Association of the Mu-opioid Receptor Gene with Type 2 Diabetes Mellitus in an African American Population

African Americans (AA) are at increased risk for developing type 2 diabetes mellitus (T2DM) relative to European Americans. We previously detected linkage of T2DM to 6q24-q27 (LOD 2.26) at 163.5 cM, closest to marker D6S1035, in a genome-wide scan of AA families. The mu-opioid receptor gene (OPRM1) is located within the LOD-1 support interval of this linkage peak. OPRM1 is an attractive positional candidate gene for T2DM susceptibility since agonists of OPRM1 affect glucose-induced insulin release and OPRM1 knockout mice have a more rapid induction of insulin resistance than wild-type. Twenty-two SNPs in this gene, at an average spacing of 3.9 kb, were genotyped in 380 AA T2DM cases and 276 AA controls. In single SNP association analyses, rs648007 demonstrated significant evidence of association with T2DM (P=0.013). Four blocks of high linkage disequilibrium were detected across the OPRM1 gene. Association analyses of haplotypes in each of these blocks revealed two haplotype blocks with significant overall P values (P=0.007 and 0.046). Significant, but rare, risk and protective haplotypes were identified as driving these associations with T2DM (P=0.034-0.047). These associations suggest that the OPRM1 gene plays a role in T2DM susceptibility in African Americans.