Peroxisome proliferator-activated receptor γ polymorphisms affect systemic inflammation and survival in end-stage renal disease patients starting renal replacement therapy

Background: Inflammation may contribute to the markedly increased cardiovascular morbidity and mortality in end-stage renal disease (ESRD). However, the prevalence of inflammation varies in different ESRD populations. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an important nuclear signaling protein that may regulate inflammatory response, and recent studies have revealed genetic polymorphisms that have significant effect on PPAR-γ signaling. The aim of this study was to clarify whether the PPAR-γ 161C/T and PPAR-γ2 Pro12Ala single-nucleotide polymorphisms (SNPs) influence the inter-individual variance of inflammation and mortality in ESRD patients. Methods: The present prospective study included 229 incident Caucasian ESRD patients (62% males) just prior to starting renal replacement therapy and 207 healthy controls (62% males). Blood samples were taken for measuring systemic inflammatory (CRP, TNF-α, IL-6) and nutritional (S-albumin) parameters. The presence of diabetes mellitus, malnutrition (subjective global assessment (SGA)) and cardiovascular disease (CVD) were also assessed. Genotyping of the two PPAR-γ SNPs was performed using Pyrosequencing™. During follow-up (1621 ± 63 days), both all-cause and CVD-mortality were investigated. Results: ESRD patients had a higher prevalence of both the PPAR-γ 161 CC and PPAR-γ2 Pro12Pro genotypes than the general population (p < 0.01). Whereas the Pro12Pro genotype was associated with higher median serum levels of both hs-CRP (p < 0.05) and TNF-α (p < 0.01) the 161CC genotype was associated with a significantly higher (6.6 mg/L versus 3.3 mg/L; p < 0.01) median hs-CRP level. Following adjustment for age, gender, SGA and CVD a significantly higher mortality rate was observed in patients with the Pro12Pro genotype. Conclusion: This study demonstrates significant differences in PPAR-γ genotype distribution between ESRD patients and healthy controls. Furthermore, as the PPAR-γ2 Pro12Pro genotype was associated with both higher levels of biomarkers of inflammation as well as shorter survival, genetic polymorphisms seem to play a role in determining systemic inflammatory status and outcome in this patient group.