: Andreas
authors: A
authors: Ziegler
authors: Nilesh J
authors: NJ
authors: Samani
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D012307:Risk Factors
chemical_list: D005819:Genetic Markers