Patients with chronic kidney disease (CKD) are at increased risk for various adverse health outcomes including cardiovascular disease. However, the rate of progression of CKD varies widely among patients, even when corrected for the etiology of renal disease and co-morbid conditions. Because high levels of circulating cytokines are observed in renal disease, it is plausible that cytokines, though naturally occurring sequence variation (polymorphisms) in their genes, modulate the rate of progression of CKD and the susceptibility to CVD outcomes. The central hypothesis of this application is that cytokine gene polymorphisms, through altered expression of pro- fibrotic and inflammatory cytokines, will modulate the rates of progression of renal disease and incidence of CVD among CKD patients. The principal aims of this proposal are: (1) Determine the prevalence of cytokine gene polymorphisms and haplotypes of interleukin-1 (IL-1), IL-1 receptor antagonist, IL-6, IL-10, tumor necrosis factor-a, and transforming growth factor-p among chronic renal insufficiency cohort (CRIC) participants;and (2) Evaluate the association between specific gene polymorphisms/haplotypes and (a) plasma cytokines, (b) the rate of decline of renal function, and (c) incidence of, severity of and mortality from CVD in the CRIC cohort. Methods: The CRIC study is examining the progression of renal and CV diseases, and health outcome variables in a large cohort of patients with CKD. In order to achieve this aim, a cohort of 3,000 patients with varying level of renal function will be followed for approximately 5 years. CRIC consortium promotes and participates in ancillary studies that complement the principal aims of the parent CRIC study. The CRIC steering committee has critically evaluated and approved this ancillary proposal. We will use the biological samples and clinical data compiled by the parent CRIC study. For genotyping cytokine genes of interest, we will combine a candidate single nucleotide polymorphism (SNP) and tag-SNP approach, for which race-specific panels of tag-SNPs will be chosen. Haplotypes for each gene will be inferred from all genotyped tag-SNPs and selected functional SNPs. Plasma cytokine levels will be measured at baseline and at the 4th year of follow-up. The association of cytokine alleles and haplotypes with plasma cytokine levels and clinical outcome measures will be determined by appropriate statistical modeling. Significance: Identification of the high risk genotypes can lead to early and aggressive interventions aimed at the target population.
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