Analysis of genes associated with focal segmental glomerular sclerosis

The Wilms tumor gene (WT1) is important for nephrogenesis and gonadogenesis. Mutations in WT1 lead to Denys Drash (DDS) and Frasier syndromes (FS), which are characterized by renal disease including diffuse mesangial sclerosis. WIT1, a gene that is transcribed in an antisense direction from a promoter that is common with WT1, is suspected to regulate transcription of WT1. The WTIP gene is associated with signal protein molecules assembled in the podocyte-slit diaphragm. The mutated WTIP represses the expression of the WT1. To test if genetic variations in WT1, WIT1 and WTIP mediate susceptibility to focal segmental glomerular sclerosis (FSGS), biopsy proven idiopathic FSGS patients were enrolled in a multicenter study. Six SNPs in the WT1 gene (SNPs 2--6 and SNP8), one SNP (SNP1) in the WIT1 gene upstream of WT1 and two SNPs in WTIP were genotyped; SNP1 is located in the WIT1 exon, SNPs 2--4 in the promoter shared by WT1 and WIT1, SNP5 in exon 6, SNP6 in intron 6, SNP7 in exon 7, SNP8 in intron 9 of WT1 and SNPs 9--10 in WTIP. African-Americans (AA) (n = 218) and Caucasians (CA) (n = 102) cases (idiopathic, collapsing or HIV-1-associated FSGS) were compared to controls (HIV-1 seropositive patients without overt nephropathy and HIV-1 seronegative subjects without obvious nephropathy) (n = 281, n = 43 in AA and CA, respectively). Single SNP analyses showed that SNPs 1 and 6 were significantly associated with FSGS in the entire AA population. Stratifying by HIV-1 status showed that SNPs 1, 4 and 8 were significantly associated with FSGS in the non-HIV-1 group amongst AA. Haplotype analyses involving WT1 and WIT1 in the AA population revealed that seven SNPs were associated with FSGS; SNPs 1--5 had the highest contingency score in the HIV-1 seropositive group. We conclude that SNPs in the WT1 and WIT1 genes are significantly associated with FSGS, suggesting that both WT1 and WIT1 may be-involved in FSGS pathogenesis and that HIV-1 status may influence this phenotype. Because the two genes are in close proximity, the SNPs could be in linkage disequilibrium with functional variants in these genes or the SNPs themselves may mediate pathogenesis by altering WT1 function.