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1 Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
2 Laboratory Genomic Diversity, National Cancer Institute, and Basic Research Program, Science Applications International Corporation, Frederick, MD, USA
3 Hypertension and Nephrology, Marshfield Clinic, Marshfield, WI, USA
4 Medicine, Division of Nephrology, University of Texas Medical Branch, Galveston, TX, USA
5 Division of Nephrology, Albert Einstein College of Medicine, Bronx, NY, USA
6 Divison of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
7 Medicine, Rush Presbyterian St. Luke's Medical Center, Chicago, IL, USA
8 Medicine, Division of Renal Diseases and Hypertension, George Washington University Medical Center, Washington, DC, USA
9 Nephrology Section SL45, Tulane University School of Medicine, New Orleans, LA, USA
10 Pediatrics, Division of Nephrology, Schneider Children's Hospital, New Hyde Park, NY, USA
11 Center for Urban Epidemiologic Studies, New York Academy of Medicine, New York, NY, USA
12 Medicine, University of West Virginia, Morgantown, WV, USA
13 The Graduate Hospital, Nephrology and Hypertension, Philadelphia, PA, USA
14 Division of Nephrology and Hypertension, University Hospitals of Cleveland, Cleveland, OH, USA
15 Medicine, Case Western Reserve University, Cleveland, OH, USA; Kidney Disease Research Center, Rammelkamp Center for Research and Education, MetroHealth System, Cleveland, OH, USA
16 Kidney Disease Section, Department of Health and Human Services, Metabolic Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: ski{at}case.edu.
The Wilms tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys Drash (DDS) and Frasier syndromes (FS), which are characterized by glomerular scarring. To test if genetic variations in WT1 and WIT1 (a 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 exon1, 3 SNPs (rs2301250, rs2301252 and 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 (AA) population. Stratifying by HIV-1 infection status, SNPs rs6508, rs2301254 and rs1799937 were significantly associated with FSGS [rs6508 OR=1.82, p=0.006; rs2301254 OR=1.65, p=0.049 and 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; 5 SNPs had the highest contingency score [-Log10(p-value) = 13.57] in the HIV-1 group. This association could not be explained by population sub-structure. We conclude that SNPs in the WT1 and WIT1 genes are significantly associated with FSGS, suggesting that both genes may be involved in FSGS pathogenesis. Further, HIV-1 infection status interacts with genetic variations in WT1 and WIT1 to influence this phenotype. We speculate that nephropathy liability alleles in the WT1 pathway genes cause podocyte dysfunction and glomerular scarring. Because the two genes are in linkage disequilibrium, variants in these genes may mediate pathogenesis by altering WT1 function.
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