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A Genome-Wide Linkage Scan for Genes Controlling Variation in Renal Function Estimated by Serum Cystatin C Levels in Extended Families With Type 2 Diabetes

¹ Research Division, Joslin Diabetes Center, Boston, Massachusetts
² Department of Medicine, Harvard Medical School, Boston, Massachusetts
³ Department of Internal Medicine and Hypertension, Warsaw Medical University, Warsaw, Poland
⁴ Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
⁵ Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence and reprint requests to Andrzej S. Krolewski, MD, PhD, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: andrzej.krolewski{at}joslin.harvard.edu

Abbreviations: ACR, albumin-to-creatinine ratio; CC-GFR, GFR estimated by cystatin C measured in micrograms per liter multiplied by 100; CG-GFR, Cockcroft-Gault estimate of GFR; ESRD, end-stage renal disease; G x DM, genotype by diabetes; GFR, glomerular filtration rate; LOD, logarithm of odds; logACR, ACR values transformed to a base 10 logarithm and multiplied by 10; MDRD, Modification of Diet in Renal Disease; MDRD-GFR, MDRD estimate of GFR; QTLs, quantitative trait loci

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results. GFR aggregates in families with significant heritability (h²) in diabetic (h² = 0.45, P < 1 x 10^–5) and nondiabetic (h² = 0.36, P < 1 x 10^–3) relatives. Genetic correlation (r_G = 0.35) between the GFR of diabetic and nondiabetic relatives was less than one (P = 0.01), suggesting that genes controlling GFR variation in these groups are different. Linkage results supported this interpretation. In diabetic relatives, linkage was strong on chromosome 2q (logarithm of odds [LOD] = 4.1) and suggestive on 10q (LOD = 3.1) and 18p (LOD = 2.2). In nondiabetic relatives, linkage was suggestive on 3q (LOD = 2.2) and 11p (LOD = 2.1). When diabetic and nondiabetic relatives were combined, strong evidence for linkage was found only on 7p (LOD = 4.0). In conclusion, partially distinct sets of genes control GFR variation in relatives with and without diabetes on chromosome 2q, possibly on 10q and 18p in the former, and on 7p in both. None of these genes overlaps with genes controlling variation in urinary albumin excretion.

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