CTLA-4 +49 A/G genotype and HLA-DRB1 polymorphisms in Turkish patients with Henoch–Schönlein purpura

Abstract

The pathogenesis of Henoch–Schönlein purpura (HSP) remains unknown; however, it is generally considered to be an immune complex-mediated disease. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is expressed on activated T cells, and, thus, it is critically involved in the immune response. We aimed to investigate the possible influence of CTLA-4 polymorphisms for susceptibility to HSP and determine if there were associations with human leukocyte antigen (HLA)-DRB1 genotypes. Using polymerase chain reaction-based DNA genotyping, we investigated the polymorphisms located in the genes encoding CTLA-4 in 100 patients with HSP and 156 ethnically matched healthy controls. When CTLA-4 +49 A/G polymorphism of HSP patients and control group was compared, no associations with joint, gastrointestinal or renal manifestations, or susceptibility to HSP, were observed. However, patients with nephrotic proteinuria had higher HLA-DRB1*13 positivity [odds ratio (OR) = 3.76, 95% confidence interval (95%CI) = 1.25–11.23, P = 0.025]. When the patients were stratified according to CTLA-4 polymorphism, a significant association between nephrotic proteinuria patients and carriage of the AG genotype was also found (OR = 15.42, 95%CI = 1.59–148.82, P = 0.008). These results suggested that CTLA-4 +49 A/G polymorphism does not contribute to susceptibility to HSP; however, the presence of CTLA-4 AG genotype and HLA-DRB1*13 could be a risk factor for developing nephrotic-range proteinuria in these patients.

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References

  1. 1.

    Tizard EJ (2002) Henoch–Schönlein purpura. Curr Paediatr 12:575–580

    Article  Google Scholar 

  2. 2.

    Halling SFE, Söderberg MP, Berg UB (2005) Henoch Schönlein nephritis: clinical findings related to renal function and morphology. Pediatr Nephrol 20:46–51

    Article  Google Scholar 

  3. 3.

    Levy M, Broyer M, Arsan A (1976) Anaphylactoid purpura nephritis in childhood natural history and immunopathology. In: Hamburger J, Crosnier J, Maxwell MH (eds) Advances in nephrology from the Necker Hospital. Year Book, Chicago, pp 183–228

    Google Scholar 

  4. 4.

    Yang YH, Lai HJ, Kao CK, Lin YT, Chiang BL (2004) The association between transforming growth factor-beta gene promoter C-509T polymorphism and Chinese children with Henoch-Schönlein purpura. Pediatr Nephrol 19:972–975

    Article  Google Scholar 

  5. 5.

    Yang YH, Huang MT, Lin SC, Lin YT, Tsai MJ, Chiang BL (2000) Increased TGF-b secreting T cells and IgA anticardiolipin antibodies levels during acute stage of childhood Henoch-Schonlein purpura. Clin Exp Immunol 122:285–290

    CAS  Article  Google Scholar 

  6. 6.

    Yang YH, Wang SJ, Chuang YH, Lin YT, Chiang BL (2002) The level of IgA antibodies to human umbilical vein endothelial cells can be enhanced by TNF-a treatment in children with Henoch-Schonlein purpura. Clin Exp Immunol 130:352–357

    CAS  Article  Google Scholar 

  7. 7.

    Feehally J, Allen AC (1999) Pathogenesis of IgA nephropathy. Ann Med Interne (Paris) 150:91–98

    CAS  Google Scholar 

  8. 8.

    Vogler C, Eliason SC, Wood EG (1999) Glomerular membranopathy in children with IgA nephropathy and Henoch Schönlein purpura. Pediatr Dev Pathol 2:227–235

    CAS  Article  Google Scholar 

  9. 9.

    Kato S, Ebina K, Naganuma H, Sato S, Maisawa S, Nakagawa H (1996) Intestinal IgA deposition in Henoch–Schönlein purpura with severe gastro-intestinal manifestations. Eur J Pediatr 155:91–95

    CAS  Article  Google Scholar 

  10. 10.

    Jin DK, Kohsaka T, Koo JW, Ha IS, Cheong HI, Choi Y (1996) Complement 4 locus II gene deletion and DQA1*0301 gene: genetic risk factors for IgA nephropathy and Henoch–Schonlein nephritis. Nephron 73:390–395

    CAS  Article  Google Scholar 

  11. 11.

    Amoroso A, Berrino M, Canale L, Coppo R, Cornaglia M, Guarrera S, Mazzola G, Scoları F (1997) Immunogenetics of Henoch-Schönlein disease. Eur J Immunogenet 24:323–333

    CAS  Article  Google Scholar 

  12. 12.

    Amoli MM, Thomson W, Hajeer AH, Calvino MC, Garcia-Porrua C, Ollier WE, Gonzalez-Gay MA (2002) HLA B35 association with nephritis in Henöch-Schonlein purpura. J Rheumatol 29:948–949

    PubMed  Google Scholar 

  13. 13.

    Peru H, Soylemezoglu O, Gonen S, Cetinyurek A, Bakkaloğlu SA, Buyan N, Hasanoglu E (2008) HLA class 1 associations in Henoch Schonlein purpura: increased and decreased frequencies. Clin Rheumatol 27:5–10

    Article  Google Scholar 

  14. 14.

    Amoli MM, Thomson W, Hajeer AH, Calvino MC, Garcia-Porrua C, Ollier WE, Gonzalez-Gay MA (2001) HLA-DRB1*01 association with Henoch-Schönlein purpura in patients from Northwest Spain. J Rheumatol 28:1266–1270

    CAS  PubMed  Google Scholar 

  15. 15.

    Noel PJ, Boise LH, Green JM, Thompson CB (1996) CD28 costimulation prevents cell death during primary T cell activation. J Immunol 157:636–642

    CAS  PubMed  Google Scholar 

  16. 16.

    Harbo HF, Celius EG, Vartdal F, Spurkland A (1999) CTLA-4 promotor and exon 1 dimorphismus in multiple sclerosis. Tissue Antigens 53:106–110

    CAS  Article  Google Scholar 

  17. 17.

    Lei C, Dongqing Z, Yeqing S, Oaks MK, Lishan C, Jianzhong J, Jie Q, Fang D, Ningli L, Xinghai H, Daming R (2005) Association of the CTLA-4 gene with rheumatoid arthritis in Chinese Han population. Eur J Hum Genet 13:823–828

    Article  Google Scholar 

  18. 18.

    Barreto M, Santos E, Ferreira R, Fesel C, Fontes MF, Pereira C, Martins B, Andreia R, Viana JF, Crespo F, Vasconcelos C, Ferreira C, Vicente AM (2004) Evidence for CTLA-4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet 12:620–626

    CAS  Article  Google Scholar 

  19. 19.

    Han S, Li Y, Mao Y, Xie Y (2005) Meta-analysis of the association of CTLA-4 exon-1 +49A/G polymorphism with rheumatoid arthritis. Hum Genet 118:123–132

    CAS  Article  Google Scholar 

  20. 20.

    Lee YH, Harley JB, Nath SK (2005) CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis. Hum Genet 116:361–367

    CAS  Article  Google Scholar 

  21. 21.

    Mills JA, Michel BA, Bloch DA Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, Arend WP, Edworthy SM, Fauci AS, Leavitt RY, Lie JT (1990) The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum 33:1114–1121

    CAS  Article  Google Scholar 

  22. 22.

    Soylemezoglu O, Ozkaya O, Erbas D, Akkok N, Buyan N, Hasanoglu E (2002) Nitric oxide in Henoch–Schönlein purpura. Scand J Rheumatol 31:271–274

    Article  Google Scholar 

  23. 23.

    Miller SA, Dykes DD, Polesky HF (1988) A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    CAS  Article  Google Scholar 

  24. 24.

    Motoyama O, Iitaka K (2005) Henoch-Schönlein purpura with hypocomplementemia in children. Pediatr Int 47:39–42

    Article  Google Scholar 

  25. 25.

    Besbas N, Saatci U, Ruacan S, Ozen S, Sungur A, Bakkaloglu A, Elnahas AM (1997) The role of cytokines in Henoch–Schönlein purpura. Scand J Rheumatol 26:456–460

    CAS  Article  Google Scholar 

  26. 26.

    Gattorno M, Vignola S, Barbano G, Sormani MP, Sabatini F, Buoncompagni A, Picco P, Pistoia V (2000) Tumor necrosis factor induced adhesion molecule serum concentrations in Henoch-Schönlein purpura and pediatric systemic lupus erythematosus. J Rheumatol 27:2251–2255

    CAS  PubMed  Google Scholar 

  27. 27.

    Amoli MM, Calviño MC, Garcia-Porrua C, Llorca J, Ollier WE, Gonzalez-Gay MA (2004) Interleukin 1beta gene polymorphism association with severe renal manifestations and renal sequelae in Henoch-Schönlein purpura. J Rheumatol 31:295–298

    CAS  PubMed  Google Scholar 

  28. 28.

    Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Restivo VA Jr, Ke X, Gray GS (1995) CTLA-4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci U S A 92:811–815

    CAS  Article  Google Scholar 

  29. 29.

    Tivol EA, Schweitzer AN, Sharpe AH (1996) Costimulation and autoimmunity. Curr Opin Immunol 8:822–830

    CAS  Article  Google Scholar 

  30. 30.

    Thompson CB, Allison JP (1997) The emerging role of CTLA-4 as an immune attenuator. Immunity 7:445–450

    CAS  Article  Google Scholar 

  31. 31.

    Zhou Y, Huang D, Paris PL, Sauter CS, Prock KA, Hoffman GS (2004) An analysis of CTLA-4 and proinflammatory cytokine genes in Wegener's granulomatosis. Arthritis Rheum 50:2645–2650

    CAS  Article  Google Scholar 

  32. 32.

    Gunesacar R, Erken E, Bozkurt B, Ozer HT, Dinkci S, Erken EG, Ozbalkan Z (2007) Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet’s disease. Int J Immunogenet 34:45–49

    CAS  Article  Google Scholar 

  33. 33.

    Sallakci N, Bacanli A, Coskun M, Yavuzer U, Alpsoy E, Yegin O (2005) CTLA-4 gene 49A/G polymorphism in Turkish patients with Behçet's disease. Clin Exp Dermatol 30:546–550

    CAS  Article  Google Scholar 

  34. 34.

    Tsuchiya N, Kobayashi S, Kawasaki A, Kyogoku C, Arimura Y, Yoshida M, Tokunaga K, Hashimoto H (2003) Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: association of HLA-DRB1*0901 with microscopic polyangiitis. J Rheumatol 30:1534–1540

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Gazi University Scientific Research Project Unit, Ankara, Turkey (project no. 01/2004-79 BAP).

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Correspondence to Harun Peru.

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Soylemezoglu, O., Peru, H., Gonen, S. et al. CTLA-4 +49 A/G genotype and HLA-DRB1 polymorphisms in Turkish patients with Henoch–Schönlein purpura. Pediatr Nephrol 23, 1239–1244 (2008). https://doi.org/10.1007/s00467-008-0837-7

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Keywords

  • Cytotoxic T lymphocyte-associated protein 4
  • Henoch–Schönlein purpura
  • Human leukocyte antigen
  • Polymorphism
  • Susceptibility