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The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes


Genetic association studies are viewed as problematic and plagued by irreproducibility1. Many associations have been reported for type 2 diabetes2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPARγ) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARγ. An initial study found a threefold effect12, but four of five subsequent publications18,19,20,21,22 failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARγ in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk—influencing as much as 25% of type 2 diabetes in the general population.

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We thank B. Langhorst and P. Almgren for contributions to patient and genotype databases; A. Berglund, L. Roslund and M. Svensson for skilful laboratory assistance; M. Erdos for PCR primers to IRS1; C. Cellier, J. Faith, P. Perron, G. Houde, C. Betard and M.-E. Allard for their contributions to the Canadian study; The Botnia Research Team for clinical contributions; and members of the Whitehead Institute Center for Genome Research for helpful discussions. J.N.H. and D.M.A. are recipients of the Post-doctoral Fellowship for Physicians from the Howard Hughes Medical Institute. C.M.L. is sponsored by the Fund for Strategic Research through NNCR. L.G. receives support from the Sigrid Juselius Foundation, the JDF Wallenberg Foundation, the Finnish Diabetes Research Foundation, The Swedish Medical Research Council, the Novo-Nordisk Foundation and an EC Paradigm grant (BH K99JD-12812-01A; L.C.G). This work was supported in part by grants from Affymetrix Inc., Millennium Pharmaceuticals Inc. and Bristol-Myers Squibb Company to E.S.L.

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Correspondence to Eric S. Lander.

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Figure 1: Estimated risk (with 95% confidence intervals) for PPARγ Pro12Ala.