TGF-β1 gene polymorphisms and primary vesicoureteral reflux in childhood

Abstract

The aim of this study was to assess the association between the transforming growth factor-β1 (TGF-β1) gene polymorphisms rs1800469 (commonly known as T-509C) and rs1982073 (commonly known as Leu 10→Pro) and primary vesicoureteral reflux (VUR) and renal scarring. Using a case–control approach, we examined 121 children with primary VUR and 169 controls. Genotyping of the TGF-β1 gene polymorphisms was performed by restriction fragment length polymorphism (RFLP) analysis. The 99mTc-DMSA– or 99mTc-unitiol–single photon emission computed tomography method was used to evaluate renal scars in 84 of 121 VUR children. Statistical analysis revealed differences in rs1800469 genotype frequencies between VUR patients and controls (p = 0.0021). Our data demonstrate that individuals homozygous for the TT genotype are at risk of primary VUR [odds ratio (95% confidence interval) = 2.7 (1.46–5.08)]. Distribution of the rs1982073 polymorphism was similar in VUR children and controls. In terms of renal scarring, patients were stratified into non-scar and scar subgroups, and no differences in the genotype frequencies of either polymorphism was found. Previous reports have shown that the TT genotype of the rs1800469 polymorphism is a risk factor for renal scarring in primary VUR, and the results of our study suggest that this same polymorphism is associated with susceptibility to this congenital uropathy.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342:1350–1358

    CAS  Article  Google Scholar 

  2. 2.

    Border WA, Noble NA (1994) Transforming growth factor β in tissue fibrosis. N Engl J Med 331:1286–1292

    CAS  Article  Google Scholar 

  3. 3.

    Ihn H (2002) Pathogenesis of fibrosis: the role of TGF-(beta) and CTGF. Curr Opin Rheumatol 14:681–685

    CAS  Article  Google Scholar 

  4. 4.

    Fujii D, Brissenden JE, Derynck R, Francke U (1986) Transforming growth factor beta gene maps to human chromosome 19 long arm and to mouse chromosome 7. Somat Cell Mol Genet 12:281–288

    CAS  Article  Google Scholar 

  5. 5.

    Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spetcor TD (1999) Genetic control of the circulating concentration of transforming growth factor type β1. Hum Mol Genet 8:93–97

    CAS  Article  Google Scholar 

  6. 6.

    Shah R, Rahaman B, Hurley CK, Posch P (2006) Allelic diversity in the TGFβ1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum Genet 119:61–74

    CAS  Article  Google Scholar 

  7. 7.

    Gou Z, Binswanger U, Knoflach A (2002) Role of codon 10 and codon 25 polymorphisms on TGF-β1 gene expression and protein synthesis in stable renal allograft recipients. Transplant Proc 34:2904–2906

    Article  Google Scholar 

  8. 8.

    Chow KM, Szeto CC, Poon P, Lau WY, Lai FM, Li PK (2005) Transforming growth factor-β1 gene polymorphism in renal transplant recipients. Ren Fail 27:671–675

    CAS  Article  Google Scholar 

  9. 9.

    Silverman ES, Palmer LJ, Subramaniam V, Hallock A, Mathew S, Vallone J, Faffe DS, Shikanai T, Raby BA, Weiss ST, Shore SA (2004) Transforming growth factor beta(1) promoter polymorphism C-509T is associated with asthma. Am J Resp Crit Care Med 169:214–219

    Article  Google Scholar 

  10. 10.

    Gressner AM, Weiskirchen R, Breitkopf K, Dooley S (2002) Roles of TGF-beta in hepatic fibrosis. Front Biosci 7:d793–d807

    CAS  Article  Google Scholar 

  11. 11.

    Ng DP, Warram JH, Krolewski AS (2003) TGF- beta 1 as a genetic susceptibility locus for advanced diabetic nephropathy in type 1 diabetes mellitus: an investigation of multiple known DNA sequence variants. Am J Kidney Dis 41:22–28

    CAS  Article  Google Scholar 

  12. 12.

    Patel A, Scott WR, Lympanyt TA, Rippin JD, Gill GV, Barnett AH, Bain SC, the Warren 3/UK GoKind Study Group (2005) The TGF-β1 gene codon 10 polymprphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes. Diabet Med 22:69–73

    CAS  Article  Google Scholar 

  13. 13.

    Salah Khalil M, El Nahas AM, Blakemore AIF (2005) Transforming growth factor-β1 SNPs: genetic and phenotypic correlations in progressive kidney insufficiency. Nephron Exp Nephrol 101:e31–e41

    Article  Google Scholar 

  14. 14.

    Lahdes-Vasama T, Niskanen K, Rönnholm K (2006) Outcome of kidneys in patients treated for vesicoureteral reflux (VUR) during childhood. Nephrol Dial Transplant 21:2491–2497

    Article  Google Scholar 

  15. 15.

    Smellie JM, Prescod NP, Shaw PJ, Ridson RA, Bryant TN (1998) Childhood reflux and urinary infections: a follow-up of 10–41 years in 226 adults. Pediatr Nephrol 12:727–736

    CAS  Article  Google Scholar 

  16. 16.

    Mehls O, Rigden S, Ehrich JH, Berthoux F, Jones EHP, Valderrábano F (1996) Report on management of renal failure in Europe XXV, 1994. The child-adult interface. Nephrol Dial Transplant 11:22–23

    Article  Google Scholar 

  17. 17.

    Cotton SA, Gbadegesin RA, Williams S, Brenchley PEC, Webb NJA (2002) Role of TGF-β1 in renal parenchymal scarring following childhood urinary tract infection. Kidney Int 61:61–67

    CAS  Article  Google Scholar 

  18. 18.

    Lee-Chen GJ, Liu KP, Lai YC, Juang HS, Huang SY, Lin CY (2004) Significance of tissue kallikrein promoter and transforming growth factor-β1 polymorphisms with renal progression in children with vesicoureteral reflux. Kidney Int 65:1467–1472

    CAS  Article  Google Scholar 

  19. 19.

    Solari V, Owen D, Puri P (2005) Association of transforming growth factor-β1 gene polymorphism with reflux nephropathy. J Urol 174:1609–1611

    CAS  Article  Google Scholar 

  20. 20.

    Yim HE, Bae IS, Yoo KH, Hong YS, Lee JW (2007) Genetic control of VEGF and TGF-(beta)1 gene polymorphism in childhood urinary tract infection and vesicoureteral reflux. Pediatr Res 62:183–187

    CAS  Article  Google Scholar 

  21. 21.

    International Reflux Study Committee (1981) Medical versus surgical treatment of primary vesicoureteral reflux: a prospective international reflux study in children. J Urol 125:277–283

    Article  Google Scholar 

  22. 22.

    Ogiński M, Rembelska M (1976) 99mTechnetium-unitiol complex, a new pharmaceutical for kidney scintigraphy. Nuklearmedizin 15:282–286

    Article  Google Scholar 

  23. 23.

    Gadzicki M, Bieńkiewicz M, Młodkowska E, Knapska M, Kowalewska-Pietrzak M, Kuśmierek J (2004) Cortical scintigraphy in the evaluation of renal defects in children with vesicoureteral reflux — optimization of the procedure and study interpretation. Nucl Med Rev Cent East Eur 7:157–164

    PubMed  Google Scholar 

  24. 24.

    Jakobsson B, Svensson L (1997) Transient pyelonephritic changes on 99 m Technetium—dimercaptosuccinic acid scan for at least five months after infection. Acta Pediatr 86:803–807

    CAS  Article  Google Scholar 

  25. 25.

    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    CAS  Article  Google Scholar 

  26. 26.

    Wenneström M, Hansson S, Jodal U, Stockland E (1998) Disappereance of Vesicoureteral Reflux in Children. Arch Pediatr Adolesc Med 152:879–883

    Google Scholar 

  27. 27.

    The International HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861

    Article  Google Scholar 

  28. 28.

    Clark AT, Young RJ, Bertram JF (2001) In vitro studies on the roles of transforming growth factor-β1 in rat metanephric development. Kidney Int 59:1641–1653

    CAS  Article  Google Scholar 

  29. 29.

    Yang SP, Woolf AS, Yuan HT, Scott RJ, Ridson RA, O’Hare MJ, Winyard PJD (2000) Potential biological role of transforming growth factor-β1 in human congenital kidney malformations. Am J Pathol 157:1633–1647

    CAS  Article  Google Scholar 

  30. 30.

    Murawski IJ, Gupta IR (2006) Vesicoureteric reflux and renal malformations: a developmental problem. Clin Genet 69:105–117

    CAS  Article  Google Scholar 

  31. 31.

    Wan J, Greenfield SP, Manyan NG, Zerin M, Ritchey ML, Bloom D (1996) Sibling reflux: a dual centre retrospective study. J Urol 156:677–679

    CAS  Article  Google Scholar 

  32. 32.

    International Reflux Study in Children (1992) Five year study of medical or surgical treatment in children with severe reflux: radiological findings. Pediatr Nephrol 6:223–230

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by Polish State Committee for Scientific Research grant # 2P05E 01830

Author information

Affiliations

Authors

Corresponding author

Correspondence to Magdalena Kowalewska-Pietrzak.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kowalewska-Pietrzak, M., Klich, I. & Mlynarski, W. TGF-β1 gene polymorphisms and primary vesicoureteral reflux in childhood. Pediatr Nephrol 23, 2195–2200 (2008). https://doi.org/10.1007/s00467-008-0927-6

Download citation

Keywords

  • Renal scarring
  • TGF-β1 gene polymorphisms
  • Vesicoureteral reflux