Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population

Mohammed S. Orloff, Sudha K. Iyengar, Cheryl A. Winkler, Katrina A B Goddard, Richard A. Dart, Tejinder S. Ahuja, Michele H. Mokrzycki, William A. Briggs, Stephen M. Korbet, Paul L. Kimmel, Eric E. Simon, Howard Trachtman, David Vlahov, Donna M. Michel, Jeffrey S. Berns, Michael C. Smith, Jeffrey R. Schelling, John R. Sedor, Jeffrey B. Kopp

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)212-221
Number of pages10
JournalPhysiological Genomics
Volume21
DOIs
StatePublished - Jul 2005

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Wilms' Tumor Genes
Focal Segmental Glomerulosclerosis
African Americans
Single Nucleotide Polymorphism
HIV-1
Odds Ratio
Population
Exons
Genes
Introns
Frasier Syndrome
HIV Infections
Cicatrix
Denys-Drash Syndrome
Podocytes
Haplotypes
Multicenter Studies
Alleles
Phenotype
Biopsy

Keywords

  • African Americans
  • Polymorphism
  • Renal failure
  • Single nucleotide polymorphism haplotype

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Orloff, M. S., Iyengar, S. K., Winkler, C. A., Goddard, K. A. B., Dart, R. A., Ahuja, T. S., ... Kopp, J. B. (2005). Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population. Physiological Genomics, 21, 212-221. https://doi.org/10.1152/physiolgenomics.00201.2004

Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population. / Orloff, Mohammed S.; Iyengar, Sudha K.; Winkler, Cheryl A.; Goddard, Katrina A B; Dart, Richard A.; Ahuja, Tejinder S.; Mokrzycki, Michele H.; Briggs, William A.; Korbet, Stephen M.; Kimmel, Paul L.; Simon, Eric E.; Trachtman, Howard; Vlahov, David; Michel, Donna M.; Berns, Jeffrey S.; Smith, Michael C.; Schelling, Jeffrey R.; Sedor, John R.; Kopp, Jeffrey B.

In: Physiological Genomics, Vol. 21, 07.2005, p. 212-221.

Research output: Contribution to journalArticle

Orloff, MS, Iyengar, SK, Winkler, CA, Goddard, KAB, Dart, RA, Ahuja, TS, Mokrzycki, MH, Briggs, WA, Korbet, SM, Kimmel, PL, Simon, EE, Trachtman, H, Vlahov, D, Michel, DM, Berns, JS, Smith, MC, Schelling, JR, Sedor, JR & Kopp, JB 2005, 'Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population', Physiological Genomics, vol. 21, pp. 212-221. https://doi.org/10.1152/physiolgenomics.00201.2004
Orloff, Mohammed S. ; Iyengar, Sudha K. ; Winkler, Cheryl A. ; Goddard, Katrina A B ; Dart, Richard A. ; Ahuja, Tejinder S. ; Mokrzycki, Michele H. ; Briggs, William A. ; Korbet, Stephen M. ; Kimmel, Paul L. ; Simon, Eric E. ; Trachtman, Howard ; Vlahov, David ; Michel, Donna M. ; Berns, Jeffrey S. ; Smith, Michael C. ; Schelling, Jeffrey R. ; Sedor, John R. ; Kopp, Jeffrey B. / Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population. In: Physiological Genomics. 2005 ; Vol. 21. pp. 212-221.
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abstract = "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.",
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AU - Orloff, Mohammed S.

AU - Iyengar, Sudha K.

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AU - Goddard, Katrina A B

AU - Dart, Richard A.

AU - Ahuja, Tejinder S.

AU - Mokrzycki, Michele H.

AU - Briggs, William A.

AU - Korbet, Stephen M.

AU - Kimmel, Paul L.

AU - Simon, Eric E.

AU - Trachtman, Howard

AU - Vlahov, David

AU - Michel, Donna M.

AU - Berns, Jeffrey S.

AU - Smith, Michael C.

AU - Schelling, Jeffrey R.

AU - Sedor, John R.

AU - Kopp, Jeffrey B.

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N2 - 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.

AB - 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.

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