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Association of IL-28B, TBX21 gene polymorphisms and predictors of virological response for chronic hepatitis C

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Abstract

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. The outcomes of both spontaneous HCV clearance and response to therapy depend on both viral and host factors. To investigate the influence of polymorphisms of IL-28B rs12979860 and TBX21 rs17250932, rs4794067 as well as viral factors (HCV genotype, F protein) on the outcome of HCV infection, we genotyped 565 patients with chronic HCV infection, 191 patients spontaneously resolved from HCV infection, 359 healthy controls and 383 treatment-naïve CHC patients with pegylated interferon-α and ribavirin (PEG IFN-α/RBV). Results showed that TBX21 rs4794067 variant genotypes significantly correlated with increased risk of HCV chronic infection (dominant model: OR = 5.690, 95% CI = 2.024-16.000) and susceptibility (dominant model: OR = 5.658, 95% CI = 2.514-12.735). We also found that the rs12979860, rs2227982 and rs36084323 polymorphisms showed no significant associations with susceptibility or spontaneous clearance of HCV in the anti-F antibody subgroup; however, the anti-F antibody positive subgroup might show an increased risk of N-SVR (all P < 0.001). Our results demonstrate that variant factors in both the host and pathogen are commonly important for HCV clearance. In addition rs4794067 and F protein status may be strong predictive markers in the Chinese population.

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References

  1. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST (2013) Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalencee. Hepatology 57:1333–1342

    Article  PubMed  Google Scholar 

  2. Chinese Society of Hepatology, Chinese Medical Association, Chinese Society of Infectious Diseases, Chinese Medical Association (2015) Guidelines for the prevention and treatment of chronic hepatitis C: a 2015 update. Chin J Liver Dis 23:888–905

    Google Scholar 

  3. Seeff LB (2002) Natural history of chronic hepatitis C. Hepatology 36:S35–S46

    PubMed  Google Scholar 

  4. Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, Barnes E (2015) Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 61:77–87

    Article  PubMed  Google Scholar 

  5. Gower E, Estes CC, Hindman S, Razavi-Shearer K, Razavi H (2014) Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 61:45–57

    Article  Google Scholar 

  6. Zeuzem S, Berg T, Moeller B, Hinrichsen H, Mauss S, Wedemeyer H, Sarrazin C, Hueppe D, Zehnter E, Manns MP (2009) Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepat 16:75–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, Otsuka M, Tateishi R, Omata M, Nakagawa H, Koike K, Kamatani N, Kubo M, Nakamura Y, Matsuda K (2011) Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 43:455–458

    Article  CAS  PubMed  Google Scholar 

  8. Fattovich G, Stroffolini T, Zagni I, Donato F (2004) Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127:S35–S50

    Article  PubMed  Google Scholar 

  9. 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 (2009) Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461:798–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461:399–401

    Article  CAS  PubMed  Google Scholar 

  11. Stättermayer AF, Stauber R, Hofer H, Rutter K, Beinhardt S, Scherzer TM, Zinober K, Datz C, Maieron A, Dulic-Lakovic E, Kessler HH, Steindl-Munda P, Strasser M, Krall C, Ferenci P (2011) Impact of IL28B genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C. Clin Gastroenterol Hepatol 9:344–350

    Article  PubMed  Google Scholar 

  12. Shin Hyun-Jin, Lee Jee-Boong, Park Sung-Hwan, Chang Jun, Lee Chang-Woo (2009) T-bet expression is regulated by EGR1-mediated signaling in activated T cells. Clin Immunol 131:385–394

    Article  CAS  PubMed  Google Scholar 

  13. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669

    Article  CAS  PubMed  Google Scholar 

  14. Chae SC, Shim SC, Chung HT (2009) Association of TBX21 polymorphisms in a Korean population with rheumatoid arthritis. Exp Mol Med 41:33–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chung HT, Kim LH, Park BL, Lee JH, Park HS (2003) Association analysis of novel TBX21 variants with asthma phenotypes. Hum Mutat 22:252–257

    Article  Google Scholar 

  16. Fyall KM, Fong AM, Rao SB, Ibrahim JG, Waxweiler WT, Thomas NE (2012) The TBX21 transcription factor T-1993C polymorphism is associated with decreased IFN-γ and IL-4 production by primary human lymphocytes. Hum Immunol 73:673–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen S, Zhao W, Tan W, Xu B, Dan Y, Mao Q, Kuang X, Wang Y, Deng G (2009) Association of TBX21 T-1993C polymorphism with viral persistence but not disease progression in hepatitis B virus carriers. Hepatol Res 39:716–723

    Article  CAS  PubMed  Google Scholar 

  18. Bergqvist A, Sundström S, Dimberg LY, Gylfe E, Masucci MG (2003) The hepatitis C virus core protein modulates T cell responses by inducing spontaneous and altering T-cell receptor-triggered Ca2+ oscillations. J Biol Chem 278:18877–18883

    Article  CAS  PubMed  Google Scholar 

  19. Large MK, Kittlesen DJ, Hahn YS (1999) Suppression of host immune response by thecore protein of hepatitis C virus: possible implications for hepatitis C virus persistence. J Immunol 162:2931–2938

    Google Scholar 

  20. Walewski JL, Keller TR, Stump DD, Branch AD (2001) Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame. RNA 7:710–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kong J, Deng X, Wang Z, Yang J, Zhang Y, Yu J (2009) Hepatitis C virus F protein: a double-sword in the potential contribution of chronic inflammation to carcinogenesis. Mol Med Rep 2:461–469

    CAS  PubMed  Google Scholar 

  22. Yue M, Deng X, Zhai X, Xu K, Kong J, Zhang J, Zhou Z, Yu X, Xu X, Liu Y, Zhu D, Zhang Y (2013) Th1 and Th2 cytokine profiles induced by hepatitis C virus F protein in peripheral blood mononuclear cells from chronic hepatitis C patients. Immunol Lett 152:89–95

    Article  CAS  PubMed  Google Scholar 

  23. Simmonds P, McOmish F, Yap PL, Chan SW, Lin CK, Dusheiko G, Saeed AA, Holmes EC (1993) Sequence variability in the 5 non-coding region of hepatitis C virus: identification of a new virus type and restrictions on sequence diversity. J Gen Virol 74:661–668

    Article  CAS  PubMed  Google Scholar 

  24. Gaunt TR, Rodríguez S, Day IN (2007) Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool ‘CubeX’. BMC Bioinform 8:428

    Article  Google Scholar 

  25. Mehta M, Hetta HF, Abdel-Hameed EA, Rouster SD, Hossain M, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, El-Mokhtar MA, Abdelwahab SF, Medhat A, Sherman KE, Shata MT (2016) Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients. Arch Virol 161:3161–3169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang P, Yao Y, Yue M, Tian T, Chen H, Chen M, Wang J, Zhang Y, Yu R (2017) Genetic variants in interferon-λ 4 influences HCV clearance in Chinese Han population. Sci Rep 7:42408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 39:322–330

    Article  CAS  PubMed  Google Scholar 

  28. Knapp S, Zakaria Z, Hashem M, Zaghla H, Khakoo SI, Waked I, Thursz M, Abdelwahab SF (2015) Influence of IFNL3. rs12979860 and IFNL4. ss469415590 polymorphism on clearance of hepatitis C virus infection among Egyptians. Hepatol Int 9:251–257

    Article  PubMed  Google Scholar 

  29. Stättermayer AF, Strassl R, Maieron A, Rutter K, Stauber R, Strasser M, Beinhardt S, Datz C, Scherzer TM, Steindl-Munda P, Gschwantler M, Trauner M, Hofer H, Ferenci P (2014) Polymorphisms of interferon-λ4 and IL28B effects on treatment response to interferon/ribavirin in patients with chronic hepatitis C. Aliment Pharmacol Ther 39:104–111

    Article  PubMed  Google Scholar 

  30. Sultana C, Oprişan G, Teleman MD, Dinu S, HepGen 88/2012 Project Team, Oprea C, Voiculescu M, Ruta S (2016) Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C. World J Gastroenterol 7:8406–8413

    Article  Google Scholar 

  31. Costantino A, Spada E, Equestre M, Bruni R, Tritarelli E, Coppola N, Sagnelli C, Sagnelli E, Ciccaglione AR (2015) Naturally occurring mutations associated with resistance to HCV NS5B polymerase and NS3 protease inhibitors in treatment-naïve patients with chronic hepatitis C. Virol J 12:186

    Article  PubMed  PubMed Central  Google Scholar 

  32. Childs K, Merritt E, Considine A, Sanchez-Fueyo A, Agarwal K, Martinez-Llordella M, Carey I (2017) Immunological predictors of nonresponse to directly acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. Open Forum Infect Dis 3:67

    Google Scholar 

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Acknowledgements

We would like to thank all of the participants in this study, particularly the patients.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant no. 81573213), and the Natural Science Foundation of Jiangsu Province, China (Grant no. BK20151089).

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Authors and Affiliations

  1. Department of Infectious Diseases, LuoYang Central Hospital Affiliated to ZhengZhou University, Luoyang, China

    Dan Yan Zhu, Yu Meng Zhu, Guo Tao Li, Guo Qiang Zhang & Ling Ju Wang

  2. Huadong Research Institute for Medicine and Biotechnics, No. 293, Zhongshan East Road, Nanjing, 210002, China

    Xiao Zhao Deng

  3. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Nanjing Medical University, Nanjing, China

    Xiao Zhao Deng & Jing Hai Zhang

  4. School of Life Science and Technology, China Pharmaceutical University, Nanjing, China

    Wen Xiao

  5. Department of Clinical Laboratory, Nanjing Second Hospital, Nanjing, China

    Zhen Xian Zhou

  6. Department of Clinical Laboratory, Yixing People’s Hospital, Yixing, China

    Wei Liang Ding

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  1. Dan Yan Zhu
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  2. Xiao Zhao Deng
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  3. Yu Meng Zhu
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Correspondence to Xiao Zhao Deng.

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All authors declare that no conflict of interest exists regarding the work reported in this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of Nanjing Medical University and ethics approval was obtained from the Human Investigation Committee of the Huadong Research Institute for Medicine and Biotechnics (Nanjing, China).

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Handling Editor: Michael A. Purdy.

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Zhu, D.Y., Deng, X.Z., Zhu, Y.M. et al. Association of IL-28B, TBX21 gene polymorphisms and predictors of virological response for chronic hepatitis C. Arch Virol 163, 1253–1262 (2018). https://doi.org/10.1007/s00705-018-3750-9

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  • DOI: https://doi.org/10.1007/s00705-018-3750-9

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