A genome-wide DNA microsatellite association screen to identify chromosomal regions harboring candidate genes in diabetic nephropathy

• Published in: Journal of the American Society of Nephrology Vol. 17; no. 3; pp. 831 - 836
• Main Authors: MCKNIGHT, Amy Jayne, MAXWELL, A. Peter, SAWCER, Stephen, COMPSTON, Alastair, SETAKIS, Efrosini, PATTERSON, Chris C, BRADY, Hugh R, SAVAGE, David A
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.03.2006
• Subjects: Adolescent; Adult; Age Distribution; Biological and medical sciences; Case-Control Studies; Child; Chromosome Mapping - methods; Chromosomes, Human, Pair 10 - genetics; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - epidemiology; Diabetic Nephropathies - genetics; DNA Primers - analysis; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic Predisposition to Disease - epidemiology; Genetic Testing; Genome, Human; Genotype; Humans; Incidence; Ireland - epidemiology; Kidneys; Male; Medical sciences; Microsatellite Repeats - genetics; Nephrology. Urinary tract diseases; Prognosis; Reference Values; Risk Assessment; Sensitivity and Specificity; Sex Distribution; Urinary system involvement in other diseases. Miscellaneous; Europe; Ireland; Endocrinopathy; Kidney disease; Human; Nephrology; Urinary system disease; Diabetes mellitus; Chromosome; Medical screening; Urology; Microsatellite DNA; Cytogenetics; Genetics; Complication; Diabetic nephropathy; Candidate gene; Genome; Public health
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2005050493

In an effort to accelerate the identification of susceptibility genes in diabetic nephropathy, the first genome-wide fluorescence-based DNA microsatellite (n=6000) association screen was performed, using pools of genomic DNA derived from Irish patients with (cases; n=200) and without (controls; n=200) type 1 diabetic nephropathy. Allele image profiles were generated for 5353 (89.2%) microsatellite markers for both case and control pools. Allele counts (estimated from allele image profiles) were compared in case versus control groups, and empirical P values were generated. Markers then were ranked on the basis of their empirical P values (lowest to highest). Repeat PCR amplification and electrophoresis of pooled samples were performed systematically on ranked markers until the 50 most associated markers with consistent results were identified. DNA samples that composed the pools then were genotyped individually for these markers. Two markers on chromosome 10, D10S558 (Pcorrected=0.005) and D10S1435 (Pcorrected=0.016), revealed statistically significant associations with diabetic nephropathy. An additional four markers (D6S281, D4S2937, D2S291, and D17S515) also are worthy of further investigation. Relevant functional candidate genes have been identified in the vicinity of these markers, demonstrating the feasibility of low-resolution genome-wide microsatellite association screening to identify possible candidate genes for diabetic nephropathy.