Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease.
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.
Schunkert
Heribert
H
Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany. heribert.schunkert@innere2.uni-luebeck.de
Götz
Anika
A
Braund
Peter
P
McGinnis
Ralph
R
Tregouet
David-Alexandre
DA
Mangino
Massimo
M
Linsel-Nitschke
Patrick
P
Cambien
Francois
F
Hengstenberg
Christian
C
Stark
Klaus
K
Blankenberg
Stefan
S
Tiret
Laurence
L
Ducimetiere
Pierre
P
Keniry
Andrew
A
Ghori
Mohammed J R
MJ
Schreiber
Stefan
S
El Mokhtari
Nour Eddine
NE
Hall
Alistair S
AS
Dixon
Richard J
RJ
Goodall
Alison H
AH
Liptau
Henrike
H
Pollard
Helen
H
Schwarz
Daniel F
DF
Hothorn
Ludwig A
LA
Wichmann
H-Erich
HE
König
Inke R
IR
Fischer
Marcus
M
Meisinger
Christa
C
Ouwehand
Willem
W
Deloukas
Panos
P
Thompson
John R
JR
Erdmann
Jeanette
J
Ziegler
Andreas
A
Samani
Nilesh J
NJ
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
D005819:Genetic Markers