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Aim: Interleukin-18 (IL-18) is a pro-inflammatory cytokine and possibly plays an important role in the pathogenesis of cardiovascular disease. The relationship between two IL-18 gene polymorphisms, namely C-607A and G-137C, and cardiovascular disease in patients with diabetic nephropathy was examined. Methods: Two hundred and twenty patients (91 male) with diabetic nephropathy were studied. The IL-18 promoter genotypes were determined. All patients were then prospectively followed for the cardiovascular events. Cardiovascular mortality and all-cause mortality were also compared. Results: Mean age was 64.3 ± 10.6 years; average follow up was 73.9 ± 33.6 months. The frequencies of CC, CA and AA genotypes of the C-607A polymorphism were 25.5%, 48.2% and 26.8%, respectively; GG, GC and CC genotypes of the G-137C polymorphism were 71.8%, 25.0% and 3.2%, respectively. Neither of the polymorphisms were associated with the development of primary cardiovascular end-point. Cardiovascular survival was 84.8% and 70.6% at 60 months for GG and GC/CC genotypes of the G-137C polymorphism, respectively ( P = 0.027); the corresponding actuarial survival was 69.0% and 54.8%, respectively ( P = 0.053). However, the G-137C genotype was not an independent predictor of cardiovascular or actuarial survival after adjusting for confounders by multivariate analysis with the Cox model. The C-607A polymorphism had no significant effect on cardiovascular or actuarial survival. Conclusion: The G-137C polymorphism of the IL-18 promoter is associated with the cardiovascular mortality, and a trend of association with all-cause mortality, in patients with diabetic nephropathy. The association, however, becomes insignificant after adjusting for confounding factors. Further studies are needed to test other genetic determinants of the association between systemic inflammation and cardiovascular disease in renal failure patients. [ABSTRACT FROM AUTHOR]

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. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]