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的进展速度在患者之间差异很大，即使在肾脏疾病和合并症的病因校正后也是如此。由于在肾脏疾病中观察到高水平的循环细胞因子，细胞因子虽然在其基因中自然发生序列变异（多态性），但似乎可以调节CKD的进展速度和对CVD结果的易感性。本应用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症细胞因子的表达，将调节CKD患者肾脏疾病的进展速度和CVD的发病率。本建议的主要目的是：(1)确定慢性肾功能不全队列（CRIC）参与者中白细胞介素-1 （IL-1）、IL-1受体拮抗剂、IL-6、IL-10、肿瘤坏死因子-a和转化生长因子-p的细胞因子基因多态性和单倍型的患病率；(2)评估特定基因多态性/单倍型与(a)血浆细胞因子、(b)肾功能下降率、(c)心血管疾病发病率、严重程度和死亡率之间的关系。方法：CRIC研究在一个大型CKD患者队列中检查肾脏和心血管疾病的进展以及健康结局变量。为了实现这一目标，将对3000名不同肾功能水平的患者进行大约5年的随访。CRIC联盟促进并参与辅助研究，以补充母体CRIC研究的主要目的。CRIC指导委员会已严格评估并批准了该辅助提案。我们将使用母体CRIC研究收集的生物样本和临床数据。对于感兴趣的细胞因子基因分型，我们将结合候选单核苷酸多态性（SNP）和标签-SNP方法，选择种族特异性标签-SNP面板。每个基因的单倍型将从所有基因型标记snp和选定的功能snp中推断出来。在基线和第4年随访时测量血浆细胞因子水平。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果的关系将通过适当的统计建模来确定。意义：识别高风险基因型可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.