Abstract 1882: Chromosome 6q25.1 and 2q36.3 Coronary Heart Disease Risk Loci Are Associated With Altered Cardiac Gene Expression Profiles in Normal Heart
Genome-wide association studies have identified three chromosomal loci, 9p21.3, 6q25.1 and 2q36.3, that are strongly associated with risk of coronary heart disease. The mechanism underlying these associations is unknown. We hypothesized that variants within these loci may subtly alter cardiac gene expression and influence cardiovascular risk. We have previously demonstrated that the 9p21.3 locus is associated with altered cardiac gene expression profiles. This study investigated associations between 6q25.1 (rs6922269) and 2q36.3 (rs2943634), cardiac gene expression and in 108 heart-transplant donors with no overt cardiac abnormality. Individual cardiac gene expression profiles were generated with Affymetrix Human Gene 1.0 ST arrays. Taqman assays were used for DNA genotyping and cDNA expression assays. Gene expression levels in individuals homozygous for the minor allele (n=11 for each variant) were compared with the other genotypes combined and bioinformatic analysis was performed with DAVID and oPOSSUM software. Donor mean age was 48 years, ancestry was predominantly European (96%) and 51% were male. For 6q25.1, in homozygotes for the minor (risk) allele, expression of 154 genes was altered (p<0.01). Up-regulated genes (55%) were enriched for lysosomal proteins (p<0.0001) and proteins with hydrolase activity (p=0.008), while down-regulated genes were enriched for protein oligomerization pathways (p=0.025). For 2q36.3, in homozygotes for the minor (protective) allele, expression of 115 genes was altered (p<0.01). Up-regulated genes (74%) were enriched for G-protein coupled receptor signaling (p=0.018). Down-regulated genes were enriched for ribosomal proteins (p=0.008) and proteins involved in carbohydrate metabolism (p=0.019). For each variant, a subset of genes with a common set of transcription factor binding sites within evolutionary-conserved promoter regions were identified (p<0.002). Expression levels of genes closest to each variant were not altered in association with either genotype. Our data suggest that 6q25.1 and 2q36.3 risk loci are associated with an altered pattern of cardiac gene expression via shared transcriptional regulatory pathways, which may influence susceptibility to heart disease.