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Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients

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Abstract

Purpose

Chronic hepatitis C progression is commonly attributed to the continuous activation of the immune response with an increased production of pro-inflammatory cytokines, leading to fibrosis and ultimately to cirrhosis. On the contrary, anti-inflammatory cytokines, mainly interleukin (IL)-10 have a modulatory effect on hepatic fibrogenesis. The association between individual polymorphisms within cytokine genes and hepatitis C outcome is often weak and non-informative. Interestingly, it has been demonstrated that a combination of specific genotypes may be a more significant and powerful approach for predicting disease risk.

Aim

This study is aimed at investigating the combined effect of single nucleotide polymorphism (SNP) in IL-18 (−607C/A, −137G/C), interferon (IFN)-γ (+874T/A) and IL-10 (−1082G/A) genes on cirrhosis risk in HCV-infected patients.

Methods

Seventy-seven chronic hepatitis C Tunisian subjects were included in this study. The patients were divided into two groups: the first included 31 non-cirrhotic patients, and the second included 46 liver cirrhosis patients. IL-18 genotyping was performed using the PCR amplification and the restriction fragment length polymorphism analysis (RFLP). IFN-γ and IL-10 polymorphisms were analyzed using the allele-specific PCR (AS-PCR).

Results

The combined high-risk genotype (IL-18 −607C/*, IL-18 −137G/*, IFN-γ +874T/*, IL-10 −1082A/A) frequency was compared between patients with and those without cirrhosis. Individuals were classified according the number of high-risk genotypes as follows: (0–2), patients with at most two high-risk genotypes; (3–4), patients with at least three of the high-risk genotypes. The logistic regression analysis showed that patients harboring 3–4 putative high-risk genotypes have a fivefold higher risk for developing cirrhosis in comparison to those harboring at most two high-risk genotypes (OR = 5.19; 95% CI = 1.49–18.05; p = 0.009).

Conclusion

Our study showed that the co-inheritance of IL-18, IFN-γ and IL-10 specific high-risk genotypes is associated with a greater risk for liver cirrhosis.

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References

  1. Thio CL, Thomas DL, Carrington M. Chronic viral hepatitis and the human genome. Hepatology 2000;31:819–827

    Article  PubMed  CAS  Google Scholar 

  2. Bertoletti A, Ferrari C. Kinetics of the immune response during HBV and HCV infection. Hepatology 2003;38:4–13

    Article  PubMed  CAS  Google Scholar 

  3. Thio CL. Host genetic factors and antiviral immune responses to hepatitis C virus. Clin Liver Dis 2008;12:713–726

    Article  PubMed  Google Scholar 

  4. Cramp ME, Carucci P, Rossol S, Chokshi S, Maertens G, Williams R, et al. Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia. Gut 1999;44:424–429

    Article  PubMed  CAS  Google Scholar 

  5. Pape GR, Gerlach TJ, Diepolder HM, Grüner N, Jung M, Santantonio T. Role of the specific T-cell response for clearance and control of hepatitis C virus. J Viral Hepat 1999;6:36–40

    Article  PubMed  Google Scholar 

  6. Marinho RT, Pinto R, Santos ML, Lobos IV, Moura MC. Effects of interferon and ribavirin combination therapy on CD4+ proliferation, lymphocyte activation, and Th1 and Th2 cytokine profiles in chronic hepatitis C. J Viral Hepat 2004;11:206–216

    Article  PubMed  CAS  Google Scholar 

  7. Kawakami Y, Nabeshima S, Furusyo N, Sawayama Y, Hayashi J, Kashiwagi S. Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection. Am J Gastroenterol 2000;95:3670–3673

    Google Scholar 

  8. Napoli J, Bishop GA, McGuinness PH, Painter DM, McCaughan GW. Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. Hepatology 1996;24:759–765

    Article  PubMed  CAS  Google Scholar 

  9. Sobue S, Nomura T, Ishikawa T, Ito S, Saso K, Ohara H, et al. Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection. J Gastroenterol 2001;36:544–551

    Article  PubMed  CAS  Google Scholar 

  10. Falasca K, Ucciferri C, Dalessandro M, Zingariello P, Mancino P, Petrarca C, Pizzigallo E, Conti P, Vecchiet J. Cytokine patterns correlate with liver damage in patients with chronic hepatitis B and C. Ann Clin Lab Sci 2006;36:144–150

    PubMed  CAS  Google Scholar 

  11. Gigi E, Raptopoulou-Gigi M, Kalogeridis A, Masiou S, Orphanou E, Vrettou E, Lalla TH, Sinakos E, Tsapas V. Cytokine mRNA expression in hepatitis C virus infection: Th1 predominance in patients with chronic hepatitis C and Th1-Th2 cytokine profile in subjects with self-limited disease. J Viral Hepat 2008;15:145–154

    PubMed  CAS  Google Scholar 

  12. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209–218

    PubMed  CAS  Google Scholar 

  13. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008;214:199–210

    Article  PubMed  CAS  Google Scholar 

  14. Sobue S, Nomura T, Ishikawa T, Ito S, Saso K, Ohara H, Joh T, Itoh M, Kakumu S. Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection. J Gastroenterol 2001;36:544–551

    Article  PubMed  CAS  Google Scholar 

  15. Mihm S, Hutschenreiter A, Fayyazi A, Pingel S, Ramadori G. High inflammatory activity is associated with an increased amount of IFNgamma transcripts in peripheral blood cells of patients with chronic hepatitis C virus infection. Med Microbiol Immunol 1996;185:95–102

    Article  PubMed  CAS  Google Scholar 

  16. Bertoletti A, D’Elios MM, Boni C, De Carli M, Zignego AL, Durazzo M, Missale G, Penna A, Fiaccadori F, Del Prete G, Ferrari C. Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections. Gastroenterology 1997;112:193–199

    Article  PubMed  CAS  Google Scholar 

  17. Zhang LJ, Wang XZ. Interleukin-10 and chronic liver disease. World J Gastroenterol 2006;12:1681–1685

    PubMed  CAS  Google Scholar 

  18. Louis H, Van Laethem JL, Wu W, Quertinmont E, Degraef C, Van den Berg K, Demols A, Goldman M, Le Moine O, Geerts A, Devière J. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology 1998;28:1607–1615

    Article  PubMed  CAS  Google Scholar 

  19. Nelson DR, Lauwers GY, Lau JY, Davis GL. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology 2000;118:655–660

    Article  PubMed  CAS  Google Scholar 

  20. Nelson DR, Tu Z, Soldevila-Pico C, Abdelmalek M, Zhu H, Xu YL, et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 2003;38:859–868

    PubMed  CAS  Google Scholar 

  21. Fehniger TA, Shah MH, Turner MJ, VanDeusen JB, Whitman SP, Cooper MA, SuzukiK Wechser M, Goodsaid F, Caligiuri MA. Differential cytokine and chemiokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: lmplication for the innate immune response. J Immunol 1999;162:4511–4520

    PubMed  CAS  Google Scholar 

  22. Puren AJ, Fantuzzi G, Gu Y, Su MS, Dinarello CA. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNF-alpha production from non-CD14þ human blood mononuclear cells. J Clin Invest 1999;101:711

    Article  Google Scholar 

  23. McGuinness PH, Painter D, Davies S, McCaughan GW. Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronichepatitis C infection. Gut 2000;46:260–269

    Article  PubMed  CAS  Google Scholar 

  24. Neuman MG, Benhamou JP, Marcellin P, Valla D, Malkiewicz IM, Katz GG, Trepo C, Bourliere M, Cameron RG, Cohen L, Morgan M, Schmilovitz-Weiss H, Ben-Ari Z. Cytokine–chemokine and apoptotic signatures in patients with hepatitis C. Transl Res 2007;149:126–136

    Article  PubMed  CAS  Google Scholar 

  25. Bouzgarrou N, Hassen E, Schvoerer E, Stoll-Keller F, Bahri O, Gabbouj S, Cheikh I, Maamouri N, Mammi N, Saffar H, Trabelsi A, Triki H, Chouchane L. Association of interleukin-18 polymorphisms and plasma level with the outcome of chronic HCV infection. J Med Virol 2008;80:607–614

    Article  PubMed  CAS  Google Scholar 

  26. Sharma A, Chakraborti A, Das A, Dhiman RK, Chawla Y. Elevation of interleukin-18 in chronic hepatitis C: Implications for hepatitis C virus pathogenesis. Immunology 2009;128(1 Suppl):e514–e522

    Article  PubMed  Google Scholar 

  27. Ollier WE. Cytokine genes and disease susceptibility. Cytokine 2004;28:174–178

    Article  PubMed  CAS  Google Scholar 

  28. Dai CY, Chuang WL, Lee LP, Chen SC, Hou NJ, Lin ZY, Hsieh MY, Hsieh MY, Wang LY, Chang WY, Yu ML. Associations of tumour necrosis factor alpha promoter polymorphisms at position -308 and -238 with clinical characteristics of chronic hepatitis C. J Viral Hepat 2006;13:770–774

    Article  PubMed  Google Scholar 

  29. Gao QJ, Liu DW, Zhang SY, Jia M, Wang LM, Wu LH, Wang SY, Tong LX. Polymorphisms of some cytokines and chronic hepatitis B and C virus infection. World J Gastroenterol 2009;15:5610–5619

    Article  PubMed  CAS  Google Scholar 

  30. Manohar K, Suneetha PV, Sukriti Pati NT, Gupta AC, Hissar S, Sakhuja P, Sarin SK. Association of IL-18 promoter polymorphism with liver disease severity in HCV-infected patients. Hepatol Int 2009;3:371–377

    Article  PubMed  CAS  Google Scholar 

  31. Paladino N, Fainboim H, Theiler G, Schroder T, Muñoz AE, Flores AC, Galdame O, Fainboim L. Gender susceptibility to chronic hepatitis C virus infection associated with interleukin 10 promoter polymorphism. J Virol 2006;80:9144–9150

    Article  PubMed  CAS  Google Scholar 

  32. Persico M, Capasso M, Persico E, Masarone M, Renzo A, Spano D, Bruno S, Iolascon A. Interleukin-10 -1082 GG polymorphism influences the occurrence and the clinical characteristics of hepatitis C virus infection. J Hepatol 2006;45:779–785

    Article  PubMed  CAS  Google Scholar 

  33. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798–801

    Article  PubMed  CAS  Google Scholar 

  34. Bouzgarrou N, Hassen E, Farhat K, Bahri O, Gabbouj S, Maamouri N, Ben Mami N, Saffar H, Trabelsi A, Triki H, Chouchane L. Combined analysis of interferon-gamma and interleukin-10 gene polymorphisms and chronic hepatitis C severity. Hum Immunol 2009;70:230–236

    Article  PubMed  CAS  Google Scholar 

  35. Dai CY, Chuang WL, Hsieh MY, Lee LP, Hou NJ, Chen SC, et al. Polymorphism of interferon-gamma gene at position +874 and clinical characteristics of chronic hepatitis C. Transl Res 2006;148:128–133

    Article  PubMed  CAS  Google Scholar 

  36. Barrett S, Collins M, Kenny C, Ryan E, Keane CO, Crowe J. Polymorphisms in tumour necrosis factor-alpha, transforming growth factor-beta, interleukin-10, interleukin-6, interferon-gamma, and outcome of hepatitis C virus infection. J Med Virol 2003;71:212–218

    Article  PubMed  CAS  Google Scholar 

  37. Abbas Z, Moatter T, Hussainy A, Jafri W. Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3. World J Gastroenterol 2005;11:6656–6661

    PubMed  Google Scholar 

  38. Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Castro Alves C, Campos ML, Van Doorn LJ, Caldas C, Seruca R, Carneiro F, Sobrinho-Simões M. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 2003;125:364–371

    Article  PubMed  CAS  Google Scholar 

  39. Richardson MM, Powell EE, Barrie HD, Clouston AD, Purdie DM, Jonsson JR. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet 2005;42:e45

    Article  PubMed  CAS  Google Scholar 

  40. Beretta L, Cappiello F, Moore JH, Barili M, Greene CS, Scorza R. Ability of epistatic interactions of cytokine single-nucleotide polymorphisms to predict susceptibility to disease subsets in systemic sclerosis patients. Arthritis Rheum 2008;59:974–983

    Article  PubMed  CAS  Google Scholar 

  41. Chen DQ, Zeng Y, Zhou J, Yang L, Jiang S, Huang JD, Lu L, Zheng BJ. Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese population. J Med Virol 2010;82:371–378

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. Mullighan CG, Marshall SE, Bunce M, Welsh KI. Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency. Genes Immun 1999;1:137–148

    Article  PubMed  CAS  Google Scholar 

  44. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV. A single nucleotide polymorphism in the first intron of the human IFNgamma gene: Absolute correlation with a polymorphic CA microsatellite marker of high IFNgamma production. Hum Immunol 2000;61:863–866

    Article  PubMed  CAS  Google Scholar 

  45. Boyer N, Marcellin P. Pathogenesis, diagnosis and management of hepatitis C. J Hepatol 2000;32:98–112

    Article  PubMed  CAS  Google Scholar 

  46. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5:215–229

    Article  PubMed  CAS  Google Scholar 

  47. Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene 2006;25:3834–3847

    Article  PubMed  CAS  Google Scholar 

  48. Wang XH, Netski DM, Astemborski J, Mehta SH, Torbenson MS, Thomas DL, Ray SC. Progression of fibrosis during chronic hepatitis C is associated with rapid virus evolution. J Virol 2007;81:6513–6522

    Article  PubMed  CAS  Google Scholar 

  49. Hu SX, Kyulo NL, Xia VW, Hillebrand DJ, Hu KQ. Factors associated with hepatic fibrosis in patients with chronic hepatitis C: A retrospective study of a large cohort of U.S. patients. J Clin Gastroenterol 2009;43:758–64

    Article  PubMed  CAS  Google Scholar 

  50. Yamada M, Kakumu S, Yoshioka K, Higashi Y, Tanaka K, Ishikawa T, et al. Hepatitis C virus genotypes are not responsible for development of serious liver disease. Dig Dis Sci 1994;39:234–239

    Article  PubMed  CAS  Google Scholar 

  51. McGuinness PH, Bishop GA, Painter DM, Chan R, McCaughan GW. Intrahepatic hepatitis C RNA levels do not correlate with degree of liver injury in patients with chronic hepatitis C. Hepatology 1996;23:676–687

    Article  PubMed  CAS  Google Scholar 

  52. Yoshizawa K, Ota M, Saito S, Maruyama A, Yamaura T, Rokuhara A, Orii K, Ichijo T, Matsumoto A, Tanaka E, Kiyosawa K. Long-term follow-up of hepatitis C virus infection: HLA class II loci influences the natural history of the disease. Tissue Antigens 2003;61:159–165

    Article  PubMed  CAS  Google Scholar 

  53. Baroni GS, Pastorelli A, Manzin A, Benedetti A, Marucci L, Solforosi L, Di Sario A, Brunelli E, Orlandi F, Clementi M, Macarri G. Hepatic stellate cell activation and liver fibrosis are associated with necroinflammatory injury and Th1-like response in chronic hepatitis C. Liver 1999;19:212–219

    Article  PubMed  CAS  Google Scholar 

  54. Chen CC, Yang SY, Liu CJ, Lin CL, Liaw YF, Lin SM, Lee SD, Chen PJ, Chen CJ, Yu MW. Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma. Int J Epidemiol 2005;34:1310–1318

    Article  PubMed  Google Scholar 

  55. Sfar S, Saad H, Mosbah F, Chouchane L. Combined effects of the angiogenic genes polymorphisms on prostate cancer susceptibility and aggressiveness. Mol Biol Rep 2009;36:37–45

    Article  PubMed  CAS  Google Scholar 

  56. Ahluwalia TS, Khullar M, Ahuja M, Kohli HS, Bhansali A, Mohan V, Venkatesan R, Rai TS, Sud K, Singal PK. Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians. PLoS One 2009;4:e5168

    Article  PubMed  Google Scholar 

  57. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765

    Article  PubMed  CAS  Google Scholar 

  58. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol 2008;180(9):5771–5777

    PubMed  CAS  Google Scholar 

  59. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P. Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999;42:1101–1108

    Article  PubMed  CAS  Google Scholar 

  60. Yilmaz V, Yentur SP, Saruhan-Direskeneli G. IL-12 and IL-10 polymorphisms and their effects on cytokine production. Cytokine 2005;30:188–194

    Article  PubMed  CAS  Google Scholar 

  61. Stanilova SA, Miteva LD, Karakolev ZT, Stefanov CS. Interleukin-10–1082 promoter polymorphism in association with cytokine production and sepsis susceptibility. Intensive Care Med 2006;32:260–266

    Article  PubMed  CAS  Google Scholar 

  62. Miteva L, Stanilova S. The combined effect of interleukin (IL)-10 and IL-12 polymorphisms on induced cytokine production. Hum Immunol 2008;69:562–566

    Article  PubMed  CAS  Google Scholar 

  63. Qiu FB, Wu LQ, Lu Y, Zhang S, Zhang BY. Predominant expression of Th1-type cytokines in primary hepatic cancer and adjacent liver tissues. Hepatobiliary Pancreat Dis Int 2007;6:63–66

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by le Ministère de l’Enseignement Supérieur, de la Recherche scientifique et de la Technologie (LR/05 Hépatites et maladies virales épidémiques) and by le Ministère de la Santé Publique de la République Tunisienne. We thank Mr. Adel Rdissi for English revision.

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Authors and Affiliations

  1. Molecular Immuno-oncology Laboratory, Faculty of Medicine, Monastir, Tunisia

    Nadia Bouzgarrou, Elham Hassen, Sallouha Gabbouj & Lotfi Chouchane

  2. Clinical Virology Laboratory, Pasteur Institute, Tunis, Tunisia

    Olfa Bahri & Henda Triki

  3. Gastroenterology B Unit, La Rabta Hospital, Tunis, Tunisia

    Nabil Ben Mami

  4. Genetic Medicine Department, Weill Cornell Medical College in Qatar, Doha, Qatar

    Lotfi Chouchane

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  1. Nadia Bouzgarrou
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  2. Elham Hassen
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  3. Olfa Bahri
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  4. Sallouha Gabbouj
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  5. Nabil Ben Mami
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  6. Henda Triki
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Correspondence to Nadia Bouzgarrou.

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Bouzgarrou, N., Hassen, E., Bahri, O. et al. Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients. Hepatol Int 5, 681–687 (2011). https://doi.org/10.1007/s12072-010-9232-0

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