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.
Similar content being viewed by others
References
Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556–559
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
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
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
Meadow SR, Sarsfield JK (1981) Steroid-responsive nephrotic syndrome and allergy: clinical studies. Arch Dis Child 56:509–516
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
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
Salsano ME, Graziano L, Luongo I, Pilla P, Giordano M, Lama G (2007) Atopy in childhood idiopathic nephrotic syndrome. Acta Paediatr 96:561–566
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Corresponding author
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-008-1003-y