Identification of Genes for ESRD in African Americans

描述（由申请人提供）： 终末期肾病（ESRD）是一个主要的临床和公共卫生问题，特别是在非裔美国人中。该提案是 NIH-NIDDK 资助的糖尿病和肾病家庭调查 (FIND) 和终末期肾病患者护理健康结果选择 (CHOICE) 研究、正在进行的确定肾病易感基因的多中心研究 (FIND) 以及终末期肾病患者心血管结局的危险因素 (CHOICE) 的一项辅助研究。 该提案的总体目标是确定新的基因座，并最终确定基因，这可能部分解释了非洲裔美国人与白人相比，终末期肾病风险过高的原因。为了实现这一目标，我们将采用混合连锁不平衡图谱 (MALD) 分析（一种特殊的连锁不平衡图谱形式）对大约 2,500 名非裔美国参与者进行全基因组关联研究，这些参与者已经被招募并进行了肾脏表型特征分析，并收集和分离了 DNA。我们假设一些肾脏疾病易感性等位基因在非裔美国人中的出现频率高于白人，并且非裔美国人基因组的特定区域包含 ALD 中具有 ESRD 易感性等位基因的标记等位基因。这一假设将通过综合评估约 1,400 名患有 ESRD 的非裔美国人病例和 750 名无肾病的非裔美国人对照患者的 MALD 标记来检验。我们将： 1) 使用先进的高通量基因分型系统，对约 2,500 名非裔美国人参与者（近 700 万种基因型）的 DNA 中约 3,000 个非裔美国人 MALD 标记（平均间距 1.2 cM）进行基因分型； 2) 利用 ~1 cM 密集遗传图谱进行全基因组关联分析，并识别病例对照设计中 ALD 伴 ESRD 的染色体位点、病例对照设计中归因于糖尿病的 ESRD，以及 1,100 名无 ESRD 个体的定量肾脏表型，3) 使用紧密间隔的 SNP 标记来精细绘制 ALD 伴 ESRD 的假定染色体区域。 所提出的遗传分析是创新的，是对更传统的连锁技术的补充，而不是母研究核心方案的一部分。这项研究将为 ESRD 易感性的基因控制提供重要见解

DESCRIPTION (provided by applicant): End stage renal disease (ESRD) is a major clinical and public health problem, especially in African Americans. This proposal is an ancillary study to the NIH-NIDDK funded Family Investigation of Diabetes and Nephropathy (FIND) and the Choices for Healthy Outcomes in Caring for ESRD patients (CHOICE) studies, ongoing multicenter studies to identify susceptibility genes for nephropathy (FIND), and risk factors for cardiovascular outcomes in ESRD patients (CHOICE). The overall objective of this proposal is to identify novel loci, and ultimately genes, that may partially account for excess risk of ESRD in African Americans compared to whites. To achieve this goal, we will employ Mapping by Admixture Linkage Disequilibrium (MALD) analysis, a specialized form of linkage disequilibrium mapping, to perform a genome-wide association study in approximately 2,500 African-American participants who have already been recruited and characterized with respect to renal phenotypes and had DNA collected and isolated. We hypothesize that some renal disease susceptibility alleles are present at higher frequency in African Americans than in whites and that specific regions of the genome in African Americans contain marker alleles that are in ALD with ESRD susceptibility alleles. This hypothesis will be tested by comprehensively evaluating MALD markers in approximately 1,400 African-American cases with ESRD and 750 African-American controls without renal disease. We will: 1) genotype ~3,000 African-American MALD markers (1.2 cM average spacing) in DNA from approximately 2,500 African-American participants (almost 7 million genotypes) using an advanced, high-throughput genotyping system; 2) perform a genome-wide association analysis utilizing a ~1 cM dense genetic map and identify chromosomal loci that are in ALD with ESRD in a case-control design, ESRD attributable to diabetes in a case-control design, and quantitative renal phenotypes amongst 1,100 individuals without ESRD, 3) use closely-spaced SNP markers to fine map putative chromosomal region in ALD with ESRD. The proposed genetic analyses are innovative and complementary to the more traditional linkage techniques and not part of the core protocols of the parent studies. This study will provide key insights into the genetic control of susceptibility of ESRD