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Peroxisome Proliferator-Activated Receptor-2 P12A and Type 2 Diabetes in Canadian Oji-Cree¹

John P. Robarts Research Institute (R.A.H., H.C., C.M.A.) and Centre for Studies in Family Medicine (S.B.H.), University of Western Ontario, London, Ontario, Canada N6A 5K8; and Samuel Lunenfeld Research Institute and Department of Medicine (B.Z., A.J.G.H.), Mount Sinai Hospital, University of Toronto, Ontario, Canada M5G 1X5

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

Among the Oji-Cree of northern Ontario, we previously identified a novel variant in the HNF1A gene, namely G319S, that was strongly associated with type 2 diabetes. However, the majority of subjects with diabetes did not have the HNF1A S319 variant, suggesting that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, we found that some of them had the PPARG A12 variant. After genotyping PPARG in the entire adult Oji-Cree population, we found that: 1) PPARG A12 was strongly associated with type 2 diabetes in women, but not men; 2) among women, the odds of being affected for carriers of PPARG A12 compared with noncarriers was 2.3 (95% confidence interval, 1.4–3.8); and 3) among women, affected carriers of PPARG A12 had a significantly earlier age-of-onset and/or age-at-diagnosis compared with noncarriers. When taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least two genes are involved in determining susceptibility to the disease in these people.

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