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: 7224532
• 负责人: Andrzej S Krolewski
• 金额: $ 56.46万
• 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/7224532
• 关键词: bioinformatics; chromosomes; chronic renal failure; clinical research; diabetes mellitus genetics; genetic mapping; genetic susceptibility; genotype; human data; human genetic material tag; human tissue; insulin dependent diabetes mellitus; medical complication; molecular genetics; pathologic process; phenotype; proteinuria; single nucleotide polymorphism

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集合中产生的全基因组SNP数据来确定增加1型糖尿病（T1 DM）肾脏并发症风险的基因。我们特别旨在鉴定位于四个候选染色体区域的T1 DM中终末期肾脏疾病（ESRD）的易感基因。我们的研究设计基于两个激励因素。首先，由于90％的Gokind病例具有ESRD或受损的肾功能，而ESRD的易感基因的搜索是有必要的，而EDIC的收集主要由控制（没有晚期糖尿病肾脏病）组成。其次，在Gokind和Edic集合中的病例数（n = 800）和对照组（n = 1600）足以检测到对ESRD易感性的寡素基因（最有可能是真正的遗传模型）。我们提出的研究计划反映了对Gokind和Edic收集的表型特征的考虑，我们的初步发现以及全基因组SNP数据的可用性。因此，我们建议在Gokind和EDIC数据中搜索与ESRD相关的“地标SNP”。这些“具有里程碑意义的SNP”代表了其他基于单块块的精细映射工作的框架。 ESRD敏感性基因的确认将在乔斯林肾脏研究的独立队列中进行，该研究患有蛋白尿，并已被遵循进展为ESRD。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，3Q，7P和10Q）中Gokind和EDIC全基因组SNP收集的基因型数据，以识别地标ESRD相关的Landmark ESRD相关SNP。 2）在四个候选染色体区域中，在已经进行了基因分型或需要是基因型以检测ESRD相关的单倍块的四个候选染色体区域中，确定了地标SNP周围的单倍块结构和单位标记的SNP。 3）使用600例蛋白尿病例的乔斯林肾脏研究队列复制与ESRD相关的单倍体块的发现，其中200例发展为ESRD。 4）研究通过生物信息学和分子遗传学方案来鉴定ESRD相关的单倍块，以鉴定ESRD易感基因。