Abstract
Genome-wide association studies (GWAS) of coronary artery disease (CAD) have revealed multiple genetic risk loci. We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci with coronary stenosis in a Pakistani sample comprising 663 clinically ascertained and angiographically confirmed cases. Genotypes were determined using the iPLEX Gold technology. All statistical analyses were performed using R software. Linkage disequilibrium (LD) between significant SNPs was determined using SNAP web portal, and functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases. Genotyping comparison was made between cases with severe stenosis (≥70%) and mild/minimal stenosis (<30%). Five SNPs demonstrated significant associations: three with additive genetic models PLG/rs4252120 (p = 0.0078), KIAA1462/rs2505083 (p = 0.005), and SLC22A3/rs2048327 (p = 0.045) and two with recessive models SORT1/rs602633 (p = 0.005) and UBE2Z/rs46522 (p = 0.03). PLG/rs4252120 was in LD with two functional PLG variants (rs4252126 and rs4252135), each with a RegulomeDB score of 1f. Likewise, KIAA1462/rs2505083 was in LD with a functional SNP, KIAA1462/rs3739998, having a RegulomeDB score of 2b. In the GTEx database, KIAA1462/rs2505083, SLC22A3/rs2048327, SORT1/rs602633, and UBE2Z/rs46522 SNPs were found to be expression quantitative trait loci (eQTLs) in CAD-associated tissues. In conclusion, five genome-wide significant SNPs previously reported in European GWAS were replicated in the Pakistani sample. Further association studies on larger non-European populations are needed to understand the worldwide genetic architecture of CAD.
Highlights
Coronary artery disease (CAD) is more prevalent among South Asians than any other ethnic groups [1, 2]
Dyslipidemia has been identified as a major risk factor for CAD [8], and growing evidence shows that endothelial dysfunction, persistent inflammatory response, and impaired coagulation cascade play central roles in the initiation and progression of the disease [9,10,11]
We evaluated 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci that are involved in lipid metabolism, inflammation, coagulation, and endothelial function
Summary
Coronary artery disease (CAD) is more prevalent among South Asians than any other ethnic groups [1, 2]. Twin studies, and established genetic associations have confirmed the important role of genetics in CAD [3,4,5,6,7]. Dyslipidemia has been identified as a major risk factor for CAD [8], and growing evidence shows that endothelial dysfunction, persistent inflammatory response, and impaired coagulation cascade play central roles in the initiation and progression of the disease [9,10,11]. Genome-wide association studies (GWAS) for CAD carried out in populations of European descent have identified multiple loci [12, 13] that highlight the potential involvement of many pathways in CAD pathogenesis. It is of great importance to replicate reported GWAS associations in independent samples and different populations to assess the generalization of such associations.
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