Advertisement

Medical Microbiology and Immunology

, Volume 206, Issue 2, pp 165–174 | Cite as

Role of serum level and genetic variation of IL-28B in interferon responsiveness and advanced liver disease in chronic hepatitis C patients

  • Abdolvahab Alborzi
  • Tayebeh HashempourEmail author
  • Javad Moayedi
  • Zahra Musavi
  • Gholamreza Pouladfar
  • Shahin Merat
Original Investigation

Abstract

Interleukin-28B (IL-28B) is suspected to be associated with response to treatment and one of the basic immunological backgrounds in liver transplant candidate (LTC). We aimed to assess whether genotypes of IL-28B can play a role in therapeutic response or advanced stages of liver disease. A total of 364 subjects were genotyped for IL-28B rs12979860 and rs8099917 SNPs using PCR-RFLP assay. Moreover, IL-28 serum level, HCV loads, and genotype were performed. A significant increase was observed in the frequencies of unfavorable rs12979860 genotypes/CT + TT in the chronic hepatitis C (CHC) and LTC groups. In the case of rs8099917, CHC group had a significantly higher frequency of unfavorable genotypes/GT + GG compared to the healthy group. IL-28B serum level was also significantly higher in healthy group compared with the CHC and LTC groups. There were no differences in the distribution of the IL-28B genotypes and haplotypes between responder and non-responder patients. Our results suggest, for the first time, that unfavorable rs12979860 genotypes can be considered one of the important immunological backgrounds in the Iranian LTC population that was confirmed with the lower IL-28 serum level compared to healthy group. Besides, there was a possible association of favorable IL-28B genotypes with lower odds of susceptibility to CHC infection but no support for a positive association between analyzed SNPs and an outcome of therapy. Moreover, non-CT haplotypes may be regarded as a genetic risk factor that can increase the chance of infection with HCV and progression toward end-stage HCV-related liver disease.

Keywords

HCV Liver transplant candidate IL-28B Treatment outcome 

Notes

Acknowledgements

The authors would like to thank personnel of Digestive Disease Research Institute (DDRI) of Shariati Hospital, affiliated with Tehran University of Medical Sciences for excellent work in collecting blood samples. We also express special thanks to Saeed Ghanbari, Ph.D. Student of Department of Biostatistics, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran, for his statistical assistance and Ali Nasimi (Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran), and Jean Krugman, retired professor of General Studies, DeVry University, Decatur, Georgia, USA, for help in revising the English of the manuscript. This study was financially supported by Iran’s National Elites Foundation, Allame Tabatabai National Award.

Compliance with ethical standards

Conflict of interest

None of the authors has any conflict of interest to disclose.

References

  1. 1.
    Hashempour T, Bamdad T, Bergamini A, Lavergne JP, Haj-Sheykholeslami A, Brakier-Gingras L et al (2015) F protein increases CD4+CD25+ T cell population in patients with chronic hepatitis C. Pathog Dis 73(4):ftv022CrossRefPubMedGoogle Scholar
  2. 2.
    Sarvari J, Moattari A, Pirbonyeh N, Moini M, Hosseini SY (2016) The impact of IFN-γ gene polymorphisms on spontaneous clearance of HCV infection in Fars Province, Southern of Iran. J Clin Lab Anal 30(4):301–307CrossRefPubMedGoogle Scholar
  3. 3.
    Merat S, Rezvan H, Nouraie M, Jafari E, Abolghasemi H, Radmard AR et al (2010) Seroprevalence of hepatitis C virus: the first population-based study from Iran. Int J Infect Dis 14:e113–e116CrossRefPubMedGoogle Scholar
  4. 4.
    Hashempoor T, Bamdad T, Merat S, Janzamin E, Nemati L, Jabbari H et al (2010) Expansion of CD4+CD25+FoxP3+ regulatory T cells in chronic hepatitis C virus infection. Iran J Immunol 7(3):177PubMedGoogle Scholar
  5. 5.
    Shi X, Pan Y, Wang M, Wang D, Li W, Jiang T et al (2012) IL28B genetic variation is associated with spontaneous clearance of hepatitis C virus, treatment response, serum IL-28B levels in Chinese population. PLoS One 7(5):e37054CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gad HH, Dellgren C, Hamming OJ, Vends S, Paludan SR, Hartmann R (2009) Interferon-λ is functionally an interferon but structurally related to the interleukin-10 family. J Biol Chem 284(31):20869–20875CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Al-Qahtani A, Al-Anazi M, Abdo AA, Sanai FM, Al-Hamoudi W, Alswat KA et al (2015) Correlation between genetic variations and serum level of interleukin 28B with virus genotypes and disease progression in chronic hepatitis C virus infection. J Immunol Res 2015:768470CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hassan MK, Haq MU, Amin M, Nawaz A, Khan HU (2014) Association between baseline parameters and end of treatment response to combination of conventional interferon and ribavirin in patients with chronic Hepatitis C. J Postgrad Med Inst 28(2):149–153Google Scholar
  9. 9.
    Aziz H, Raza A, Waheed Y, Gill U, Gill ML (2012) Analysis of variables and interactions among variables associated with a sustained virological response to pegylated interferon alfa-2a plus ribavirin in hepatitis C virus genotype 3-infected patients. Int J Infect Dis 16(8):e597–e602CrossRefPubMedGoogle Scholar
  10. 10.
    Lin K-H, Yu H-C, Hsu P-I, Tsai W-L, Chen W-C, Lin C-K et al (2013) Baseline high viral load and unfavorable patterns of alanine aminotransferase change predict virological relapse in patients with chronic hepatitis C genotype 1 or 2 obtaining rapid virological response during antiviral therapy. Hepat Mon 13(10):e11892CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lai M, Afdhal NH (2012) Clinical utility of interleukin-28B testing in patients with genotype 1. Hepatology 56(1):367–372CrossRefPubMedGoogle Scholar
  12. 12.
    Aziz H, Gil ML, Waheed Y, Adeeb U, Raza A, Bilal I et al (2011) Evaluation of prognostic factors for peg interferon alfa-2b plus ribavirin treatment on HCV infected patients in Pakistan. Infect Genet Evol 11(3):640–645CrossRefPubMedGoogle Scholar
  13. 13.
    Saludes V, Bascuñana E, Jordana-Lluch E, Casanovas S, Ardèvol M, Soler E et al (2013) Relevance of baseline viral genetic heterogeneity and host factors for treatment outcome prediction in hepatitis C virus 1b-infected patients. PLoS One 8(8):e72600CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chen MY, Liu CH, Chen TC, Su TH, Chen PJ, Chen DS et al (2014) Value of interleukin-28B genetic polymorphism on retreatment outcomes of chronic hepatitis C genotype 1 relapsers by peginterferon alfa plus ribavirin. J Gastroenterol Hepatol 29(1):102–109CrossRefPubMedGoogle Scholar
  15. 15.
    Ivanova I, Kotsev I, Atanassova M, Atanassova A, Manevska B, Krasnaliev I et al (2013) Baseline viral load-a predictor of treatment response in advanced hepatitis C. Scrip Sci Med 45(3):53–57Google Scholar
  16. 16.
    Faisal A, Zytoon AA, Allah A-NG, Dawood A (2013) Predictors of early virological response of viral hepatitis C to combination therapy with pegylated interferon plus ribavirin. Am J Clin Med Res 1(4):54–60CrossRefGoogle Scholar
  17. 17.
    Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL et al (2005) Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD)/ribavirin. J Hepatol 43(3):425–433CrossRefPubMedGoogle Scholar
  18. 18.
    Sharifi A, Haj-Sheykholeslami A, Poustchi H, Golzari R, Merat S, Malekzadeh R et al (2016) Efficacy of locally manufactured Sofosbuvir and Daclatasvir (Sovodak) in combination with ribavirin in treating patients with chronic hepatitis C and cirrhosis in Iran-preliminary report. Govaresh 21(2):93–97Google Scholar
  19. 19.
    Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’hUigin C et al (2009) Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461(7265):798–801CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ et al (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461(7262):399–401CrossRefPubMedGoogle Scholar
  21. 21.
    Eurich D, Boas-Knoop S, Bahra M, Neuhaus R, Somasundaram R, Neuhaus P et al (2012) Role of IL28B polymorphism in the development of hepatitis C virus-induced hepatocellular carcinoma, graft fibrosis, and posttransplant antiviral therapy. Transplantation 93(6):644–649PubMedGoogle Scholar
  22. 22.
    Sharafi H, Pouryasin A, Alavian SM, Behnava B, Keshvari M, Salimi S et al (2012) Distribution of IL28B genotypes in Iranian patients with chronic hepatitis C and healthy individuals. Hepat Mon 12(12):e8387CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sarrazin C, Susser S, Doehring A, Lange CM, Müller T, Schlecker C et al (2011) Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 54(3):415–421CrossRefPubMedGoogle Scholar
  24. 24.
    Melis R, Fauron C, McMillin G, Lyon E, Shirts B, Hubley LM et al (2011) Simultaneous genotyping of rs12979860 and rs8099917 variants near the IL28B locus associated with HCV clearance and treatment response. J Mol Diagn 13(4):446–451CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    He J, Yu G, Li Z, Liang H (2014) Influence of interleukin-28B polymorphism on progression to hepatitis virus-induced hepatocellular carcinoma. Tumor Biol 35(9):8757–8763CrossRefGoogle Scholar
  26. 26.
    Jabari H, Zamani F, Hatami K, Sheikholeslami A, Fakharzadeh E, Shahzamani K et al (2011) Pegaferon in hepatitis C: results of a multicenter study. Middle East J Dig Dis 3(2):110–114Google Scholar
  27. 27.
    Heidar S, Ali P, Bita B, Maryam K, Leila M, Shima S et al (2012) Development and validation of a simple, rapid and inexpensive PCR-RFLP method for genotyping of common IL28B polymorphisms: a useful pharmacogenetic tool for prediction of hepatitis C treatment response. Hepat Mon 2012:190–195Google Scholar
  28. 28.
    Sullivan S, Jensen D, Bernstein D, Hassanein T, Foster G, Lee S et al (2004) Cost-effectiveness of combination peginterferon α-2a and ribavirin compared with interferon α-2b and ribavirin in patients with chronic hepatitis C. Am J Gastroenterol 99(8):1490–1496CrossRefPubMedGoogle Scholar
  29. 29.
    De Re V, Gragnani L, Fognani E, Piluso A, Izzo F, Mangia A et al (2014) Impact of immunogenetic IL28B polymorphism on natural outcome of HCV infection. Biomed Res Int 2014Google Scholar
  30. 30.
    Firdaus R, Biswas A, Saha K, Mukherjee A, Chaudhuri S, Chandra A et al (2014) Impact of host IL28B rs12979860, rs8099917 in interferon responsiveness and advanced liver disease in chronic genotype 3 hepatitis C patients. PLoS One 9(6):e99126CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Khattab MA, Abdelghany HM, Ramzy MM, Khairy RM (2016) Impact of IL28B gene polymorphisms rs8099917 and rs12980275 on response to pegylated interferon-α/ribavirin therapy in chronic hepatitis C genotype 4 patients. J Biomed Res 30(1):40CrossRefGoogle Scholar
  32. 32.
    Jabbari H, Bayatian A, Sharifi AH, Zaer-Rezaee H, Fakharzadeh E, Asadi R et al (2010) Safety and efficacy of locally manufactured pegylated interferon in hepatitis C patients. Arch Iran Med 13(4):306PubMedGoogle Scholar
  33. 33.
    Moghaddam MA, Zali MR, Andabili SHA, Derakhshan F, Miri SM, Alavian SM (2012) High rate of virological response to Peginterferon α-2a-Ribavirin among non-cirrhotic Iranian hemophilia patients with chronic hepatitis C. Iran Red Crescent Med J 14(8):466–473Google Scholar
  34. 34.
    Montes-Cano MA, García-Lozano JR, Abad-Molina C, Romero-Gómez M, Barroso N, Aguilar-Reina J et al (2010) Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology 52(1):33–37CrossRefPubMedGoogle Scholar
  35. 35.
    Akkiz H, Kuran S, Akgöllü E, Usküdar O, Bekar A, Bayram S (2014) The role of Interleukin 28B gene polymorphism in Turkish patients with hepatocellular carcinoma. Ann Hepatol 13:788–795PubMedGoogle Scholar
  36. 36.
    Domagalski K, Pawlowska M, Tretyn A, Halota W, Tyczyno M, Kozielewicz D et al (2013) Association of IL28B polymorphisms with the response to peginterferon plus ribavirin combined therapy in Polish patients infected with HCV genotype 1 and 4. Hepat Mon 13(11)Google Scholar
  37. 37.
    Venegas Santos ME, Villanueva Arancibia RA, González Lagos KV, Brahm Barril JR (2011) IL28B polymorphisms associated with therapy responsee in Chilean chronic hepatitis C patients. World J Gastroenterol 17(31):3636–3639CrossRefGoogle Scholar
  38. 38.
    Rashidi R, Toosi MN, Siya RS, Forutan H, Merat S, Daryani NE (2010) The effect of interleukin 28 B polymorphism on sustained virology response (SVR) in patients with chronic hepatitis C. Govaresh 15(3):202–208Google Scholar
  39. 39.
    Haj-sheykholeslami A, Keshvari M, Sharafi H, Pouryasin A, Hemmati K, Mohammadzadehparjikolaei F (2015) Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients. World J Gastroenterol 21(29):8935CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Schreiber J, Moreno C, Garcia BG, Louvet A, Trepo E, Henrion J et al (2012) Meta-analysis: the impact of IL28B polymorphisms on rapid and sustained virological response in HCV-2 and-3 patients. Aliment Pharmacol Ther 36(4):353–362CrossRefPubMedGoogle Scholar
  41. 41.
    Jiménez-Sousa MA, Fernández-Rodríguez A, Guzmán-Fulgencio M, García-Álvarez M, Resino S (2013) Meta-analysis: implications of interleukin-28B polymorphisms in spontaneous and treatment-related clearance for patients with hepatitis C. BMC Med 11(1):1CrossRefGoogle Scholar
  42. 42.
    Chen J, Lin C, Wang C, Lin Y, Kuo S, Shiu C et al (2011) IL28B genetic variations are associated with high sustained virological response (SVR) of interferon-α plus ribavirin therapy in Taiwanese chronic HCV infection. Genes Immun 12(4):300–309CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Martínez-Gómez LE, Chávez-Tapia NC, Burguete-García AI, Aguilar-Olivos N, Madrid-Marina V, Román-Bahena M et al (2012) IL28B polymorphisms predict the response to chronic hepatitis C virus infection treatment in a Mexican population. Ann Hepatol 11(6):876–881PubMedGoogle Scholar
  44. 44.
    Wiesmann F, Naeth G, Berger A, Hirsch H, Regenass S, Ross R et al (2016) Multicentric performance analysis of HCV quantification assays and its potential relevance for HCV treatment. Med Microbiol Immunol (Berl) 205(3):263–268CrossRefGoogle Scholar
  45. 45.
    Jabłonowska E, Piekarska A, Koślińska-Berkan E, Omulecka A, Szymańska B, Wójcik K (2012) Sustained virologic response and IL28B single-nucleotide polymorphisms in patients with chronic hepatitis C treated with pegylated interferon alfa and ribavirin. Age 19(80.39):0.05Google Scholar
  46. 46.
    Mach T, Ciesla A, Sanak M, Golwacki M, Warunek W (2012) The importance of IL28B polymorphism in response to pegylated interferon α and ribavirin in chronic hepatitis caused by HCV genotype 1b. Prz Gastroenterol 7:38–42Google Scholar
  47. 47.
    Fabris C, Falleti E, Cussigh A, Bitetto D, Fontanini E, Bignulin S et al (2011) IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: role in the course of chronic viral hepatitis and the development of HCC. J Hepatol 54(4):716–722CrossRefPubMedGoogle Scholar
  48. 48.
    Biggins SW, Trotter J, Gralla J, Burton JR, Bambha KM, Dodge J et al (2013) Differential effects of donor and recipient IL28B and DDX58 SNPs on severity of HCV after liver transplantation. J Hepatol 58(5):969–976CrossRefPubMedGoogle Scholar
  49. 49.
    Ren S, Lu J, Du X, Huang Y, Ma L, Huo H et al (2012) Genetic variation in IL28B is associated with the development of hepatitis B-related hepatocellular carcinoma. Cancer Immunol Immunother 61(9):1433–1439CrossRefPubMedGoogle Scholar
  50. 50.
    Chen J, Wang L, Li Y, Cai B, Fu Y, Liao Y et al (2012) Association analysis between SNPs in IL-28B gene and the progress of hepatitis B infection in Han Chinese. PLoS One 7(12):e50787CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Agúndez JA, García-Martin E, Maestro ML, Cuenca F, Martínez C, Ortega L et al (2012) Relation of IL28B gene polymorphism with biochemical and histological features in hepatitis C virus-induced liver disease. PLoS One 7(5):e37998CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lee DH, Cho Y, Seo JY, Kwon JH, Cho EJ, Jang ES et al (2013) Polymorphisms near interleukin 28B gene are not associated with hepatitis B virus clearance, hepatitis B e antigen clearance and hepatocellular carcinoma occurrence. Intervirology 56(2):84–90CrossRefPubMedGoogle Scholar
  53. 53.
    Chiu K-W, Nakano T, Chen K-D, Lin C-C, Hu T-H, Goto S et al (2016) Association of IL28B SNPs rs12979860 and rs8099917 on hepatitis C virus-RNA status in donors/recipients of living donor Liver transplantation. PLoS One 11(6):e0156846CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Joshita S, Umemura T, Katsuyama Y, Ichikawa Y, Kimura T, Morita S et al (2012) Association of IL28B gene polymorphism with development of hepatocellular carcinoma in Japanese patients with chronic hepatitis C virus infection. Hum Immunol 73(3):298–300CrossRefPubMedGoogle Scholar
  55. 55.
    Tseng C-W, Chen C-Y, Chang T-T, Tzeng S-J, Hsieh Y-H, Hung T-H et al (2014) Peginterferon alfa-2a is associated with elevations in alanine aminotransferase at the end of treatment in chronic hepatitis C patients with sustained virologic response. PLoS One 9(6):e100207CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Lin C-C, Wu C-H, Chen H-L, Lin I-T, Wang S-Y, Wang T-E et al (2014) Peginterferon alpha-2b plus ribavirin for chronic hepatitis C virus mixed genotype infection. Ann Hepatol 13(4):350PubMedGoogle Scholar
  57. 57.
    Berenguer J, Alvarez-Pellicer J, Carrero A, Von Wichmann MA, López-Aldeguer J, Mallolas J et al (2013) Clinical effects of viral relapse after interferon plus ribavirin in patients co-infected with human immunodeficiency virus and hepatitis C virus. J Hepatol 58(6):1104–1112CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Abdolvahab Alborzi
    • 1
  • Tayebeh Hashempour
    • 1
    Email author
  • Javad Moayedi
    • 1
  • Zahra Musavi
    • 1
  • Gholamreza Pouladfar
    • 1
  • Shahin Merat
    • 2
  1. 1.Clinical Microbiology Research Center, Nemazee HospitalShiraz University of Medical SciencesShirazIran
  2. 2.Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research InstituteTehran University of Medical SciencesTehranIran

Personalised recommendations