Association Study of Coronary Artery Disease-Associated Genome-Wide Significant SNPs with Coronary Stenosis in Pakistani Population

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.

Sorting through the extensive and confusing roles of sortilin in metabolic disease

“…In addition to the SNPs at the 1p13.3 CELSR2-PSRC1-SORT1 locus being strongly associated with circulating LDL-C levels, this locus is also associated with several contributors of CAD, including atherosclerosis and arterial calcification ( 17 , 18 , 229 , 244 , 246 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 ). While LDL-C is a major risk factor for atherosclerosis, studies have found that sortilin may play a role in the development of atherosclerosis independent of its effect on circulating LDL-C levels.…”

Large-Scale Whole Genome Sequencing Study Reveals Genetic Architecture and Key Variants for Breast Muscle Weight in Native Chickens

“…SNF8 , UBE2Z , CALCOCO2 , and ATP5MC1 have been shown a core function in metabolic disease and cancer. Partial QTLs or SNPs have been associated with coronary artery disease ( SNF8 and UBE2Z ) [ 54 , 55 ]. CALCOCO2 is associated with autophagy-related genes, influencing tumorigenesis and progression of osteosarcoma [ 56 ].…”

MRASin coronary artery disease—Unchartered territory

“…51 Furthermore, in Pakistani populations, no associations were detected between this Single Nucleotide Polymorphism (SNP) and CAD or lipid parameters. 52 Besides CAD, stroke is another clinical manifestation of atherosclerosis. Association of MRAS with atherosclerotic stroke was observed in a Han Chinese population including 202 patients and 188 controls.…”

“…In Czeck Slavonic population, rs9818870 was not associated with acute coronary syndrome or mortality 51 . Furthermore, in Pakistani populations, no associations were detected between this Single Nucleotide Polymorphism (SNP) and CAD or lipid parameters 52 …”

“…Furthermore, a study of Pakistani patients suffering from premature CAD demonstrated cytokine imbalance, manifested as a significant rise in the TNF‐to‐interleukin 10 (IL10) ratio, in carriers of the MRAS rs9818870 risk allele 61 . Although the variant rs9818870 was not associated with common CAD in a Pakistani cohort, 52 this association of a MRAS SNV with cytokine imbalance highlights its potential function in immune inflammatory pathogenic pathways underlying premature CAD 61 …”