Peroxisome Proliferator-Activated Receptor-Gamma Gene Polymorphism and Risk of Cardiovascular Disease in Patients with Diabetic Nephropathy

Abstract

Background: Peroxisome proliferator-activator receptor-gamma (PPAR-γ) is a nuclear receptor that serves important roles in intermediate metabolism. We examined the relationship between two PPAR-γ gene polymorphisms, namely the P12A and C161T, and cardiovascular disease in patients with diabetic nephropathy. Methods: We studied 170 predialysis and 50 peritoneal dialysis patients with diabetic nephropathy. The PPAR-γ genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assay. The patients were then followed prospectively for the development of cardiovascular events. Cardiovascular mortality and all-cause mortality were also compared. Results: There were 91 male cases. The mean age was 64.3 ± 10.6 years. The frequencies of Pro/Pro and Pro/Ala genotypes of the P12A polymorphism were 95 and 5%, respectively; CC, CT and TT genotypes of the C161T polymorphism were 55.5, 39.5 and 5.0%, respectively. For the P12A polymorphism, the event-free survival was 56.5 and 9.1% at 60 months for Pro/Pro and Pro/Ala genotypes, respectively (p = 0.0005). For the C161T polymorphism, the event-free survival was 61.5 and 44.9% for CC and CT/TT genotypes, respectively (p = 0.0044). By multivariate analysis with the Cox proportional hazard model to adjust for confounders, the independent factors for event-free survival were P12A and C161T polymorphisms, age and diastolic blood pressure. In this model, the Pro/Ala genotype conferred 7.6-fold (95% CI 2.1- to 28.0-fold, p = 0.002) excess hazard of developing primary cardiovascular end point as compared to the Pro/Pro genotype, while each T allele at the 161 position conferred 83.4% (95% CI 15.2–291.9%, p = 0.011) excess hazard. Conclusions: We conclude that P12A and C161T polymorphisms of the PPAR-γ gene are important predictors of cardiovascular event in patients with diabetic nephropathy. Further studies are needed to examine the interaction of PPAR-γ gene polymorphisms and thiazolidinedione treatment on the cardiovascular risk in this group of patients.