https://doi.org/10.5812/hepatmon.19879

Interleukin-18 Gene Promoter Polymorphisms and Susceptibility to Chronic Hepatitis B Infection: A Review Study

authors:

avatar Mahsa Motavaf 1 , avatar Saeid Safari 1 , 2 , avatar Seyed Moayed Alavian ORCID 1 , 3 , *

Department of Molecular Hepatology, Middle East Liver Disease Center (MELD), Tehran, IR Iran
Department of Anesthesiology and Pain Medicine, Tehran University of Medical Sciences, Tehran, IR Iran
Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
Hepatitis Monthly: Vol.14, issue 7; e19879
published online: July 1, 2014
article type: Review Article
received: April 30, 2014
accepted: May 1, 2014

How To Cite Motavaf M, Safari S, Alavian S M. Interleukin-18 Gene Promoter Polymorphisms and Susceptibility to Chronic Hepatitis B Infection: A Review Study. Hepat Mon. 2014;14(7):e19879. https://doi.org/10.5812/hepatmon.19879.

Abstract

Context:

The variation in clinical outcome of hepatitis B virus (HBV) infection is determined by virological, immunological and host genetic factors. Genes encoding cytokines are one of the candidates among host genetic factors. Polymorphisms in gene promoter can lead to different levels of cytokine expression and unique immune response. Being involved in the inflammatory cytokine network, interleukin-18 (IL-18) plays an important role in pathogenesis of HBV infection. The aim of this review is considering available literature on the association between IL-18 gene promoter single nucleotide polymorphisms (-137 C/G and -607 A/C) and susceptibility to chronic HBV infection.

Evidence Acquisition:

Published literature from PubMed, EMBASE, and other databases were retrieved. All studies investigating the association of IL-18 gene promoter SNPs, -137 C/G and -607 A/C, with susceptibility to chronic HBV infection were included.

Results:

Findings showed that the genotype -607A/A is associated with the susceptibility to chronic hepatitis B. Furthermore, allele C at position -137 is suggested to play a protective role against development of chronic HBV infection.

Conclusions:

Host genetic factors play an important role in determining the outcome of HBV infection. It is suggested that IL-18 genotype -607 A/A is associated with susceptibility to chronic hepatitis B. Furthermore, the carriage of allele C at position -137 may play a protective role in the development of chronic HBV infection.

2. Evidence Acquisition

Published literature from PubMed, EMBASE, and other databases were reviewed and all studies investigating the association of IL-18 gene promoter SNPs, -137 C/G, -607 A/C, or both with susceptibility to chronic HBV were included.

In a study by Hirankarn et al. (26) the genotype frequencies of IL-18 polymorphism at positions -607A/C between Thai patients with chronic HBV infection and healthy individuals were compared to assess whether these genes are involved in susceptibility to chronic HBV infection. The results indicated that the -607A/A genotype was significantly higher in the patients with chronic hepatitis B than in the controls. They hypothesized that -607A/A genotype likely results in markedly lower transcription activity and lower production of IL-18 from hepatic macrophage in the liver, leading to decreased inhibition of HBV replication. This hypothesis was approved by study of Khripko et al. (28) in which the authors analyzed the effect of polymorphic variants in the IL-18 gene promoter region at −607 A→C on IL-18 protein production by PBMC of healthy donors. They indicated that, the level of spontaneous IL-18 secretion in carriers of -607A/A is lower compare to C/A and C/C carriers.

In other study by Na Li et al. (27) the effect of SNP -607A/C in IL-18 gene on susceptibility to chronic HBV infection was investigated between chronic HBV infected patients and HBV natural clearance controls in Chinese population. The results showed that the genotype A/A at position -607 was present at higher frequency in patients with chronic hepatitis B compared to controls. Both studies suggested that the genotype A/A at position -607 is closely associated with the susceptibility to chronic hepatitis B and may be the susceptible gene. In contrast, a study by Zhang et al. (25) showed no significant difference in position -607 A/C gene polymorphism between patients with chronic hepatitis B and healthy controls in Chinese Han population. Ethnic and racial differences and association with other genetic markers are likely to explain these contradictory results.

Comparing genotype frequency at position -137, Zhang et al. (25) observed significant difference between the patients with chronic hepatitis B and the healthy controls in Han Chinese population. At this position, genotype G/G was present at a significantly higher frequency in the patients with chronic hepatitis B compared to those in the controls. Hirankarn et al. (26) observed the same results indicating the higher frequency of genotype -137 G/G in patients with chronic hepatitis B compared to healthy controls. However, this difference was not significant. This result does not support the hypothesis that lower production of IL-18 is associated with susceptibility to chronic HBV infection, because it is indicated that the production of IL-18 is higher in carriers of G/G compare to other genotypes (20). Investigating the distribution of allele frequency, Zhang et al. showed that the frequencies of haplotypes which bear C at position -137, in the patients with chronic hepatitis B were significantly lower than that in the healthy controls. It is in agreement with the result of Na Li et al. study (27) in which the frequency of allele C indicated to be less frequent in patients with chronic HBV compared to controls. These findings suggest that C allele at position -137 plays a protective role in the development of HBV infection. They suggested that -137 C was related with high production of IL-18, which result in better elimination of HBV.

3. Results

The SNPs in promoter of IL-18 gene at position -607 and -137 were suggested to have a critical impact on IL-18 gene activity, which result in different level of IL-18 production. As IL-18 plays an important role in host defense against HBV infection, difference in level of its production is suggested to be associated with HBV outcome.

Recent studies indicated that -607A/A genotype is associated by lower level of IL-18 production compare to C/A and C/C genotypes. Investigating the association between this genotype and susceptibility to development of chronic hepatitis B infection indicated a higher frequency of -607A/A in patients with chronic hepatitis B, suggesting this genotype as a susceptible gene (26, 27).

In the case of haplotype studies on -137 genotypes it has been indicated that the frequency allele C at position -137 is lower in patients with chronic HBV infection, suggesting that this allele may play a protective role in the development of chronic HBV infection (25).

4. Conclusions

Findings show that host genetic factors play an important role in determining the outcome of HBV infection. Because cytokines play an important role in initiation and regulation of immune responses against HBV infection, they might affect susceptibility to HBV infection. IL-18 is involved in the inflammatory cytokine network so it has an important role in the pathogenesis of various diseases including HBV infection. The SNPs in promoter of IL-18 gene at position -607 and -137 were contributed to difference in IL-18 gene activity, which result in variable level of IL-18 production. A number of recent studies have demonstrated the association between -607A/A genotype and the susceptibility to development of chronic hepatitis B (26, 27). Furthermore, the carriage of allele C at position -137 in the promoter of IL-18 gene is suggested to play a protective role against development of chronic HBV infection (25). However, the real roles of IL-18 gene promoter polymorphisms in the pathogenesis of developing chronic hepatitis B needs to be further investigated within large population from different ethnic groups and geographic regions.

References

  • 1.

    Fathimoghaddam F, Hedayati-Moghaddam MR, Bidkhori HR, Ahmadi S, Sima HR. The prevalence of hepatitis B antigen-positivity in the general population of Mashhad, Iran. Hepat Mon. 2011;11(5):346-50. [PubMed ID: 22087159].

  • 2.

    Ganji A, Esmaeilzadeh A, Ghafarzadegan K, Helalat H, Rafatpanah H, Mokhtarifar A. Correlation between HBsAg quantitative assay results and HBV DNA levels in chronic HBV. Hepat Mon. 2011;11(5):342-5. [PubMed ID: 22087158].

  • 3.

    Mohebbi SR, Sanati A, Cheraghipour K, Rostami Nejad M, Shalmani HM, Zali MR. Hepatitis C and hepatitis B virus infection: epidemiology and risk factors in a large cohort of pregnant women in Lorestan, West of Iran. Hepat Mon. 2011;11(9):736-9. [PubMed ID: 22235217]. https://doi.org/10.5812/kowsar.1735143X.749.

  • 4.

    Thio CL, Thomas DL, Carrington M. Chronic viral hepatitis and the human genome. Hepatology. 2000;31(4):819-27. [PubMed ID: 10733534]. https://doi.org/10.1053/he.2000.4316.

  • 5.

    Arababadi MK, Mohammadzadeh A, Pourfathollah AA, Kennedy D. Polymorphisms within Fas gene are not associated with occult hepatitis B virus infection: Polymorphisms within Fas gene in occult HBV infection. Hepat Mon. 2011;11(1):23-6. [PubMed ID: 22087112].

  • 6.

    Abel L, Dessein AJ. Genetic epidemiology of infectious diseases in humans: design of population-based studies. Emerg Infect Dis. 1998;4(4):593-603. [PubMed ID: 9866735]. https://doi.org/10.3201/eid0404.980409.

  • 7.

    He YL, Zhao YR, Zhang SL, Lin SM. Host susceptibility to persistent hepatitis B virus infection. World J Gastroenterol. 2006;12(30):4788-93. [PubMed ID: 16937459].

  • 8.

    Danis VA, Millington M, Hyland VJ, Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol. 1995;99(2):303-10. [PubMed ID: 7851026].

  • 9.

    Sharafi H, Pouryasin A, Alavian SM, Behnava B, Keshvari M, Salimi S, et al. Distribution of IL28B Genotypes in Iranian Patients with Chronic Hepatitis C and Healthy Individuals. Hepat Mon. 2012;12(12). [PubMed ID: 23550102]. https://doi.org/10.5812/hepatmon.8387.

  • 10.

    Wu L, Chen L, Zhou L, Xie H, Wei B, Yin S, et al. Association of interleukin 18 gene promoter polymorphisms with HBV recurrence after liver transplantation in Han Chinese population. Hepat Mon. 2011;11(6):469-74. [PubMed ID: 22087180].

  • 11.

    Li W, Jiang Y, Jin Q, Shi X, Jin J, Gao Y, et al. Expression and gene polymorphisms of interleukin 28B and hepatitis B virus infection in a Chinese Han population. Liver Int. 2011;31(8):1118-26. [PubMed ID: 21745278]. https://doi.org/10.1111/j.1478-3231.2011.02507.x.

  • 12.

    Wang S, Huang D, Sun S, Ma W, Zhen Q. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa. Virol J. 2011;8:28. [PubMed ID: 21251301]. https://doi.org/10.1186/1743-422X-8-28.

  • 13.

    Zecchina G, Novick D, Rubinstein M, Barak V, Dinarello C, Nagler A. Interleukin-18 binding protein in acute graft versus host disease and engraftment following allogeneic peripheral blood stem cell transplants. J Hematother Stem Cell Res. 2001;10(6):769-76. [PubMed ID: 11798503]. https://doi.org/10.1089/152581601317210863.

  • 14.

    Kieszko R, Krawczyk P, Jankowska O, Chocholska S, Krol A, Milanowski J. The clinical significance of interleukin 18 assessment in sarcoidosis patients. Respir Med. 2007;101(4):722-8. [PubMed ID: 17015003]. https://doi.org/10.1016/j.rmed.2006.08.019.

  • 15.

    Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001;19:423-74. [PubMed ID: 11244043]. https://doi.org/10.1146/annurev.immunol.19.1.423.

  • 16.

    McInnes IB, Gracie JA, Leung BP, Wei XQ, Liew FY. Interleukin 18: a pleiotropic participant in chronic inflammation. Immunol Today. 2000;21(7):312-5. [PubMed ID: 10871869].

  • 17.

    Kalina U, Ballas K, Koyama N, Kauschat D, Miething C, Arnemann J, et al. Genomic organization and regulation of the human interleukin-18 gene. Scand J Immunol. 2000;52(6):525-30. [PubMed ID: 11119255].

  • 18.

    Tone M, Thompson SA, Tone Y, Fairchild PJ, Waldmann H. Regulation of IL-18 (IFN-gamma-inducing factor) gene expression. J Immunol. 1997;159(12):6156-63. [PubMed ID: 9550417].

  • 19.

    Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol. 2001;112(1-2):146-52. [PubMed ID: 11108943].

  • 20.

    Arimitsu J, Hirano T, Higa S, Kawai M, Naka T, Ogata A, et al. IL-18 gene polymorphisms affect IL-18 production capability by monocytes. Biochem Biophys Res Commun. 2006;342(4):1413-6. [PubMed ID: 16516851]. https://doi.org/10.1016/j.bbrc.2006.02.096.

  • 21.

    Bouzgarrou N, Hassen E, Schvoerer E, Stoll-Keller F, Bahri O, Gabbouj S, et al. Association of interleukin-18 polymorphisms and plasma level with the outcome of chronic HCV infection. J Med Virol. 2008;80(4):607-14. [PubMed ID: 18297714]. https://doi.org/10.1002/jmv.21079.

  • 22.

    Sobti R, Sharma V, Abitew A, Berhane N, Mahdi S, Askari M, et al. IL-18 Gene Promoter Region 607C/A Polymorphism in HIV-1 Infected North Indian Population. Balkan J Med Genet : BJMG. 2011;14(2):41-8. [PubMed ID: 24052711]. https://doi.org/10.2478/v10034-011-0046-8.

  • 23.

    Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. J Virol. 2002;76(21):10702-7. [PubMed ID: 12368312].

  • 24.

    Sun Y, Chen HY, Wang F, Zhang X, Jiang HQ, Shao FJ, et al. [Effect of IL-18 on peripheral blood monocytes from chronic hepatitis B patients]. Zhonghua Gan Zang Bing Za Zhi. 2003;11(8):470-3. [PubMed ID: 12939178].

  • 25.

    Zhang PA, Wu JM, Li Y, Yang XS. [Relationship of interleukin-18 gene promoter polymorphisms with chronic hepatitis B in Chinese Han population]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005;22(5):528-32. [PubMed ID: 16215941].

  • 26.

    Hirankarn N, Manonom C, Tangkijvanich P, Poovorawan Y. Association of interleukin-18 gene polymorphism (-607A/A genotype) with susceptibility to chronic hepatitis B virus infection. Tissue Antigens. 2007;70(2):160-3. [PubMed ID: 17610422]. https://doi.org/10.1111/j.1399-0039.2007.00865.x.

  • 27.

    Li N, Gao YF, Zhang TC, Chen P, Li X, Su F. Relationship between interleukin 18 polymorphisms and susceptibility to chronic hepatitis B virus infection. World J Hepatol. 2012;4(3):105-9. [PubMed ID: 22489263]. https://doi.org/10.4254/wjh.v4.i3.105.

  • 28.

    Khripko OP, Sennikova NS, Lopatnikova JA, Khripko JI, Filipenko ML, Khrapov EA, et al. Association of single nucleotide polymorphisms in the IL-18 gene with production of IL-18 protein by mononuclear cells from healthy donors. Mediators Inflamm. 2008;2008:309721. [PubMed ID: 18949051]. https://doi.org/10.1155/2008/309721.