Xia J, Scherer S W, Cohen P T, Majer M, Xi T, Norman R A, Knowler W C, Bogardus C, Prochazka M
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA.
Diabetes. 1998 Sep;47(9):1519-24. doi: 10.2337/diabetes.47.9.1519.
Selected candidate genes have been analyzed in the Pima Indians of Arizona based on evidence that insulin resistance and type 2 diabetes have significant genetic determinants. An amino acid substitution at codon 905 of the glycogen-targeting subunit of type 1 protein phosphatase that regulates skeletal muscle glycogenesis was recently reported to be associated with changes in insulin action in Danish subjects. In addition to the variant at 905, we report here a novel substitution at codon 883 and common variant of an "ATTTA" element in the 3'-untranslated region (UTR) of the corresponding gene (PPP1R3). The 3'-UTR variant resembled the mRNA-destabilizing AT(AU)-rich elements (AREs) and resulted in a 10-fold difference in reporter mRNA half-life, was correlated with PPP1R3 transcript and protein concentrations in vivo, and was associated with insulin resistance and type 2 diabetes in the Pimas. The variant is more common in Pimas (0.56) than in Caucasians (0.40). Because of its apparent effect on expression of PPP1R3, it may, in part, contribute to the higher prevalence of type 2 diabetes in this Native American population.
基于胰岛素抵抗和2型糖尿病具有重要遗传决定因素的证据，已对亚利桑那州皮马印第安人选定的候选基因进行了分析。最近有报道称，在调节骨骼肌糖原生成的1型蛋白磷酸酶的糖原靶向亚基密码子905处的氨基酸替换与丹麦受试者胰岛素作用的变化有关。除了905处的变异外，我们在此报告了相应基因（PPP1R3）3'非翻译区（UTR）密码子883处的一种新替换以及“ATTTA”元件的常见变异。该3'-UTR变异类似于使mRNA不稳定的富含AT（AU）的元件（ARE），导致报告基因mRNA半衰期相差10倍，与体内PPP1R3转录本和蛋白质浓度相关，并与皮马人的胰岛素抵抗和2型糖尿病相关。该变异在皮马人（0.56）中比在高加索人（0.40）中更常见。由于其对PPP1R3表达的明显影响，它可能在一定程度上导致了这个美国原住民群体中2型糖尿病的较高患病率。
