Cardiovascular risk in type 2 diabetes is associated with variation at the PPARG locus: A go-DARTS study

Objective - The Pro12Ala polymorphism of PPARG modulates risk of developing type 2 diabetes. The Ala allele has also been associated with a reduced risk of cardiovascular events. We have shown previously that the linked T allele of the C1431T polymorphism influences Ala12-associated diabetes risk and that the 2 polymorphisms have opposing associations with body weight. We therefore investigated the association of these 2 variants with cardiovascular events in people with type 2 diabetes. Methods and Results - We performed a cohort study of 2016 individuals and used Cox proportional hazards to analyze risk of myocardial infarction or death by PPARG Pro12Ala and C1431T genotypes, adjusting for age, sex, and smoking status. In individuals enrolled <70 years of age, the hazard for a first nonfatal event associated with the Ala12 allele was 0.21 (CI, 0.06 to 0.69; P=0.01) and the T1431 allele 9.9 (CI, 1.90 to 51.29; P=0.007). These opposing associations remained significant after correction for other conventional risk factors. The T1431 allele was also associated with all-cause mortality. Conclusions - This study confirms the association of the Ala12 allele with reduced risk of myocardial infarction in a type 2 diabetic population and demonstrates that the T allele independently associates with an increased risk.