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Genotype by Diabetes Interaction Effects on the Detection of Linkage of Glomerular Filtration Rate to a Region on Chromosome 2q in Mexican Americans

¹ Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
² Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
³ Division of Nephrology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Address correspondence and reprint requests to Sobha Puppala, Southwest Foundation for Biomedical Research, Genetics, P.O. Box 760549, San Antonio, TX 78254. E-mail: spuppala{at}sfbrgenetics.org

Abbreviations: CIDR, Center for Inherited Disease Research; ESRD, end-stage renal disease; G x DM, genotype by diabetes; G x E, genotype by environment; GFR, glomerular filtration rate; GFR-4VMDRD, recalculated simplified four-variable Modification of Diet in Renal Disease (MDRD) study equation; GFR-CC, GFR estimated from serum cystatin C concentrations; GFR-CGc Cockcroft-Gault equation adjusted for body surface area and corrected for bias in the MDRD data; IBD, identical by descent; LOD, logarithm of odds; QTL, quantitative trait locus; SAFDGS, San Antonio Family Diabetes/Gallbladder Study

OBJECTIVE—Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G x DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetic and nondiabetic subjects.

RESEARCH DESIGN AND METHODS—GFR (N = 453) was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRD) formulae. Both estimates of GFR exhibited significant heritabilities, but only GFR-CGc showed significant G x DM interaction. We therefore performed multipoint linkage analyses on both GFR measures using models that did not include G x DM interaction effects (Model 1) and that included G x DM interaction effects (Model 2, in the case of GFR-CGc).

RESULTS—The strongest evidence for linkage (Model 1) of both GFR-CGc (logarithm of odds [LOD] 2.9) and GFR-4VMDRD (LOD 2.6) occurred between markers D9S922 and D9S1120 on chromosome 9q. However, using Model 2, the strongest evidence for linkage of GFR-CGc on chromosome 2q was found near marker D2S427 (corrected LOD score [LOD_C] 3.3) compared with the LOD score of 2.7 based on Model 1. Potential linkages (LOD or LOD_C 1.2) were found only for GFR-CGc on chromosomes 3p, 3q, 4p, 8q, 11q, and 14q.

CONCLUSIONS—We found a major locus on chromosome 2q that differentially influences GFR in diabetic and nondiabetic environments in the Mexican-American population.

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