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

• Published in: Diabetic medicine Vol. 25; no. 3; pp. 268 - 276
• Main Authors: Freedman, B. I., Bowden, D. W., Rich, S. S., Xu, J., Wagenknecht, L. E., Ziegler, J., Hicks, P. J., Langefeld, C. D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2008; Blackwell
• Subjects: Aged; albuminuria; Albuminuria - genetics; Associated diseases and complications; Biological and medical sciences; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - genetics; diabetic nephropathy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Genetic Linkage - genetics; Genetic Predisposition to Disease; genome scan; Genome, Human - genetics; Glomerular Filtration Rate; Humans; Male; Medical sciences; Middle Aged; Type 2 diabetes mellitus; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Heart; Type 2 diabetes; Glomerular filtration; Renal function; Type 2 diabetes mellitus; Genetics; Diabetic nephropathy; Nutritional status; Kidney disease; Urine; Obesity; Urinary system disease; Nutrition; glomerular filtration rate; Rate; Nutrition disorder; genome scan; Albumin; Metabolic diseases; albuminuria; Concomitant disease; Genetic linkage; Circulatory system; Endocrinology; Proteinuria
• ISSN: 0742-3071; 1464-5491
• DOI: 10.1111/j.1464-5491.2007.02361.x

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.