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Variation in the AU(AT)-Rich Element within the 3'-Untranslated Region of PPP1R3 Is Associated with Variation in Plasma Glucose in Aboriginal Canadians¹

Robarts Research Institute and Department of Medicine (R.A.H., J.W., H.C.), and the Center for Studies in Family Medicine (S.B.H.), University of Western Ontario, London, Ontario, Canada N6A 5K8; and the Samuel Lunenfeld Research Institute and Department of Medicine, Mount Sinai Hospital (B.Z., A.J.G.H.), and the Department of Genetics, The Hospital for Sick Children, University of Toronto (L.-C.T., S.W.S.), Toronto, Ontario, Canada M5G 1X8

Address all correspondence and requests for reprints to: Robert A. Hegele, M.D., Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406–100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail: robert.hegele{at}rri.on.ca

We are investigating associations between variations in candidate genes on chromosome 7q and diabetes-related phenotypes in Canadian Oji-Cree. One of these genes encodes the skeletal muscle regulatory G subunit of the glycogen-associated form of protein phosphatase 1 (PPPIR3), which may play a key role in muscle glycogen metabolism. There is a common 5-bp insertion-deletion polymorphism in a messenger ribonucleic acid-stabilizing AU(AT)-rich element within the 3'-untranslated region (UTR) of PPPIR3. The D allele had a frequency of 0.30 in the Oji-Cree. We found that this 3'-UTR variation of PPPIR3 was significantly associated with variation in 2-h postprandial glucose in adult Oji-Cree with type 2 diabetes or impaired glucose tolerance (IGT). Specifically, Oji-Cree with diabetes or IGT who were D/D homozygotes had significantly lower 2-h postprandial plasma glucose than subjects with the other genotypes. There was no association of the PPPIR3 genotype either with the presence of type 2 diabetes or IGT or with other quantitative traits in this sample. These findings suggest that common PPPIR3 3'-UTR variation that potentially affects messenger ribonucleic acid stability is associated with variation in glycemia in Oji-Cree subjects with type 2 diabetes.

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