Abstract

Objective- Prior genome-wide association and exon array expression studies both provided suggestive evidence that ASK1 may influence in vivo insulin action in Pima Indians. Genetic variants in/near ASK1 were analyzed to assess the role of this gene in insulin action and type 2 diabetes.

Research Design And Methods- Genotypic data from 31 variants were used to determine the linkage disequilibrium pattern across ASK1 in Pima Indians. Eight tag SNPs were initially genotyped in 3,501 full-heritage Pima Indians. Replication for association with diabetes was assessed in a second population-based sample of 3,723 Native Americans and the published DIAGRAM study. Quantitative traits were analyzed in 536 non-diabetic Native Americans and ASK1 expression was examined in skeletal muscle of 153 non-diabetic Native Americans.

Results- Three tag SNPs were associated with type 2 diabetes (rs35898099, P = 0.003, OR[95%CI] = 1.27[1.08-1.47]; rs1570056, P = 0.007, OR[95%CI] = 1.19[1.05-1.36]; rs7775356, P = 0.04, OR[95%CI] = 1.14[1.01-1.28]) in the full-heritage Pima Indians. The association with rs35898099 was replicated in a second sample of Native Americans (P = 0.04, OR[95%CI] = 1.22[1.01-1.47]), while that for rs1570056 was replicated in the DIAGRAM study of Caucasians (Z-statistic based P = 0.026; fixed-effect model, OR[95%CI] = 1.06[1.00-1.12]). The diabetes risk allele for rs1570056 was associated with reduced insulin action as assessed by either HOMA-IR in 2,549 non-diabetic full-heritage Pima Indians (P = 0.027) or a hyperinsulinemic-euglycemic clamp among 536 non-diabetic Native Americans (P = 0.02). Real-time PCR identified a positive correlation between ASK1 expression in skeletal muscle biopsies and in vivo insulin action (P = 0.02, r = 0.23) and the risk allele for rs1570056 was associated with lower ASK1 expression (P = 0.003, r = −0.22).

Conclusions- ASK1 variants may increase susceptibility to type 2 diabetes by decreasing insulin sensitivity via reduced ASK1 expression.