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Genome-Wide Scan for Estimated Glomerular Filtration Rate in Multi-Ethnic Diabetic Populations

The Family Investigation of Nephropathy and Diabetes (FIND)

Address correspondence and reprint requests to Dr. Sudha Iyengar, Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building, Rm. 1300, 10900 Euclid Ave., Cleveland, OH 44106-7281. E-mail: ski{at}case.edu

Key Words: ARB, angiotensin receptor blocker • CKD, chronic kidney diseases • eGFR, estimated glomerular filtration rate • ESRD, end-stage renal disease • FIND, Family Investigation of Nephropathy and Diabetes • GFR, glomerular filtration rate • IBD, identity by descent • LOD, logarithm of odds • MDRD, Modification of Diet in Renal Disease

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

RESEARCH DESIGN AND METHODS— Estimated GFR (eGFR) was calculated for 882 diabetic sibpairs (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, who 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 multi-ethnic 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 diabetic nephropathy.

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