Abstract P112: Genes in Genome-wide Association Study-identified Loci and Risk of Atherosclerosis in Adolescents and Young Adults

Abstract

Background: Genome-wide association studies (GWASs) have identified multiple genomic loci associated with atherosclerotic diseases. However, specific genes underlying the observed associations are largely unknown. Objectives: We aimed to examine the associations between genes that harbor variants in high LD with index variants in GWAS-identified loci and pathologically determined atherosclerosis in major arteries from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Methods and Results: Data for 1,938 single nucleotide polymorphisms (SNPs) from 28 genes were retrieved from whole exome sequence data. Atherosclerosis was confirmed by postmortem examination of major arteries from 1,005 young persons (aged 15-34 years) who died from non-cardiovascular causes. Logistic regression was used to evaluate associations between common SNPs and atherosclerosis controlling for age and sex. Gene-based analysis was conducted using Sequence Kernel Association Test (SKAT) method to test the combined effect of rare and common variants on atherosclerosis controlling for age and gender. All analyses were performed separately in blacks and whites. Statistical significance was determined by false positive discovery rate (FDR) method. In gene-based analyses, BUD13 ( P =1.11х10 -2 ) and COL4A1 ( P =3.58х10 -2 ) were associated with atherosclerosis among young blacks; none of the 28 genes was associated with atherosclerosis in whites. In single marker analysis of common SNPs, LRP1 missense variant rs7397167 ( P =8.50х10 -3 ), COL4A1 variant rs16975492 ( P =4.60х10 -3 ), STK32B variant rs168985 ( P =4.00х10 -3 ), and SMARCA4 variant rs8104480 ( P =1.20х10 -3 ) were associated with atherosclerosis in blacks; MIA3 variant rs17465637 ( P =8.00х10 -3 ), DUS4L missense variant rs6957510 ( P =6.4х10 -3 ), BOLL variant rs771018 ( P =6.2х10 -3 ), BUD3 missense variant rs11820589 ( P =2.1х10 -3 ), and COL4A1 variant rs1133219 ( P =1.8х10 -3 ) were associated with atherosclerosis in whites. Conclusion: Genes in GWAS-identified loci may play a role in the development of atherosclerosis at a young age.