Identification of genetic variants that influence atherosclerosis in young persons
Atherosclerosis is widely accepted as a complex genetic phenotype and is the usual cause of cardiovascular disease, the world’s leading killer. Genetic factors have been proven to be important risk contributors for atherosclerosis and much work has been done to identify promising candidates that might play a role in the development of atherosclerosis. It is well known that many independent replications are needed to unequivocally establish a valid genotype-phenotype association across different populations before the findings are extended to clinical settings and to the expensive follow-up studies designed to identify causal genetic variants. Aiming to replicate the association with atherosclerosis in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, we assessed the relationship of 32 atherosclerosis candidate SNPs to atherosclerosis in the PDAY cohort, consisting of AA and EA young people aged 15-34 years who died of non-medical causes. Two association studies, a whole sample study and a 1:1 matched case control study were performed by use of multiple linear regression and logistic regression analyses, respectively. For the whole sample association study, 32 SNPs among 2,650 individuals (1,369 AA and 1,281 EA) were tested for the association with six early atherosclerosis phenotypes: abdominal aorta fatty streaks, abdominal aorta raised lesions, right coronary artery fatty streaks, right coronary artery raised lesions, thoracic aorta fatty streaks, and thoracic aorta raised lesions. For the matched case-control association study, 337 case-control paired samples were included; cases were chosen with the highest total raised lesion scores from the studied population, while controls were randomly selected from individuals that had no raised lesions and matched to cases by age, gender and race. Sixteen SNPs in 13 genes were found to be significantly associated with atherosclerosis in at least one of the PDAY association studies. Among these 16 findings: eight SNPs (rs9579646, rs6053733, rs3849150, rs10499903, rs2148079, rs5073691, rs10116277, and rs17228212) successfully replicated previous results, six SNPs (rs17222814, rs10811661, rs7028570, rs7291467, rs16996148 and rs10401969) were reported as new findings exclusive to our study, the last two of the 16 SNPs, rs501120 and rs6922269, showed either intriguing or conflicting result. SNP rs17222814 in ALOX5AP and SNP rs3849150 in LRRC18 were consistently associated with atherosclerosis in both prior and the two PDAY association studies. SNP rs3849150 was also identified to be highly correlated with a non-synonymous coding SNP, rs17772611, which may damage the protein (polyphen score = 0.996), suggesting that SNP rs17772611 may be the causal functional variant. In conclusion, our study added more support for the association of these candidate genes with atherosclerosis. SNPs rs3849150 and rs17772611 of LRRC18, as well as SNP rs17222814 of ALOX5AP, were the most significant findings from our study, and may be ranked among the best for further study.
Gong, Yun, "Identification of genetic variants that influence atherosclerosis in young persons" (2011). Texas Medical Center Dissertations (via ProQuest). AAI1506924.