Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Association between polymorphisms in Interleukin-17 receptor A gene and childhood IgA nephropathy

IgA 신병증 환자에서 Interleukin-17 수용체 A 유전자의 단일염기다형성 연관성 연구

  • Baek, Seung-Ah (Department of Pediatrics, School of Medicine, Kyung Hee University) ;
  • Han, Won-Ho (Department of Pediatrics, School of Medicine, Kyung Hee University) ;
  • Cho, Byoung-Soo (Department of Pediatrics, School of Medicine, East West Kidney Diseases Research Institute, Kyung Hee University) ;
  • Kim, Sung-Do (Department of Pediatrics, School of Medicine, East West Kidney Diseases Research Institute, Kyung Hee University)
  • 백승아 (경희대학교 의과대학 소아과학교실) ;
  • 한원호 (경희대학교 의과대학 소아과학교실) ;
  • 조병수 (경희대학교 의과대학 소아과학교실,경희대 동서신장병 연구소) ;
  • 김성도 (경희대학교 의과대학 소아과학교실,경희대 동서신장병 연구소)
  • Received : 2009.07.31
  • Accepted : 2009.10.19
  • Published : 2010.02.15
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Abstract

Purpose : Interleukin-17 (IL-17) is produced by activated CD4+T cells and exhibits pleiotropic biological activity on various cell types. IL-17 was reported to be involved in the immunoregulatory response in IgA nephropathy (IgAN). Our aim was to investigate the association between single-nucleotide polymorphisms (SNPs) in IL-17 receptor A (IL-17RA) gene and childhood IgAN. Methods : We analyzed the SNPs in the IL-17RA in 156 children with biopsy-proven IgAN and 245 healthy controls. We divided the IgAN patients into 2 groups and compared them with respect to proteinuria (${\leq}4$ and >$4mg/m^2/h$, ${\leq}40$ and >$40mg/m^2/h$, respectively) and the presence of pathological levels of biomarkers of diseases such as interstitial fibrosis, tubular atrophy, or global sclerosis. Results : No difference was observed between the SNP genotypes rs2895332, rs1468488, and rs4819553 between IgAN patients and control subjects. In addition, no significant difference was observed between allele frequency of SNPs rs2895 332, rs1468488, and rs4819553 between patients in the early and advanced stage of the disease. However, significant difference was observed between the genotype of SNP rs2895332 between patients with proteinuria (>$4mg/m^2/h$) and those without proteinuria (codominant model OR 0.36, 95% CI 0.19-.66, P <0.001; dominant model OR 0.35, 95% CI 0.17-.69 P =0.002; recessive model OR 0.12, 95% CI 0.01-.06 P =0.025). Conclusion : Our results indicate that the SNP in IL-17RA (rs2895332) may be related to the development of proteinuria in IgAN patients.

목 적 : IgA 신병증은 세계적으로 가장 흔한 사구체 질환으로 최근 들어 interleukin (IL)-17의 면역조절 반응에 있어서의 관련성이 밝혀지고 있다. 이 연구에서는 IL-17RA 유전자의 단일 염기다형성과 소아 IgA 신병증의 발생 및 진행과의 연관성을 알아보고자 하였다. 방 법 : 조직 검사를 통해 확인된 IgA 신병증 환아 156명과 건강한 정상 성인 245명을 대조군으로 하여 말초혈액을 채취하였다. PCR 방법으로 IL-17RA 유전자의 SNP (rs2895332, rs1468488, rs4819553)를 분석하였다. 환자군을 단백뇨(${\leq}4$ and >$4mg/m^2/hr$, ${\leq}40$ and >$40mg/m^2/hr$)와 병리학적 진행 여부에 따라서 두 그룹으로 나누어 IL-17RA SNP와의 연관성을 확인하였다. 결 과 : IgA 신병증 환자군과 정상 대조군에서 IL-17RA 유전자 rs2895332, rs1468488, rs4819553의 발현율은 통계적으로 유의한 차이가 없었다. 또한 IL-17RA 유전자 각각에 대하여, 병리학적 진행성 병변을 가진 군과 그렇지 못한 군 사이에 통계학적으로 유의한 차이가 없었다. 그러나 rs2895332 유전자의 경우, 단백뇨가 있는 군(단백뇨>$4mg/m^2/hr$)과 없는 군(단백뇨${\leq}4mg/m^2/hr$)에서는 두 군간에 통계적으로 유의한 차이를 보였다. 결 론 : IL-17RA 유전자 rs2895332의 단일염기다형성은 소아의 IgA 신병증에서 단백뇨의 발생과 통계학적으로 의미 있는 연관성이 있었다.

Keywords

Acknowledgement

Supported by : MSD

References

  1. Syrjanen J, Hurme M, Lehtimaki T, Mustonen J, Pasternack A. Polymorphism of the cytokine genes and IgA nephropathy. Kidney Int 2002;61:1079–85 https://doi.org/10.1046/j.1523-1755.2002.00193.x
  2. Hsu SI, Ramirez SB, Winn MP, Bonventre JV, Owen WF. Evidence for genetic factors in the development and progression of IgA nephropathy. Kidney Int 2000;57:1818-35 https://doi.org/10.1046/j.1523-1755.2000.00032.x
  3. Galla JH. Molecular genetics in IgA nephropathy. Nephron 2001;88:107-12 https://doi.org/10.1159/000045969
  4. Abbas AK, Lichtman AH, Pober JS. Cytokines, in cellular and molecular immunology. 1st ed. Philadelphia: WB Saunders Co, 1997:249-77
  5. Matsumoto K, Kanmatsuse K. Interleukin-17 stimulates the release of pro-inflammatory cytokines by blood monocytes in patients with IgA nephropathy. Scand J Urol Nephrol 2003;37:164-71 https://doi.org/10.1080/00365590310008929
  6. McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 2007;8:913-9 https://doi.org/10.1038/ni1507
  7. Toh ML, Miossec P. The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheumatol 2007;19:284-8 https://doi.org/10.1097/BOR.0b013e32805e87e0
  8. Koshy PJ, Henderson N, Logan C, Life PF, Cawston TE, Rowan AD. Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Ann Rheum Dis 2002;61:704–13 https://doi.org/10.1136/ard.61.8.704
  9. Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 2002;71:1-8
  10. van Kooten C, Boonstra JG, Paape ME, Fossiez F, Banchereau J, Lebecque S, et al. Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection. J Am Soc Nephrol 1998;9:1526–34
  11. Liu Z, Yang J, Chen Z, Gong R, Li L. Gene polymorphism in IL-1 receptor antagonist affects its production by monocytes in IgA nephropathy and Henoch-Schonlein nephritis. Chin Med J(Engl) 2001;114:1313–6
  12. Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 1992;22:396–402 https://doi.org/10.1111/j.1365-2362.1992.tb01480.x
  13. Ellis DA, William EH, Patrick N. Pediatric nephrology. 5th ed. Philadelphia: Lippincott Co, 2003:475-6
  14. Lee HS, Lee MS, Lee SM, Lee SY, Lee ES, Lee EY et al. Histological grading of IgA nephropathy predicting renal outcome: revisiting H.S. Lee’s glomerular grading system. Nephrol Dial Transplant 2005;20:342–8 https://doi.org/10.1093/ndt/gfh633
  15. D'Amico G. The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 1987;64:709–27
  16. Galla J. IgA nephropathy. Kidney Int 1995;47:377–87 https://doi.org/10.1038/ki.1995.50
  17. Yao Z, Painter SL, Fanslow FC, Ulrich D, Macduff BM, Spriggs MK, et al. Human IL-17: a novel cytokine derived from T cells. J Immunol 1995;155:5483–6
  18. Aarvak T, Chabaud M, Miossec P, Natvig JB. IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol 1999;162:1246–51
  19. Laan M, Cui Z-H, Hoshino H, Lotvall J, Sjostrand M, Gruenert DC, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol 1999;162:2347–52
  20. Chabaud M, Duraqnd JM, Buchs N, Fossiez F, Page G, Frappart L, et al. Human interleukin-17, a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 1999;42:963–70 https://doi.org/10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E
  21. Hwang SY, Kim JY, Kim KW, Park MK, Moon YM, Kim WU, et al. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB-and PI3 kinase/Akt-dependent pathways. Arthritis Res Ther 2004;6;120-8 https://doi.org/10.1186/ar1190
  22. McGeachy MJ, Anderton SM. Cytokines in the induction and resolution of experimental autoimmune encephalomyelitis. Cytokine 2005;32:81-4 https://doi.org/10.1016/j.cyto.2005.07.012
  23. Lubbets E, Koenders MI, van den Berg WB. The role of Tcell interukine-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 2005;7:29-37 https://doi.org/10.1186/ar1478
  24. Hahn WH, Cho BS, Kim SD, Kim SK, Kang SW. Interleukin-1 cluster gene polymorphisms in childhood IgA nephropathy. Pediatr Nephrol 2009;24:1329-36 https://doi.org/10.1007/s00467-009-1146-5
  25. Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 2003;14:155-74 https://doi.org/10.1016/S1359-6101(03)00002-9
  26. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007;8:345-50 https://doi.org/10.1038/ni0407-345
  27. Bau B, Haag J, Schmid E, Kaiser M, Gebhard PM, Aigner T. Bone morphogenetic protein-mediating receptor-associated Smads as well as common Smad are expressed in human articular chondrocytes but not up-regulated or down-regulated in osteoarthritic cartilage. J Bone Miner Res 2002;17:2141-50 https://doi.org/10.1359/jbmr.2002.17.12.2141
  28. Fossiez F, Djossou O, Chomarat P, Flores-Romo L, Ait-Yahia S, Maat C, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 1996;183:2593-603 https://doi.org/10.1084/jem.183.6.2593
  29. Stamp LK, James MJ, Cleland LG. Interleukin-17: the missing link between T-cell accumulation and effector cell actions in rheumatoid arthritis? Immunol Cell Biol 2004;82:1-9 https://doi.org/10.1111/j.1440-1711.2004.01212.x
  30. Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 2007;148:32-46 https://doi.org/10.1111/j.1365-2249.2007.03356.x
  31. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005;201:233-40 https://doi.org/10.1084/jem.20041257
  32. Matsumoto K. Increased release of tumor necrosis factor-α by monocytes from patients with glomerulonephritis. Clin Nephrol 1993;40:148-54
  33. Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-1$\beta$ and TNF-$\alpha$, by macrophages. J Immunol 1998;160:3513-21
  34. Matsumoto K, Kanmatsuse K. Increased urinary excretion of interleukin-17 in Nephrotic patients. Nephron 2002;91:243–9 https://doi.org/10.1159/000058399
  35. Maruyama K, Yoshida M, Nishio H, Shirakawa T, Kawamura T, Tanaka R, et al. Polymorphisms of renin-angiotensin system genes in childhood IgA nephropathy. Pediatr Nephrol 2001;16:350–5 https://doi.org/10.1007/s004670000555
  36. Nakanishi K, Sako M, Yata N, Aoyagi N, Nozu K, Tanaka R, et al. A-20C angiotensinogen gene polymorphism and proteinuria in childhood IgA nephropathy. Pediatr Nephrol 2004;19:144–7 https://doi.org/10.1007/s00467-003-1350-7