A COMMON VARIANT IN PPP1R3 ASSOCIATED WITH INSULIN-RESISTANCE AND TYPE-2 DIABETES

Selected candidate genes have been analyzed in the Pima Indians of Ari zona based on evidence that insulin resistance and type 2 diabetes hav e significant genetic determinants, An amino acid substitution at codo n 905 of the glycogen-targeting subunit of type 1 protein phosphatase that regulates skeletal muscle glycogenesis was recently reported to b e associated with changes in insulin action in Danish subjects. In add ition to the variant at 905, we report here a novel substitution at co don 883 and common variant of an ''ATTTA'' element in the 3'-untransla ted region (UTR) of the corresponding gene (PPP1R3), The 3'-UTR varian t resembled the mRNA-destabilizing AT(AU)-rich elements (AREs) and res ulted in a 10-fold difference in reporter mRNA half-life, was correlat ed with PPP1R3 transcript and protein concentrations in vivo, and was associated with insulin resistance and type 2 diabetes in the Pimas. T he variant is more common in Pimas (0.56) than in Caucasians (0.40). B ecause of its apparent effect on expression of PPP1R3, it may, in part , contribute to the higher prevalence of type 2 diabetes in this Nativ e American population.