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

Genetic association studies are viewed as problematic and plagued by irreproducibility(1). Many associations have been reported for type 2 diabetes(2-17), 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-gamma (PPAR gamma) 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 (similar to 85% frequency). Moreover. our results resolve a controversy about common variation in PPAR gamma. An initial study found a threefold effect(12). but four of five subsequent publications(18-22) failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPAR gamma 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.