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Association of HLA-G gene promoter haplotype with childhood IgA nephropathy in the Korean population

한국인에서의 소아 IgA 신병증과 HLA-G유전자의 promoter haplotype과의 관계

  • Jung, Hwan-Hee (Department of Pediatrics, Kyunghee University College of Medicine) ;
  • Hahn, Won-Ho (Department of Pediatrics, Kyunghee University College of Medicine) ;
  • Cho, Byoung-Soo (Department of Pediatrics, Kyunghee University College of Medicine) ;
  • Kim, Sung-Do (Department of Pediatrics, Kyunghee University College of Medicine)
  • 정환희 (경희대학교 의과대학 소아과학교실) ;
  • 한원호 (경희대학교 의과대학 소아과학교실) ;
  • 조병수 (경희대학교 의과대학 소아과학교실) ;
  • 김성도 (경희대학교 의과대학 소아과학교실)
  • Received : 2009.07.17
  • Accepted : 2009.10.19
  • Published : 2010.04.15

Abstract

Purpose : IgA nephropathy (IgAN) is the most commonly occurring form of chronic glomerulonephritis in pediatric cases. Human leukocyte antigen (HLA) genes have been implicated in various inflammatory and autoimmune diseases. The present study was conducted to investigate the association between 2 single nucleotide polymorphisms (SNPs) of the HLA-G gene and childhood IgAN. Methods : The authors analyzed and compared $HLA-G$ gene SNPs (rs1736936 and rs2735022) in 174 patients with childhood IgAN and in 438 healthy controls. In addition, IgAN patients were dichotomized and compared with respect to proteinuria (< and >$4mg/m^2/hour$), the presence or absence of podocyte foot process effacement, and the presence of pathologically early and advanced disease markers such as interstitial fibrosis, tubular atrophy, or global sclerosis. Results : No significant SNP frequency differences were observed for the $HLA-G$ gene between IgAN patients and the control group. Moreover, no significantly associated SNP was observed with the presence of proteinuria, podocyte foot process effacement, or pathologically advanced markers. However, the haplotype, composed of rs1736936 and rs2735022, showed a significant association with the susceptibility to develop childhood IgAN (haplotype T/C: dominant model, $P$=0.049; haplotype C/T: recessive model, $P$=0.030). Conclusion : Our results indicate that rs1736936 and rs2735022 as the $HLA-G$ gene promoter haplotype might be associated with the susceptibility to develop childhood IgAN in the Korean population.

목 적: IgA 신병증은 소아들의 만성 사구체 신염 중에서 가장 흔하게 일어나며, HLA유전자는 다양한 염증성 질환과 자가면역질환과 연관이 있어 왔다. 이 연구에서는 한국인에서 건강한 대조군과 IgA 신병증 환자군을 비교하여 IgA 신병증 발생 감수성 및 병리, 임상 양상과 $HLA-G$ 유전자의 SNP와의 연관성에 관해 알아보고자 하였다. 방 법: 소아 IgA 신병증을 앓고 있는 174명의 환자군과 438명의 정상 대조군에서 $HLA-G$ 유전자의 promoter SNP (rs1736936과 rs2735022)를 분석하고 비교하였다. 또한 IgA 신병증 환자들을 단백뇨($4mg/m^2/hour$ 이하군과 이상군)의 유무, 족세포 돌기의 소실 유무, 간질의 섬유화 및 세뇨관 위축이나 미만성 사구체 경화와 같은 병리학적 소견상 진행성 질환의 표지자유무에 따라 하위그룹으로 나누어 비교하였다. 결 과: IgA 신병증 환자군과 정상 대조군 간의 HLA-G에서의 SNP (rs1736936과 rs2735022) 빈도에 대한 유의한 차이는 발견되지 않았다. 또한 단백뇨의 유무, 족세포 돌기의 소실 유무, 질환의 병리학적 진행 정도을 의미하는 표지자의 유무와 SNP사이에서도 유의한 연관성을 보이지는 않았다. 그러나, 일체 배형으로서 rs1736936과 rs2735022는 소아 IgA 신병증을 일으키는 감수성에 대해 통계학적으로 유의한 연관성을 나타내었다(haplotype T/C: dominant model OR 1.71, 95% CI 1.00-2.92, $P$=0.049; haplotype C/T: recessive model OR 0.54, 95% CI 0.31-0.94, $P$=0.030). 결 론: 이번 연구에서 $HLA-G$ 유전자의 SNP 중 rs1736936와 rs2735022로 이루어진 일체배형과 IgA 신병증의 발생간에 유의한 관계를 관찰하였으며, IgA 신병증 환자들의 단백뇨 발생 유무, 족세포 돌기의 소실 유무 및 질병 진행 정도로 구분된 하위그룹과 후보 SNP들간의 유의한 관계는 확인할 수 없었다.

Keywords

References

  1. Veit TD, Vianna P, Scheibel I, Brenol CV, Brenol JC, Xavier RM, et al. Association of the HLA-G 14-bp insertion/deletion polymorphism with juvenile idiopathic arthritis and rheumatoid arthritis. Tissue Antigens 2008;71:440-6. https://doi.org/10.1111/j.1399-0039.2008.01019.x
  2. Verbruggen LA, Rebmann V, Demanet C, De Cock S, Grosse- Wilde H. Soluble HLA-G in rheumatoid arthritis. Hum Immunol 2006;67:561-7. https://doi.org/10.1016/j.humimm.2006.03.023
  3. Warren HS, Smyth MJ. NK cells and apoptosis. Immunol Cell Biol 1999;77:64-75. https://doi.org/10.1046/j.1440-1711.1999.00790.x
  4. Rouas-Freiss N, Goncalves RM, Menier C, Dausset J, Carosella ED. Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci U S A 1997;94:11520-5. https://doi.org/10.1073/pnas.94.21.11520
  5. Baricordi OR, Stignani M, Melchiorri L, Rizzo R. HLA-G and inflammatory diseases. Inflamm Allergy Drug Targets 2008;7:67-74. https://doi.org/10.2174/187152808785107615
  6. Wiendl H. HLA-G in the nervous system. Hum Immunol 2007;68:286-93. https://doi.org/10.1016/j.humimm.2006.10.021
  7. Veit TD, Cordero EA, Mucenic T, Monticielo OA, Brenol JC, Xavier RM, et al. Association of the HLA-G 14 bp polymorphism with systemic lupus erythematosus. Lupus 2009;18: 424-30. https://doi.org/10.1177/0961203308098187
  8. HS Lee, MS Lee, SM Lee, SY Lee, ES Lee. 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
  9. Ellis DA, William EH, Patrick N. Pediatric nephrology. 5th ed. Philadelphia:Lippincott Co, 2003:475-6.
  10. Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 2006;22:1928-9. https://doi.org/10.1093/bioinformatics/btl268
  11. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21:263-5. https://doi.org/10.1093/bioinformatics/bth457
  12. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science 2002;296:2225-9. https://doi.org/10.1126/science.1069424
  13. LeMaoult J, Le Discorde M, Rouas-Freiss N, Moreau P, Menier C, McCluskey J, et al. Biology and functions of human leukocyte antigen-G in health and sickness. Tissue Antigens 2003;62:273-84. https://doi.org/10.1034/j.1399-0039.2003.00143.x
  14. Tollefsen S, Arentz-Hansen H, Fleckenstein B, Molberg O, Raki M, Kwok WW, et al. HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest 2006; 116:2226-36. https://doi.org/10.1172/JCI27620
  15. Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, et al. HLA types in celiac disease patients not carrying the DQA105-DQB102 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003;64:469-77. https://doi.org/10.1016/S0198-8859(03)00027-2
  16. Redondo MJ, Babu S, Zeidler A, Orban T, Yu L, Greenbaum C, et al. Specific human leukocyte antigen DQ influence on expression of antiislet autoantibodies and progression to type 1 diabetes. J Clin Endocrinol Metab 2006 ;91:1705-13. https://doi.org/10.1210/jc.2005-1695
  17. Rogus JJ, Poznik GD, Pezzolesi MG, Smiles AM, Dunn J, Walker W, et al. High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach. Diabetes 2008;57:2519-26. https://doi.org/10.2337/db07-1086
  18. Li JY, Yong TY, Bennett G, Barbara JA, Coates PT. Human leucocyte antigen DQ alpha heterodimers and human leucocyte antigen DR alleles in tubulointerstitial nephritis and uveitis syndrome. Nephrology (Carlton) 2008;13:755-7. https://doi.org/10.1111/j.1440-1797.2008.00984.x
  19. Karahan GE, Seyhun Y, Oguz FS, Kekik C, Onal AE, Yazici H, et al. Impact of HLA on the underlying primary diseases in Turkish patients with end-stage renal disease. Ren Fail 2009;31:44-9. https://doi.org/10.1080/08860220802546297
  20. Crispim JC, Mendes-Junior CT, Wastowski IJ, Palomino GM, Saber LT, Rassi DM, et al. HLA polymorphisms as incidence factor in the progression to end-stage renal disease in Brazilian patients awaiting kidney transplant. Transplant Proc 2008; 40:1333-6. https://doi.org/10.1016/j.transproceed.2008.02.086
  21. Spriewald BM, Witzke O, Wassmuth R, Wenzel RR, Arnold ML, Philipp T, et al. Distinct tumour necrosis factor alpha, interferon gamma, interleukin 10, and cytotoxic T cell antigen 4 gene polymorphisms in disease occurrence and end stage renal disease in Wegener's granulomatosis. Ann Rheum Dis 2005;64:457-61.
  22. Kitagawa W, Imai H, Komatsuda A, Maki N, Wakui H, Hiki Y, et al. The HLA-DRB11501 allele is prevalent among Japanese patients with anti-glomerular basement membrane antibody-mediated disease. Nephrol Dial Transplant 2008;23: 3126-9. https://doi.org/10.1093/ndt/gfn179
  23. Wada J, Sugiyama H, Makino H. Pathogenesis of IgA nephropathy. Semin Nephrol 2003;23:556-63. https://doi.org/10.1053/S0270-9295(03)00134-7
  24. Scolari F. Inherited forms of IgA nephropathy. J Nephrol 2003;16:317-20.
  25. Doxiadis, II, De Lange P, De Vries E, Persijn GG, Claas FH. Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure. Tissue Antigens 2001;57:344-7. https://doi.org/10.1034/j.1399-0039.2001.057004344.x
  26. Cao HX, Li M, Nie J, Wang W, Zhou SF, Yu XQ. Human leukocyte antigen DRB1 alleles predict risk and disease progression of immunoglobulin A nephropathy in Han Chinese. Am J Nephrol 2008;28:684-91. https://doi.org/10.1159/000122111
  27. Vidan-Jeras B, Kunilo S, Fae I, Kandus A, Fischer GF. A novel HLA-B2730 allele found in a Slovene patient affected with IgA nephropathy. Int J Immunogenet 2006;33:371-3. https://doi.org/10.1111/j.1744-313X.2006.00629.x
  28. Akiyama F, Tanaka T, Yamada R, Ohnishi Y, Tsunoda T, Maeda S, et al. Single-nucleotide polymorphisms in the class II region of the major histocompatibility complex in Japanese patients with immunoglobulin A nephropathy. J Hum Genet 2002;47:532-8. https://doi.org/10.1007/s100380200080
  29. Seliger B, Schlaf G. Structure, expression and function of HLA-G in renal cell carcinoma. Semin Cancer Biol 2007;17: 444-50. https://doi.org/10.1016/j.semcancer.2007.07.001
  30. Bukur J, Seliger B. The role of HLA-G for protection of human renal cell-carcinoma cells from immune-mediated lysis: implications for immunotherapies. Semin Cancer Biol 2003;13:353-9. https://doi.org/10.1016/S1044-579X(03)00026-9
  31. Bukur J, Rebmann V, Grosse-Wilde H, Luboldt H, Ruebben H, Drexler I, et al. Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma. Cancer Res 2003;63:4107-11.
  32. Dunker K, Schlaf G, Bukur J, Altermann WW, Handke D, Seliger B. Expression and regulation of non-classical HLA-G in renal cell carcinoma. Tissue Antigens 2008 ;72:137-48. https://doi.org/10.1111/j.1399-0039.2008.01090.x
  33. Komohara Y, Harada M, Ishihara Y, Suekane S, Noguchi M, Yamada A, et al. HLA-G as a target molecule in specific immunotherapy against renal cell carcinoma. Oncol Rep 2007;8:1463-8.
  34. Crispim JC, Duarte RA, Soares CP, Costa R, Silva JS, Mendes- Junior CT, et al. Human leukocyte antigen-G expression after kidney transplantation is associated with a reduced incidence of rejection. Transpl Immunol 2008;18:361-7. https://doi.org/10.1016/j.trim.2007.10.010