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

• 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
• 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

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收集的全基因组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。我们的目标是明确T1 DM患者终末期肾病（ESRD）的易感基因，这些基因位于4个候选染色体区域。我们的研究设计基于两个激励因素。首先，需要寻找ESRD的易感基因，而不是蛋白尿，因为90%的GoKinD病例患有ESRD或肾功能受损，而EDIC收集主要由对照组（没有晚期糖尿病肾病的糖尿病患者）组成。其次，GoKinD和EDIC组合集合中的病例（n=800）和对照（n=1600）的数量足以检测对ESRD易感性具有小至中度遗传效应（最有可能是真正的遗传模型）的寡核苷酸基因。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“里程碑SNP”。这些“标志性SNP”代表了用于额外的基于单倍块的精细作图工作的框架。ESRD易感基因的确认将在Joslin肾脏研究的一个独立队列中进行，该队列患有蛋白尿并已接受进展为ESRD的随访。该提案的具体目的是：1）分析来自四个候选染色体区域（2q、3q、7p和10q）中的GoKinD和EDIC全基因组SNP集合的基因型数据，以鉴定标志性ESRD相关SNP。2)在已经进行基因分型或需要进行基因分型以检测ESRD相关单倍块的四个候选染色体区域中的标志性SNP周围鉴定单倍块结构和单倍标记SNP。3)使用Joslin肾脏研究队列的600例蛋白尿患者（其中200例进展为ESRD）复制ESRD相关单倍阻滞的结果。4)通过生物信息学和分子遗传学方法，研究ESRD相关的单倍块以鉴定ESRD易感基因。