Journal of Clinical Immunology

, Volume 29, Issue 5, pp 620–628 | Cite as

Interleukin 18 Promoter Variants (−137G>C and −607C>A) in Patients with Chronic Hepatitis C: Association with Treatment Response

  • Stephan L. Haas
  • Christel Weiß
  • Peter Bugert
  • Jutta Gundt
  • Heiko Witt
  • Manfred V. Singer
  • Thomas Berg
  • Ulrich Böcker
Article

Abstract

Background

Recently, two functional IL18 promoter variants, −607C>A (rs1946518) and −137G>C (rs187238), were associated with viral clearance in patients with hepatitis C. The present study focused on their relevance for treatment response.

Methods

Seven hundred fifty-seven chronically infected European patients and 791 controls were enrolled in the study. IL18 genotyping was performed by allele-specific PCR. Liver histology was available in 67.9%.

Results

Genotype and allele frequencies were equally distributed in patients and controls. No significant association with various disease characteristics was observed. However, when comparing patients with sustained virological response (SR) and non-SR, statistically significant associations were found for both variants (p = 0.0416 and p = 0.0274, respectively). In viral genotype 1, the −607A allele was positively associated with treatment response (p = 0.0190; OR 1.537; 95% CI, 1.072–2.205) and the −137G allele with a higher rate of nonresponse (p = 0.0302; OR 1.524; 95% CI, 1.040–2.233).

Conclusions

The association of IL18 variants with treatment response in genotype 1 hepatitis C patients implies a predictive and modifying role of these genetic variants.

Keywords

Hepatitis C antiviral therapy treatment outcome genetic alterations interleukin 18 

Notes

Acknowledgement

The authors would like to thank Sigrid Hugues for helping with the preparation of the manuscript.

This work was supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF, Grant No. 01 KI 0437, Project No. 10.1.3 Core Project No. 10.1 Genetic host factors in viral hepatitis and Genetic Epidemiology Group in viral hepatitis) and by the EU-Vigilanz network of excellence combating viral resistance (VIRGIL, Projekt No. LSHM-CT-2004-503359) and by the BMBF Project: Host and viral determinants for susceptibility and resistance to hepatitis C virus infection.

References

  1. 1.
    Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat. 1999;6:35–47. doi: 10.1046/j.1365-2893.1999.6120139.x
  2. 2.
    Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41–52. doi: 10.1056/NEJM200107053450107.PubMedCrossRefGoogle Scholar
  3. 3.
    Feld JJ, Liang TJ. Hepatitis C—identifying patients with progressive liver injury. Hepatology. 2006;43:S194–206. doi: 10.1002/hep. 21065.PubMedCrossRefGoogle Scholar
  4. 4.
    Massard J, Ratziu V, Thabut D, et al. Natural history and predictors of disease severity in chronic hepatitis C. J Hepatol. 2006;44:S19–24. doi: 10.1016/j.jhep. 2005.11.009.PubMedCrossRefGoogle Scholar
  5. 5.
    Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436:967–72. doi: 10.1038/nature04082.PubMedCrossRefGoogle Scholar
  6. 6.
    Paladino N, Fainboim H, Theiler G, et al. Gender susceptibility to chronic hepatitis C virus infection associated with interleukin 10 promoter polymorphism. J Virol. 2006;80:9144–50. doi: 10.1128/JVI.00339-06.PubMedCrossRefGoogle Scholar
  7. 7.
    Dharel N, Kato N, Muroyama R, et al. MDM2 promoter SNP309 is associated with the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Clin Cancer Res. 2006;12:4867–71. doi: 10.1158/1078-0432.CCR-06-0111.PubMedCrossRefGoogle Scholar
  8. 8.
    Sartori M, Andorno S, Pagliarulo M, et al. Heterozygous beta-globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis C. Gut. 2007;56:693–8. doi: 10.1136/gut.2006.106641.PubMedCrossRefGoogle Scholar
  9. 9.
    Strnad P, Lienau TC, Tao GZ, et al. Keratin variants associate with progression of fibrosis during chronic hepatitis C infection. Hepatology. 2006;43:1354–63. doi: 10.1002/hep.21211.PubMedCrossRefGoogle Scholar
  10. 10.
    Kato N, Ji G, Wang Y, et al. Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C. Hepatol. 2005;42:846–53. doi: 10.1002/hep.20860.CrossRefGoogle Scholar
  11. 11.
    Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol. 2003;73:213–24. doi: 10.1189/jlb.0602313.PubMedCrossRefGoogle Scholar
  12. 12.
    Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001;19:423–74. doi: 10.1146/annurev.immunol.19.1.423.PubMedCrossRefGoogle Scholar
  13. 13.
    Reddy P. Interleukin-18: recent advances. Curr Opin Hematol. 2004;11:405–10. doi: 10.1097/01.moh.0000141926.95319.42.PubMedCrossRefGoogle Scholar
  14. 14.
    Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995;378:88–91. doi: 10.1038/378088a0.PubMedCrossRefGoogle Scholar
  15. 15.
    Tsutsui H, Matsui K, Okamura H, Nakanishi K. Pathophysiological roles of interleukin-18 in inflammatory liver diseases. Immunol Rev. 2000;174:192–209. doi: 10.1034/j.1600-0528.2002.017418.x.PubMedCrossRefGoogle Scholar
  16. 16.
    Faggioni R, Jones-Carson J, Reed DA, et al. Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18. Proc Natl Acad Sci U S A. 2000;97:2367–72. doi: 10.1073/pnas.040561297.PubMedCrossRefGoogle Scholar
  17. 17.
    Faggioni R, Cattley RC, Guo J, et al. IL-18-binding protein protects against lipopolysaccharide- induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice. J Immunol. 2001;167:5913–20.PubMedGoogle Scholar
  18. 18.
    Vecchiet J, Falasca K, Cacciatore P, et al. Association between plasma interleukin-18 levels and liver injury in chronic hepatitis C virus infection and non-alcoholic fatty liver disease. Ann Clin Lab Sci. 2005;35:415–22.PubMedGoogle Scholar
  19. 19.
    Jia HY, Du J, Zhu SH, et al. The roles of serum IL-18, IL-10, TNF-alpha and sIL-2R in patients with chronic hepatitis C. Hepatobiliary Pancreat Dis Int. 2002;1:378–82.PubMedGoogle Scholar
  20. 20.
    Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol. 2001;112:146–52. doi: 10.1016/S0165-5728(00)00407-0.PubMedCrossRefGoogle Scholar
  21. 21.
    Hirankarn N, Manonom C, Tangkijvanich P, Poovorawan Y. Association of interleukin-18 gene polymorphism (-607A/A genotype) with susceptibility to chronic hepatitis B virus infection. Tissue Antigens. 2007;70:160–3. doi: 10.1111/j.1399-0039.2007.00865.x.PubMedCrossRefGoogle Scholar
  22. 22.
    Imboden M, Nicod L, Nieters A, et al. The common G-allele of interleukin-18 single-nucleotide polymorphism is a genetic risk factor for atopic asthma. The SAPALDIA Cohort Study. Clin Exp Allergy. 2006;36:211–8. doi: 10.1111/j.1365-2222.2006.02424.x.PubMedCrossRefGoogle Scholar
  23. 23.
    Tiret L, Godefroy T, Lubos E, et al. Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation. 2005;112:643–50. doi: 10.1161/CIRCULATIONAHA.104.519702.PubMedCrossRefGoogle Scholar
  24. 24.
    Takada T, Suzuki E, Morohashi K, Gejyo F. Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population. Tissue Antigens. 2002;60:36–42. doi: 10.1034/j.1399-0039.2002.600105.x.PubMedCrossRefGoogle Scholar
  25. 25.
    Bossu P, Ciaramella A, Salani F, et al. Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment. Brain Behav Immun. 2008;22:487–92. doi: 10.1016/j.bbi.2007.10.001.PubMedCrossRefGoogle Scholar
  26. 26.
    Bossu P, Ciaramella A, Moro ML, et al. Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2007;78:807–11. doi: 10.1136/jnnp.2006.103242.PubMedCrossRefGoogle Scholar
  27. 27.
    Hiromatsu Y, Mukai T, Kaku H, et al. IL-18 gene polymorphism confers susceptibility to the development of anti-GAD65 antibody in Graves’ disease. Diabet Med. 2006;23:211–5. doi: 10.1111/j.1464-5491.2005.01734.x.PubMedCrossRefGoogle Scholar
  28. 28.
    Sugiura T, Maeno N, Kawaguchi Y, et al. A promoter haplotype of the interleukin-18 gene is associated with juvenile idiopathic arthritis in the Japanese population. Arthritis Res Ther. 2006;8:R60. doi: 10.1186/ar1930.PubMedCrossRefGoogle Scholar
  29. 29.
    Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991;13:372–4. doi: 10.1016/0168-8278(91)90084-O.PubMedCrossRefGoogle Scholar
  30. 30.
    Lloyd AR, Jagger E, Post JJ, et al. Host and viral factors in the immunopathogenesis of primary hepatitis C virus infection. Immunol Cell Biol. 2007;85:24–32. doi: 10.1038/sj.icb.7100010.PubMedCrossRefGoogle Scholar
  31. 31.
    Oleksyk TK, Thio CL, Truelove AL, et al. Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance. Genes Immun. 2005;6:347–57. doi: 10.1038/sj.gene.6364188.PubMedCrossRefGoogle Scholar
  32. 32.
    Abbott WG, Rigopoulou E, Haigh P, et al. Single nucleotide polymorphisms in the interferon-gamma and interleukin-10 genes do not influence chronic hepatitis C severity or T-cell reactivity to hepatitis C virus. Liver Int. 2004;24:90–7. doi: 10.1111/j.1478-3231.2004.00904.x.PubMedCrossRefGoogle Scholar
  33. 33.
    Minton EJ, Smillie D, Smith P, et al. Clearance of hepatitis C virus is not associated with single nucleotide polymorphisms in the IL-1, -6, or -10 genes. Hum Immunol. 2005;66:127–32. doi: 10.1016/j.humimm.2004.11.001.PubMedCrossRefGoogle Scholar
  34. 34.
    Hennig BJ, Frodsham AJ, Hellier S, et al. Influence of IL-10RA and IL-22 polymorphisms on outcome of hepatitis C virus infection. Liver Int. 2007;27:1134–43. doi: 10.1111/j.1478-3231.2007.01518.x.PubMedCrossRefGoogle Scholar
  35. 35.
    Finotto S, Siebler J, Hausding M, et al. Severe hepatic injury in interleukin 18 (IL-18) transgenic mice: a key role for IL-18 in regulating hepatocyte apoptosis in vivo. Gut. 2004;53:392–400. doi: 10.1136/gut.2003.018572.PubMedCrossRefGoogle Scholar
  36. 36.
    Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. J Virol. 2002;76:10702–7. doi: 10.1128/JVI.76.21.10702-10707.2002.PubMedCrossRefGoogle Scholar
  37. 37.
    Fujioka N, Akazawa R, Ohashi K, Fujii M, Ikeda M, Kurimoto M. Interleukin-18 protects mice against acute herpes simplex virus type 1 infection. J Virol. 1999;73:2401–9.PubMedGoogle Scholar
  38. 38.
    Tanaka-Kataoka M, Kunikata T, Takayama S, et al. In vivo antiviral effect of interleukin 18 in a mouse model of vaccinia virus infection. Cytokine. 1999;11:593–9. doi: 10.1006/cyto.1998.0453.PubMedCrossRefGoogle Scholar
  39. 39.
    Shapiro L, Puren AJ, Barton HA, et al. Interleukin 18 stimulates HIV type 1 in monocytic cells. Proc Natl Acad Sci USA. 1998;95:12550–5. doi: 10.1073/pnas.95.21.12550.PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang PA, Wu JM, Li Y, Yang XS. Association of polymorphisms of interleukin-18 gene promoter region with chronic hepatitis B in Chinese Han population. World J Gastroenterol. 2005;11:1594–8.PubMedGoogle Scholar
  41. 41.
    An P, Thio CL, Kirk GD, Donfield S, Goedert JJ, Winkler CA. Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance. J Infect Dis. 2008;198:1159–65. doi: 10.1086/592047.PubMedCrossRefGoogle Scholar
  42. 42.
    Bouzgarrou N, Hassen E, Schvoerer E, et al. Association of interleukin-18 polymorphisms and plasma level with the outcome of chronic HCV infection. J Med Virol. 2008;80:607–14. doi: 10.1002/jmv.21079.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Stephan L. Haas
    • 1
  • Christel Weiß
    • 2
  • Peter Bugert
    • 3
  • Jutta Gundt
    • 1
  • Heiko Witt
    • 4
  • Manfred V. Singer
    • 1
  • Thomas Berg
    • 4
  • Ulrich Böcker
    • 1
  1. 1.Department of Medicine II, Medical Faculty at MannheimUniversity of HeidelbergMannheimGermany
  2. 2.Department of Biostatistics, Medical Faculty at MannheimUniversity of HeidelbergMannheimGermany
  3. 3.Institute for Transfusion Medicine and Immunology, Medical Faculty at MannheimUniversity of HeidelbergMannheimGermany
  4. 4.Department of Hepatology and GastroenterologyCampus Virchow-Klinikum, CharitéBerlinGermany

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