Peroxisome proliferator-activated receptor gamma 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-gamma) is an important nuclear signaling protein that may regulate inflammatory response, and recent studies have revealed genetic polymorphisms that have significant effect on PPAR-gamma signaling. The aim of this study was to clarify whether the PPAR-gamma 161C/T and PPAR-gamma2 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-alpha, 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-gamma 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-gamma 161 CC and PPAR-gamma2 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-alpha (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.


CONCLUSIONS
This study demonstrates significant differences in PPAR-gamma genotype distribution between ESRD patients and healthy controls. Furthermore, as the PPAR-gamma2 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.
Yao
Q
Q
Division of Baxter Novum and Renal Medicine, Department of Clinical Science, Karolinska Institute, Stockholm, Sweden.
Nordfors
L
L
Axelsson
J
J
Heimbürger
O
O
Qureshi
A R
AR
Báràny
P
P
Lindholm
B
B
Lönnqvist
F
F
Schalling
M
M
Stenvinkel
P
P
D000328:Adult; D000368:Aged; D015415:Biomarkers; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000401:mortality; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D017582:Renal Replacement Therapy; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015415:Biomarkers; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha