? 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. ? ?
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