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

Abstract

Abstract Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed multipoint variance components linkage analysis to localize genes that influence GFR, using estimated GFR data and a 10 cM map from the San Antonio Family Diabetes/Gallbladder Study. Importantly, we also examined the effect of genotype by diabetes interaction (G × DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetics and non-diabetics. GFR was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRDc) formulae. Both estimates of GFR exhibited significant heritabilities (GFR-CGc = 40%; GFR-4VMDRDc 36%), but only GFR-CGc showed significant G × DM interaction. We therefore performed linkage analyses on both GFR measures using models that did not include G × DM interaction effects (Model 1), and that included G × DM interaction effects (Model 2, in the case of GFR-CGc). The strongest evidence for linkage (Model 1) of both GFR-CGc (LOD = 2.9, empirical P = 7.6 x 10^-4, genomewide P = 0.045) and GFR-4VMDRD (LOD = 2.6, empirical P = 2.3 x 10^-4, genomewide P = 0.083) 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 (LOD_C = 3.3, empirical P = 3.2 x 10^-4, genomewide P = 0.019) compared to the LOD score of 2.7 (empirical P = 1.1 x 10^-3, genomewide P = 0.075) 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. In conclusion, we found a major locus on chromosome 2q that differentially influences GFR in diabetic and non-diabetic environments in the Mexican American population.