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Diabetic Medicine
Year: 2008  |  Volume: 25  |  Issue: 3  |  Page No.: 268 - 276

Genome-wide linkage scans for renal function and albuminuria in Type 2 diabetes mellitus: the Diabetes Heart Study

B. I. Freedman, D. W. Bowden, S. S. Rich, J. Xu, L. E. Wagenknecht, J. Ziegler, P. J. Hicks and C. D. Langefeld    

Abstract: Aims/hypothesis  Glomerular filtration rate (GFR), end-stage renal disease and albuminuria are highly heritable. We performed a genome-wide linkage scan in 416 Diabetes Heart Study (DHS) families to detect loci that contributed to renal function and albuminuria.

Materials and methods  A total of 1067 individuals (900 with Type 2 diabetes mellitus) from 348 European American and 68 African American DHS families had measures of urine albumin : creatinine ratio (ACR), serum creatinine concentration and Modification of Diet in Renal Disease estimated GFR (eGFR). Variance components quantitative trait linkage analysis (using SOLAR) was computed.

Results  Participants had mean ± sd age 61.4 ± 9.4 years; diabetes duration 10.5 ± 7.4 years; eGFR 1.15 ± 0.32 ml/sec; and urine ACR 15.8 ± 67.2 mmol/l (median 1.4). In all families, significant evidence for linkage of GFR was observed on chromosome 2p16 (log of the odds; LOD = 4.31 at 72.0 cM, ATA47C04P/D2S1352) and 1p36 (LOD = 3.81 at 45.0 cM, D1S3669/D1S3720), with suggestive evidence on 7q21 (LOD = 2.42 at 99.0 cM, D7S820/D7S821) and 13q13 (LOD = 2.28 at 28.0 cM, D13S1493/D13S894). The evidence for linkage to ACR was far weaker, on 13q21-q22 (LOD = 1.84 at 50 cM, D13S1807/D13S800), 3p24-p23 (LOD = 1.81 at 58 cM, D3S3038/D3S2432) and 10p11 (LOD = 1.78 at 71.0 cM, D10S1208/D10S1221).

Conclusions/interpretations  The eGFR linkage peaks on 2p16, 7q21 and 13q13 closely overlap with nephropathy peaks identified in family studies enriched for severe kidney disease. These diabetes-enriched families provide an opportunity to map genes regulating renal function, potentially leading to the identification of genes producing nephropathy susceptibility in subjects with Type 2 diabetes.

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