Genome Wide Association of Renal Progression in the CRIC Study

描述(由申请人提供)： 在这份NIH恢复法案竞争性修订基金申请提案中，我们建议利用NIDDK资助的慢性肾功能不全队列(CRIC)研究提供的独特丰富的数据集，这与其主要目标有关，即更好地了解与慢性肾脏疾病(CKD)进展相关的因素。目的是通过增加全面的基因分型作为在进展性慢性肾脏病和相关结果的背景下研究的关键变量的附加维度，显著扩大原始研究的范围。我们的主要假设是，在已确诊的慢性肾脏病患者中，不明原因的基因变异对肾功能的可变性进行性丧失有显著影响。CRIC研究是一项大型前瞻性、多中心、CKD队列研究，共有3939名参与者。我们计划对3750名同意使用Affymetrix(R)6.0阵列进行基因研究的参与者进行全基因组基因分型。我们将能够利用对众多CKD危险因素和中间表型的系列标准化测量，并计划将SNP标记和拷贝数变异与肾脏结果相关联，包括肾小球滤过率的变化、终末期肾脏疾病的发展时间以及胱抑素C的测量变化。我们还将研究我们最常见的基因变异的潜在途径和效果修饰物。所有统计分析将分别在白人(CEU)和非裔美国人(AA)参与者中进行。我们将使用现有的全基因组研究结果复制我们的发现，这些结果来自几个代表高加索人和无CKD的AA受试者的大型队列研究。 相关性：这项研究的结果有望增加我们对进行性慢性肾脏病的遗传基础及其相关结果的理解。

DESCRIPTION (provided by applicant): In this NIH Recovery Act Funds for Competitive Revision Application proposal, we propose to leverage the unique rich data set available from the NIDDK-funded Chronic Renal Insufficiency Cohort (CRIC) study, as related to its principal aims of better understanding factors associated with progression of chronic kidney disease (CKD). The goal is to significantly expand the scope of the original study by adding comprehensive genotyping as an added dimension of critical variables to be studied in the context of progressive CKD and related outcomes. Our primary hypothesis is that unidentified gene variants contribute significantly to the variable progressive loss of renal function in subjects with established CKD. The CRIC study is a large prospective, multi-center, CKD cohort with 3939 participants. We plan to complete a genome-wide genotyping on 3750 participants who have consented for genetic studies using the Affymetrix(R) 6.0 array. We will be able to take advantage of the serial standardized measurement of numerous CKD risk factors and intermediate phenotypes and plan to associated SNP markers and copy number variants with renal outcomes including change in glomerular filtration rate, time to development of end-stage renal disease, and change in measures of cystatin C. We will also investigate potential pathways and effect modifiers of our top identified gene variants. All statistical analyses will be undertaken separately within white (CEU) and African American (AA) participants. We will replicate our findings in silico using existing genome-wide results available from several large cohort studies representing Caucasian and AA subjects without CKD. RELEVANCE: The results from this study is expected to increase our understanding the genetic underpinning of progressive CKD and associated outcomes.