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Genome-Wide Scan for Estimated GFR in Multi-Ethnic Diabetic Populations: The Family Investigation of Nephropathy and Diabetes

Objective: Diabetic nephropathy (DN), the most common cause of end stage renal disease, aggregates in families and specific ethnic groups. Deconstructing DN into intermediate, quantitative phenotypes may increase feasibility of detecting susceptibility loci by genetic screens. Glomerular filtration rate (GFR), which characterizes DN, was employed as a quantitative trait in a preliminary whole genome scan.

Research Design and Methods: Estimated GFR (eGFR) was calculated for 882 diabetic sib pairs (mean age 57 years) of African American (25.6% of total), American Indian (8.6%), European American (14.2%), and Mexican American (51.6%) descent enrolled in the initial phase of the Family Investigation of Nephropathy and Diabetes (FIND). A whole genome scan was performed using 404 microsatellite markers (average spacing = 9 cM) and model-free linkage analysis.

Results: For all ethnicities combined, strong evidence for linkage was observed on chromosomes 1q43 (P = 3.6 x 10^–3), 7q36.1 (P = 2.1 x 10^–4), 8q13.3 (P = 4.6 x 10^–4) and 18q23.3 (P = 2.7 x 10^–3) . Mexican American families, which comprised the major ethnic subpopulation in FIND, contributed to linkage on chromosomes 1q43, 2p13.3, 7q36.1, 8q13.3, and 18q23.3, whereas African American and American Indian families displayed linkage peaks on chromosomes 11p15.1 and 15q22.3, respectively.

Conclusions: We have demonstrated multiple chromosomal regions linked to eGFR in a multiethnic collection of families ascertained by a proband with diabetic nephropathy. Identification of genetic variants within these loci that are responsible for the linkage signals could lead to predictive tests or novel therapies for subsets of patients at risk for DN.

Key Words: eGFR • diabetic nephropathy • renal failure • genetic • ESRD

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