A genome-wide DNA microsatellite association screen to identify chromosomal regions harboring candidate genes in diabetic nephropathy.
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.
Nephrology Research Group, Department of Epidemiology & Public Health, Queen's University Belfast, Northern Ireland.
Amy Jayne
AJ
McKnight
A Peter
AP
Maxwell
Stephen
S
Sawcer
Alastair
A
Compston
Efrosini
E
Setakis
Chris C
CC
Patterson
Hugh R
HR
Brady
David A
DA
Savage
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D016022:Case-Control Studies; D002648:Child; D002874:Chromosome Mapping / Q000379:methods; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D017931:DNA Primers / Q000032:analysis; D003928:Diabetic Nephropathies / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D015994:Incidence; D007494:Ireland / Q000453:epidemiology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D011379:Prognosis; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D017678:Sex Distribution
D017931:DNA Primers