Abstract 12170: Chromosome 1q41 and 3q22.3 Coronary Artery Disease Risk Loci are Associated with Altered Cardiac Gene Expression Profiles in Normal and Diseased Heart
Meta-analyses of genome-wide association studies have confirmed association of chromosomal loci 1q41 and 3q22.3 with coronary artery disease (CAD). Although these loci are located in close proximity to the melanoma inhibitory activity family, member 3 gene (MIA3) for 1q41 (rs17465637) and muscle RAS gene (MRAS) for 3q22.3 (rs9818870), the mechanisms underlying these associations are unclear. To understand pathways by which these loci might influence CAD risk, we investigated associations between genotype and global gene expression in heart tissue from 110 heart-transplant patients and 108 donors (no diagnosed heart disease). Genotyping was performed with Taqman assays and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with additive (1q41) or recessive (3q22.3) models and unadjusted p-values have been reported. In patients, the 1q41 minor (protective) allele was associated with less previous history of myocardial infarction (p=0.001) and with altered expression of 781 genes (p<0.05), whilst 2971 genes were altered in donors (p<0.05) including MIA3 (+1.07-fold, p=0.008). Differentially expressed genes with 1q41 were enriched for immune response pathways in patients (p=3.2x10-8) and donors (p=2.1x10-8) and for cytoskeleton remodeling (p=3.5x10-13) and cell adhesion (p=5.0x10-8) processes in donors only, consistent with a reported role of MIA3 in reducing monocyte adhesion. Having two copies of the 3q22.3 minor (risk) allele was associated in patients with lower cardiac output (p=0.037), higher systemic vascular resistance (p=0.022) and with altered expression of 622 genes, (p<0.05), with 622 genes also altered in donors (p<0.05) including MRAS (+1.58-fold, p=0.0009). Genes differentially expressed between 3q22.3 genotypes were enriched for cell adhesion and muscle contraction processes in patients (p=1.3x10-4, p=1.1x10-2 respectively) and donors (p=5.8x10-5, p=8.2x10-5 respectively), and formed regulatory networks with MRAS. A subset of genes was altered in both patients and donors (1q41, 159 genes; 3q22.3, 36 genes). These data suggest that networks of genes may be altered in association with 1q41 and 3q22.3 in heart, both before and after disease onset, and may influence risk of CAD.
- © 2011 by American Heart Association, Inc.