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。这项建议是NIH-NIDDK资助的糖尿病和肾病家庭调查(FIND)和护理ESRD患者的健康结果选择(CHOICE)研究的辅助研究，正在进行的多中心研究旨在确定ESRD患者的肾病易感基因(FIND)和心血管结果的风险因素(CHOICE)。 这项建议的总体目标是识别新的基因座，并最终确定可能部分解释非裔美国人与白人相比患ESRD风险过高的基因。为了实现这一目标，我们将使用连锁不平衡图谱的一种特殊形式--混合物连锁不平衡图谱(MALD)分析，在大约2500名非洲裔美国人参与者中进行全基因组关联研究，这些参与者已经被招募，并根据肾脏表型进行了表征，并收集和分离了DNA。我们假设一些肾脏疾病易感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和ESRD易感基因的标记等位基因。这一假设将通过对大约1400名患有终末期肾病的非裔美国人和750名没有肾脏疾病的非裔美国人对照的MALD标志物进行综合评估来验证。我们将：1)使用先进的高通量基因分型系统，从大约2,500名非裔美国人参与者(近700万种基因型)的DNA中分型约3,000个非裔美国人的MALD标记(平均间距1.2 cM)；2)利用~1 cM的高密度遗传图谱进行全基因组关联分析，并在病例对照设计中识别与ESRD有关的ALD染色体座位，在病例对照设计中识别可归因于糖尿病的ESRD，以及在1,100名没有ESRD的个体中进行肾脏表型定量分析；3)使用紧密间距的SNP标记精细定位ALD与ESRD中可能的染色体区域。 拟议的遗传分析是对更传统的连锁技术的创新和补充，而不是亲代研究的核心方案的一部分。这项研究将为ESRD易感性的遗传控制提供关键的见解

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