Archives of Virology

, Volume 162, Issue 1, pp 181–189 | Cite as

IL28B rs12980275 and HLA rs4273729 genotypes as a powerful predictor factor for rapid, early, and sustained virologic response in patients with chronic hepatitis C

  • Parvaneh Sedighimehr
  • Shiva Irani
  • Fatemeh Sakhaee
  • Farzam Vaziri
  • Mohammadreza Aghasadeghi
  • Seyed Mehdi Sadat
  • Fatemeh Rahimi Jamnani
  • Abolfazl FatehEmail author
  • Seyed Davar Siadat
Original Article


Single-nucleotide polymorphisms (SNPs) in the Interleukin-28B (IL28B) gene and rs4273729 in the human leukocyte antigen (HLA) gene in chronic hepatitis C (CHC) virus infection are important for predicting treatment outcome. In this study, the distribution of IL28B SNPs (rs12979860 and rs12980275) and HLA rs4273729 in rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) in HCV Iranian patients with CHC virus infection was assessed. IL28B genotyping and rs4273729 were performed using the amplification refractory mutation system (ARMS)-PCR and direct sequencing in 190 CHC virus infections, respectively. RVR, cEVR, and SVR were 53.2 %, 78.9 %, and 65.8 %, respectively. Multivariate regression analysis demonstrated that the responses significantly predicted SVR in patients with age <40 years (p = 0.008), HCV genotypes (p = 0.032), IL28B rs12979860 CC genotype (p < 0.001), rs12980275 AA genotype (p < 0.001), rs4273729 GG genotype (p < 0.001), RVR (p < 0.001) and cEVR (p = 0.024). Three critical predictor factors based on RVR response were rs12979860 CC genotype (p = 0.033), rs12980275 AA genotype (p < 0.001) and rs4273729 GG genotype (p < 0.001), while rs12980275 AA (p = 0.003) and rs4273729 GG genotypes (p < 0.001) predicted cEVR. For the first time in Iran, these results revealed that the rs12980275 and HLA rs4273729 are important for the treatment of CHC infection. These findings may help predict responses to CHC infection treatment and reduce the cost and side effects of therapy.


Human Leukocyte Antigen Sustained Virologic Response Human Leukocyte Antigen Class Sustained Virologic Response Rate Rapid Virologic Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank all of the patients who participated in the study. We are particularly grateful to Naser Kalhor for their valuable comments and sharing their knowledge.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Afdhal NH, McHutchison JG, Zeuzem S, Mangia A, Pawlotsky JM, Murray JS, Shianna KV, Tanaka Y, Thomas DL, Booth DR (2011) Hepatitis C pharmacogenetics: state of the art in 2010. Hepatol 53:336–345CrossRefGoogle Scholar
  2. 2.
    Aziz H, Raza A, Ali K, Khattak JZK, Irfan J, Gill ML (2015) Polymorphism of the IL28B gene (rs8099917, rs12979860) and virological response of Pakistani hepatitis C virus genotype 3 patients to pegylated interferon therapy. Int J Infect Dis 30:91–97CrossRefPubMedGoogle Scholar
  3. 3.
    Covolo L, Bibert S, Donato F, Bochud PY, Lagging M, Negro F, Fattovich G (2014) The novel ss469415590 variant predicts virological response to therapy in patients with chronic hepatitis C virus type 1 infection. Aliment Pharmacol Ther 39:322–330CrossRefPubMedGoogle Scholar
  4. 4.
    Dong ZX, Zhou HJ, Xiang XG, Guo SM, Zhuang Y, Zhao GD, Xie Q (2015) IL28B genetic variations are associated with treatment response of patients with chronic hepatitis C in a Chinese Han population. J Dig Dis 16:90–97CrossRefPubMedGoogle Scholar
  5. 5.
    Duggal P, Thio CL, Wojcik GL, Goedert JJ, Mangia A, Latanich R, Kim AY, Lauer GM, Chung RT, Peters MG, Kirk GD, Mehta SH, Cox AL, Khakoo SI, Alric L, Cramp ME, Donfield SM, Edlin BR, Tobler LH, Busch MP, Alexander G, Rosen HR, Gao X, Abdel-Hamid M, Apps R, Carrington M, Thomas DL (2013) Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann Intern Med 158:235–245CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Fateh A, Aghasadeghi M, Keyvani H, Mollaie H, Yari S, Hadizade TA, Ghazanfari M, Monavari S (2015) High Resolution Melting Curve Assay for Detecting rs12979860 IL28B Polymorphisms Involved in Response of Iranian Patients to Chronic Hepatitis C Treatment. Asian Pac J Cancer Prev 16:1873–1880CrossRefPubMedGoogle Scholar
  7. 7.
    Fateh A, Aghasadeghi M, Siadat SD, Vaziri F, Sadeghi F, Fateh R, Keyvani H, Tasbiti AH, Yari S, Ataei-Pirkooh A (2016) Comparison of three different methods for the detection of IL28 rs12979860 polymorphisms as treatment predictor factor for the hepatitis C virus. Osong Public Health and Research Perspectives. Osong Public Health Res Perspect. 7:83–89CrossRefPubMedGoogle Scholar
  8. 8.
    Fathy MM, Taleb MEA, El Hawary MS, Nabih MI, Aref WM, Makhlouf MM (2015) Assessment of interleukin 28B genotype as a predictor of response to combined therapy with pegylated interferon plus ribavirin in HCV infected Egyptian patients. Cytokine 74:268–272CrossRefPubMedGoogle Scholar
  9. 9.
    Ferenci P, Laferl H, Scherzer TM, Gschwantler M, Maieron A, Brunner H, Stauber R, Bischof M, Bauer B, Datz C (2008) Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 135:451–458CrossRefPubMedGoogle Scholar
  10. 10.
    Franco S, Tural C, Clotet B, Martinez MA (2012) Alleles at rs4273729 in the chromosome 6 do not predict response to peg-interferon-α and ribavirin therapy in hepatitis C virus/HIV-1—coinfected patients. AIDS 26:1973–1974CrossRefPubMedGoogle Scholar
  11. 11.
    Ghany MG, Strader DB, Thomas DL, Seeff LB (2009) Diagnosis, management, and treatment of hepatitis C: an update. Hepatol 49:1335–1374CrossRefGoogle Scholar
  12. 12.
    Golden-Mason L, Klarquist J, Wahed A, Rosen H (2008) PD-1 expressin is increased on immunocytes in chronic HCV and predicts failure of response to antiviral therapy, race-dependent differences. J Immunol. 180:3637–3641CrossRefPubMedGoogle Scholar
  13. 13.
    Imran M, Manzoor S, Azam S, Resham S (2015) Genetic variant of IL28B rs12979860, as predictive marker of interferon-based therapy in Pakistani population. APMIS 123:342–349CrossRefPubMedGoogle Scholar
  14. 14.
    Khubaib B, Saleem S, Idrees M, Afzal S, Wasim M (2015) The genotype CC of IL-28B SNP rs12979860 is significantly associated with a sustained virological response in chronic HCV-infected Pakistani patients. J Dig Dis 16:293–298CrossRefPubMedGoogle Scholar
  15. 15.
    Ling Q, Chen J, Zhou H, Zhong J, Chen Y, Ye Q, Zhuo Y, Min N, Shang B (2015) Baseline factors associated with treatment response in patients infected with hepatitis C virus 1b by stratification of IL28B polymorphisms. Arch Virol 160:1105–1112CrossRefPubMedGoogle Scholar
  16. 16.
    European Association for The Study of The Liver (2014) EASL recommendations on treatment of hepatitis C 2014. J Hepatol 61:373–395CrossRefGoogle Scholar
  17. 17.
    Namazee N, Sali S, Asadi S, Shafiei M, Behnava B, Alavian SM (2012) Real response to therapy in chronic hepatitis C virus patients: a study from iran. Hepat Mon 12:e6151CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    World Health Organization (2014) Guidelines for the screening, care and treatment of persons with hepatitis C infection. Accessed April 2014
  19. 19.
    Resham S, Manzoor S, Imran M, Saalim M, Naseem S, Azam S (2015) Interleukin-28B: a prognostic marker in interferon based therapy of chronic HCV patients of the Pakistan with variable treatment response. APMIS 123:765–771CrossRefPubMedGoogle Scholar
  20. 20.
    Rosen HR, Weston SJ, Im K, Yang H, Burton JR Jr, Erlich H, Klarquist J, Belle SH (2007) Selective decrease in hepatitis C virus-specific immunity among African Americans and outcome of antiviral therapy. Hepatol 46:350–358CrossRefGoogle Scholar
  21. 21.
    Sarrazin C, Susser S, Doehring A, Lange CM, Müller T, Schlecker C, Herrmann E, Lötsch J, Berg T (2011) Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 54:415–421CrossRefPubMedGoogle Scholar
  22. 22.
    Scherzer T-M, Hofer H, Staettermayer AF, Rutter K, Beinhardt S, Steindl-Munda P, Kerschner H, Kessler HH, Ferenci P (2011) Early virologic response and IL28B polymorphisms in patients with chronic hepatitis C genotype 3 treated with peginterferon alfa-2a and ribavirin. J Hepatol 54:866–871CrossRefPubMedGoogle Scholar
  23. 23.
    Shaikh N, Waryah AM, Devrajani BR, Rajput MI, Hayat AS, Shaikh S (2015) IL28B rs12980275 polymorphism shows association with response to treatment in Pakistani patients with Chronic Hepatitis C. J Med Virol 87:814–820CrossRefPubMedGoogle Scholar
  24. 24.
    Sixtos-Alonso MS, Avalos-Martinez R, Sandoval-Salas R, Dehesa-Violante M, García-Juarez I, Chávez-Ayala A, Domínguez-López A, Vargas-Vorácková F, Toapanta-Yanchapaxi L, Amezcua-Guerra LM (2015) A genetic variant in the interleukin 28B gene as a major predictor for sustained virologic response in chronic hepatitis C virus infection. Arch Med Res 46:448–453CrossRefPubMedGoogle Scholar
  25. 25.
    Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, Simmonds P (2014) Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatol 59:318–327CrossRefGoogle Scholar
  26. 26.
    Taherkhani R, Farshadpour F (2015) Epidemiology of hepatitis C virus in Iran. World J Gastroenterol 21:10790–10810CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’hUigin C, Kidd J, Kidd K, Khakoo SI, Alexander G (2009) Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461:798–801Google Scholar
  28. 28.
    Xu Y, Huang P, Yue M, Su J, Chen H, Chen M, Wang J, Li J, Peng Z, Zhang Y, Yu R (2016) A novel polymorphism near HLA class II region is associated with spontaneous clearance of HCV and response to interferon treatment in Chinese patients. J Hum Genet 61:301–305CrossRefPubMedGoogle Scholar
  29. 29.
    Yu JW, Wang GQ, Sun LJ, Li XG, Li SC (2007) Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon α-2a and ribavirin. J Gastroenterol Hepatol 22:832–836CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang L, Jilg N, Shao R-X, Lin W, Fusco DN, Zhao H, Goto K, Peng LF, Chen W-C, Chung RT (2011) IL28B inhibits hepatitis C virus replication through the JAK–STAT pathway. J Hepatol 55:289–298CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang XH, Cai QX, Hong CX, Lin CS, Zhao ZX (2013) Prevalence of IL-28B and ITPA genotypes in Chinese Han population infected persistently with hepatitis C virus genotype 6 or HCV-1. J Med Virol 85:1163–1169CrossRefPubMedGoogle Scholar
  32. 32.
    Zheng H, Li M, Chi B, Wu XX, Wang J, Liu DW (2015) IL28B rs12980275 variant as a predictor of sustained virologic response to pegylated-interferon and ribavirin in chronic hepatitis C patients: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 39:576–583CrossRefPubMedGoogle Scholar
  33. 33.
    Domagalski K, Pawlowska M, Tretyn A, Halota W, Tyczyno M, Kozielewicz D, Dybowska D (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:e13678CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Boyum A (1968) Separation of leukocytes from blood and bone marrow. Introduction. Scand J Clin Lab Invest Suppl. 97:7PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Parvaneh Sedighimehr
    • 1
  • Shiva Irani
    • 1
  • Fatemeh Sakhaee
    • 2
  • Farzam Vaziri
    • 2
    • 3
  • Mohammadreza Aghasadeghi
    • 4
  • Seyed Mehdi Sadat
    • 4
  • Fatemeh Rahimi Jamnani
    • 2
    • 3
  • Abolfazl Fateh
    • 2
    • 3
    Email author
  • Seyed Davar Siadat
    • 2
    • 3
  1. 1.Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
  2. 2.Departments of Mycobacteriology and Pulmonary ResearchPasteur Institute of IranTehranIran
  3. 3.Microbiology Research Center (MRC)Pasteur Institute of IranTehranIran
  4. 4.Department of Hepatitis and AIDSPasteur Institute of IranTehranIran

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