DIABETIC AND NONDIABETIC NEPHROPATHY SUSCEPTIBILITY GENE

这项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1000名发生ESRD的患者进行了研究，其中已经建立了一个DNA库。我们将与透析诊所公司合作，这是一家照顾10,000多名透析患者的非营利性连锁店。国家癌症基因组多样性实验室的斯蒂芬·奥布莱恩博士和迈克尔·史密斯博士将使用一项创新技术。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个基因(ESRD先证者、儿童和儿童的其他亲生父母)，以识别单倍型，以准确寻找控制ESRD风险的基因。我们将检验以下假设：1.肾脏疾病易感基因的存在会增加糖尿病和非糖尿病肾脏疾病的风险。2.存在一些肾脏疾病易感基因，可同时增加糖尿病和非糖尿病肾病的风险。2.一些肾脏疾病易感等位基因在非裔美国人中的出现频率高于白人。3.非裔美国人基因组10-20 cM的特定区域与ESRD易感等位基因处于混合连锁不平衡状态。为了进行这项研究，我们将招募1000名非洲裔美国人三人组，他们包括糖尿病和其他类型的终末期肾病、后代和孩子的另一个亲生父母。我们将利用一套新开发的452个微卫星标记进行全基因组MALD扫描。来自孩子和其他亲生父母的数据将被用来对先证者进行单倍型分析，以确定基因。我们还将对先证者及其受影响的子女进行混合连锁不平衡测试(TDT)分析，以筛选基因多态和突变，以测试候选基因。ESRD患者的数据收集可以非常高效地完成，因为DCI内部已经建立了基础设施，作为常规护理的一部分，可以快速且廉价地收集DNA。我们已经在80个透析诊所培训了研究协调员，并展示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，是对更传统的连锁技术的补充。我们期待着与该联盟的其他成员合作，贡献我们的数据，为实现RFA的总体目标提供更大的动力。

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.