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

Genetic association studies are viewed as problematic and plagued by irrepr oducibility(1). Many associations have been reported for type 2 diabetes(2- 17), but none have been confirmed in multiple samples and with comprehensiv e controls. We evaluated 16 published genetic associations to type 2 diabet es and related sub-phenotypes using a family-based design to control for po pulation stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorp hism 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 wit h the more common proline allele (similar to 85% frequency). Moreover. our results resolve a controversy about common variation in PPAR gamma. An init ial study found a threefold effect(12). but four of five subsequent publica tions(18-22) failed to confirm the association. All six studies are consist ent with the odds ratio we describe. The data implicate inherited variation in PPAR gamma in the pathogenesis of type 2 diabetes. Because the risk all ele occurs at such high frequency, its modest effect translates into a larg e population attributable risk-influencing as much as 25% of type 2 diabete s in the general population.