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Analysis of Separate and Combined Effects of Common Variation in KCNJ11 and PPARG on Risk of Type 2 Diabetes

Steno Diabetes Center and Hagedorn Research Institute (S.K.H., E.-M.D.N., J.E., G.A., C.G., B.C., K.B.-J., T.H., O.P.), Gentofte, Copenhagen, Denmark; Research Center for Prevention and Health, Copenhagen County, Glostrup University Hospital (C.G., T.D., K.B.-J., T.J.), Glostrup, Denmark; Exiqon A/S (P.M.), Vedbæk, Denmark; and Faculty of Health Science, University of Aarhus (K.B.-J., O.P.), Aarhus, Denmark

Address all correspondence and requests for reprints to: Professor Oluf Pedersen, M.D., D.M.Sc., Steno Diabetes Center and Hagedorn Research Institute, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. E-mail: oluf{at}steno.dk.

The separate and combined effects of the PPARG Pro¹²Ala polymorphism and the KCNJ11 Glu²³Lys polymorphisms on risk of type 2 diabetes were investigated in relatively large-scale, case-control studies. Separate effects of the variants were examined among 1187/1461 type 2 diabetic patients and 4791/4986 middle-aged, glucose-tolerant subjects. The combined analysis involved 1164 type 2 diabetic patients and 4733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of the KCNJ11 Glu²³Lys associated with type 2 diabetes (odds ratio, 1.19; P = 0.0002), whereas the PPARG Pro¹²Ala showed no significant association with type 2 diabetes. The combined analysis indicated that the two polymorphisms acted in an additive manner to increase the risk of type 2 diabetes, and we found no evidence for a synergistic interaction between them. Analysis of a model with equal additive effects of the two variants showed that the odds ratio for type 2 diabetes increased with 1.14/risk allele (P = 0.003). Together, the two polymorphisms conferred a population-attributable risk for type 2 diabetes of 28%. In conclusion, our results showed no evidence of a synergistic interaction between the KCNJ11 Glu²³Lys and PPARG Pro¹²Ala polymorphisms, but indicated that they may act in an additive manner to increase the risk of type 2 diabetes.

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