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1 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
2 Laboratory of Genomic Diversity, National Cancer Institute, and Basic Research Program, Science Applications International Corporation, National Cancer Institute, National Institutes of Health, Frederick, Maryland
3 Department of Hypertension and Nephrology, Marshfield Clinic, Marshfield, Wisconsin
4 Department of Medicine, Division of Nephrology, University of Texas Medical Branch, Galveston, Texas
5 Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York
6 Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
7 Department of Medicine, Rush University Medical Center, Chicago, Illinois
8 Department of Medicine, Division of Renal Diseases and Hypertension, George Washington University Medical Center, Washington, District of Columbia
9 Nephrology Section, Tulane University School of Medicine, New Orleans, Louisiana
10 Department of Pediatrics, Division of Nephrology, Schneider Children’s Hospital, New Hyde Park
11 Center for Urban Epidemiologic Studies, New York Academy of Medicine, New York, New York
12 Department of Medicine, West Virginia University, Morgantown, West Virginia
13 Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania
14 Division of Nephrology and Hypertension, University Hospitals of Cleveland, Cleveland
15 Department of Medicine, Case Western Reserve University, Cleveland
16 Kidney Disease Research Center, Rammelkamp Center for Research and Education, MetroHealth System, Cleveland, Ohio
17 Kidney Disease Section, Kidney Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
Wilms’ tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular scarring. To test whether genetic variations in WT1 and WIT1 (gene immediately 5' to WT1) associate with focal segmental glomerulosclerosis (FSGS), patients with biopsy-proven idiopathic and HIV-1-associated FSGS were enrolled in a multicenter study. We genotyped SNP rs6508 located in WIT1 exon 1, three SNPs (rs2301250, rs2301252, rs2301254) in the promoter shared by WT1 and WIT1, rs2234590 in exon 6, rs2234591 in intron 6, rs16754 in exon 7, and rs1799937 in intron 9 of WT1. Cases (n = 218) and controls (n = 281) were compared in the African American population. Stratification by HIV-1 infection status showed that SNPs rs6508, rs2301254, and rs1799937 were significantly associated with FSGS [rs6508 odds ratio (OR) 1.82, P = 0.006; rs2301254 OR 1.65, P = 0.049; rs1799937 OR 1.91, P = 0.005] in the non-HIV-1 group and rs2234591 (OR 0.234, P = 0.011) in the HIV-1 group. Haplotype analyses in the population revealed that seven SNPs were associated with FSGS; five SNPs had the highest contingency score [–log10(P value) = 13.57] in the HIV-1 group. This association could not be explained by population substructure. We conclude that SNPs in WT1 and WIT1 genes are significantly associated with FSGS, suggesting that variants in these genes may mediate pathogenesis by altering WT1 function. Furthermore, HIV-1 infection status interacts with genetic variations in both genes to influence this phenotype. We speculate that nephropathy liability alleles in WT1 pathway genes cause podocyte dysfunction and glomerular scarring.
renal failure; single nucleotide polymorphism haplotype; polymorphism; African Americans
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