A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex.
BACKGROUND
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.


RESULTS
We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.


CONCLUSIONS
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
Cardiovascular Research Methods Center, John and Jennifer Ruddy Canadian Cardiovascular Research Center, University of Ottawa Heart Institute, Ottawa, ON, Canada. rwdavies@well.ox.ac.uk
Robert W
RW
Davies
George A
GA
Wells
Alexandre F R
AF
Stewart
Jeanette
J
Erdmann
Svati H
SH
Shah
Jane F
JF
Ferguson
Alistair S
AS
Hall
Sonia S
SS
Anand
Mary S
MS
Burnett
Stephen E
SE
Epstein
Sonny
S
Dandona
Li
L
Chen
Janja
J
Nahrstaedt
Christina
C
Loley
Inke R
IR
König
William E
WE
Kraus
Christopher B
CB
Granger
James C
JC
Engert
Christian
C
Hengstenberg
H-Erich
HE
Wichmann
Stefan
S
Schreiber
W H Wilson
WH
Tang
Stephen G
SG
Ellis
Daniel J
DJ
Rader
Stanley L
SL
Hazen
Muredach P
MP
Reilly
Nilesh J
NJ
Samani
Heribert
H
Schunkert
Robert
R
Roberts
Ruth
R
McPherson
D000328:Adult; D000368:Aged; D000483:Alleles; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics
D015395:Histocompatibility Antigens Class I