A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex

Abstract

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.

Methods and 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).

Figure 1

Forest plot for association of rs3869109 with CAD

Figure 2

Manhattan plot of rs3869109 and surrounding genes at 6p21.3. Local Manhattan plot generated using LocusZoom. Shown is rs3869109 and flanking region. The final meta-analysis p-value is given for rs3869109, while for all other SNPs, the p-value indicated is from the discovery analysis.

Figure 3

The effect of ethnicity of rs3869109. A) A map of Europe with countries colored to reflect collected ethnic information B) First main principal component for PCA performed on SNPs genotyped in the entire discovery cohort, broadly corresponding to Northern versus Southern geographic background, with a subset colored according to ethnicity. Horizontal axis variation is uniform normal random distribution for ease of visual interpretation. See Figure S2 for the second main principal component and more details. C) Predicted frequency of rs3869109 in cases and controls with respect to first main principal component. This graph is aligned vertically with Panel C.

Figure 4

Association of common MHC Class I alleles with CAD. Association of common (>2% frequency) MHC Class I alleles with CAD in discovery population unadjusted (left) and adjusted (right) for rs3869109.