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

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.

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