Skip to main content
SpringerLink
Log in

Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

The natural outcome and response to treatment in hepatitis C virus (HCV) infection varies between individuals. Whereas some variation may be attributable to viral and environmental variables, it is probable that host genetic background also plays a significant role. Interleukin (IL)-10 has a key function in the regulation of cellular immune responses and in the suppression of pro-inflammatory cytokine secretion. Functional polymorphisms in the IL-10 gene have been described. We investigated the role of these polymorphisms in the outcome of HCV infection, treatment response and development of fibrosis in a case-control association study. Self-limiting infection was associated with the IL-10 (−592) AA genotype (OR=2.05; P=0.028). Persistent infection was associated with the IL-10 (−1082) GG genotype (OR=0.48; P=0.018). Sustained response to interferon therapy was associated with the IL-10 (−1082) GG genotype (OR=2.28; P=0.005) and the haplotype GCC (OR=2.27; P=0.020). The IL-10 (−1082) AA genotype and the ATA/ATA and ACC/ACC homozygous haplotypes were more frequent among patients with rapid fibrosis. Furthermore, the microsatellites IL-10.R and IL-10.G were associated with interferon response with IL-10R.2 conveying susceptibility (OR=1.80; P=0.034), and IL-10R.3 and IL-10.G13 being protective (OR=0.47; P=0.003 and OR=0.59; P=0.042, respectively). We conclude that polymorphisms in the IL-10 promoter appear to have some influence on the outcome of HCV infection, treatment and development of fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, Hu PY, Miller JK, Gerber MA, Sampliner RE, et al (1992) The natural history of community acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team (see comments). N Engl J Med 327:1899–1905

    CAS  PubMed  Google Scholar 

  • Constantini PK, Wawrzynowicz-Syczewska M, Clare M, Boron-Kaczmarska A, McFarlane IG, Cramp ME, Donaldson PT (2002) Interleukin-1, interleukin-10 and tumour necrosis factor-alpha gene polymorphisms in hepatitis C virus infection: an investigation of the relationships with spontaneous viral clearance and response to alpha-interferon therapy. Liver 22:404–412

    Article  CAS  PubMed  Google Scholar 

  • Cramp ME, Carucci P, Underhill J, Naoumov NV, Williams R, Donaldson PT (1998a) Association between HLA class II genotype and spontaneous clearance of hepatitis C viraemia. J Hepatol 29:207–213

    Article  CAS  PubMed  Google Scholar 

  • Cramp ME, Rossol S, Carucci P, Williams R, Naumov NV, Donaldson PT (1998b) The influence of the HLA class II allele DQB1*0301 on HCV specific T helper cell responses. J Hepatol 28:94

    Article  Google Scholar 

  • D'Alfonso S, Rampi M, Rolando V, Giordano M, Momigliano-Richiardi P (2000) New polymorphisms in the IL-10 promoter region. Genes Immun 1:231–233

    Article  CAS  PubMed  Google Scholar 

  • Davis GL, Lau JY (1997) Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 26:122S–127S

    CAS  PubMed  Google Scholar 

  • Diepolder HM, Zachoval R, Hoffmann RM, Jung MC, Gerlach T, Pape GR (1996) The role of hepatitis C virus specific CD4+ T lymphocytes in acute and chronic hepatitis C. J Mol Med 74:583–588

    Article  CAS  PubMed  Google Scholar 

  • Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE (1999) Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 30:526–530

    CAS  PubMed  Google Scholar 

  • Eskdale J, Gallagher G (1995) A polymorphic dinucleotide repeat in the human IL-10 promoter. Immunogenetics 42:444–445

    CAS  PubMed  Google Scholar 

  • Eskdale J, Kube D, Gallagher G (1996) A second polymorphic dinucleotide repeat in the 5′ flanking region of the human IL10 gene. Immunogenetics 45:82–83

    Article  CAS  PubMed  Google Scholar 

  • Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW (1998) Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 95:9465–9470

    Article  CAS  PubMed  Google Scholar 

  • Eskdale J, Keijsers V, Huizinga T, Gallagher G (1999) Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun 1:151–155

    Article  CAS  PubMed  Google Scholar 

  • Fickenscher H, Hor S, Kupers H, Knappe A, Wittmann S, Sticht H (2002) The interleukin-10 family of cytokines. Trends Immunol 23:89–96

    Article  CAS  PubMed  Google Scholar 

  • Germer S, Holland MJ, Higuchi R (2000) High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res 10:258–266

    CAS  PubMed  Google Scholar 

  • Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP (2001) Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166:3915–3922

    CAS  PubMed  Google Scholar 

  • Godkin A, Jeanguet N, Thursz M, Openshaw P, Thomas H (2001) Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and nonviremic patients. Eur J Immunol 31:1438–1446

    Article  CAS  PubMed  Google Scholar 

  • Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, Waggoner JG, Park Y, Jones EA (1986) Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 315:1575–1578

    CAS  PubMed  Google Scholar 

  • Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309

    Article  CAS  PubMed  Google Scholar 

  • Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN, et al (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22:696–699

    Article  CAS  PubMed  Google Scholar 

  • Kenny Walsh E (1999) Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 340:1228–1233

    Article  PubMed  Google Scholar 

  • Lau JY, Tam RC, Liang TJ, Hong Z (2002) Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 35:1002–1009

    Article  CAS  PubMed  Google Scholar 

  • Lio D, Caruso C, Di Stefano R, Colonna RG, Ferraro D, Scola L, Crivello A, Licata A, Valenza LM, Candore G, Craxi A, Almasio PL (2003) IL-10 and TNF-alpha polymorphisms and the recovery from HCV infection. Hum Immunol 64:674–680

    Article  CAS  PubMed  Google Scholar 

  • Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958–965

    Article  CAS  PubMed  Google Scholar 

  • Marcellin P (1999) Hepatitis C: the clinical spectrum of the disease. J Hepatol 31 [Suppl 1]:9–16

    Google Scholar 

  • McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK (1998) Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group (see comments). N Engl J Med 339:1485–1492

    CAS  PubMed  Google Scholar 

  • Moore KW, O'Garra A, de Waal MR, Vieira P, Mosmann TR (1993) Interleukin-10. Annu Rev Immunol 11:165–190

    CAS  PubMed  Google Scholar 

  • Powell EE, Edwards-Smith CJ, Hay JL, Clouston AD, Crawford DH, Shorthouse C, Purdie DM, Jonsson JR (2000) Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 31:828–833

    CAS  PubMed  Google Scholar 

  • Poynard T, Bedossa P, Opolon P (1997) Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 349:825–832

    Article  CAS  PubMed  Google Scholar 

  • Rees LE, Wood NA, Gillespie KM, Lai KN, Gaston K, Mathieson PW (2002) The interleukin-10-1082 G/A polymorphism: allele frequency in different populations and functional significance. Cell Mol Life Sci 59:560–569

    Article  Google Scholar 

  • Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Hohler T (2002) Differential regulation of interleukin-10 production by genetic and environmental factors— a twin study. Genes Immun 3:407–413

    Article  CAS  PubMed  Google Scholar 

  • Rothman KJ (1990) No adjustments are needed for multiple comparisons. Epidemiology 1:43–46

    CAS  PubMed  Google Scholar 

  • Seeff LB, Buskell Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger FB, Gitnick G, Knodell RG, Perrillo RP, et al (1992) Long-term mortality after transfusionassociated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med 327:1906–1911

    CAS  PubMed  Google Scholar 

  • Sham PC, Curtis D (1995) MOnte Caro tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 59:97–105

    PubMed  Google Scholar 

  • Thursz MR, Yallop R, Goldin R, Trepo C, Thomas HC (1999) Influence of MHC class II genotype on outcome of infection with hepatitis C virus. Lancet 354:2119–2124

    CAS  PubMed  Google Scholar 

  • Tong MJ, el Farra NS, Reikes AR, Co RL (1995) Clinical outcomes after transfusionassociated hepatitis C (see comments). N Engl J Med 332:1463–1466

    Article  CAS  PubMed  Google Scholar 

  • Touzet S, Kraemer L, Colin C, Pradat P, Lanoir D, Bailly F, Coppola RC, Sauleda S, Thursz MR, Tillmann H, Alberti A, Braconier JH, Esteban JI, Hadziyannis SJ, Manns MP, Saracco G, Thomas HC, Trepo C (2000) Epidemiology of hepatitis C virus infection in seven European Union countries: a critical analysis of the literature. HENCORE Group. (Hepatitis C European Network for Co-operative Research. Eur J Gastroenterol. Hepatol 12:667–678

    CAS  Google Scholar 

  • Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8

    CAS  Google Scholar 

  • Vidigal PG, Germer JJ, Zein NN (2002) Polymorphisms in the interleukin-10, tumor necrosis factor-alpha, and transforming growth factor-beta1 genes in chronic hepatitis C patients treated with interferon and ribavirin. J Hepatol 36:271–277

    Article  CAS  PubMed  Google Scholar 

  • Westendorp R, Langermans J, Huizinga T, Elouali A, Verweij C, Boomsma D, Vandenbrouke J (1997) Genetic influence on cytokine production and fatal meningococcal disease. Lancet 349:170–173

    Article  CAS  PubMed  Google Scholar 

  • Wright M, Goldin R, Fabre A, Lloyd J, Thomas H, Trepo C, Pradat P, Thursz M (2003) Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study. Gut 52:574–579

    Article  CAS  PubMed  Google Scholar 

  • Yee LJ, Tang J, Gibson AW, Kimberly R, Van Leeuwen DJ, Kaslow RA (2001) Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection. Hepatology 33:708–712

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

HENCORE is the Hepatitis C European Network for Cooperative Research. The participants were: Howards C Thomas, Mark R Thursz (Faculty of Medicine, Imperial College School of Medicine at St Mary's Hospital, Praed Street, London W2 1NY, UK), Pierre Pradat PhD, Christian Trepo (Hopitaux de Lyon, 1 Place de l'Hopital, 69288 Lyon Cedex 02, France), Juan Esteban MD (Hospital General Valle Hebron, Pasea Valle, Hebron S/U o8035, Barcelona, Spain), Stephanos Hadziyannis MD (University of Athens Medical School, 2nd Department of Medicine, Hippokration Hospital, 114 Vasilissis Sophias Avenue, Athens 610, Greece), Michael Manns PhD, Hans Tillmann MD (Medizinische Hochschule Hannover, Carl Neuburg Strasse 1, 30623 Hannover, Germany), Alfredo Alberti MD, Liliana Chemello MD (Department of Clinical and Experimental Medicine, Via Guistiniani 2, 35126 Padua, Italy), Giorgio Saracco MD, Mario Rizzetto PhD (Department of Gastroenterology, Molinette Hospital, Turin, Italy), Jean-Henrik Braconier MD (Department of Infectious Diseases, University Hospital, Lund, Sweden). This work was generously supported by Roche Discovery, Welwyn, UK and the Charmot-Horton Foundation. M.W. is a Medical Research Council of Great Britain clinical training fellow. A.V.S.H. is a Wellcome Trust Principal Fellow.

Author information

Authors and Affiliations

  1. Faculty of Medicine, Imperial College, St Mary's Hospital Campus, Norfolk Place, London, W2 1NY, UK

    Susanne Knapp, Mark Wright, Rob Goldin, Howard C. Thomas & Mark R. Thursz

  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Branwen J. W. Hennig, Angela J. Frodsham, Lyna Zhang, Simon Hellier & Adrian V. S. Hill

Authors
  1. Susanne Knapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Branwen J. W. Hennig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela J. Frodsham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lyna Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simon Hellier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rob Goldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adrian V. S. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Howard C. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark R. Thursz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark R. Thursz.

Additional information

Susanne Knapp and Branwen Hennig contributed equally to this study

Rights and permissions

Reprints and permissions

About this article

Cite this article

Knapp, S., Hennig, B.J.W., Frodsham, A.J. et al. Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Immunogenetics 55, 362–369 (2003). https://doi.org/10.1007/s00251-003-0594-5

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-003-0594-5

Keywords

Search

Navigation