Candidate loci for insulin sensitivity and disposition index from a genome-wide association analysis of Hispanic participants in the Insulin Resistance Atherosclerosis (IRAS) Family Study

The majority of type 2 diabetes genome-wide association studies (GWAS) to date have been performed in European-derived populations and have identified few variants that mediate their effect through insulin resistance. The aim of this study was to evaluate two quantitative, directly assessed measures of insulin resistance, namely insulin sensitivity index (S-I) and insulin disposition index (DI), in Hispanic-American participants using an agnostic, high-density single nucleotide polymorphism (SNP) scan, and to validate these findings in additional samples. A two-stage GWAS was performed in Hispanic-American samples from the Insulin Resistance Atherosclerosis Family Study. In Stage 1, 317,000 SNPs were assessed using 229 DNA samples. SNPs with evidence of association with glucose homeostasis and adiposity traits were then genotyped on the entire set of Hispanic-American samples (n = 1,190). This report focuses on the glucose homeostasis traits: S-I and DI. Although evidence of association did not reach genome-wide significance (p = 5 x 10(-7)), in the combined analysis SNPs had admixture-adjusted p values of p (ADD) = 0.00010-0.0020 with 8 to 41% differences in genotypic means for S-I and DI. Several candidate loci were identified that are nominally associated with S-I and/or DI in Hispanic-American participants. Replication of these findings in independent cohorts and additional focused analysis of these loci is warranted.