Epidemiological data indicate that progressive renal disease (CRF) is genetically determined. However, CRF is complex, with multiple genes contributing to disease phenotype. Diabetic nephropathy is the leading cause of CRF in the industrialized world, accounting for 40-50 percent of incident ESRD cases. To limit genetic heterogeneity, we have initiated a funded, multicenter study to identify type 2 diabetes nephropathy susceptibility genes in multiplex families. Dissecting complex diseases, like CRF, can be facilitated by deconstructing phenotypes into intermediate, quantitative traits. We hypothesize that the intermediate CRF phenotypes, proteinuria and GFR change, which respectively predict and measure progression of diabetic nephropathy, are inherited. In conjunction with an ESRD whole genome scan from the ongoing, cross-sectional family study, we will identify loci which control continuous, quantitative components of the CRF phenotype. Quantitative traits may be more proximal to mutated genes than a discrete diagnostic category like ESRD. In addition, genes regulating intermediate phenotypes are likely to be fewer in number, with less environmental factors confounding the analysis. Our approach is to prospectively study sibs of ESRD probands, to isolate loci that regulate proteinuria and GFR decline.
Specific aims : 1. To characterize intermediate phenotypes of proteinuria and GFR change, carefully phenotyped diabetic siblings of index patients with ESRD due to type 2 diabetic nephropathy, with (concordant) or without (discordant) kidney disease, will be followed longitudinally. Sibs, and where possible parents, unaffected by diabetes or renal disease will serve as controls. The projected cohort will include 250 sibships and an additional 100 family members unaffected by diabetes. Primary, dependent outcomes will include urinary albumin excretion and GFR measured every 6 months. Specific socioeconomic, demographic, environmental and clinical variables will also be ascertained in this population and each individual genotyped. 2. To assess linkage of genomic regions with the intermediate, quantitative phenotypes of proteinuria and GFR change, molecular and statistical methods will be used to examine either a genome-wide scan or candidate regions identified by the ESRD genome scan or by synteny with regions that control proteinuria in model organisms. Model-free approaches based on sibling pairs will be emphasized and analyzed by both univariate and multivariate approaches.
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