Skip to main content

Advertisement

Log in

Polymorphisms in interleukin-4-related genes in patients with minimal change nephrotic syndrome

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Minimal change nephrotic syndrome (MCNS) in children is frequently associated with allergy and immunoglobulin E production. T helper subtype 2 cytokines, such as interleukin (IL)-4 and IL-13, may have an important role in the development of atopy. We investigated the association of genetic variations of IL-4 receptor α chain (IL-4Rα), IL-13 and signal transducer and activator of transcription 6 (STAT6) genes with MCNS. We analyzed these polymorphisms in 85 Japanese children (55 males, 30 females) with MCNS and 127 healthy controls with neither allergic nor renal diseases. Genomic DNA was extracted from peripheral blood leukocytes. The single nucleotide polymorphisms of IL-4Rα (Ile50Val) and IL-13 (R130Q) were detected by primer-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism analysis, respectively. GT repeat polymorphism in STAT6 gene exon 1 was investigated by fragment length analysis. A significant difference in allelic frequencies in the STAT6 gene was detected between the MCNS and control groups. There was no significant difference between the two groups for genetic variations of IL-4Rα and IL-13 genes. We found a significant difference in IL-4Rα gene polymorphism between MCNS subgroups divided according to the number of relapses. These results suggested that the genetic variation in the first exon of the STAT6 gene may be associated with a predisposition to MCNS and that the genetic variation in the IL-4Rα gene may be associated with its clinical course.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556–559

    Article  CAS  PubMed  Google Scholar 

  2. Clark AG, Barratt TM (1998) Steroid-responsive nephrotic syndrome. In: Barratt TM, Avner ED, Harmon WE (eds) Pediatric Nephrology, 4th edn. Lippincott Williams & Wilkins, Baltimore, pp 731–747

    Google Scholar 

  3. Maruyama K, Tomizawa S, Shimabukuro N, Fukuda T, Johshita T, Kuroume T (1989) Studies of vascular permeability factor and inhibitory effect of supernatants derived from T lymphocytes culture in minimal change nephrotic syndrome on rat kidney capillaries. Nephron 51:73–76

    Article  CAS  PubMed  Google Scholar 

  4. Garin EH, Laflam PF, Muffly K (2006) Proteinuria and fusion of podocyte foot processes in rats after infusion of cytokine from patients with idiopathic minimal lesion nephrotic syndrome. Nephron Exp Nephrol 102:e105–112

    Article  CAS  PubMed  Google Scholar 

  5. Meadow SR, Sarsfield JK (1981) Steroid-responsive nephrotic syndrome and allergy: clinical studies. Arch Dis Child 56:509–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Groshong T, Mendelson L, Mendoza S, Bazaral M, Hamburger R, Tune B (1973) Serum IgE in patients with minimal-change nephrotic syndrome. J Pediatr 83:767–771

    Article  CAS  PubMed  Google Scholar 

  7. Cheung W, Wei CL, Seah CC, Jordan SC, Yap HK (2004) Atopy, serum IgE, and interleukin-13 in steroid-responsive nephrotic syndrome. Pediatr Nephrol 19:627–632

    Article  PubMed  Google Scholar 

  8. Salsano ME, Graziano L, Luongo I, Pilla P, Giordano M, Lama G (2007) Atopy in childhood idiopathic nephrotic syndrome. Acta Paediatr 96:561–566

    Article  PubMed  Google Scholar 

  9. Kimata H, Fujimoto M, Furusho K (1995) Involvement of interleukin (IL)-13, but not IL-4, in spontaneous IgE and IgG4 production in nephrotic syndrome. Eur J Immunol 25:1497–1501

    Article  CAS  PubMed  Google Scholar 

  10. Yap HK, Cheung W, Murugasu B, Sim SK, Seah CC, Jordan SC (1999) Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol 10:529–537

    CAS  PubMed  Google Scholar 

  11. Sahali D, Pawlak A, Valanciute A, Grimbert P, Lnag P, Remy P, Bensman A, Guellaen G (2002) A novel approach to investigation of the pathogenesis of active minimal-change nephritic syndrome using subtracted cDNA library screening. J Am Soc Nephrol 13:1238–1247

    CAS  PubMed  Google Scholar 

  12. Stefanović V, Golubović E, Mitić-Zlatković M, Vlahović P, Jovanović O, Bogdanović R (1998) Interleukin-12 and interferon-gamma production in childhood idiopathic nephrotic syndrome. Pediatr Nephrol 12:463–466

    Article  PubMed  Google Scholar 

  13. Valanciute A, Gouvello SI, Solhonne B, Pawlak A, Grimbert P, Lyonnet L, Hue S, Lnag P, Remy P, Salomon R, Bensman A, Guellaen G, Sahali D (2004) NF-kB p65 antagonize IL-4 induction by c-maf in minimal change nephrotic syndrome. J Immunol 172:688–698

    Article  CAS  PubMed  Google Scholar 

  14. Kobayashi Y, Arakawa H, Suzuki M, Takizawa T, Tokuyama K, Morikawa A (2003) Polymorphisms of interleukin 4-related genes in Japanese children with minimal change nephrotic syndrome. Am J Kidney Dis 42:271–276

    Article  CAS  PubMed  Google Scholar 

  15. Acharya B, Shirakawa T, Pungky A, Damanik P, Massi MN, Miyata M, Gotoh A (2005) Polymorphism of the interleukin-4, interleukin-13 and signal transducer and activator of transcription 6 genes in Indonesian children with minimal change nephrotic syndrome. Am J Nephrol 25:30–35

    Article  CAS  PubMed  Google Scholar 

  16. Parry RG, Gillespie KM, Parnham A, Clark AG, Mathieson PW (1999) Interleukin-4 and interleukin-4 receptor polymorphisms in minimal change nephropathy. Clin Sci (Lond) 96:665–668

    CAS  Google Scholar 

  17. Tenbrock K, Schubert A, Stapenhorst L, Kemper MJ, Gellermann J, Timmermann K, Müller-Wiefel DE, Querfeld U, Hoppe B, Michalk D (2002) Type I IgE receptor, interleukin 4 receptor and interleukin 13 polymorphisms in children with nephrotic syndrome. Clin Sci (Lond) 102:507–512

    Article  CAS  Google Scholar 

  18. Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr (1997) Prognostic significance of the early course of minimal change nephritic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephrol 8:769–776

    CAS  PubMed  Google Scholar 

  19. Mitsuyasu H, Yanagihara Y, Mao XQ, Gao PS, Arinobu Y, Ihara K, Takabayashi A, Hara T, Enomoto T, Sasaki S, Kawai M, Hamasaki N, Shirakawa T, Hopkin JM, Izuhara K (1999) Dominant effect of Ile50Val variant of the human IL-4 receptor a-chain in IgE synthesis. J Immunol 162:1227–1231

    CAS  PubMed  Google Scholar 

  20. Noguchi E, Nukaga-Nishio Y, Jian Z, Yokouchi Y, Kamioka M, Yamakawa-Kobayashi K, Hamaguchi H, Matsui A, Shibasaki M, Arinami T (2001) Haplotypes of the 5′ region of the IL-4 gene and SNPs in the intergene sequence between the IL-4 and IL-13 genes are associated with atopic asthma. Hum Immunol 62:1251–1257

    Article  CAS  PubMed  Google Scholar 

  21. Tamura K, Arakawa H, Suzuki M, Kobayashi Y, Mochizuki H, Kato M, Tokuyama K, Morikawa A (2001) Novel dinuculeotide repeat polymorphism in the first exon of the STAT-6 gene is associated with allergic diseases. Clin Exp Allergy 31:1509–1514

    Article  CAS  PubMed  Google Scholar 

  22. Shao C, Suzuki Y, Kamada F, Kanno K, Tamari M, Hasegawa K, Aoki Y, Kure S, Yang X, Endo H, Takayanagi R, Nakazawa C, Morikawa T, Morikawa M, Miyabayashi S, Chiba Y, Karahashi M, Saito S, Tamura G, Shirakawa T, Matsubara Y (2004) Linkage and association of childhood asthma with the chromosome 12 genes. J Hum Genet 49:115–122

    Article  CAS  PubMed  Google Scholar 

  23. Gao PS, Heller NM, Walker W, Chen CH, Moller M, Plunkett B, Roberts MH, Shleimer RP, Hopkin JM, Hung SK (2004) Variation in dinucleotide (GT) repeat sequence in the first exon of the STAT6 gene is associated with atopic asthma and differentially regulates the promoter activity in vitro. J Med Genet 41:535–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kawashima T, Noguchi E, Arinami T, Yamakawa KK, Nakagawa H, Otsuka F, Hamaguchi H (1998) Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. J Med Genet 35:502–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gao PS, Mao XQ, Roberts MH, Arinobu Y, Akaiwa M, Enomoto T, Dake Y, Kawai M, Sasaki S, Hamasaki N, Izuhara K, Shirakawa T, Hopkin JM (2000) Variants of STAT6 (signal transducer and activator of transcription 6) in atopic asthma. J Med Genet 37:380–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ho IC, Lo D, Glimcher LH (1998) c-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both Interleukin 4-dependent and -independent mechanisms. J Exp Med 188:1856–1866

    Article  Google Scholar 

  27. Van Den Berg JG, Aten J, Chand MA, Cleassen N, Dijkink L, Wijdenes J, Lakkis FG, Weening JJ (2000) Interleukin-4 and Interleukin-13 act on glomerular visceral epithelial cells. J Am Soc Nephrol 11:413–422

    Google Scholar 

  28. Vladich FD, Brazille M, Stern D, Peck ML, Ghittoni R, Vercelli D (2005) IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation. J Clin Invest 115:747–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Heinzmann A, Mao XQ, Akaiwa M, Kreomer RT, Gao PS, Ohshima K, Umeshita R, Abe Y, Braun S, Yamashita T, Roberts MH, Sugimoto R, Arima K, Arinobu Y, Yu B, Kruse S, Enomoto T, Dake Y, Kawai M, Shimazu S, Sasaki S, Adra CN, Kitaichi M, Inoue H, Yamauchi K, Tomichi N, Kurimoto F, Hamasaki N, Hopkin JM, Izuhara K, Shirakawa T, Deichimann DA (2000) Genetic variations of IL-13 signalling and human asthma and atopy. Hum Mol Genet 9:549–559

    Article  CAS  PubMed  Google Scholar 

  30. Wei CL, Cheung W, Heng CK, Arty N, Chog SS, Lee BW, Puah KL, Yap HK (2005) Interleukin-13 genetic polymorphisms in Singapore Chinese children correlate with long-term outcome of minimal-change disease. Nephrol Dial Transplant 20:728–734

    Article  CAS  PubMed  Google Scholar 

  31. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee (1998) Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 351:1225–1232

    Article  Google Scholar 

Download references

Acknowledgments

We thank Mrs. Tomoko Endo and Mrs. Chinori Iijima for technical assistance. This work was supported in part by Health Science Research Grants (Research on Eye and Ear Science, Immunology, Allergy and Organ Transplantation) from the Ministry of Health Labor and Welfare of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasuko Kobayashi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ikeuchi, Y., Kobayashi, Y., Arakawa, H. et al. Polymorphisms in interleukin-4-related genes in patients with minimal change nephrotic syndrome. Pediatr Nephrol 24, 489–495 (2009). https://doi.org/10.1007/s00467-008-1003-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-008-1003-y

Keywords

Navigation