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Heiat M, Javanbakht M, Jafari D, Poudineh M, Heydari F, Sharafi H, Alavian SM. Correlation of IL-10 and IL18 with the development of liver cirrhosis associated with hepatitis B virus infection: A systematic review. Cytokine 2025; 186:156818. [PMID: 39671883 DOI: 10.1016/j.cyto.2024.156818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/02/2024] [Accepted: 11/16/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC. METHODS We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023. RESULT We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. CONCLUSION IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.
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Affiliation(s)
- Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fatemeh Heydari
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Sarhadi M, Pahlavani E, Hosseini Razavi N, Ghadyani F, Abdollahi Z, Sarhadi S, Sabeti Akbar Abad M, Shahriari H, Majidpour M. IL-18 and CD14 variants in chronic HBV predisposition: a case-control study with in silico analyses focused on transcription and splicing. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024:1-21. [PMID: 38459706 DOI: 10.1080/15257770.2024.2326132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/26/2024] [Indexed: 03/10/2024]
Abstract
Hepatitis B virus (HBV), a vaccine-avoidable infection, is a health concern worldwide, leading to liver disorders such as acute self-constraint and chronic hepatitis, liver failure, hepatic cirrhosis, and even hepatocellular carcinoma if untreated. 'Immunogeneticprofiling', genetic variations of the pro- and anti-inflammatory cytokines responsible for regulating the immune responses, cause person-to-person differences and impact the clinical manifestation of the disease. The current experimental-bioinformatics research was conducted to examine whether promoteric IL-18-rs187238 C > G and -rs1946518 T > G and intronic CD14-rs2569190 A > G variations are associated with chronic HBV. A total of 400 individuals (200 in each case and control group) participated in the study and were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The data was also assessed bioinformatics-wise for conservation, genomic transcription and splicing, and protein interactions. Findings proposed that unlike the IL-18-rs1946518 T > G and CD14-rs2569190 A > G, the IL-18-rs187238 C > G is a protector against chronic HBV (odds ratio [OR] = 0.62, 95% confidence intervals [CI]: 0.46-0.83, and p = 0.002). The TG/CC/AA, TG/CC/AG, TT/CC/AG, and GG/CC/AA combined genotypes significantly increased chronic HBV risk (p < 0.05), while the IL-18 G/T and G/G haplotypes lessened it (p < 0.05). Moreover, IL-18-rs1946518 T > G is in the protected genomic regions across mammalian species. In contrast to the IL-18-rs1946518 T > G, IL-18-rs187238 C > G is likely to create novel binding sites for transcription factors, and the CD14-rs2569190 A > G presumably changed the ribonucleic acid splicing pattern. More research on larger populations and other ethnicities is required to authenticate these results.
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Affiliation(s)
- Mohammad Sarhadi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Elham Pahlavani
- Infectious Diseases and Tropical Medicine Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Niloufar Hosseini Razavi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Fatemeh Ghadyani
- Department of Cellular and Molecular, Faculty of Biology Sciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Zahra Abdollahi
- Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, Kashan, Iran
| | - Somayeh Sarhadi
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Mahboobeh Sabeti Akbar Abad
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hossein Shahriari
- Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mahdi Majidpour
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan, Iran
- Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
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Ali T, Saxena R, Rani I, Sharma R, More D, Ola R, Agarwal S, Chawla YK, Kaur J. Association of interleukin-18 genotypes (-607C > A) and (-137 G > C) with the hepatitis B virus disease progression to hepatocellular carcinoma. Mol Cell Biochem 2021; 476:3923-3933. [PMID: 34165682 DOI: 10.1007/s11010-021-04206-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 06/08/2021] [Indexed: 01/20/2023]
Abstract
Chronic infection with HBV has been reported to be associated with the development of HCC. The inflammation mounted by cytokine-mediated immune system plays an important role in the pathogenesis of HBV-associated HCC. IL-18 is a pro-inflammatory cytokine whose role in the development of HBV-associated chronic to malignant disease state has not been much studied. The present study was conceived to determine the role of genetic polymorphisms in IL-18, serum levels of IL-18, and expression level of its signal transducers in the HBV disease progression. A total of 403 subjects were enrolled for this study including 102 healthy subjects and 301 patients with HBV infection in different diseased categories. Polymorphism was determined using PCR-RFLP. Genotypic distributions between the groups were compared using odd's ratio and 95% CI were calculated to express the relative risk. Circulating IL-18 levels were determined by ELISA. Expression levels of pSTAT-1 and pNFƙB was determined by western blotting. In case of IL-18(- 607C > A), the heterozygous genotype (CA) was found to be a protective factor while in case of IL-18(- 137G > C) the heterozygous genotype (GC) acted as a risk factor for disease progression from HBV to HCC. Moreover, serum IL-18 levels were significantly increased during HBV disease progression to HCC as compared to controls. Also the levels of activated signal transducers (pSTAT-1 and pNF-κB) of IL-18 in stimulated PBMCs were significantly increased during HBV to HCC disease progression. These findings suggest that IL-18 has the potential to act as a biomarker of HBV-related disease progression to HCC.
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Affiliation(s)
- Taqveema Ali
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Roli Saxena
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Isha Rani
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Renuka Sharma
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Deepti More
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Rajendra Ola
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Stuti Agarwal
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Yogesh Kumar Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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4
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Li M, Xu Y, Pu K, Fan J, Cheng Z, Chen H, Zhou L. Genetic polymorphisms of chemokine (C-X-C motif) ligand 10 gene associated with hepatitis B virus infection in a Chinese Han population. Int Immunopharmacol 2021; 98:107888. [PMID: 34153670 DOI: 10.1016/j.intimp.2021.107888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/11/2021] [Accepted: 06/11/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND AIMS Chemokine (C-X-C motif) ligand 10 (CXCL10) has been recently shown to be associated with inflammatory diseases. However, the association between the genetic variation of this gene and the susceptibility to hepatitis B virus (HBV) infection remains unclear, especially in children. This study aimed to investigate the relationship between CXCL10 polymorphisms and the risk of chronic HBV infection in a Chinese Han population. METHODS A two-stage case-control study of 1048 adults and 627 children was performed. A total of 5 tagging SNPs in CXCL10 were genotyped. Dual-Luciferase Reporter Assay was used to assess the effect of the rs4508917 polymorphism on transcriptional activity of CXCL10. RESULTS CXCL10 rs4508917 and rs4256246 polymorphisms were significantly associated with an increased risk of chronic HBV infection in Chinese Han adults (p = 0.036 and p = 0.033), of which rs4508917 AA genotype could increase the serum CXCL10 level (p = 0.014). In addition, the rs4508917 AA genotype was identified to facilitate HBV persistent infection (p = 0.017) and breakthrough infection (p = 0.013) in children. Subsequent functional analysis indicated that rs4508917 A allele could promote the transcriptional activity of CXCL10. Additionally, we observed that the rs4508917 A allele carriers (AA and AG genotypes) had a limited HBV viral load suppression in patients treated with nucleos(t)ide analogues (NAs). CONCLUSION The A allele of the CXCL10 rs4508917 may be a risk factor of the persistent HBV infection both in adults and children, which may influence the response to NAs treatment.
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Affiliation(s)
- Mengmeng Li
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Ying Xu
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Kexue Pu
- College of Medical Informatics, Chongqing Medical University, Chongqing, China
| | - Jie Fan
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Zheng Cheng
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Hao Chen
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Li Zhou
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China.
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Li M, Zhuo Y, Xu Y, Chen H, Cheng Z, Zhou L. Genetic Association of Interleukin-6 Polymorphism (rs1800796) with Chronic Hepatitis B Virus Infection in Chinese Han Population. Viral Immunol 2020; 34:267-272. [PMID: 33305999 DOI: 10.1089/vim.2020.0211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global health care burden that can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. We conducted this study to identify the association between interleukin-6 (IL-6) gene rs1800796 (-572G/C) polymorphism and the risk of chronic HBV infection in adults. A total of 1,048 participants including 518 cases and 530 controls were recruited for this study. The Mass Array time-of-flight mass spectrometer was applied for single-nucleotide polymorphism rs1800796 genotyping. There was a significant correlation between genotype CG in rs1800796 and chronic HBV infection in the Chinese Han population (odds ratio [OR] = 0.759, 95% confidence interval [CI]: 0.586-0.983, p = 0.04), which was also observed at allele G (OR = 0.800, 95% CI: 0.657-0.975, p = 0.02). Furthermore, significant differences in the ≤45 years old group (CC vs. CG+GG, OR = 0.616, 95% CI: 0.413-0.918, p = 0.02) and in the male group (CC vs. CG+GG, OR = 0.666, 95% CI: 0.483-0.920, p = 0.01) were found in the subgroups analysis. Our data revealed a significant association of IL-6 rs1800796 with the risk of chronic HBV infection in the Chinese Han population; meanwhile, age and gender are two coordinative risk factors, which provides new clues for the study of susceptibility of chronic HBV infection in adults.
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Affiliation(s)
- Mengmeng Li
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yang Zhuo
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Ying Xu
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Hao Chen
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Zheng Cheng
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Li Zhou
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
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Ben Selma W, Alibi S, Smach MA, Saad A, Boukadida J. IL-18 variant increases risk of enhanced HBV DNA replication in chronic hepatitis. Immunol Lett 2020; 228:70-75. [DOI: 10.1016/j.imlet.2020.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/24/2020] [Accepted: 10/01/2020] [Indexed: 12/13/2022]
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Association of interleukin-18 gene polymorphisms with Takayasu arteritis in a Chinese Han population. Chin Med J (Engl) 2020; 133:2315-2320. [PMID: 32826615 PMCID: PMC7546839 DOI: 10.1097/cm9.0000000000001047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Background: Interleukin-18 (IL18) gene polymorphisms are related to many inflammatory and autoimmune diseases. However, a correlation analysis between IL18 −607C/A and −137G/C gene polymorphisms and Takayasu arteritis (TA) is lacking. Methods: This study enrolled 200 patients with TA as the case group and 334 region-, age-, and sex-matched healthy subjects as the control group. We genotyped alleles and genotypes at positions −607 and −137 of the IL18 gene and analyzed the distribution frequencies. Mann-Whitney U test, t test, Chi-squared test and Hardy-Weinberg equilibrium were performed. Results: After adjusting for risk factors, the adjusted odds ratios and 95% confidence intervals at position −607C/A were 0.533, 0.391 to 0.880 (P = 0.010); 0.266, 0.586 to 1.002 (P = 0.051); and 0.122, 0.552 to 1.420 (P = 0.613) under the dominant, additive, and recessive models, respectively. For the −137G/C polymorphism, the adjusted odds ratios and 95% confidence intervals were 1.571, 1.068 to 2.311 (P = 0.022); 1.467, 1.086 to 1.980 (P = 0.012); and 1.815, 0.901 to 3.656 (P = 0.095) under the dominant, additive, and recessive models, respectively. Moreover, regardless of the model used, we found no statistical difference in distribution frequency between the active and quiescent states of TA for the −607C/A (P = 0.355, 0.631, and 0.705, respectively) and −137G/C polymorphisms (P = 0.205, 0.385, and 0.208, respectively). Conclusions: The IL18 −607C/A gene polymorphism may decrease the risk of TA, and thus is a protective factor, whereas −137G/C may increase the risk of TA, and thus is a risk factor. However, neither polymorphism was related to activity (active vs. quiescent) of TA.
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Amirpour-Rostami S, Kazemi Arababadi M. IL-18 and IL-1β Gene Polymorphisms: The Plausible Risk Factors for Chronic Hepatitis B. Viral Immunol 2019; 32:208-213. [PMID: 31084469 DOI: 10.1089/vim.2018.0155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Chronic inflammation is the main risk factor for induction of liver cirrhosis and also hepatocellular carcinoma in chronic hepatitis B (CHB) patients. Although our knowledge is growing regarding molecular mechanisms of immune responses against viruses, the main mechanisms that lead to the progression of chronic inflammation and then CHB are yet to be clarified. IL-18 and IL-1β are the members of the IL-1 family and produced in the cytoplasm of a wide range of immune and nonimmune cells and activated by inflammasome pathways. The cytokines play key roles in the pathologies of CHB. IL-18 and IL-1β productions are altered in CHB patients. It has been hypothesized that the polymorphisms within IL-18 and IL-1β genes may be the main reasons for the induction of chronic inflammation in CHB patients. This review article discusses the related investigations regarding the main correlation between the polymorphisms within IL-18 and IL-1β genes and CHB pathogenesis.
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Affiliation(s)
- Sahar Amirpour-Rostami
- 1 Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Kazemi Arababadi
- 2 Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,3 Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Dadmanesh M, Ranjbar MM, Ghorban K. Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review. Immunol Lett 2019; 208:11-18. [PMID: 30831142 PMCID: PMC7112799 DOI: 10.1016/j.imlet.2019.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 02/26/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023]
Abstract
Inflammasomes are a set of innate receptors which are the responsible molecules for activation of pro-interleukin (IL)-1β and IL-18 and induction of inflammation. Due to the key roles of the inflammasomes in the induction of inflammation, it has been hypothesized that the molecules may be the main parts of immune responses against viral infections and the tissue damage. Because some cases of viral hepatitis infections, including hepatitis B and C, are diagnosed as chronic and may be associated with various complications such as liver cirrhosis and hepatocellular carcinoma (HCC), several studies focused on the roles played by the inflammation on the pathogenesis of viral hepatitis. Based on the roles played by inflammasomes in induction of inflammation, it has been hypothesized that inflammasomes may be the main parts of the puzzle of the viral hepatitis complications. This article reviews the roles of the inflammasomes in the pathogenesis of hepatitis B and C viral infections and their complications, liver cirrhosis, and HCC.
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Affiliation(s)
- Maryam Dadmanesh
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Infectious Diseases, Medical School, Aja University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Ranjbar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran.
| | - Khodayar Ghorban
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Immunology, Medical School, Aja University of Medical Sciences, Tehran, Iran.
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10
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Karamitros T, Papatheodoridis G, Paraskevis D, Hatzakis A, Mbisa JL, Georgopoulou U, Klenerman P, Magiorkinis G. Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma. Front Immunol 2018; 9:777. [PMID: 29713327 PMCID: PMC5911724 DOI: 10.3389/fimmu.2018.00777] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 03/28/2018] [Indexed: 12/22/2022] Open
Abstract
Background and aims Genetic polymorphisms within the promoter of interferon-α receptor type-1 (IFNAR1) have been associated with the susceptibility to and the outcome of chronic hepatitis B virus (HBV) infection. However, the impact of these polymorphisms in the transcriptome of the HBV-associated hepatocellular carcinoma (HCC) remains largely unexplored. Methods Using whole-genome and exome sequencing data from The Cancer Genome Atlas project, we characterized three single-nucleotide polymorphisms (SNPs: −568G/C, −408C/T, −3C/T) and one variable number tandem repeat [VNTR: −77(GT)n] within the IFNAR1 promoter sequence in 49 HCC patients. RNAseq data from 10 genotyped HCC samples were grouped according to their −77VNTR or −3SNP genotype to evaluate the impact of these polymorphisms on the differential expression on the HCC transcriptome. Results There is a fourfold higher impact of the −77VNTR on the HCC transcriptome compared to the −3SNP (q < 0.1, p < 0.001). The expression of the primary IFNAR1 transcript is not affected by these polymorphisms but a secondary, HCC-specific transcript is expressed only in homozygous −77VNTR ≤8/≤8(GT)n samples (p < 0.05). At the same time, patients carrying at least one −77VNTR >8(GT) allele, presented a strong upregulation of the fibronectin-1 (FN-1) gene, which has been associated with the development of HCC. Gene Ontology and pathway enrichment analysis of the differentially expressed genes revealed a strong disruption of the PI3K–AKT signaling pathway, which can be partially triggered by the extracellular matrix FN-1. Conclusion The IFNAR-1 promoter polymorphisms are not involved in the expression levels of the main IFNAR-1 transcript. The −77VNTR has a regulatory role on the expression of a secondary, truncated, HCC-specific transcript, which in turn coincides with disruptions in cancer-associated pathways and in FN-1 expression modifications.
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Affiliation(s)
- Timokratis Karamitros
- Department of Zoology, University of Oxford, Oxford, United Kingdom.,Department of Microbiology, Public Health Laboratories, Hellenic Pasteur Institute, Athens, Greece
| | - George Papatheodoridis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Paraskevis
- Department of Hygiene and Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Angelos Hatzakis
- Department of Hygiene and Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Jean L Mbisa
- Virus Reference Department, Public Health England, London, United Kingdom
| | - Urania Georgopoulou
- Department of Microbiology, Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research and Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom
| | - Gkikas Magiorkinis
- Department of Zoology, University of Oxford, Oxford, United Kingdom.,Department of Hygiene and Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, Greece
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Dondeti MF, El-Maadawy EA, Talaat RM. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms. World J Gastroenterol 2016; 22:6800-6816. [PMID: 27570418 PMCID: PMC4974580 DOI: 10.3748/wjg.v22.i30.6800] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/11/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC.
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12
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Lu Y, Bao JG, Deng Y, Rong CZ, Liu YQ, Huang XL, Song LY, Li S, Qin X. Role of IL-18 Gene Promoter Polymorphisms, Serum IL-18 Levels, and Risk of Hepatitis B Virus-related Liver Disease in the Guangxi Zhuang Population: a Retrospective Case-Control Study. Asian Pac J Cancer Prev 2016; 16:6019-26. [PMID: 26320490 DOI: 10.7314/apjcp.2015.16.14.6019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The aim of this study was to assess the relationship between IL-18 gene polymorphisms and HBV-related diseases and whether these polymorphisms influence its expression in the Guangxi Zhuang population. MATERIALS AND METHODS We enrolled 129 chronic HBV infected (CHB) patients, 86 HBV-related liver cirrhosis (LC) patients and 160 healthy controls in our study. Polymerase chain reaction-restriction fragment length polymorphism methods were used to detect IL-18 gene -607C/A, -137G/C polymorphisms, and an ELISA kit was employed to determine serum IL-18 levels. RESULTS No correlation was found between the -607C/A polymorphism and risk of HBV-related disease. For the -137G/C polymorphism, the GC genotype and C allele were associated with a significantly lower risk of CHB (95%CI: 0.32-0.95, p=0.034 and 95%CI: 0.35-0.91, p=0.018) and HBV-related LC (95%CI: 0.24-0.89, p=0.022 and 95%CI: 0.28-0.90, p=0.021). A similar decreased risk was also found with the A-607C-137 haplotype. With respect to IL-18 expression, it was significantly lower in both patient groups, but no association was noted between the two polymorphisms in the IL-18 gene and its expression. CONCLUSIONS Our study indicated that the -137C allele in the IL-18 gene may be a protective factor for HBV-related disease, and serum IL-18 level may be inversely associated with CHB and HBV-related LC.
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Affiliation(s)
- Yu Lu
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China E-mail : ;
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IL6 gene allele-specific C/EBPα-binding activity affects the development of HBV infection through modulation of Th17/Treg balance. Genes Immun 2015; 16:528-35. [PMID: 26447433 DOI: 10.1038/gene.2015.40] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 08/13/2015] [Accepted: 08/20/2015] [Indexed: 12/15/2022]
Abstract
Interleukin-6 (IL-6) has an important role in the pathogenesis of chronic viral hepatitis and related liver diseases. Although host genetics associated with the response to anti-viral treatment have been reported, little is known about the relationship between IL6 genetic polymorphisms and the outcome of hepatitis B virus (HBV) infection. In this study, we determined the genotype distribution of rs1800796 polymorphism in healthy controls and cases including chronic HBV (CHB), hepatitis C virus and HIV infection. The rs1800796 was found to be associated with clinical outcome of CHB in experimental and validation cohort. The rs1800796C allele has twofold higher promoter activity than G allele. Consistently, CD14(+) monocytes from subjects carrying the rs1800796C allele produced more IL-6 in response to in vitro HBV core antigen stimulation than those carrying G allele. Moreover, CHB patients carrying rs1800796C allele have significantly higher T-helper 17 (Th17) and regulatory T cell (Treg) ratio. Finally, a transcription factor C/EBPα binds in higher affinity to rs1800796C allele than to G allele. These results suggest that genetic predisposition to higher IL-6 production is associated with increased risk to HBV infection and hepatic inflammation, which might be due to C/EBPα-mediated regulatory effect on Th17 and Treg responses. Appropriate manipulation of IL-6 expression might be used to prevent and treat HBV infection.
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Ferreira SDC, Chachá SGF, Souza FF, Teixeira AC, Santana RDC, Deghaide NHS, Rodrigues S, Marano LA, Mendes-Junior CT, Zucoloto S, Donadi EA, Martinelli ADLC. IL-18, TNF, and IFN-γ alleles and genotypes are associated with susceptibility to chronic hepatitis B infection and severity of liver injury. J Med Virol 2015; 87:1689-96. [PMID: 25952099 DOI: 10.1002/jmv.24225] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2015] [Indexed: 12/31/2022]
Abstract
This study evaluated the association of polymorphisms in the IL-18 (-607C/A and -137C/G), IFNγ (+874 A/T), and TNF (-238 A/G and -308 A/G) genes with susceptibility to HBV infection and severity of liver injury. A total of 259 chronic HBV-infected patients followed at the University Hospital, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil, and 202 healthy individuals were studied. Four Single Nucleotide Polymorphisms (SNPs) were amplified by Polymerase Chain Reaction (PCR). Liver biopsy was performed in 212 HBV-infected patients and classified according to severity of liver fibrosis (scores 0-4) and necroinflammatory activity (HAI scores 0-18). TNF-308*A allele (P < 0.001; OR = 2.16) and TNF -308 AA genotype (P = 0.026; OR = 5.43) were associated with susceptibility to HBV infection. An association was found between severe liver fibrosis when compared to mild fibrosis and the following polymorphisms: Alleles IL-18 -137*G (P = 0.004; OR = 3.45), TNF -308*A (P < 0.001; OR = 3.39), and IFNγ +874*T (P = 0.029; OR = 1.85) and IL-18 -137 GG genotype (P = 0.009; OR = 3.70). No significant association was found between IL-18 (-607 A/C) polymorphism and severity of liver fibrosis. Alleles IL-18 -137*G (P = 0.028; OR = 2.64) and TNF-308*A (P = 0.002; OR = 3.06) and IL-18 -137 GG genotype (P = 0.011; OR = 4.20) were associated with severe necroinflammatory activity (HAI>12) when compared to mild necroinflammatory activity (HAI 1-8). The results suggest that IL-18 -137C/G, TNF-308 G/A and IFNγ +874 A/T SNPs were associated to more severe liver injury in chronic HBV infection. TNF -308*A allele and TNF -308 AA genotype could play a role in the susceptibility to HBV infection.
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Affiliation(s)
- Sandro da Costa Ferreira
- Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Silvana Gama Florêncio Chachá
- Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.,Department of Medicine, Federal University of São Carlos (UFSCAR), Ribeirão Preto, São Paulo, Brazil
| | - Fernanda Fernandes Souza
- Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Andreza Corrêa Teixeira
- Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Rodrigo de Carvalho Santana
- Infectious Diseases Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Neifi Hassan Saloun Deghaide
- Clinical Immunology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Sandra Rodrigues
- Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Leonardo Arduíno Marano
- Genetics Department, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Celso Teixeira Mendes-Junior
- Departamento de Química - Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP - USP), Ribeirão Preto, São Paulo, Brazil
| | - Sérgio Zucoloto
- Pathology Department, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Eduardo Antônio Donadi
- Clinical Immunology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Ana de Lourdes Candolo Martinelli
- Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
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Motavaf M, Safari S, Alavian SM. Interleukin 18 gene promoter polymorphisms and susceptibility to chronic hepatitis B infection: a review study. HEPATITIS MONTHLY 2014; 14:e19879. [PMID: 25031585 PMCID: PMC4080096 DOI: 10.5812/hepatmon.19879] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 05/01/2014] [Indexed: 12/11/2022]
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.
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Affiliation(s)
- Mahsa Motavaf
- Department of Molecular Hepatology, Middle East Liver Disease Center (MELD), Tehran, IR Iran
| | - Saeid Safari
- 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
| | - Seyed Moayed Alavian
- Department of Molecular Hepatology, Middle East Liver Disease Center (MELD), Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Seyed Moayed Alavian, Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran. Tel: +98-2188945186, Fax: +98-2188945188, E-mail:
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Zeng Z. Human genes involved in hepatitis B virus infection. World J Gastroenterol 2014; 20:7696-7706. [PMID: 24976707 PMCID: PMC4069298 DOI: 10.3748/wjg.v20.i24.7696] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/10/2014] [Accepted: 03/07/2014] [Indexed: 02/06/2023] Open
Abstract
Persistent hepatitis B virus (HBV) infection is a significant public health problem because it is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Roughly one-third of the world population has been infected with HBV and there are about 350 million (5%-6%) persistent carriers. HBV causes 80% of all liver cancer cases and is the second most important carcinogen, after smoking tobacco. There is an approximate 90% risk of becoming a persistent carrier following perinatal infection in infants born to e antigen positive carrier mothers and a 30% risk in pre-school children. Only 5%-10% of adults become persistent carriers following infection. Of individuals persistently infected with HBV, 10%-30% will develop liver cirrhosis and HCC. These highly variable outcomes in both clearance rates and disease outcomes in persistently infected individuals cannot be fully explained by differences in immunological, viral or environmental factors. Thus, differences in host genetic factors may affect the natural history of hepatitis B.
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Xia P, Zhou M, Dong DS, Xing YN, Bai Y. Association of polymorphisms in interleukin-18 and interleukin-28B genes with outcomes of hepatitis B virus infections: a meta-analysis. Tumour Biol 2014; 35:1129-37. [PMID: 24026885 DOI: 10.1007/s13277-013-1151-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 08/26/2013] [Indexed: 01/03/2023] Open
Abstract
Several polymorphisms in the interleukin-18 (IL-18) and nterleukin-28B (IL-28B) genes have been reported to influence hepatitis B virus (HBV) infection. However, the published findings have been conflicting. We conducted meta-analyses of randomized, controlled trials to address the association of IL-18 or IL-28B polymorphisms and the outcomes of HBV infection. Weipu, Wanfang, CNKI, MEDLINE, PubMed, EMBASE, and Cochrane Library databases were employed to search for citations using the MeSH terms as "interleukin-18"/"interleukin-28B" AND "HBV" AND "gene" AND "polymorphism" without any restriction in language and publication year. Meta-analysis was conducted by RevMan 5.0 software. The results showed that the IL28B rs8099917 AA genotype (AA vs AC + CC: odds ratio (OR) = 0.63, 95 % confidence interval (CI) = 0.46-0.87) was associated with a decreased risk of hepatocellular carcinoma (HCC). Carriage of IL28B rs12979860 CC genotype was associated with an increased risk for developing liver cirrhosis among patients with HBV infection (CC vs CT + TT: OR = 1.39, 95 % CI = 1.04-1.85). Further well-designed large studies are warranted to confirm the mechanisms by which these are involved in these outcomes of HBV infection.
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Affiliation(s)
- Pu Xia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, China Medical University, Shenyang, 110001, Liaoning, People's Republic of China,
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