Cytokine Gene Polymorphism in CRIC Cohort

描述（由申请人提供）：慢性肾脏疾病（CKD）患者发生各种不良健康结局（包括心血管疾病）的风险增加。然而，CKD的进展率在患者之间差异很大，即使校正了肾脏疾病和共病的病因。由于在肾脏疾病中观察到高水平的循环细胞因子，因此细胞因子虽然在其基因中天然存在序列变异（多态性），但可能调节CKD的进展速率和对CVD结局的易感性。本申请的中心假设是，细胞因子基因多态性通过改变促纤维化和炎性细胞因子的表达，将调节CKD患者中肾脏疾病的进展速率和CVD的发病率。（1）确定慢性肾功能不全队列（CRIC）参与者中细胞因子基因多态性和白细胞介素-1（IL-1）、IL-1受体拮抗剂、IL-6、IL-10、肿瘤坏死因子-α和转化生长因子-β单倍型的患病率;和（2）评价特定基因多态性/单倍型与（a）血浆细胞因子，（B）肾功能下降速率，和（c）以下疾病的发生率之间的关联，CRIC队列中CVD的严重程度和死亡率。方法：CRIC研究正在检查一个大型CKD患者队列中肾脏和CV疾病的进展以及健康结局变量。为了实现这一目标，将对3，000例不同肾功能水平的患者进行约5年的随访。审评委联合体促进和参与辅助研究，补充审评委母研究的主要目标。审评委指导委员会严格评估并批准了这一辅助建议。我们将使用母CRIC研究编制的生物样本和临床数据。为了对感兴趣的细胞因子基因进行基因分型，我们将结合联合收割机候选单核苷酸多态性（SNP）和tag-SNP方法，选择种族特异性的tag-SNP组。每个基因的单倍型将从所有基因分型的tag-SNP和选择的功能SNP推断。将在基线和第4年随访时测量血浆细胞因子水平。将通过适当的统计建模确定细胞因子等位基因和单倍型与血浆细胞因子水平和临床结局指标的相关性。意义：识别高危基因型可以导致针对目标人群的早期和积极干预。

DESCRIPTION (provided by applicant): 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.