J Appl Biomed 20:37-43, 2022 | DOI: 10.32725/jab.2022.001

Association between interferon-gamma (IFN-γ) gene polymorphisms (+874A/T and +2109A/G), and susceptibility to hepatitis B viral infection (HBV)

Mahmoud F. Dondeti1, 2, Mohamed S. Abdelkhalek1, Hosam El-Din M Elezawy3, Walaa F. Alsanie4, Bassem M. Raafat5, Amira M. Gamal-Eldeen4, Roba M. Talaat1, *
1 University of Sadat City (USC), Genetic Engineering and Biotechnology Research Institute (GEBRI), Molecular Biology Department, Sadat City, Egypt
2 National Research Centre (NRC), Genetic Engineering and Biotechnology Research Division, Dokki, Cairo, Egypt
3 Menoufia University, National Liver Institute (NLI), Clinical Biochemistry and Molecular Diagnostics Department, Menoufia, Egypt
4 Taif University, College of Applied Medical Sciences, Clinical Laboratory Sciences Department, Taif, Saudi Arabia
5 Taif University, College of Applied Medical Sciences, Radiological Sciences Department, Taif, Saudi Arabia

Background: Interferon-gamma (IFN-γ) is a chief proinflammatory cytokine with a significant role in the immune response against viral infections. Today there is increasing evidence about the association between individual genetic polymorphisms and cytokines in predicting HBV infection susceptibility.

Aim: This study aimed to investigate the association between IFN-γ gene polymorphisms and susceptibility to hepatitis B viral infection (HBV), and the impact of these genetic polymorphisms on IFN-γ production. IFN-γ (+874A/T, rs2430561, and +2109A/G, rs1861494) was genotyped by single-stranded polymorphism-polymerase chain reaction (SSP-PCR) in 126 Egyptians with chronic HBV infection and in 100 healthy control subjects. The plasma levels of IFN-γ were measured by Enzyme-linked immunosorbent assay (ELISA).

Results: Compared to the control subjects there was a slight increase in +874TT genotype frequency in HBV patients. However, no statistical significance in IFN-γ (+874A/T and +2109A/G) genotype/allele distribution was demonstrated, indicating the lack of association between these SNPs and susceptibility to HBV infection. In +2109A/G, only AG genotype was observed with a complete abrogation of GG and AA genotypes. Haplotypes between different loci on selected genes showed insignificant changes in their frequency in patients and control subjects. HBV patients had a significantly higher level of IFN-γ (P < 0.001) compared to controls. The maximum significant increase in IFN-γ production was observed in subjects harboring the +874TA genotype.

Conclusions: As no association could be characterized between the polymorphism in IFN-γ (+874A/T and +2109A/G) and susceptibility to chronic HBV infection, our data support the concept that IFN-γ gene polymorphisms are not predictors of HBV susceptibility in this segment of the Egyptian population.

Keywords: Egyptian; HBV; IFN-γ; Polymorphism
Grants and funding:

This work was funded by Taif University Researchers Supporting Project number TURSP-2020/103 and the National Liver Institute (NLI) of Menoufia University, Egypt.

Conflicts of interest:

The authors have no conflict of interests to declare.

Received: October 10, 2020; Revised: December 30, 2020; Accepted: December 16, 2021; Prepublished online: January 12, 2022; Published: March 17, 2022  Show citation

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Dondeti MF, Abdelkhalek MS, El-Din Elezawy HM, Alsanie WF, Raafat BM, Gamal-Eldeen AM, Talaat RM. Association between interferon-gamma (IFN-γ) gene polymorphisms (+874A/T and +2109A/G), and susceptibility to hepatitis B viral infection (HBV). J Appl Biomed. 2022;20(1):37-43. doi: 10.32725/jab.2022.001. PubMed PMID: 35099129.
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References

  1. Abana CO, Bingham BS, Cho JH, Graves AJ, Koyama T, Pilarski RT, et al. (2017). IL-6 variant is associated with metastasis in breast cancer patients. PLoS One 12(7): e0181725. DOI: 10.1371/journal.pone.0181725. Go to original source... Go to PubMed...
  2. Akcay IM, Katrinli S, Ozdil K, Doganay GD, Doganay L (2018). Host genetic factors affecting hepatitis B infection outcomes: Insights from genome-wide association studies. World J Gastroenterol. 24(30): 3347-3360. DOI: 10.3748/wjg.v24.i30.3347. Go to original source... Go to PubMed...
  3. Al-Kadi M, Monem F (2017). Polymorphism of IFN-γ (+874 T/A) in Syrian patients with chronic hepatitis B. Gastroenterol Hepatol Bed Bench 10(1): 34-38.
  4. Arababadi MK, Pourfathollah AA, Jafarzadeh A, Hassanshahi G, Daneshmandi S, Shamsizadeh A, et al. (2011). Non-association of IL-12 +1188 and IFN-gamma +874 polymorphisms with cytokines serum level in occult HBV infected patients. Saudi J Gastroenterol 17(1): 30-35. DOI: 10.4103/1319-3767.74461. Go to original source... Go to PubMed...
  5. Bahgat NA, Kamal MM, Abdelaziz AO, Mohye MA, Shousha HI, Ahmed MM, et al. (2015). Interferon-γ and interleukin-10 gene polymorphisms are not predictors of chronic hepatitis C (genotype-4) disease progression. Asian Pac J Cancer Prev 16(12): 5025-5030. DOI: 10.7314/apjcp.2015.16.12.5025. Go to original source... Go to PubMed...
  6. Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, et al. (2003). Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol 98(1): 144-150. DOI: 10.1111/j.1572-0241.2003.07179.x. Go to original source... Go to PubMed...
  7. Brunetto MR, Bonino F (2014). Interferon therapy of chronic hepatitis B. Intervirology 57(3-4): 163-170. DOI: 10.1159/000360941. Go to original source... Go to PubMed...
  8. Cheok MH, Pottier N, Kager L, Evans WE (2009). Pharmacogenetics in acute lymphoblastic leukemia. Semin Hematol 46(1): 39-51. DOI: 10.1053/j.seminhematol.2008.09.002. Go to original source... Go to PubMed...
  9. Chevillard C, Moukoko CE, Elwali NE, Bream JH, Kouriba B, Argiro L, et al. (2003). IFN-gamma polymorphisms (IFN-gamma +2109 and IFN-gamma +3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni). J Immunol 171(10): 5596-5601. DOI: 10.4049/jimmunol.171.10.5596. Go to original source... Go to PubMed...
  10. Chisari FV, Ferrari C (1995). Hepatitis B virus immunopathogenesis. Annu Rev Immunol 13: 29-60. DOI: 10.1146/annurev.iy.13.040195.000333. Go to original source... Go to PubMed...
  11. Dai C-Y, Chuang W-L, Hsieh M-Y, Lee L-P, Hou N-J, Chen S-C, et al. (2006). Polymorphism of interferon-gamma gene at position +874 and clinical characteristics of chronic hepatitis C. Transl Res 148: 128-133. DOI: 10.1016/j.trsl.2006.04.005. Go to original source... Go to PubMed...
  12. Dondeti MF, El-Maadawy EA, Talaat RM (2016). Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms. World J Gastroenterol 22(30): 6800-6816. DOI: 10.3748/wjg.v22.i30.6800. Go to original source... Go to PubMed...
  13. Dondeti MF, Talaat RM, El-Shenawy SZ, Khamiss OA (2017). Transforming growth factor (TGF-β1) gene polymorphisms in Egyptian patients with hepatitis B virus infection. Meta Gene 13: 5-12. DOI: 10.1016/j.mgene.2017.03.005. Go to original source...
  14. Dorman SE, Holland SM (2000). Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 11(4): 321-333. DOI: 10.1016/s1359-6101(00)00010-1. Go to original source... Go to PubMed...
  15. El-Maadawy EA, Talaat RM, Ahmed MM, El-Shenawy SZ (2019). Interleukin-6 promoter gene polymorphisms and susceptibility to chronic hepatitis B virus in Egyptians. Hum Immunol 80(3): 208-214. DOI: 10.1016/j.humimm.2018.12.009. Go to original source... Go to PubMed...
  16. Gao Q-J, Liu D-W, Zhang S-Y, Jia M, Wu L-H (2010). Association between IFN-gamma + 874 polymorphisms and the clinical outcomes of hepatitis B and/or hepatitis C virus infection. Zhonghua Liu Xing Bing Xue Za Zhi 31: 324-328. Go to PubMed...
  17. Ghasemian N, Shahbazi M (2016). Interferon Gamma Gene Polymorphism (+874 T > A) and Chronic Hepatitis B in the Population of Gorgan, North-Eastern Iran. Jundishapur J Microbiol 9(8): e33639. DOI: 10.5812/jjm.33639. Go to original source... Go to PubMed...
  18. Gisler FM, von Kanel T, Kraemer R, Schaller A, Gallati S (2013). Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis. Eur J Hum Genet 21(4): 397-403. DOI: 10.1038/ejhg.2012.181. Go to original source... Go to PubMed...
  19. Habil FE, Mahdi WK, Abdelwahab SF, Abdel-Hamid M (2013). Hepatitis B virus genotype D predominates HBsAg-positive Egyptian blood donors and is mainly associated with a negative HBeAg serostatus. Intervirology 56(5): 278-283. DOI: 10.1159/000353105. Go to original source... Go to PubMed...
  20. Hollegaard MV, Bidwell JL (2006). Cytokine gene polymorphism in human disease: online databases, Supplement 3. Genes Immun 7(4): 269-276. DOI: 10.1038/sj.gene.6364301. Go to original source... Go to PubMed...
  21. Hosseini Khorami SH, Nejatollahi F, Davarpanah MA (2018). Serum Levels of Interleukin-4, Interleukin-10 and Interferon-γ in Patients with Chronic Hepatitis B Infection. Hepat Mon 18(4): e60377. DOI: 10.5812/hepatmon.60377. Go to original source...
  22. Huang C-F, Lin S-S, Ho Y-C, Chen, F-L, Yang C-C (2006). The immune response induced by hepatitis B virus principal antigens. Cell Mol Immunol 3(2): 97-106.
  23. Hui C-K, Lau GK (2005). Immune system and hepatitis B virus infection. J Clin Virol 34 Suppl. 1: S44-S48. DOI: 10.1016/s1386-6532(05)80009-5. Go to original source... Go to PubMed...
  24. Hyvärinen K, Ritari J, Koskela S, Niittyvuopio R, Nihtinen A, Volin L, et al. (2017). Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease. Sci Rep 7: 15666. DOI: 10.1038/s41598-017-15915-3. Go to original source... Go to PubMed...
  25. Koziel MJ (1999). Cytokines in viral hepatitis. Semin Liver Dis 19(2): 157-169. DOI: 10.1055/s-2007-1007107. Go to original source... Go to PubMed...
  26. Lan T, Chang L, Wu L, Yuan Y-F (2015). IL-6 plays a crucial role in HBV infection. J Clin Transl Hepatol 3(4): 271-276. DOI: 10.14218/JCTH.2015.00024. Go to original source... Go to PubMed...
  27. Lee HM, Banini BA (2019). Updates on Chronic HBV: Current Challenges and Future Goals. Curr Treat Options Gastroenterol 17(2): 271-291. DOI: 10.1007/s11938-019-00236-3. Go to original source... Go to PubMed...
  28. Li M, Sun X, Zhou Z, Zhang X, Jin S, Gao Y, Gao Y (2016). [Alterations of IFN-γ and IL-4 of peripheral blood T cells in patients with chronic HBV infection]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 32(2): 240-244.
  29. Liu M, Cao B, Zhang H, Dai Y, Liu X, Xu C (2006). Association of interferon-gamma gene haplotype in the Chinese population with hepatitis B virus infection. Immunogenetics 58(11): 859-864. DOI: 10.1007/s00251-006-0161-y. Go to original source... Go to PubMed...
  30. Manolova I, Miteva L, Ivanova M, Kundurzhiev T, Stoilov R, Stanilova S (2018). The Synergistic Effect of TNFA and IL10 Promoter Polymorphisms on Genetic Predisposition to Systemic Lupus Erythematosus. Genet Test Mol Biomarkers 22(2): 135-140. DOI: 10.1089/gtmb.2017.0169. Go to original source... Go to PubMed...
  31. Masoodi TA, Al Shammari SA, Al-Muammar MN, Alhamdan AA, Talluri VR (2013). Exploration of deleterious single nucleotide polymorphisms in late-onset Alzheimer disease susceptibility genes. Gene 512(2): 429-437. DOI: 10.1016/j.gene.2012.08.026. Go to original source... Go to PubMed...
  32. Mihm S, Hutschenreiter A, Fayyazi A, Pingel S, Ramadori G (1996). High inflammatory activity is associated with an increased amount of IFN-gamma transcripts in peripheral blood cells of patients with chronic hepatitis C virus infection. Med Microbiol Immunol 185(2): 95-102. DOI: 10.1007/s004300050020. Go to original source... Go to PubMed...
  33. Naghizadeh MS, Naseri M, Fereyduni M, Ziaee M, Tane A, Safari H, et al. (2018). Single Nucleotide Polymorphism of the Interferon-γ Gene (IFN-γ+ 874 T/A) and the Prognosis of Hepatitis B Infection. J Med Microbiol Infect Dis 6(2-3): 43-47. DOI: 10.29252/JoMMID.6.2.3.43. Go to original source...
  34. Nguyen MH, Wong G, Gane E, Kao J-H, Dusheiko G (2020). Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy. Clin Microbiol Rev 33(2): e00046-19. DOI: 10.1128/CMR.00046-19. Go to original source... Go to PubMed...
  35. Ollier WE (2004). Cytokine genes and disease susceptibility. Cytokine 2(4-5): 174-178. DOI: 10.1016/j.cyto.2004.07.014. Go to original source... Go to PubMed...
  36. Pan CJ, Wu H-L, Kuo SF, Kao J-H, Tseng T-C, Liu C-H, et al. (2012). Serum interleukin 6 level correlates with outcomes of chronic hepatitis B. Hepatol Int 6(3): 591-597. DOI: 10.1007/s12072-011-9299-2. Go to original source... Go to PubMed...
  37. Peng XM, Lei RX, Gu L, Ma HH, Xie QF, Gao ZL (2007). Influences of MxA gene -88 G/T and IFN-gamma +874 A/T on the natural history of hepatitis B virus infection in an endemic area. Int J Immunogenet 34(5): 341-346. DOI: 10.1111/j.1744-313X.2007.00696.x. Go to original source... Go to PubMed...
  38. Peresi E, Oliveira LR, da Silva WL, da Costa EA, Araujo JP, Jr., Ayres JA, et al. (2013). Cytokine polymorphisms. Their influence and levels in Brazilian patients with pulmonary tuberculosis during antituberculosis treatment. Tuberc Res Treat 2013: 285094. DOI: 10.1155/2013/285094. Go to original source... Go to PubMed...
  39. Pfeffer LM (2011). The role of nuclear factor κB in the interferon response. J Interferon Cytokine Res 31(7): 553-539. DOI: 10.1089/jir.2011.0028. Go to original source... Go to PubMed...
  40. Prasad KN, Nyati KK, Verma A, Rizwan A, Paliwal VK (2010). Tumor necrosis factor-α polymorphisms and expression in Guillain-Barré syndrome. Hum Immunol 71(9): 905-910. DOI: 10.1016/j.humimm.2010.06.013. Go to original source... Go to PubMed...
  41. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV (2000). A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 61(9): 863-866. DOI: 10.1016/s0198-8859(00)00167-1. Go to original source... Go to PubMed...
  42. Qi S, Cao B, Jiang M, Xu C, Dai Y LK (2005). Association of the -183 polymorphism in the IFN-gamma gene promoter with hepatitis B virus infection in the Chinese population. J Clin Lab Anal 19(6): 276-281. DOI: 10.1002/jcla.20090. Go to original source... Go to PubMed...
  43. Ribeiro CS, Visentainer JE, Moliterno RA (2007). Association of cytokine genetic polymorphism with hepatitis B infection evolution in adult patients. Mem Inst Oswaldo Cruz 102(4): 435-440. DOI: 10.1590/s0074-02762007005000043. Go to original source... Go to PubMed...
  44. Sarvari J, Norozian H, Fattahi MR, Pirbonyeh N, Moattari A (2014). The role of interferon-gamma gene polymorphism (+874A/T, +2109A/G, and -183G/T) in response to treatment among hepatitis C infected patients in Fars province, southern Iran. Hepat Mon 14(1): e14476. DOI: 10.5812/hepatmon.14476. Go to original source... Go to PubMed...
  45. Saxena R, Chawla YK, Verma I, Kaur J (2014). IFN-gamma (+874) and not TNF-alpha (-308) is associated with HBV-HCC risk in India. Mol Cell Biochem 385(1-2): 297-307. DOI: 10.1007/s11010-013-1838-9. Go to original source... Go to PubMed...
  46. Srivastava M, Ranjan A, Choudhary JK, Tripathi MK, Verma S, Dixit VK, et al. (2014). Role of proinflammatory cytokines (interferon-gamma) and anti-inflammatory cytokine (interleukin-10) gene polymorphisms in chronic hepatitis B infection: an Indian scenario. J Interferon Cytokine Res 34(7): 547-551. DOI: 10.1089/jir.2013.0054. Go to original source... Go to PubMed...
  47. Stark GR (2007). How cells respond to interferons revisited from early history to current complexity. Cytokine Growth Factor Rev 18(5-6): 419-423. DOI: 10.1016/j.cytogfr.2007.06.013. Go to original source... Go to PubMed...
  48. Sun X-R, Wu J, Tang K-F (2014). The interferon-gamma (IFN-γ) +874T allele reduces the risk of hepatitis B infection in an Asian population. J Viral Hepat 21(4): 281-287. DOI: 10.1111/jvh.12140. Go to original source... Go to PubMed...
  49. Sun Y, Lu Y, Li T, Xie L, Deng Y, Li S, Qin X (2015a). Interferon gamma+ 874T/A polymorphism increases the risk of hepatitis virus-related diseases: evidence from a meta-analysis. PloS One 10(5): e0121168. DOI: 10.1371/journal.pone.0121168. Go to original source... Go to PubMed...
  50. Sun Y, Lu Y, Xie L, Deng Y, Li S, Qin X (2015b). Interferon-gamma polymorphisms, and hepatitis B virus-related liver cirrhosis risk in a Chinese population. Cancer Cell Int 15: 35. DOI: 10.1186/s12935-015-0184-2. Go to original source... Go to PubMed...
  51. Talaat RM, Abdelkhalek MS, El-Maadawy EA, Abdel-Mageed WS, El-Shenawy SZ, Osman MA (2017). Association of TNF-Alpha gene polymorphisms and susceptibility to hepatitis B virusinfection in Egyptians. Hum Immunol 78(11-12): 739-746. DOI: 10.1016/j.humimm.2017.10.006. Go to original source... Go to PubMed...
  52. Talaat RM, Dondeti MF, El-Shenawy SZ, Khamiss OA (2013). Transforming Growth Factor-β 1 Gene Polymorphism (T29C) in Egyptian Patients with Hepatitis B Virus Infection: A Preliminary Study. Hepat Res Treat 2013: 293274. DOI: 10.1155/2013/293274. Go to original source... Go to PubMed...
  53. Talaat RM, Dondeti MF, El-Shenawy SZ, Khamiss OA (2014). Association between IL-10 gene promoter polymorphism and hepatitis B viral infection in an Egyptian population. Biochem Genet 52(9-10): 387-402. DOI: 10.1007/s10528-014-9655-8. Go to original source... Go to PubMed...
  54. Tang LS, Covert E, Wilson E, Kottilil S (2018). Chronic hepatitis B infection: a review. Jama 319(17): 1802-1813. DOI: 10.1001/jama.2018.3795. Go to original source... Go to PubMed...
  55. Teixeira AC, Mendes CT, Jr., Marano LA, Deghaide NH, Secaf M, Elias J, Jr., et al. (2013). Alleles and genotypes of polymorphisms of IL-18, TNF-alpha, and IFN-gamma are associated with a higher risk and severity of hepatocellular carcinoma (HCC) in Brazil. Hum Immunol 74(8): 1024-1029. DOI: 10.1016/j.humimm.2013.04.029. Go to original source... Go to PubMed...
  56. Trehanpati N, Hissar S, Shrivastav S, Sarin SK (2013). Immunological mechanisms of hepatitis B virus persistence in newborns. Indian J Med Res 138(5): 700-710.
  57. Tunçbilek, S (2014). Relationship between cytokine gene polymorphisms and chronic hepatitis B virus infection. WorldJ Gastroenterol 20(20): 6226-6235. DOI: 10.3748/wjg.v20.i20.6226. Go to original source... Go to PubMed...
  58. Wai CT, Fontana RJ (2003). Cytokine gene polymorphisms in chronic hepatitis B: a step up the immunology ladder. Am J Gastroenterol 98(1): 6-8. DOI: 10.1111/j.1572-0241.2003.07169.x Go to original source... Go to PubMed...
  59. Wei Y, Tian Q, Li L, Zhang D (2016). Association between IFN-γ genetic polymorphisms and susceptibility to hepatitis B virus infection: A meta-analysis. Ann Hum Biol 43(6): 527-536. DOI: 10.3109/03014460.2015.1106583. Go to original source... Go to PubMed...
  60. WHO (2017). Global Hepatitis Report; World Health Organization: Geneva, Switzerland. Go to PubMed...
  61. Wu J-F, Chang M-H (2015). Natural history of chronic hepatitis B virus infection from infancy to adult life-the mechanism of inflammation triggering and long-term impacts. J Biomed Science 22: 92. DOI: 10.1186/s12929-015-0199-y. Go to original source... Go to PubMed...
  62. Yu H, Zhu Q-R, Gu S-Q, Fei L-E (2006). Relationship between IFN-gamma gene polymorphism and susceptibility to intrauterine HBV infection. World J Gastroenterol 12(18): 2928-2931. DOI: 10.3748/wjg.v12.i18.2928. Go to original source... Go to PubMed...
  63. Zhang P-A, Wu JM, Li Y (2006). [Relationship between genetic polymorphisms of Interferon-gamma gene intron 1 +874 site and susceptibility of hepatitis B virus infection]. Zhonghua Liu Xing Bing Xue Za Zhi 27(1): 41-43. Go to PubMed...

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