Mapping Genes for End-Stage Renal Disease in Type 1 Diabetes

绘制 1 型糖尿病终末期肾病基因图谱

基本信息

批准号：
7290994
负责人：
Andrzej S Krolewski
金额：
$ 55.34万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7290994
关键词：
10q Area Bioinformatics Characteristics Chromosome Mapping Chromosomes Cohort Studies Collection Complement DNA Data Development Diabetes Mellitus Diabetic Nephropathy Disease susceptibility End stage renal failure Environment European Evaluation Follow-Up Studies Genes Genetic Genetic Models Genetic Polymorphism Genetic Predisposition to Disease Genome Genotype Hyperglycemia Impaired Renal Function Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Lead Maps Metabolic Molecular Genetics Non-Insulin-Dependent Diabetes Mellitus Numbers Oligonucleotides Patients Population Predisposition Proteinuria Protocols documentation Renal function Research Research Design Research Personnel Risk Staging Stratification Structure Susceptibility Gene Testing base cohort diabetic disorder control disorder risk interdisciplinary approach programs success

项目摘要

DESCRIPTION (provided by applicant): In this research, we propose to identify genes that increase risk of kidney complications in type 1 diabetes (T1 DM) using the genome-wide SNP data generated in the GoKinD and the EDIC collections. We specifically aim to identify susceptibility genes for end stage renal disease (ESRD) in T1 DM located in four candidate chromosomal regions. Our study design is based upon two motivating factors. First, the search for susceptibility genes for ESRD, but not proteinuria, is warranted as 90% of the GoKinD cases have ESRD or impaired renal function, while the EDIC collection consists primarily of controls (diabetics without advanced diabetic kidney disease). Second, the number of cases (n=800) and controls (n=1600) in the combined GoKinD and EDIC collections is sufficient to detect oligo-genes that have small to moderate genetic effects (most likely the true genetic model) on predisposition to ESRD. Our proposed research plan reflects this consideration of the phenotypic characteristics of the GoKinD and EDIC collections, our initial findings, and the availability of genome-wide SNP data. Thus, we propose to search for "landmark SNPs" associated with ESRD in the GoKinD and EDIC data. These "landmark SNPs" represents the framework for additional haplo-block based fine mapping efforts. Confirmation of the ESRD susceptibility genes will be performed in an independent cohort from the Joslin Kidney Study who had proteinuria and have been followed for progression to ESRD. The specific aims of this proposal are to: 1) Analyze the genotype data from the GoKinD and EDIC genome-wide SNP collections in the four candidate chromosomal regions (2q, 3q, 7p and 10q) to identify landmark ESRD-associated SNPs. 2) Identify haplo-block structure and haplo-tagging SNPs around landmark SNPs in the four candidate chromosomal regions that had been already genotyped or will need to be genotype to detect ESRD- associated haplo-blocks. 3) Replicate the findings of the ESRD-associated haplo-blocks using the Joslin Kidney Study cohort of 600 cases with proteinuria, among whom 200 progressed to ESRD. 4) Investigate the ESRD-associated haplo-blocks to identify ESRD susceptibility genes through bioinformatics and molecular genetics protocols.

描述（由申请人提供）：在这项研究中，我们建议使用 GoKinD 和 EDIC 集合中生成的全基因组 SNP 数据来识别增加 1 型糖尿病 (T1 DM) 肾脏并发症风险的基因。我们的具体目标是确定位于四个候选染色体区域的 T1 型糖尿病终末期肾病 (ESRD) 的易感基因。我们的研究设计基于两个激励因素。首先，有必要寻找 ESRD（而非蛋白尿）的易感基因，因为 90% 的 GoKinD 病例患有 ESRD 或肾功能受损，而 EDIC 收集主要由对照（没有晚期糖尿病肾病的糖尿病患者）组成。其次，GoKinD 和 EDIC 联合收集中的病例 (n=800) 和对照 (n=1600) 数量足以检测对易感性具有小到中度遗传效应（最有可能是真正的遗传模型）的寡基因。终末期肾病。我们提出的研究计划反映了对 GoKinD 和 EDIC 集合的表型特征、我们的初步发现以及全基因组 SNP 数据的可用性的考虑。因此，我们建议在 GoKinD 和 EDIC 数据中搜索与 ESRD 相关的“标志性 SNP”。这些“标志性 SNP”代表了基于其他单倍体块的精细定位工作的框架。 ESRD 易感基因的确认将在来自 Joslin 肾脏研究的独立队列中进行，该队列患有蛋白尿并跟踪进展为 ESRD。该提案的具体目标是： 1) 分析来自 GoKinD 和 EDIC 全基因组 SNP 集合的四个候选染色体区域（2q、3q、7p 和 10q）的基因型数据，以确定具有里程碑意义的 ESRD 相关 SNP。 2) 识别已经进行基因分型或需要进行基因分型以检测 ESRD 相关单倍体块的四个候选染色体区域中标志性 SNP 周围的单倍体块结构和单倍体标记 SNP。 3) 使用包含 600 例蛋白尿病例的 Joslin 肾脏研究队列重复 ESRD 相关单倍体的发现，其中 200 例进展为 ESRD。 4) 通过生物信息学和分子遗传学方案研究 ESRD 相关单倍体，以识别 ESRD 易感基因。