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 CAD and/or MI 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 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). 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; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10-10 versus 3.2×10-7) suggesting 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).

Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease

“…The dataset used in this study comprised 25,491 cases with coronary artery disease, myocardial infarction or both and 66,819 controls from the 14 cohorts within CARDIoGRAM and two GWAS by the Ottawa Heart Institute in collaboration with Cleveland Clinic and Duke University [17].…”

Genetics of Coronary Artery Disease

“…The discovery of a genetic risk variant in the major histocompatibility locus at 6p21.3 would strongly indicate that it acts through the innate immune system to enhance the vascular inflammatory response. 43 There are other potential candidates that have been shown to be part of the inflammatory network, including the interleukin 6 receptor, CXCL12, mitochondrial ribosomal protein S6, and muscle RAS oncogene homolog gene. To prove that their risk is mediated through inflammation will require confirmation by more direct in vivo and in vitro studies.…”

A 680 kb duplication at the FTO locus in a kindred with obesity and a distinct body fat distribution

“…The duplicated region on chromosome 16 spans the entire GWAS risk locus for obesity shown in Figure 1 and encompasses RBL2, AKTIP, RPGRIP1L and all but the last exon of the FTO gene (Figure 2b). This CNV was not present in any other member of the extremes of obesity sample (OBLE) or in two distinct samples of 4778 subjects genotyped as part of a separate GWAS for coronary artery disease 17 Interphase FISH analysis also confirmed the presence of the duplication in the proband (Subject no. 0001) as compared with a normal male control, with the majority of nuclei from the proband exhibiting either an enhanced signal or two distinct signals for the probe within the duplication (RP11-834H11, SpectrumOrange) relative to another probe outside the duplication (RP11-939K9, SpectrumGreen) (Figure 3a).…”

“…16 Replication of copy number variant findings was sought in two distinct samples of 4778 subjects genotyped as part of a separate GWAS for coronary artery disease. 17 The study was approved by the Human Ethics Experimentation Committees of the Ottawa Hospital and University of Ottawa Heart Institute.…”