Cytokine Gene Polymorphism in CRIC Cohort

描述(由申请人提供)：慢性肾脏疾病(CKD)患者发生包括心血管疾病在内的各种不良健康后果的风险增加。然而，CKD的进展速度在不同患者之间差异很大，即使在校正了肾脏疾病的病因和合并疾病后也是如此。由于在肾脏疾病中观察到高水平的循环细胞因子，细胞因子尽管其基因中自然发生的序列变异(多态)，但调节CKD的进展速度和CVD结局的易感性是可信的。这一应用的中心假设是，细胞因子基因多态性通过改变促纤维化和炎性细胞因子的表达，将调节CKD患者肾脏疾病的进展速度和心血管疾病的发生率。这项建议的主要目的是：(1)确定白细胞介素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在慢性肾功能不全(CRIC)队列中的细胞因子基因多态和单倍型的患病率；以及(2)评估特定基因多态/单倍型与(A)血浆细胞因子、(B)肾功能减退率和(C)心血管疾病在CRIC队列中的发生率、严重程度和死亡率之间的关系。方法：CRIC研究正在检查一大批CKD患者的肾脏和心血管疾病的进展情况，以及健康结局变量。为了实现这一目标，将对3000名肾功能水平不同的患者进行约5年的跟踪调查。审评委联合体促进和参与辅助研究，以补充上级审评委研究的主要目标。审评委指导委员会对这项辅助提案进行了严格的评估并予以批准。我们将使用母公司CRIC研究汇编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，我们将结合候选单核苷酸多态(SNP)和TAG-SNP方法，为此将选择TAG-SNP的种族特异性小组。每个基因的单倍型将从所有基因分型的Tag-SNPs和选定的功能性SNPs中推断出来。在基线和随访4年时测定血浆细胞因子水平。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指标的关联将通过适当的统计模型来确定。意义：识别高危基因类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.