Genetic Variation in Adiponectin Receptor 1 and Adiponectin Receptor 2 Is Associated With Type 2 Diabetes in the Old Order Amish

Abstract

Adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) are newly identified receptors for adiponectin, an adipocytokine with anti-inflammatory and insulin-sensitizing properties. We screened for polymorphisms by performing sequence analysis on all eight exons, splice junctions, and ∼2 kb of the 5′ flanking regions of each receptor. We detected 5 single nucleotide polymorphisms (SNPs) in ADIPOR1 and 16 SNPs in ADIPOR2. We genotyped these SNPs in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) to test for association with type 2 diabetes. Three intronic SNPs in ADIPOR1 were significantly associated with type 2 diabetes (P = 0.014–0.007; odds ratio [OR] 1.61–1.65) and in high linkage disequilibrium (r2 = 0.97–1.0). In ADIPOR2, we found that five SNPs delineated one large haplotype block (r2 = 0.9–1.0) spanning >98 kb of the gene and promoter region, which was strongly associated with the combined type 2 diabetes/IGT trait (P ≤ 0.001; OR 1.64–1.71). To our knowledge, these data provide the first evidence for association between variation in the adiponectin receptors and type 2 diabetes.