Molecular Biology Reports

, Volume 38, Issue 8, pp 5125–5132 | Cite as

CTLA-4 exon 1 +49 polymorphism alone and in a haplotype with −318 promoter polymorphism may confer susceptibility to chronic HBV infection in Chinese Han patients

  • Shaoqiong Duan
  • Guoyu Zhang
  • Qunying Han
  • Zhu Li
  • Zhengwen Liu
  • Jinghong Chen
  • Yi Lv
  • Na Li
  • Yawen Wang
  • Man Li
  • Sai Lou
  • Mingbo Yang
  • Qianqian Zhu
  • Fanfan Xing
Article

Abstract

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) plays a pivotal role in regulating T cell activation, which is believably critical for the outcome of hepatitis B virus (HBV) infection. The expression and function of CTLA-4 may be affected by gene polymorphisms. This study investigated the influence of CTLA-4 polymorphisms on disease susceptibility in Chinese Han patients with chronic HBV infection. CTLA-4 +49A/G and −318C/T polymorphisms were evaluated by DNA amplification with polymerase chain reaction followed by the restriction fragment length polymorphism analysis. The patients with chronic HBV infection had higher frequencies of genotype AA and allele A of CTLA-4 +49A/G polymorphism. The haplotype +49A−318C was significantly over-represented (P < 0.001) and haplotype +49G−318C under-represented (P = 0.006) in the patients. The +49GG genotype was more frequent (P = 0.009) and +49A allele was less frequent in patients with lower ALT levels (P = 0.012) in HBeAg positive chronic hepatitis B. It is indicated that CTLA-4 +49A/G polymorphism alone and in a haplotype with −318C allele may confer susceptibility to chronic HBV infection in Chinese Han patients.

Keywords

Chronic HBV infection CTLA-4 Genetic polymorphism Association 

Notes

Acknowledgments

This work was supported in part by funding from National Natural Science Foundation of China (Grant no. 30972758). We thank Dr. Bofeng Zhu and Chunxia Yan from the Department of Forensic Science, School of Medicine, Xi’an Jiaotong University, for assistance in statistical analysis. We thank Dr. Ostabela Mutashaga for English editing of the manuscript.

Conflict of interest statement

The authors declare that they have no conflict of interest related to the publication of this manuscript.

Supplementary material

11033_2010_660_MOESM1_ESM.doc (35 kb)
Supplementary material 1 (DOC 35 kb)

References

  1. 1.
    Lee WM (1997) Hepatitis B virus infection. N Engl J Med 337:1733–1745PubMedCrossRefGoogle Scholar
  2. 2.
    Löhr HF, Krug S, Herr W et al (1998) Quantitative and functional analysis of core-specific T-helper cell and CTL activities in acute and chronic hepatitis B. Liver 18:405–413PubMedGoogle Scholar
  3. 3.
    Heathcote J, McHutchison J, Lee S et al (1999) A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group. Hepatology 30:531–536PubMedCrossRefGoogle Scholar
  4. 4.
    Walunas TL, Lenschow DJ, Bakker CY et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413PubMedCrossRefGoogle Scholar
  5. 5.
    Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465PubMedCrossRefGoogle Scholar
  6. 6.
    Krummel MF, Allison JP (1996) CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 183:2533–2540PubMedCrossRefGoogle Scholar
  7. 7.
    Ueda H, Howson JM, Esposito L et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511PubMedCrossRefGoogle Scholar
  8. 8.
    Aguilar F, Torres B, Sánchez-Román J, Núñez-Roldán A, González-Escribano MF (2003) CTLA4 polymorphism in Spanish patients with systemic lupus erythematosus. Hum Immunol 64:936–940PubMedCrossRefGoogle Scholar
  9. 9.
    Parks CG, Hudson LL, Cooper GS et al (2004) CTLA-4 gene polymorphisms and systemic lupus erythematosus in a population-based study of whites and African-Americans in the southeastern United States. Lupus 13:784–791PubMedCrossRefGoogle Scholar
  10. 10.
    Bouqbis L, Izaabel H, Akhayat O et al (2003) Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population. Genes Immun 4:132–137PubMedCrossRefGoogle Scholar
  11. 11.
    Agarwal K, Czaja AJ, Jones DE, Donaldson PT (2000) Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 31:49–53PubMedCrossRefGoogle Scholar
  12. 12.
    Agarwal K, Jones DE, Daly AK et al (2000) CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol 32:538–541PubMedCrossRefGoogle Scholar
  13. 13.
    Djilali-Saiah I, Ouellette P, Caillat-Zucman S, Debray D, Kohn JI, Alvarez F (2001) CTLA-4/CD 28 region polymorphisms in children from families with autoimmune hepatitis. Hum Immunol 62:1356–1362PubMedCrossRefGoogle Scholar
  14. 14.
    Fan LY, Tu XQ, Cheng QB et al (2004) Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population. World J Gastroenterol 10:3056–3059PubMedGoogle Scholar
  15. 15.
    Thio CL, Mosbruger TL, Kaslow RA et al (2004) Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection. J Virol 78:11258–11262PubMedCrossRefGoogle Scholar
  16. 16.
    Mohammad Alizadeh AH, Hajilooi M, Ranjbar M, Fallahian F, Mousavi SM (2006) Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to chronic hepatitis B. World J Gastroenterol 12:630–635PubMedGoogle Scholar
  17. 17.
    Schott E, Witt H, Pascu M et al (2007) Association of CTLA4 single nucleotide polymorphisms with viral but not autoimmune liver disease. Eur J Gastroenterol Hepatol 19:947–951PubMedCrossRefGoogle Scholar
  18. 18.
    Gu X, Qi P, Zhou F et al (2010) +49G>A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population. Hum Immunol 71:83–87PubMedCrossRefGoogle Scholar
  19. 19.
    Lee YJ, Lo FS, Shu SG et al (2001) The promoter region of the CTLA4 gene is associated with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 14:383–388PubMedCrossRefGoogle Scholar
  20. 20.
    Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98PubMedCrossRefGoogle Scholar
  21. 21.
    Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J (2001) CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2:145–152PubMedCrossRefGoogle Scholar
  22. 22.
    Mäurer M, Loserth S, Kolb-Mäurer A et al (2002) A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 54:1–8PubMedCrossRefGoogle Scholar
  23. 23.
    Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ (2000) CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease. J Immunol 165:6606–6611PubMedGoogle Scholar
  24. 24.
    Slot MC, Sokolowska MG, Savelkouls KG, Janssen RG, Damoiseaux JG, Cohen Tervaert JW (2008) Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis. Clin Immunol 128:39–45PubMedCrossRefGoogle Scholar
  25. 25.
    Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502–507PubMedCrossRefGoogle Scholar
  26. 26.
    Takahashi T, Tagami T, Yamazaki S et al (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310PubMedCrossRefGoogle Scholar
  27. 27.
    Jonson CO, Hedman M, Karlsson Faresjö M et al (2006) The association of CTLA-4 and HLA class II autoimmune risk genotype with regulatory T cell marker expression in 5-year-old children. Clin Exp Immunol 145:48–55PubMedCrossRefGoogle Scholar
  28. 28.
    Xu D, Fu J, Jin L et al (2006) Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol 177:739–747PubMedGoogle Scholar
  29. 29.
    Stoop JN, van der Molen RG, Baan CC et al (2005) Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41:771–778PubMedCrossRefGoogle Scholar
  30. 30.
    Jiang Z, Feng X, Zhang W et al (2007) Recipient cytotoxic T lymphocyte antigen-4 +49 G/G genotype is associated with reduced incidence of hepatitis B virus recurrence after liver transplantation among Chinese patients. Liver Int 27:1202–1208PubMedGoogle Scholar
  31. 31.
    Wang XB, Zhao X, Giscombe R, Lefvert AK (2002) A CTLA-4 gene polymorphism at position −318 in the promoter region affects the expression of protein. Genes Immun 3:233–234PubMedCrossRefGoogle Scholar
  32. 32.
    Chistiakov DA, Savost’anov KV, Turakulov RI, Efremov IA, Demurov LM (2006) Genetic analysis and functional evaluation of the C/T(−318) and A/G(−1661) polymorphisms of the CTLA-4 gene in patients affected with Graves’ disease. Clin Immunol 118:233–242PubMedCrossRefGoogle Scholar
  33. 33.
    Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. Annu Rev Immunol 24:65–97PubMedCrossRefGoogle Scholar
  34. 34.
    Jain N, Nguyen H, Chambers C, Kang J (2010) Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci USA 107:1524–1528PubMedCrossRefGoogle Scholar
  35. 35.
    Johnson GC, Esposito L, Barratt BJ et al (2001) Haplotype tagging for the identification of common disease genes. Nat Genet 29:233–237PubMedCrossRefGoogle Scholar
  36. 36.
    Anjos SM, Tessier MC, Polychronakos C (2004) Association of the cytotoxic T lymphocyte-associated antigen 4 gene with type 1 diabetes: evidence for independent effects of two polymorphisms on the same haplotype block. J Clin Endocrinol Metab 89:6257–6265PubMedCrossRefGoogle Scholar
  37. 37.
    Yee LJ, Perez KA, Tang J, van Leeuwen DJ, Kaslow RA (2003) Association of CTLA4 polymorphisms with sustained response to interferon and ribavirin therapy for chronic hepatitis C virus infection. J Infect Dis 187:1264–1271PubMedCrossRefGoogle Scholar
  38. 38.
    Hou R, Cao B, Chen Z et al (2010) Association of cytotoxic T lymphocyte-associated antigen-4 gene haplotype with the susceptibility to gastric cancer. Mol Biol Rep 37:515–520PubMedCrossRefGoogle Scholar
  39. 39.
    Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736PubMedCrossRefGoogle Scholar
  40. 40.
    Sutmuller RP, van Duivenvoorde LM, van Elsas A et al (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823–832PubMedCrossRefGoogle Scholar
  41. 41.
    Phan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377PubMedCrossRefGoogle Scholar
  42. 42.
    Korman A, Yellin M, Keler T (2005) Tumor immunotherapy: preclinical and clinical activity of anti-CTLA4 antibodies. Curr Opin Investig Drugs 6:582–591PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Shaoqiong Duan
    • 1
  • Guoyu Zhang
    • 1
  • Qunying Han
    • 1
  • Zhu Li
    • 1
  • Zhengwen Liu
    • 1
  • Jinghong Chen
    • 2
  • Yi Lv
    • 3
  • Na Li
    • 1
  • Yawen Wang
    • 1
  • Man Li
    • 1
  • Sai Lou
    • 1
  • Mingbo Yang
    • 1
  • Qianqian Zhu
    • 1
  • Fanfan Xing
    • 1
  1. 1.Department of Infectious Diseases, First Affiliated Hospital, School of MedicineXi’an Jiaotong UniversityXi’anPeople’s Republic of China
  2. 2.Key Laboratory of Environment and Genes related to Diseases, Ministry of Education, Institute of Endemic Diseases, School of MedicineXi’an Jiaotong UniversityXi’anPeople’s Republic of China
  3. 3.Department of Hepatobiliary Surgery, First Affiliated Hospital, School of MedicineXi’an Jiaotong UniversityXi’anPeople’s Republic of China

Personalised recommendations