There is strong evidence that genetic susceptibility is necessary for the development of diabetic nephropathy. Our research so far showed that genes involved in susceptibility to diabetic nephropathy may be different in type 1 and type 2 diabetes. The proposed research aims to identify a putative gene on chromosome 7q that seems to contribute specifically to susceptibility to diabetic nephropathy in type 2 diabetes. In addition, we will search for other chromosomal regions that harbor a major susceptibility locus for diabetic nephropathy in type 2 diabetes. The study design is based on sib-pairs with type 2 diabetes that are discordant for diabetic nephropathy (DSP). These families will be used for linkage analysis as well as for association studies using the Sibling Transmission Disequilibrium Test (s-TDT) approach.
The specific aims of the proposed research are: 1) To establish two panels of sibling pairs that are concordant for type 2 diabetes and discordant for diabetic nephropathy (DSP): Already recruited is a Screening Panel of 89 extended families to be examined further to increase the specificity of nephropathy diagnoses; To be recruited is an Extension Panel of at least 200 nuclear families having a DSP, and groups of cases and controls for studies of the genetics of diabetic nephropathy. 2) To examine the promising chromosomal region on chromosome 7q for a locus contributing to susceptibility to diabetic nephropathy in type 2 diabetes; 3) To search for other chromosomal regions segregating with diabetic nephropathy in the Panels of DSPs using a chromosome specific panel of genetic markers; 4) To narrow chromosomal regions with evidence of linkage by genotyping panels of DSPs for additional markers in those regions and to initiate positional cloning of susceptibility genes for diabetic nephropathy in the most promising regions. The research has great significance given the current """"""""epidemic"""""""" of end-stage renal failure due to type 2 diabetes in the U.S. population. Further, based upon our existing data, the probability of identifying genes for susceptibility to diabetic nephropathy in type 2 diabetes is very high. The innovation of this proposal is the study of genetic susceptibility for diabetic nephropathy in type 2 diabetes using a DSPs study design. This study design seems to be more efficient in detecting linkage for nephropathy than the traditional ASP (affected sib-pair) design.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SSS-M (02))
Program Officer
Rasooly, Rebekah S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Joslin Diabetes Center
United States
Zip Code
Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto et al. (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415-29
Martini, Sebastian; Nair, Viji; Patel, Sanjeevkumar R et al. (2013) From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy. Diabetes 62:2605-12
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
Sebro, Ronnie; Rogus, John J (2010) The power of the Transmission Disequilibrium Test in the presence of population stratification. Eur J Hum Genet 18:1032-8
Ng, Daniel P K; Nurbaya, Siti; Ye, Sandra H J et al. (2008) An IL-6 haplotype on human chromosome 7p21 confers risk for impaired renal function in type 2 diabetic patients. Kidney Int 74:521-7
Ng, Daniel P K; Nurbaya, Siti; Choo, Serena et al. (2008) Genetic variation at the SLC12A3 locus is unlikely to explain risk for advanced diabetic nephropathy in Caucasians with type 2 diabetes. Nephrol Dial Transplant 23:2260-4
Krolewski, A S; Poznik, G D; Placha, G et al. (2006) A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes. Kidney Int 69:129-36

Showing the most recent 10 out of 19 publications