? 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077532-03
Application #
7479335
Study Section
Special Emphasis Panel (ZDK1-GRB-S (O1))
Program Officer
Rasooly, Rebekah S
Project Start
2006-09-30
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2010-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$553,026
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto et al. (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415-29
Pezzolesi, Marcus G; Krolewski, Andrzej S (2013) The genetic risk of kidney disease in type 2 diabetes. Med Clin North Am 97:91-107
Pezzolesi, Marcus G; Jeong, Jackson; Smiles, Adam M et al. (2013) Family-based association analysis confirms the role of the chromosome 9q21.32 locus in the susceptibility of diabetic nephropathy. PLoS One 8:e60301
Pezzolesi, Marcus G; Poznik, G David; Skupien, Jan et al. (2011) An intergenic region on chromosome 13q33.3 is associated with the susceptibility to kidney disease in type 1 and 2 diabetes. Kidney Int 80:105-11
Kure, Masahiko; Pezzolesi, Marcus G; Poznik, G David et al. (2011) Genetic variation in the matrix metalloproteinase genes and diabetic nephropathy in type 1 diabetes. Mol Genet Metab 103:60-5
Pezzolesi, Marcus G; Skupien, Jan; Mychaleckyj, Josyf C et al. (2010) Insights to the genetics of diabetic nephropathy through a genome-wide association study of the GoKinD collection. Semin Nephrol 30:126-40
Garrett, Michael R; Pezzolesi, Marcus G; Korstanje, Ron (2010) Integrating human and rodent data to identify the genetic factors involved in chronic kidney disease. J Am Soc Nephrol 21:398-405
Tsaih, Shirng-Wern; Pezzolesi, Marcus G; Yuan, Rong et al. (2010) Genetic analysis of albuminuria in aging mice and concordance with loci for human diabetic nephropathy found in a genome-wide association scan. Kidney Int 77:201-10
Pezzolesi, Marcus G; Poznik, G David; Mychaleckyj, Josyf C et al. (2009) Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58:1403-10
Pezzolesi, Marcus G; Katavetin, Pisut; Kure, Masahiko et al. (2009) Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy. Diabetes 58:2698-702

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