Diabetic kidney disease (nephropathy) is a major health problem in most developed countries. Several studies have shown strong familial clustering of diabetic nephropathy, consistent with a hypothesis that one or more major gene effects predispose individuals with IDDM as well as NIDDM to develop nephropathy. The goal of this proposal, which is submitted as a component of an IRPG, is to may any chromosomal regions harboring genes that confer risk of nephropathy. The strategy to find linkage will be based on discordant sib pairs (DSPs), siblings concordant for IDDM but discordant for nephropathy. For a disease with a high sibling risk, DSPs are much more powerful than an equivalent number of affected sib pairs. Once positive findings are obtained, we will then narrow promising regions by applying linkage disequilibrium mapping methods to the DSP families and to additional data.
The specific aims of this proposal are as follows: 1. To establish two panels of DNA from families with pairs of IDDM siblings that are discordant for diabetic nephropathy: 120 families in Boston and 120 families in Finland 2. To establish two panels of DNA from simplex families having probands with IDDM and diabetic nephropathy and both parents living: 200 families in Boston and 200 families in Finland 3. To search for genetic loci segregating with diabetic nephropathy with a total genome scan of the 120 DSP families in Boston with high throughput genotyping methods and multipoint linkage analysis 4. To confirm and refine positive findings by examining the same regions using the 120 DSP families in Finland and African-American diabetic families collected at the Bowman-Gray Medical School 5. To narrow critical region(s) through linkage disequilibrium analysis of all 240 multiplex and 400 simplex families in preparation for the next step, positional cloning. The proposed project has a high probability of success. By combining our effort with that of investigators from Bowman-Gray School of Medicine who are mapping genes for nephropathy in African-American NIDDM families, the proposed IRPG will have a very chance of mapping most chromosomal regions which harbor susceptibility genes for the development of nephropathy either in IDDM or NIDDM and in whites as well as in blacks.
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