DIABETIC AND NONDIABETIC NEPHROPATHY SUSCEPTIBILITY GENE

该建议建立在我们团队在肾脏疾病流行病学，遗传流行病学和合作研究方面的丰富经验基础上。它利用了一项成功的全国性队列研究的基础设施，该研究对近1,000名事件ESRD患者进行了研究，并建立了DNA库。我们将与Dialysis Clinic，Inc.合作，一家为一万多名透析患者提供护理的非盈利连锁机构。国家癌症中心基因组多样性实验室的斯蒂芬奥布莱恩和迈克尔史密斯博士将使用一种创新技术。通过混合连锁不平衡（MALD）定位，以确定增加ESRD风险的基因。我们还将通过描述先证者的单倍型来扩展MALD。我们的研究将收集三人组（ESRD先证者、儿童和儿童的其他生物学父母），以鉴定单倍型，从而精确地寻找控制ESRD风险的基因。 我们将测试以下假设：1。存在增加糖尿病和非糖尿病肾病风险的肾病易感基因。2.一些肾脏疾病易感基因的存在增加了糖尿病和非糖尿病肾脏疾病的风险。2.一些肾脏疾病易感性等位基因在非洲裔美国人中的频率高于白人。3.非裔美国人基因组中约10-20 cM的特定区域与ESRD易感性等位基因处于混合连锁不平衡。为了进行这项研究，我们将招募1,000名非洲裔美国人，包括糖尿病和其他类型的ESRD病例，后代和孩子的另一个生物学父母。我们将利用一组新开发的452个微卫星标记进行全基因组MALD扫描。来自孩子和其他生物学父母的数据将用于先证者的单倍型以识别基因。我们还将在先证者及其患病儿童的混合连锁不平衡检验（TDT）分析区域中筛选基因多态性和突变，以测试候选基因。ESRD患者的数据收集可以非常有效地完成，因为DCI内部已经有了基础设施，可以快速廉价地收集DNA作为常规护理的一部分。我们已经在80家透析诊所培训了研究协调员，并证明了我们收集高质量临床信息的能力。我们提出的遗传分析是创新的，补充了更传统的连锁技术。我们期待着与联盟的其他成员合作，并贡献我们的数据，以提供更强大的力量，实现RFA的总体目标。

This proposal builds on our team's considerable experience in renal disease epidemiology, genetic epidemiology, and collaborative research. It utilizes the infrastructure of a successful, nationwide cohort study of nearly 1,000 incident ESRD patients in which a DNA bank has been established. We will collaborate with Dialysis Clinic, Inc., a not-for-profit chain that cares for over 10,000 dialysis patients. Drs. Stephen O'Brien and Michael Smith at the Laboratory of Genomic Diversity at the National Cancer will use an innovative technique. Mapping by admixture Linkage Disequilibrium (MALD), to identify genes that increase risk of ESRD. We will extend MALD by also characterizing the haplotypes of the probands. Our study will collect trios (ESRD proband, child, and other biological parent of child) to allow identification of haplotypes to pinpoint the search for the genes controlling risk for ESRD. We will test the following hypotheses: 1. Renal disease susceptibility genes exist which increase the risk of both diabetic and non-diabetic renal disease. 2. Some renal disease susceptibility genes exist which increase the risk of both diabetic and non-diabetic renal disease. 2. Some renal disease susceptibility alleles are present at higher frequency in African-Americans than in whites. 3. Specific regions of the genome in African-Americans on the order of 10-20 cM are in admixture linkage disequilibrium with ESRD susceptibility alleles. To carry out the study we will recruit 1,000 African-Americans trios consisting of cases of diabetic and other types of ESRD, progeny, and the other biological parent of the child. We will utilize a newly developed set of 452 microsatellite markers to perform a whole genome MALD scan. Data from the child and other biological parent will be used to haplotype the proband to identify the gene. We will also screen for polymorphisms and mutations in genes in the region of admixture linkage disequilibrium test (TDT) analysis of the probands and their affected children to test candidate genes. Data collection in ESRD patients can be accomplished very efficiently because the infrastructure is already in place within DCI to collect DNA quickly and cheaply as part of routine care. We have trained study coordinators in 80 dialysis clinics and demonstrated our ability to collect high quality clinical information. The genetic analyses that we propose are innovative and complement more traditional linkage techniques. We look forward to working with other members of the Consortium and contributing our data to provide enhanced power to meet the overall goal of the RFA.