Abstract 358: Genetic Determinants of Lower-Extremity Claudication in South Asians

Abstract

OBJECTIVES: The prevalence of peripheral arterial disease (PAD) in South Asian populations is less than that reported in populations of Western descent despite higher rates of MI and diabetes. This suggests that there may be a different underlying genetic predisposition to PAD in South Asian individuals. This study was designed to investigate the genetic determinants of PAD in a large Pakistani cohort. METHODS: We examined the association between single nucleotide polymorphisms (SNPs) and clinical symptoms of claudication in participants of the Pakistan Risk of Myocardial Infarction Study (PROMIS), a multicenter case-control study of MI in Pakistan, using its 1000-Genome imputed data set. RESULTS: 724 (4.8%) of the 15,570 individuals enrolled in PROMIS had symptoms of claudication. These subjects had an average (SD) age of 56 (9.7) years and 536 (74%) were male. To assess the role of known MI risk loci, 250 kBP regions flanking the 45 reported MI risk SNPs were examined for their association with claudication. No SNP in any of the known MI risk loci met the pre-determined Bonferroni p-value threshold for significance (<1x10-5). Likewise, a composite risk score based on reported MI risk related SNPs was not associated with claudication symptoms despite a highly significant correlation with MI (p=4.7x10-34). In genome wide analysis no SNP achieved significance with a p-value <5 x 10-8. There were, however, three SNPs with p-values <5 x 10-7, suggestive of potential associations with claudication: rs7580101 (p=1.1 x 10-7), rs4655022 (p=1.4 x 10-7), and rs57859654 (p=2.1 x 10-7). Interestingly, rs7580101 occurs within an intron of the gene for CD59, a complement inhibitor that has been demonstrated to modulate atherosclerosis in multiple mouse models. The CD59 gene has not been previously reported as a MI or PAD risk locus. CONCLUSIONS: These findings argue for a different genetic risk profile for PAD and CAD in South Asians, supporting the differences in PAD prevalence between this population and those of Western descent. Additionally, they identify numerous novel potential risk loci for PAD. Replication studies are currently underway to validate these findings.