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Ferreira J, Oliveira M, Bicho M, Serejo F. Role of Inflammatory/Immune Response and Cytokine Polymorphisms in the Severity of Chronic Hepatitis C (CHC) before and after Direct Acting Antiviral (DAAs) Treatment. Int J Mol Sci 2023; 24:1380. [PMID: 36674897 PMCID: PMC9865726 DOI: 10.3390/ijms24021380] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/20/2022] [Accepted: 01/04/2023] [Indexed: 01/13/2023] Open
Abstract
Host regulatory immune response is involved in the hepatic inflammatory process caused by the hepatitis C virus (HCV). We aimed to determine if HCV clearance with direct-acting antivirals (DAAs) changes the hepatic fibrosis stage, biochemical parameters of liver injury, and inflammatory/immune responses. Sample: 329 chronic hepatitis C (CHC) patients, 134 of them treated with DAAs. Liver fibrosis was evaluated by transient elastography (FibroScan), biochemical and cellular parameters were determined by standard methods, cytokine concentration by enzyme-linked immunoabsorbent assay (ELISA), and genetic polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or endpoint genotyping. Before DAA treatment, severe fibrosis or cirrhosis (F3/4) was associated with higher values of tumor necrosis factor-alpha (TNF-α) and genotypes transforming growth factor-beta-509 C/T_CC (TGF-β-509 C/T_CC), interleukine-10-1082 T/C_CC (IL-10-1082 T/C_CC), and IL-10-592 G/T_GT. After DAA treatment, fewer F3/4 patients and lower values of TNF-α were found. Patients with TNF-α-308 G/A_GG and IL-10-592 G/T_GT were at risk for F3/4. Lack of improvement of liver fibrosis was associated with lower baseline values of platelet count for genotypes TNF-α-308 G/A_GG and haplotype TT/GG of IL-10-1082 T/C and IL-10-592 G/T. Our study showed decreased liver fibrosis/inflammation and normalization of liver injury biomarkers after DAA treatment. It also points to the importance of suppressing the pro-inflammatory response by DAAs in the resolution of hepatitis C, contributing to the improvement of liver damage evaluated by transient elastography.
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Affiliation(s)
- Joana Ferreira
- Institute for Scientific Research Bento Rocha Cabral, Calçada Bento da Rocha Cabral 14, 1250-012 Lisboa, Portugal
- ISAMB, Genetics Laboratory, Lisbon Medical School, University of Lisbon, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
| | - Mariana Oliveira
- Institute for Scientific Research Bento Rocha Cabral, Calçada Bento da Rocha Cabral 14, 1250-012 Lisboa, Portugal
- ISAMB, Genetics Laboratory, Lisbon Medical School, University of Lisbon, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
| | - Manuel Bicho
- Institute for Scientific Research Bento Rocha Cabral, Calçada Bento da Rocha Cabral 14, 1250-012 Lisboa, Portugal
- ISAMB, Genetics Laboratory, Lisbon Medical School, University of Lisbon, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
| | - Fátima Serejo
- ISAMB, Genetics Laboratory, Lisbon Medical School, University of Lisbon, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
- Gastroenterology and Hepatology Department, Hospital de Santa Maria, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal
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Liu C, Yang S. A Meta-Analysis of the Influence of Tumor Necrosis Factor- α-308 Gene Polymorphism on Liver Cirrhosis. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:9764770. [PMID: 35345657 PMCID: PMC8957422 DOI: 10.1155/2022/9764770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/15/2022] [Indexed: 01/30/2023]
Abstract
Cirrhosis is an active hepatic inflammation process of the liver considered as the serious phase of different liver injuries. Epidemiological studies have evaluated the possible association between TNF-α-308G/A gene polymorphism and liver cirrhosis. In this study, we have furthered the study to assess the exact association of TNF-α-308G/A gene polymorphism with liver cirrhosis susceptibility by integrating all available data. Eligible case-control studies were carried out from the establishment of the project to September 2021. Published literature from multiple databases was retrieved, collected, and analyzed by two investigators independently. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for every study. Review Manager 5.2 and Stata 15.0 software were used for meta-analysis and stability was assessed by both subgroup analysis and sensitivity analysis. Begg's funnel plot and Egger's regression across the studies were also explored. We examined 22 case-control studies with 2683 cirrhosis patients and 2905 normal controls in four genetic models (GA vs. GG: OR = 0.95, 95%CI: (0.70, 1.30); AA vs. GG: OR = 1.11, 95% CI: (0.66, 1.85), GA + AA vs. GG: OR = 1.00, 95% CI: (0.73, 1.37); AA vs. GA + GG: OR = 1.07, 95%CI: (0.70,1.63)). TNF-α-308G/A gene polymorphism was relatively independent, and the results did not show a significant difference between the two groups. In the subgroup analysis by etiological classification of liver cirrhosis, cirrhosis after HCV infection was positively associated with the risk of TNF-α-308G/A polymorphism (AA vs. GG: OR = 3.02, 95% CI: (1.15, 7.88), AA vs. GA + GG: OR = 2.68, 95% CI: (1.04, 6.95)). The meta-analysis showed TNF-α-308G/A gene polymorphism might not have affected susceptibility for liver cirrhosis. Nevertheless, further and well-designed studies were needed to confirm the findings.
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Affiliation(s)
- Chang Liu
- Department of Gastroenterology, The First People's Hospital of Chong Qing Liang Jiang New Area, Chongqing 401121, China
| | - Songtao Yang
- Department of Gastroenterology, The First People's Hospital of Chong Qing Liang Jiang New Area, Chongqing 401121, China
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Cytokine (IL-10, IL-6, TNF-α and TGF-β1) Gene Polymorphisms in Chronic Hepatitis C Virus Infection among Malay Male Drug Abusers. Biomedicines 2021; 9:biomedicines9091115. [PMID: 34572300 PMCID: PMC8469205 DOI: 10.3390/biomedicines9091115] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/24/2021] [Accepted: 08/28/2021] [Indexed: 11/17/2022] Open
Abstract
Cytokines play an important role in modulating inflammation during viral infection, including hepatitis C virus (HCV) infection. Genetic polymorphisms of cytokines can alter the immune response against this infection. The objective of this study was to investigate the possible association between chronic hepatitis C virus infection susceptibility and cytokine gene polymorphism for interleukin-10 (IL-10) rs1800896 and rs1800871, interleukin 6 (IL-6) rs1800795, TNF-α rs1800629, and TGF-β1 rs1800471 in Malay male drug abusers. The study was conducted on 76 HCV-positive (HP) male drug abusers and 40 controls (HCV-negative male drug abusers). We found that there were significant differences in the frequencies of genotype for IL-10 rs1800871 (p = 0.0386) and at the allelic level for IL-10 rs1800896 A versus G allele (p = 0.0142) between the HP group and the control group. However, there were no significant differences in gene polymorphism in interleukin 6 rs1800795, TNF-α rs1800629 and TGF-β1 rs1800471. These findings suggest significant associations between gene polymorphism for IL-10 rs1800871, IL-10 rs1800896 (at the allelic level) and susceptibility to HCV infection among Malay male drug abusers.
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Yue M, Huang P, Wang C, Fan H, Tian T, Wu J, Luo F, Fu Z, Xia X, Zhu P, Li J, Han Y, Zhang Y, Hou W. Genetic Variation on TNF/LTA and TNFRSF1A Genes is Associated with Outcomes of Hepatitis C Virus Infection. Immunol Invest 2021; 50:1-11. [PMID: 31928491 DOI: 10.1080/08820139.2019.1708384] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infections are a serious global-scaled public health problem. Tumor necrosis factor (TNF)/lymphotoxin alpha (LTA) has been found to play a crucial role in relation to the outcomes of HCV infection after it binds to TNF receptor superfamily member 1A (TNFRSF1A). Thus, we investigated whether or not the TNF/LTA gene cluster and TNFRSF1A gene polymorphisms were associated with the outcomes of HCV infection. 1103 control participants without HCV infection, 497 patients with spontaneous clearance of HCV infection, and 713 patients with persistent HCV infection were enrolled. Rs2229094, rs1041981, rs1799964, and rs767455 were genotyped using the ABI TaqMan allelic discrimination assay. After adjusting for age, gender, and after determining a high-risk population, we used logistic regression analyses for which results indicated that the rs767455-C allele was associated with a reduced risk of HCV infection compared to respective results for the wild-type T allele (dominant model: adjusted OR = 0.74, 95% CI = 0.60-0.92, P = .006; additive model: adjusted OR = 0.76, 95% CI = 0.62-0.91, P = .004). Results also indicated that the rs1041981-A allele was associated with a decreased risk of persistent HCV infection compared to respective results for the wild-type C allele (additive model: adjusted OR = 0.81, 95% CI = 0.68-0.96, P = .017). Genetic polymorphisms in the LTA and TNFRSF1A genes were found to have been potentially important in relation to the susceptibility and chronicity of HCV infection among Chinese Han population.
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Affiliation(s)
- Ming Yue
- The State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University , Wuhan, China
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
| | - Peng Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University , Nanjing, China
| | - Chunhui Wang
- Institute of Epidemiology and Microbiology, Eastern Theater Command Centers for Disease Control and Prevention , Nanjing, China
| | - Haozhi Fan
- Department of Information Technology, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
| | - Ting Tian
- Institute of Food Safety and Assessment, Jiangsu Provincial Center for Disease Control and Prevention , Nanjing, China
| | - Jingjing Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University , Nanjing, China
| | - Fan Luo
- The State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University , Wuhan, China
| | - Zuqiang Fu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University , Nanjing, China
| | - Xueshan Xia
- Faculty of Life Science and Technology, Kunming University of Science and Technology , Kunming, China
| | - Ping Zhu
- Department of Medical Affairs, the First Affiliated Hospital of Nanjing Medical University , Nanjing, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
| | - Yaping Han
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
| | - Yun Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University , Nanjing, China
- Institute of Epidemiology and Microbiology, Eastern Theater Command Centers for Disease Control and Prevention , Nanjing, China
| | - Wei Hou
- The State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University , Wuhan, China
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Abstract
Hepatic fibrosis is a complex mechanism defined by the net deposition of the extracellular matrix (ECM) owing to liver injury caused by multiple etiologies such as viral hepatitis and nonalcoholic fatty liver disease. Many cell types are implicated in liver fibrosis development and progression. In general, liver fibrosis starts with the recruitment of inflammatory immune cells to generate cytokines, growth factors, and other activator molecules. Such chemical mediators drive the hepatic stellate cells (HSCs) to activate the production of the ECM component. The activation of HSC is thus a crucial event in the fibrosis initiation, and a significant contributor to collagen deposition (specifically type I). This review explores the causes and mechanisms of hepatic fibrosis and focuses on the roles of key molecules involved in liver fibro genesis, some of which are potential targets for therapeutics to hamper liver fibro genesis.
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Affiliation(s)
- Reham M Dawood
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mai A El-Meguid
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Ghada Maher Salum
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mostafa K El Awady
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
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Matsuura K, Tanaka Y. Host genetic variations associated with disease progression in chronic hepatitis C virus infection. Hepatol Res 2018; 48:127-133. [PMID: 29235266 DOI: 10.1111/hepr.13042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 12/19/2022]
Abstract
Treatment with recently developed interferon-free oral regimens combining direct-acting antiviral agents (DAAs) results in the elimination of hepatitis C virus (HCV) in almost all chronic hepatitis C (CHC) patients. In the era of DAAs, surveillance of hepatocellular carcinoma (HCC) after eradication of HCV by anti-HCV therapy is particularly important. As is well known, an advanced state of hepatic fibrosis is the major risk factor for developing HCC. Therefore, an increased understanding of various factors associated with disease progression and development of HCC in CHC patients is essential for implementing personalized treatment and surveillance of disease progression and HCC. Recent genome-wide association studies (GWAS) have identified several host genetic variants influencing treatment efficacy or clinical course in HCV infection. This review focuses on these host genetic variations recently identified, mainly by GWAS, which are associated with the clinical course of chronic HCV infection, especially disease progression and hepatocarcinogenesis.
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Affiliation(s)
- Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Biswas A, Gupta N, Gupta D, Datta A, Firdaus R, Chowdhury P, Bhattacharyya M, Sadhukhan PC. Association of TNF-alpha (-308 A/G) and IFN-gamma (+874 A/T) gene polymorphisms in response to spontaneous and treatment induced viral clearance in HCV infected multitransfused thalassemic patients. Cytokine 2017; 106:148-153. [PMID: 29196132 DOI: 10.1016/j.cyto.2017.10.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 10/25/2017] [Accepted: 10/25/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Multitransfused thalassemic individuals are at high risk of developing transfusion transmitted Hepatitis C virus (HCV) infection. The aim of the study was to correlate the effects of host cytokine single nucleotide polymorphisms of TNF-α (-308 A/G) and IFN-γ (+874 A/T) in spontaneous or IFN induced treatment response in the HCV infected thalassemic individuals. METHODS A total of 427 HCV sero-reactive thalassemic individuals were processed for HCV viral genomic diversity and host gene polymorphisms analysis of TNF-α (-308 A/G) and IFN-γ (+874 A/T). RESULTS Out of 427 HCV sero-reactive individuals, 69.09% were found to be HCV RNA positive with genotype 3 as the predominant infecting strain (94.29%). Study highlighted that, A allele was significantly associated with (p < .05) spontaneous clearance of HCV infection and G allele was correlated with viral persistence at TNF-α (-308) gene polymorphism. Whereas in case of IFN-γ (+874) SNPs, A allele was significantly responsible (p < .05) for spontaneous clearance than T allele. Our study also indicated that in relapsed cases, IFN-γ (+874) T allele is more responsible than A allele. Though no significant correlation was found at both TNF-α (-308) and IFN-γ (+874) gene polymorphism among SVR and relapsed thalassemic patients. CONCLUSION A allele at both TNF-α (-308) and IFN-γ (+874) were strongly associated with spontaneous clearance among this population. But in case of SVR and relapsed cases no significant association was found. This cytokine gene polymorphisms pattern will help clinicians to take an informed decision about therapeutic management of HCV infected thalassemic individuals.
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Affiliation(s)
- Aritra Biswas
- ICMR Virus Unit, Kolkata; I.D & B.G Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr. Suresh Chandra Banerjee Road; Beliaghata, Kolkata 700010, India
| | - Nabyendu Gupta
- ICMR Virus Unit, Kolkata; I.D & B.G Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr. Suresh Chandra Banerjee Road; Beliaghata, Kolkata 700010, India
| | - Debanjali Gupta
- ICMR Virus Unit, Kolkata; I.D & B.G Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr. Suresh Chandra Banerjee Road; Beliaghata, Kolkata 700010, India
| | - Abira Datta
- ICMR Virus Unit, Kolkata; I.D & B.G Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr. Suresh Chandra Banerjee Road; Beliaghata, Kolkata 700010, India
| | - Rushna Firdaus
- ICMR Virus Unit, Kolkata; I.D & B.G Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr. Suresh Chandra Banerjee Road; Beliaghata, Kolkata 700010, India
| | - Prosanto Chowdhury
- Peerless Hospital & B. K. Roy Research Centre, 360 Panchasayar, Kolkata 700094, India
| | | | - Provash C Sadhukhan
- ICMR Virus Unit, Kolkata; I.D & B.G Hospital Campus, GB-4 (East Wing) 1st Floor, 57, Dr. Suresh Chandra Banerjee Road; Beliaghata, Kolkata 700010, India.
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Yan Z, Wang Y. Viral and host factors associated with outcomes of hepatitis C virus infection (Review). Mol Med Rep 2017; 15:2909-2924. [PMID: 28339063 DOI: 10.3892/mmr.2017.6351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/13/2017] [Indexed: 11/05/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major health issue globally. Owing to the progress made in host genetics and HCV molecular virology, emerging data have suggested that the natural course and treatment response in patients with HCV infection are largely determined by complex host‑viral interactions. HCV genotype is the most important viral factor predicting the response to pegylated interferon‑α plus ribavirin therapy. The subtype of HCV genotype 1 is the key viral factor that predicts the efficacy of direct‑acting antiviral therapy. HCV genome heterogeneity and baseline viral load are additionally associated with the treatment response. Multiple host genetic variants localized in genes associated with the immune response have been identified as predictors of spontaneous disease course and therapy outcome in chronic HCV. However, most findings from candidate gene association studies have not been proven universal for all investigated populations and independent studies. Previous findings in independent large genome wide association studies confirmed that interferon‑λ3 gene polymorphisms are associated with spontaneous clearance and treatment responsiveness. A polymorphism of the inosine triphosphatase gene has been identified as a protective factor against ribavirin‑induced anemia and dose reductions. Another genetic variant in the patatin‑like phospholipase domain containing 3 genes is associated with hepatic steatosis and fibrosis in patients with HCV. The present review focused on the identified viral and host factors associated with outcomes of patients with HCV, and assessed the involvement of viral and host genetics in the natural history and treatment outcomes of HCV infection. This will provide novel ideas concerning personalized prevention and individualized clinical management.
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Affiliation(s)
- Zehui Yan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Yuming Wang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
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Bader El Din NG, Farouk S, El-Shenawy R, Elhady MM, Ibrahim MK, Dawood RM, Salem AM, El Awady MK. The Synergistic Effect of TNFα -308 G/A and TGFβ1 -509 C/T Polymorphisms on Hepatic Fibrosis Progression in Hepatitis C Virus Genotype 4 Patients. Viral Immunol 2017; 30:127-135. [PMID: 28151059 DOI: 10.1089/vim.2016.0083] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFβ1) cytokines are highly implicated in liver fibrosis. Polymorphisms in these cytokines affect their expression, secretion, and activity. This study aimed to evaluate the influence of TNFα -308 G/A and TGFβ1 -509 C/T polymorphism on hepatic fibrosis progression in Egyptian patients with hepatitis C virus (HCV) genotype 4. Genotyping of TNFα -308 G/A and TGFβ1 -509 C/T was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 122 subjects (50 healthy controls and 72 HCV patients). Also, serum TNFα and TGFβ1 levels were detected by enzyme-linked immunosorbent assay (ELISA). The genotyping results of early (F0-F1, n = 36) and late (F2-F4, n = 36) HCV fibrosis patients showed that late fibrosis patients had higher TNFα -308 AA genotype and TGFβ1 -509 TT genotype than early fibrosis patients (p = 0.016, 0.028, respectively). Moreover, the TNFα and TGFβ1 serum levels were significantly higher in HCV patients with TNFα A containing genotypes (GA+AA) (p = 0.004) and patients with TGFβ1 T containing genotypes (CT+TT) (p = 0.001), respectively. The combined unfavorable TNFα (GA/AA) and TGFβ1 (CT/TT) genotypes were highly associated with abnormal liver function parameters and were significantly higher in high activity (A2-A3) and late fibrosis (F2-F4) HCV patients (p = 0.023, 0.029). The multivariate analysis results confirmed that the combined TNFα-308 (AA) and TGFβ1 -509 (TT) unfavorable genotypes increased the risk of hepatic fibrosis progression by 6.4-fold than combined favorable genotypes (odds ratio: 6.417, 95% confidence interval [1.490-27.641], p = 0.013). In conclusion, both TNFα -308 G/A and TGFβ1 -509 C/T polymorphisms synergistically influence the hepatic fibrosis progression and can be used as potential biomarkers to predict hepatic disease progression in chronic hepatitis C patients.
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Affiliation(s)
- Noha G Bader El Din
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Sally Farouk
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reem El-Shenawy
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Mostafa M Elhady
- 2 Department of Biochemistry, Faculty of Science, Ain Shams University , Cairo, Egypt
| | - Marwa K Ibrahim
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reham M Dawood
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Ahmed M Salem
- 2 Department of Biochemistry, Faculty of Science, Ain Shams University , Cairo, Egypt
| | - Mostafa K El Awady
- 1 Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
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Rehman SU, Rauf M, Abbas Z, Hamed MH, Qadri I. Role of Some Predominant Host Immunomodulators' Single Nucleotide Polymorphisms in Severity of Hepatitis B Virus and Hepatitis C Virus Infection. Viral Immunol 2016; 29:536-545. [PMID: 27676210 DOI: 10.1089/vim.2016.0062] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B and C infections can be either acute or chronic. The chronic infection can culminate in liver cirrhosis and hepatocellular carcinoma. Influence of the host genetic makeup on conversion of acute to chronic infection, development of cirrhosis, and hepatocellular carcinoma is an interesting area of research. Variability in different immune system genes may account for such differences in the outcome of infection. This article discusses single nucleotide polymorphisms in different host immunomodulator genes that have been frequently reported to influence the outcome of infection and severity of disease. The genetic variability could be utilized for the prediction of disease outcome and treatment responses.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- HLA Antigens/genetics
- HLA Antigens/immunology
- Hepacivirus/immunology
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/immunology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/immunology
- Humans
- Immunologic Factors/genetics
- Immunologic Factors/immunology
- Interleukins/genetics
- Interleukins/immunology
- Liver Cirrhosis/etiology
- Liver Cirrhosis/immunology
- Liver Neoplasms/immunology
- Mannose-Binding Lectin/genetics
- Mannose-Binding Lectin/immunology
- Polymorphism, Single Nucleotide
- Receptor, Interferon alpha-beta/genetics
- Receptor, Interferon alpha-beta/immunology
- Receptors, CCR5/genetics
- Receptors, CCR5/immunology
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/immunology
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Affiliation(s)
- Shafiq Ur Rehman
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Mahd Rauf
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Zaigham Abbas
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Muhammed Haroon Hamed
- 2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia
| | - Ishtiaq Qadri
- 2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia
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Moreira ST, Silva GF, de Moraes CFV, Grotto RMT, de Moura Campos Pardini MI, Bicalho MDG, Moliterno RA. Influence of cytokine and cytokine receptor gene polymorphisms on the degree of liver damage in patients with chronic hepatitis C. Meta Gene 2016; 9:90-6. [PMID: 27200267 PMCID: PMC4864212 DOI: 10.1016/j.mgene.2016.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Revised: 04/05/2016] [Accepted: 04/20/2016] [Indexed: 01/06/2023] Open
Abstract
Hepatic fibrosis may be the result of repetitive injury to hepatocytes caused by HCV infection and the immune response to it. Cytokines regulate the inflammatory response to injury and modulate hepatic fibrogenesis. Single nucleotide polymorphisms (SNPs) located in cytokine genes may influence the cytokine expression and secretion that may contribute to hepatic fibrogenesis in HCV infection. The aim of this study was to determine the genotype of 22 SNPs found in the genes of 13 cytokines/cytokine receptors to assess the influence of polymorphic variants on the stage of liver damage in Brazilian patients chronically infected with HCV genotype 1 only. 141 unrelated patients were grouped according to their stage of fibrosis: absence of fibrosis or patients in the initial stages of fibrosis (F0-F2, n = 84), patients with advanced stages of fibrosis or cirrhosis (F3-F4, n = 57), without cirrhosis (F0-F3, n = 103), and with cirrhosis (F4, n = 38). The comparison of frequencies in each sub-sample was performed by 2 × 2 contingency tables using the chi-square or Fisher's exact test. Stepwise logistic regression was also used to assess independent associations between cirrhosis or fibrosis with polymorphic variants. The TNFA-308G:A genotype conferred increased risk of fibrosis and cirrhosis. The TNFA-238G:G genotype was associated with protection from cirrhosis. The IL10-819C:T genotype conferred protection from fibrosis and the IL1B-511C:T genotype conferred increased risk of cirrhosis. Some of these genotypes showed results on the borderline of statistical significance in the bivariate analysis. We conclude that gene variants of cytokines/receptors may influence liver damage in patients chronically infected by HCV genotype 1.
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Affiliation(s)
- Sara Tatiana Moreira
- Human Molecular Genetics Laboratory, Parana Federal University of Technology, UTFPR, Santa Helena, Parana, Brazil
- Corresponding author at: Human Molecular Genetics Laboratory, Parana Federal University of Technology, UTFPR, Extension of Cherry Street, Santa Helena, Parana 85892-000, Brazil.Human Molecular Genetics LaboratoryParana Federal University of Technology, UTFPRExtension of Cherry StreetSanta HelenaParana85892-000Brazil
| | - Giovanni Faria Silva
- Gastroenterology Division, Internal Medicine Department, Botucatu Medical School, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | - Camila Fernanda Verdichio de Moraes
- Molecular Biology Laboratory of Blood Transfusion Center, Botucatu Medical School, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | - Rejane Maria Tomasini Grotto
- Molecular Biology Laboratory of Blood Transfusion Center, Botucatu Medical School, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | - Maria Inês de Moura Campos Pardini
- Molecular Biology Laboratory of Blood Transfusion Center, Botucatu Medical School, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil
| | - Maria da Graça Bicalho
- Immunogenetics and Histocompatibility Laboratory, Genetics Department, Paraná Federal University, UFPR, Curitiba, Parana, Brazil
| | - Ricardo Alberto Moliterno
- Immunogenetics Laboratory, Department of Basic Health Sciences, Maringa State University, UEM, Maringa, PR, Brazil
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12
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Aroucha DC, Carmo RF, Vasconcelos LRS, Lima RE, Mendonça TF, Arnez LE, Cavalcanti MDSM, Muniz MTC, Aroucha ML, Siqueira ER, Pereira LB, Moura P, Pereira LMMB, Coêlho MR. TNF-αandIL-10polymorphisms increase the risk to hepatocellular carcinoma in HCV infected individuals. J Med Virol 2016; 88:1587-95. [DOI: 10.1002/jmv.24501] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2016] [Indexed: 12/16/2022]
Affiliation(s)
- Dayse Celia Aroucha
- Instituto do Fígado de Pernambuco (IFP); Recife Brasil
- Faculdade de Ciências Médicas (FCM); Universidade de Pernambuco (UPE); Recife Brasil
| | - Rodrigo Feliciano Carmo
- Colegiado de Farmácia; Universidade Federal do Vale do São Francisco (UNIVASF); Petrolina Brasil
- Rede Nordeste de Biotecnologia (RENORBIO); Recife Brasil
| | - Luydson Richardson Silva Vasconcelos
- Instituto do Fígado de Pernambuco (IFP); Recife Brasil
- Departamento de Parasitologia, Centro de Pesquisas Aggeu Magalhães (CPqAM); Fundação Oswaldo Cruz (FIOCRUZ); Recife Brasil
| | - Raul Emidio Lima
- Instituto de Ciências Biológicas (ICB); Universidade de Pernambuco (UPE); Recife Brasil
| | | | - Lucia Elena Arnez
- Laboratório de Hanseníase, Instituto Oswaldo Cruz; Fundação Oswaldo Cruz (FIOCRUZ); Rio de Janeiro Brasil
| | | | | | - Marcilio Lins Aroucha
- Centro de Ciências da Saúde (CCS); Universidade Federal de Pernambuco (UFPE); Brazil
| | | | | | - Patrícia Moura
- Instituto de Ciências Biológicas (ICB); Universidade de Pernambuco (UPE); Recife Brasil
| | | | - Maria Rosangela Coêlho
- Setor de Virologia do Laboratório de Imunopatologia Keizo-Asami (LIKA); Universidade Federal de Pernambuco (UFPE); Brazil
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13
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Matsuura K, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis C virus infection. J Med Virol 2016; 88:185-195. [PMID: 26211651 DOI: 10.1002/jmv.24334] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2015] [Indexed: 12/16/2022]
Abstract
The clinical course of hepatitis C virus (HCV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HCV infection. Recent genome-wide association studies identified several host genetic factors influencing treatment efficacy or clinical course in HCV infection. A landmark discovery was that IFNL3-IFNL4 variants are strongly associated with responses to interferon-based treatment. Genetic variants in IFNL3-IFNL4 as well as those in HLA class II loci influence the spontaneous clearance of acute HCV infection. Interestingly, these genetic variants also affect the activity of hepatitis, or disease progression in chronic hepatitis C. In addition, polymorphisms in apoptosis-related genes such as RNF7, TULP1, and MERTK are associated with fibrosis progression, and DEPDC5 and MICA variants are associated with HCV-related hepatocellular carcinoma. Understanding the genetic factors associated with the clinical course of HCV infection is essential for personalized treatment and surveillance of disease progression and hepatocellular carcinoma.
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Affiliation(s)
- Kentaro Matsuura
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
- Department of Transfusion Medicine, Clinical CenterInfectious Disease and Immunogenetics Section, National Institutes of Health, Bethesda, Maryland
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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14
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Bader El Din NG, Anany MA, Dawood RM, Ibrahim MK, El-Shenawy R, El Abd YS, El Awady MK. Impact of OAS1 Exon 7 rs10774671 Genetic Variation on Liver Fibrosis Progression in Egyptian HCV Genotype 4 Patients. Viral Immunol 2015; 28:509-516. [PMID: 26505957 DOI: 10.1089/vim.2015.0041] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
The aim of this study was to assess the impact of genetic variants of oligoadenylate synthetase 1 (OAS1) single-nucleotide polymorphism (SNP) rs10774671 at the exon 7 splice acceptor site on liver fibrosis progression and hepatitis C virus (HCV) outcome in Egyptian HCV genotype 4 patients. In this study, 195 subjects were enrolled; 60 controls and 135 chronic HCV genotype 4 patients with different fibrosis grades. All subjects were genotyped for OAS1 SNP rs10774671 polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There was an increasing trend of liver fibrosis progression as 52.9% GG, 73.6% GA, and 83.3% AA genotypes were detected in late fibrosis patients (p = 0.025). The AA genotype was higher in the late fibrosis group than in the early fibrosis group (83.3% vs. 16.7%) (p = 0.001). The A allele was significantly affecting the liver fibrosis progression rate, more than the G allele (p = 0.001). The multivariate analysis showed that the OAS1 GA and AA genotypes were independent factors associated with liver progression (p = 0.009, odds ratio [OR] 3.467, 95% confidence interval [CI] 1.273-7.584). In addition, the A allele was associated with liver fibrosis progression (p = 0.014, OR 2.525, 95% CI 1.157-4.545). The polymorphism at OAS1 exon 7 rs3741981 might be a potential genetic marker and can be useful in the assessment of liver fibrosis progression and disease outcome in HCV-infected patients.
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Affiliation(s)
- Noha G Bader El Din
- Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Mohamed A Anany
- Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reham M Dawood
- Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Marwa K Ibrahim
- Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reem El-Shenawy
- Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Yasmin S El Abd
- Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
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15
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Guo PF, Jin J, Sun X. Influence of IL10 gene polymorphisms on the severity of liver fibrosis and susceptibility to liver cirrhosis in HBV/HCV-infected patients. INFECTION GENETICS AND EVOLUTION 2014; 30:89-95. [PMID: 25514046 DOI: 10.1016/j.meegid.2014.12.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 12/04/2014] [Accepted: 12/08/2014] [Indexed: 01/17/2023]
Abstract
BACKGROUND Previous studies about the association of the interleukin-10 (IL-10) polymorphisms with the progression of liver fibrosis or cirrhosis susceptibility in chronic hepatitis B/C (CHB/C) disease were inconsistent. The aim of this meta-analysis was to derive a more precise estimation of the association. METHODS We searched Medline, PubMed, EMBASE and Web of Science electronic databases using the following key words: liver fibrosis/cirrhosis, IL10, and polymorphism. Statistical analyses were performed by STATA11.0 software, with odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS 12 independent studies in relation to IL10-1082A/G, -819C/T and -592C/A polymorphisms were included in our study, which consisted of 197 moderate/severe liver fibrosis cases and 426 mild fibrosis controls as well as 536 liver cirrhosis cases and 881 non-cirrhosis controls. The results indicated that a significantly decreased risk of moderate/severe fibrosis was associated with the GCC haplotype (IL10-1082G, -819C and -592C) in the overall CHB/C patients (OR: 0.547, 95% CI: 0.317-0.946, P=0.031). We did not detect any significant association between these polymorphisms and liver cirrhosis susceptibility in the total population or a subgroup of Asians. However, subgroup analyses by different aetiologies showed that the -819T heterozygotes (TC) were associated with a significantly increased risk of HCV-related liver cirrhosis in the Japanese population (OR: 1.254, 95% CI: 1.033-1.522, P=0.022). CONCLUSIONS The putative high IL-10 production haplotype GCC is more likely to be associated with less severe liver fibrosis in CHB/C patients. Additionally, the IL10-819T allele may be a susceptible factor for HCV-related liver cirrhosis in the Japanese population.
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Affiliation(s)
- Peng-Fei Guo
- Department of Mathematics, South China University of Technology, Guangzhou, China.
| | - Juan Jin
- School of Laboratory Medicine, Xinxiang Medical University, 601 Jinsui Road, Hongqi District, Xinxiang, Henan 453003, China
| | - Xiangru Sun
- Institute of Reproductive Medicine, Panyu Hexian Memorial Hospital of Guangzhou, 2 East of Qinghe Road, Panyu District, Guangzhou 511400, China
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16
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Tarragô AM, da Costa AG, Pimentel JPD, Gomes STM, Freitas FB, Lalwani P, de Araújo ARS, Victória FDS, Victória MB, Vallinoto ACR, Sadahiro A, Teixeira-Carvalho A, Martins-Filho OA, Malheiro A. Combined impact of hepatitis C virus genotype 1 and interleukin-6 and tumor necrosis factor-α polymorphisms on serum levels of pro-inflammatory cytokines in Brazilian HCV-infected patients. Hum Immunol 2014; 75:1075-83. [PMID: 25193024 DOI: 10.1016/j.humimm.2014.08.198] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 08/18/2014] [Accepted: 08/18/2014] [Indexed: 12/31/2022]
Abstract
We investigated the association between hepatitis C virus (HCV) genotypes and host cytokine gene polymorphisms and serum cytokine levels in patients with chronic hepatitis C. Serum IL-6, TNF-α, IL-2, IFN-γ, IL-4, IL-10, and IL-17A levels were measured in 67 HCV patients (68.2% genotype 1 [G1]) and 47 healthy controls. The HCV patients had higher IL-6, IL-2, IFN-γ, IL-10, and IL-17A levels than the controls. HCV G1 patients had higher IL-2 and IFN-γ levels than G2 patients. The -174IL6G>C, -308TNFαG>A, and -1082IL10A>G variants were similarly distributed in both groups. However, HCV patients with the -174IL6GC variant had higher IL-2 and IFN-γ levels than patients with the GG and CC variants. Additionally, HCV patients with the -308TNFαGG genotype had higher IL-17A levels than patients with the AG genotype, whereas patients with the -1082IL10GG variant had higher IL-6 levels than patients with the AA and AG variants. A significant proportion of HCV patients had high levels of both IL-2 and IFN-γ. The subgroup of HCV patients with the G1/IL6CG/TNFαGG association displayed the highest proportions of high producers of IL-2 and IFN-γ whereas the subgroup with the G1/TNFαGG profile showed high proportions of high producers of IL-6 and IL-17A. HCV patients with other HCV/cytokine genotype associations showed no particular cytokine profile. Our results suggest that HCV genotype G1 and IL-6 and TNF-α polymorphisms have a clinically relevant influence on serum pro-inflammatory cytokine profile (IL-2 and IFN-γ) in HCV patients.
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Affiliation(s)
- Andréa Monteiro Tarragô
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil
| | - Allyson Guimarães da Costa
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | - João Paulo Diniz Pimentel
- Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil; Instituto Leônidas e Maria Deane - FIOCRUZ-Amazônia, 476 Terezina St., Manaus, AM, Brazil
| | | | | | - Pritesh Lalwani
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil
| | - Ana Ruth S de Araújo
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | - Flamir da Silva Victória
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | - Marilú Barbieri Victória
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, 25 Pedro Teixeira Av., Manaus, AM, Brazil
| | | | - Aya Sadahiro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Instituto Nacional de Pesquisas da Amazônia - INPA, 2936 André Araújo Av., Manaus, AM, Brazil
| | - Andréa Teixeira-Carvalho
- Centro de Pesquisas René Rachou - FIOCRUZ-Minas, 1715 Augusto de Lima Av., Belo Horizonte, MG, Brazil
| | | | - Adriana Malheiro
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, 3000, Rodrigo Otávio Av., Manaus, AM, Brazil; Fundação de Hematologia e Hemoterapia do Amazonas - HEMOAM, 3497 Constantino Nery Av., Manaus, AM, Brazil.
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17
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Devi SG, Kumar A, Kar P, Husain SA, Sharma S. Association of pregnancy outcome with cytokine gene polymorphisms in HEV infection during pregnancy. J Med Virol 2014; 86:1366-76. [DOI: 10.1002/jmv.23925] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Salam Gyaneshwori Devi
- Department of Obstetrics & Gynaecology; Maulana Azad Medical College and Lok Nayak Hospital; New Delhi India
| | - Ashok Kumar
- Department of Obstetrics & Gynaecology; Maulana Azad Medical College and Lok Nayak Hospital; New Delhi India
| | - Premashis Kar
- Department of Medicine; Maulana Azad Medical College and Lok Nayak Hospital; New Delhi India
| | | | - Shashi Sharma
- Department of Statistics and Epidemiology; Institute of Cytology and Preventive Oncology; Noida India
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18
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Corchado S, Márquez M, Montes de Oca M, Romero-Cores P, Fernández-Gutiérrez C, Girón-González JA. Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients. PLoS One 2013; 8:e66619. [PMID: 23840511 PMCID: PMC3694087 DOI: 10.1371/journal.pone.0066619] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 05/09/2013] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients. PATIENTS AND METHODS Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied. RESULTS Evolution time of the infection was 21 years in both patients' groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis. CONCLUSION It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis among HIV-infected patients with established chronic HCV infections.
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Affiliation(s)
- Sara Corchado
- Unidad de Enfermedades Infecciosas, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - Mercedes Márquez
- Unidad de Enfermedades Infecciosas, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | | | - Paula Romero-Cores
- Unidad de Enfermedades Infecciosas, Hospital Universitario Puerta del Mar, Cádiz, Spain
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19
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Pasha HF, Radwan MI, Hagrass HA, Tantawy EA, Emara MH. Cytokines genes polymorphisms in chronic hepatitis C: impact on susceptibility to infection and response to therapy. Cytokine 2013; 61:478-484. [PMID: 23219017 DOI: 10.1016/j.cyto.2012.11.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2012] [Revised: 10/31/2012] [Accepted: 11/02/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cytokines play a key role in the regulation of immune responses. In hepatitis C virus infection, the production of abnormal cytokine levels appears to contribute in the progression of the disease, viral persistence, and affects response to therapy. Cytokine genes polymorphisms located within the coding/regulatory regions have been shown to affect the overall expression and secretion of cytokines. The aim of the study was to evaluate the association of of IL28B rs12979860, TGF-β1-509, TNF-α 308, and IL-10-1082 polymorphisms with the susceptibility to hepatitis C virus genotype 4 infection and response to pegylated interferon-α and ribavirin therapy. METHODS IL28B, TGF-β1 and TNF-α genes polymorphisms were genotyped using polymerase chain reaction (PCR)-based restriction fragment length polymorphism assay while IL-10 gene polymorphism was detected by sequence specific primer-PCR in 220 healthy individuals and 440 hepatitis C infected patients (220 sustained virological response and 220 non-responder to combination therapy). RESULTS IL28 B CT and TT, TGF-β1 CT and TT and TNF-α AG and AA genotypes were significantly associated with susceptibility to hepatitis C infection and response to therapy. While no association was found between IL-10 gene polymorphism and susceptibility to HCV infection and response to treatment. CONCLUSIONS These results suggested that inheritance of IL28B CT and TT, TGF-β1 CT and TT and TNF-α AG and AA genotypes which appear to affect the cytokine production may be associated with susceptibility to HCV infection and resistance to combined antiviral therapy.
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Affiliation(s)
- Heba F Pasha
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
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20
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Abstract
Combination therapy with pegylated interferon and ribavirin is the standard of care (SOC) for the treatment of chronic hepatitis C (CHC). Treating CHC with SOC may show a sustained virological response (SVR) in approximately 50-70 % of genotype 1 CHC patients and an SVR in 70-90 % of genotype 2 CHC patients. The genotype, baseline viral load, and viral kinetics (i.e., rapid virologic response and early virologic response) can be used as predictors of response-guided therapy. Nonetheless, host factors, e.g. age, ethnicity, insulin resistance, and genetic variations, may also play important roles in the SVR in CHC patients treated with SOC. Recent genome-wide association studies have demonstrated that single-nucleotide polymorphisms near the interleukin 28B gene (IL28B) were associated with SVR to treatment with SOC in CHC patients. The IL28B polymorphisms may contribute to the viral kinetics during treatment. Asian people have favorable IL28B polymorphisms. This factor may at least partly explain the high eradication rate of hepatitis C by SOC in Asia. Combination therapy with direct-acting antivirals (DAAs) and SOC can increase the SVR rates both in treatment-naïve and treatment-experienced patients. Although the IL28B polymorphisms also affect the SVR of triple therapy with SOC and first-generation protease inhibitors, pilot studies have demonstrated that potent DAAs might overcome the influence of IL28B polymorphisms. Thus, the treatment of hepatitis C virus infection could be simplified in the near future.
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Affiliation(s)
- Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
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21
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Holmes JA, Thompson AJ, Adams LA. Biomarkers of Fibrosis and Fibrosis Progression in Chronic Hepatitis C. CURRENT HEPATITIS REPORTS 2012; 11:231-242. [DOI: 10.1007/s11901-012-0148-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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23
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Yaghobi R, Karimi MH, Namayandeh M, Geramizadeh B, Nikeghbalian S, Malekhosseini SA, Hosseini Y. The Association of Polymorphisms in Cytokine Genes with Acute Rejection and the Pathogenesis of Hepatitis B and C in Liver Transplant Recipients. Lab Med 2012. [DOI: 10.1309/lmkdxbh3kun51orb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Amini M, Poustchi H. Hepatitis C virus spontaneous clearance: immunology and genetic variance. Viral Immunol 2012; 25:241-8. [PMID: 22823386 DOI: 10.1089/vim.2011.0052] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) infection is one of the most common chronic viral infections in the world. Approximately 80-90% of acutely infected individuals develop persistent infection, which is a major risk for liver cirrhosis and liver cancer. However, a small portion of patients (10-20%) clear the virus. Clinical outcomes of HCV infection are determined by the interplay between the host immune response, and viral and environmental factors. In regulating immune responses, cytokines play an indispensable role that controls the underlying pathogenesis and the resulting outcome of HCV infection. Cytokines themselves are manipulated by polymorphisms in their genes. In fact, the majority of genetic variants that apparently confer a significant risk for chronic HCV infection have been localized in genes involved in cytokine synthesis and the ultimate immune response. So far, treatment strategies for HCV infection have remained controversial. Genotyping of different polymorphisms will aid clinical decision making for both current standard and personalized care. Genotyping can potentially be useful for future integration of other agents, which provides an opportunity for clinicians to personalize treatment regimens for HCV patients. This review summarizes findings of different studies on host immune responses after HCV infection and the association between cytokine gene polymorphisms and the likelihood of HCV clearance.
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Affiliation(s)
- Marzyeh Amini
- Digestive Disease Research Centre, Shariati Hospital, Tehran University of Medical science, Tehran, Iran
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25
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Danilovic DLS, Mendes-Correa MC, Lima EU, Zambrini H, K Barros R, Marui S. Correlations of CTLA-4 gene polymorphisms and hepatitis C chronic infection. Liver Int 2012; 32:803-8. [PMID: 22136395 DOI: 10.1111/j.1478-3231.2011.02694.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 09/28/2011] [Accepted: 10/29/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cytotoxic T lymphocyte-associated factor 4 (CTLA-4) functions as a negative regulator of T cell-mediated immune response. Molecular changes associated to CTLA-4 gene polymorphisms could reduce its ability to suppress and control lymphocyte proliferation. AIMS To evaluate the frequency of CTLA-4 gene polymorphisms in chronic hepatitis C virus (HCV) infected patients and correlate to clinical and histological findings. METHODS We evaluated 112 HCV-infected subjects prospectively selected and 183 healthy controls. Clinical and liver histological data were analysed. -318C > T, A49G and CT60 CTLA-4 single-nucleotide polymorphisms (SNPs) were studied by PCR-RFLP and AT(n) polymorphism by DNA fragment analysis by capillary electrophoresis in automatic sequencer. RESULTS Eight AT repetitions in 3'UTR region were more frequent in HCV-infected subjects. We found a positive association of -318C and + 49G with HCV genotype 3 (P = 0.008, OR 9.13, P = 0.004, OR 2.49 respectively) and an inverse association of both alleles with HCV genotype 1 (P = 0.020, OR 0.19, P = 0.002, OR 0.38 respectively). Allele + 49G was also associated to aminotransferases quotients > 3 (qALT, P = 0.034, qAST, P = 0.041). Allele G of CT60 SNP was also associated with qAST > 3 (P = 0.012). Increased number of AT repetitions was positively associated to severe necroinflammatory activity scores in liver biopsies (P = 0.045, OR 4.62). CONCLUSION CTLA-4 gene polymorphisms were associated to HCV-infection. Eight AT repetitions were more prevalent in HCV-infected subjects. -318C and + 49G alleles were associated to genotypes 1 and 3 infections and increased number of AT repetitions in 3'UTR region favoured severe necroinflammatory activity scores in liver biopsies.
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Affiliation(s)
- Debora L S Danilovic
- Unidade de Tireóide - Laboratório de Endocrinologia Celular e Molecular - LIM 25 Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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Li YY. Tumor necrosis factor-alpha g308α gene polymorphism and essential hypertension: a meta-analysis involving 2244 participants. PLoS One 2012; 7:e35408. [PMID: 22536381 PMCID: PMC3334913 DOI: 10.1371/journal.pone.0035408] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Accepted: 03/15/2012] [Indexed: 11/18/2022] Open
Abstract
Background The tumor necrosis factor-alpha (TNFα) G308A gene polymorphism has been implicated in susceptibility to essential hypertension (EH), but study results are still controversial. Objective and Methods The present meta-analysis is performed to investigate the relationship between the TNFα G308A gene polymorphism and EH. Electronic databases were searched and seven separate studies on the association of the TNF α G308A gene polymorphism with EH were analyzed. The meta-analysis involved 1092 EH patients and 1152 controls. The pooled odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated by a fixed or random effect model. Results A significant relationship between the TNFα G308A gene polymorphism and EH was found in an allelic genetic model (OR: 1.45, 95% CI: 1.17 to 1.80, P = 0.0008), a recessive genetic model (OR: 3.181, 95% CI: 1.204 to 8.408, P = 0.02), and a homozygote model (OR: 3.454, 95% CI: 1.286 to 9.278, P = 0.014). No significant association between them was detected in both a dominant genetic model (OR: 1.55, 95% CI: 0.99 to 2.42, P = 0.06) or a heterozygote genetic model (OR: 1.45, 95% CI: 0.90 to 2.33, P = 0.13). Conclusion The TNFα G308A gene polymorphism is associated with EH susceptibility.
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Affiliation(s)
- Yan-yan Li
- Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Talaat RM, Esmail AA, Elwakil R, Gurgis AA, Nasr MI. Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients. CHINESE JOURNAL OF CANCER 2012; 31:29-35. [PMID: 22200181 PMCID: PMC3777466 DOI: 10.5732/cjc.011.10258] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 09/20/2011] [Accepted: 09/21/2011] [Indexed: 12/14/2022]
Abstract
Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-α may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure. We hypothesized that SNPs in TNF-α may be important in determining the outcome of an HCV infection. To test this hypothesis, we investigated the role of the polymorphism -308G/A, which is located in the promoter region of the TNF-α gene, in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR). The distribution of this polymorphism and its impact on the serum level of TNF-α was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV-related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease. Our results showed that at the TNF-α -308 position, the G/G allele was most common (78.5%) in the study population, with the G/A and A/A alleles occurring less frequently (13.3% and 8.1%, respectively). Frequencies of G/G, G/A, and A/A genotypes were 87%, 7%, and 6% in patients with liver cirrhosis and were 94%, 4%, and 2% in patients with HCC, respectively. Serum levels of TNF-α were significantly higher in HCV-infected patients than in healthy controls, indicating that the TNF-α -308 polymorphism does not influence the production of TNF-α. The serum level of TNF-α was positively correlated with HCV infection. Taken together, these findings suggest that the TNF-α -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection, but may be an independent risk factor for HCC.
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Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Menofia University, Sadat, Egypt.
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Sawhney R, Visvanathan K. Polymorphisms of toll-like receptors and their pathways in viral hepatitis. Antivir Ther 2011; 16:443-58. [PMID: 21685532 DOI: 10.3851/imp1820] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) are an important part of the innate immune response to a variety of pathogens including hepatic viral infections. Activation of TLRs stimulates a complex intracellular signalling cascade that results in production of proinflammatory cytokines and interferons important for antiviral responses as well as induction of the adaptive arm of the immune system. There is substantial evidence for an important role for TLRs and TLR-mediated signalling in the pathogenesis and outcomes of hepatitis B and C in particular, but it might also influence responses to other viral hepatitis infections. Several single nucleotide polymorphisms (SNPs) of TLRs, relevant adaptor molecules and cytokines mediated by TLR signalling have been described that alter innate immune responses and have been implicated in a variety of human diseases including viral and other infections. There is now significant evidence that a number of TLR SNPs can affect various clinical outcomes in Caucasian patients with chronic HCV. However, the role of these polymorphisms in acute and other chronic hepatitis infections, including HBV as well as in non-Caucasian populations, has not been elucidated. In addition, results for SNPs downstream of TLR activation, such as in relevant cytokines, are inconsistent and their influence requires further investigation to determine the clinical significance of genetic variations in these mediators.
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Affiliation(s)
- Rohit Sawhney
- Innate Immunity Laboratory, Department of Medicine, Monash University, Melbourne, Australia
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Dogra G, Chakravarti A, Kar P, Chawla YK. Polymorphism of tumor necrosis factor-α and interleukin-10 gene promoter region in chronic hepatitis C virus patients and their effect on pegylated interferon-α therapy response. Hum Immunol 2011; 72:935-9. [PMID: 21756957 DOI: 10.1016/j.humimm.2011.06.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2011] [Revised: 06/15/2011] [Accepted: 06/27/2011] [Indexed: 12/20/2022]
Abstract
The development and resolution of an inflammatory process is regulated by a complex interplay among cytokines that have pro- and anti-inflammatory effects. Regulatory mechanisms that control the production of cytokines include genetic polymorphism in particular promoter/leader region. Polymorphisms may directly or indirectly affect the binding of transcriptional factors, consequently increasing or decreasing the production of mRNA, thus regulating cytokine production. A total of 70 hepatitis C virus (HCV) RNA-positive patients and 70 healthy control subjects were included in the present study, who were attending the medical outpatient department (OPD) and wards of a tertiary care hospital in New Delhi during 2006-2008. This study was designed to determine the polymorphism of tumor necrosis factor-α and interleukin-10 genes in patients with chronic HCV infection patients and their effect on pegylated interferon-α therapy response. Polymorphism in the tumor necrosis factor-α G/G, G/A, and A/A genotype was significant between HCV patients and healthy controls. Interleukin-10 variants (G/G, G/A) were nonsignificant among HCV patients compared with healthy controls. As this is a preliminary study on small sample size, we believe that our findings may stimulate further studies on larger number of patients from this geographic region.
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Affiliation(s)
- Gaurav Dogra
- Department of Microbiology, Maulana Azad Medical College & Associated Lok Nayak Hospital, New Delhi, India
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Romero-Gomez M, Eslam M, Ruiz A, Maraver M. Genes and hepatitis C: susceptibility, fibrosis progression and response to treatment. Liver Int 2011; 31:443-460. [PMID: 21382156 DOI: 10.1111/j.1478-3231.2011.02449.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus contact and infection show three different phenotypes: spontaneous viral clearance (SVC), chronic hepatitis C (CHC) and sustained virological response (SVR) following antiviral treatment. Many factors, including genetics, influence the evolution of these three phenotypes. We performed a literature search (PubMed) up to 31 January 2010 without language restriction to identify relevant studies on genes and hepatitis C. Additional studies were sought by reviewing the reference lists of the identified articles. Meta-analysis (using Meta-disk 1.4) was conducted to evaluate the association of single nucleotide polymorphism (SNP) in the IL28B region and SVR. The candidate gene approach showed strong relationships between human leucocyte antigen class II (DQB1(*) 0301 and DRB1(*) 1101) and SVC. A cirrhosis risk score involving 7 SNPs has been validated recently. The set of odds ratios of studies demonstrated an association between SNP (rs12987960/rs8099917) in the IL28B and SVR in CHC treated with peginterferon plus ribavirin (OR: 4.6; 95% CI: 2.9-7.3). The overall distribution of protective allele correlated with ethnic differences in SVR (Asians, Europeans, Hispanic and Afro-Americans) together with SVC, but not with fibrosis stage or viral load. These polymorphisms did not influence SVR in very-easy-to-treat patients such as genotype 2/3, rapid virological responders or patients with acute hepatitis C. While the genetic fingerprint for fibrosis progression remains elusive, IL28b polymorphism predicts SVC and SVR. However, nearly half of patients achieving SVR did not show favourable genotype. Further genetic signals are warranted to complete the puzzle of factors influencing hepatitis C.
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Affiliation(s)
- Manuel Romero-Gomez
- Unit for the Clinical Management of Digestive Diseases and Ciberehd, Hospital Universitario de Valme, Sevilla, Spain.
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Grünhage F, Nattermann J. Viral hepatitis: human genes that limit infection. Best Pract Res Clin Gastroenterol 2010; 24:709-23. [PMID: 20955972 DOI: 10.1016/j.bpg.2010.07.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Revised: 07/20/2010] [Accepted: 07/22/2010] [Indexed: 01/31/2023]
Abstract
Treatment response and susceptibility to chronic viral hepatitis C and B may be modified by host genetic factors. The majority of genetic variants that confer a significant risk have been localized in genes involved in immune response. However, many findings could not be replicated and almost none of the identified risk factors had a noticeable impact on clinical decisions. In contrast, recent findings in independent large genome wide association studies confirmed genetic variants in the interferon gamma gene locus as strong predictors of outcome with outstanding clinical relevance. This review gives an overview on significant genetic susceptibility factors for susceptibility and treatment outcome in chronic viral hepatitis C and B that have been identified by the classical candidate gene approach and genome wide studies and also highlights some recent findings on genetic factors for common adverse drug reactions.
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Affiliation(s)
- Frank Grünhage
- Medical Department II, Saarland University Hospital, Kirrbergerstr. 1, 66421 Homburg, Germany.
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Cui Q, Ding KQ, Yu RB. Relationship between host genetic polymorphisms and the outcome of hepatitis C virus infection. Shijie Huaren Xiaohua Zazhi 2010; 18:2731-2738. [DOI: 10.11569/wcjd.v18.i26.2731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acute hepatitis C virus (HCV) infection can induce host innate and adaptive immune responses. Approximately 15%-25% of HCV-infected patients successfully eliminated the virus whereas the majority of these patients developed chronic liver disease, cirrhosis and hepatocellular carcinoma. Numerous studies have demonstrated that host genetic polymorphisms may lead to differences in host immune function and therefore influence the clinical outcome of HCV infection. This review briefly summarizes the relationship between host genetic polymorphisms and the outcome of HCV infection.
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Bouzgarrou N, Hassen E, Gabbouj S, Schvoerer E, Ben Mami N, Triki H, Chouchane L. Lack of effect of tumor necrosis factor-alpha -308 G/A polymorphism on severity of liver fibrosis in Tunisian hepatitis C virus (HCV)-infected patients. ACTA ACUST UNITED AC 2010; 34:297-304. [DOI: 10.1016/j.gcb.2010.03.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Revised: 03/23/2010] [Accepted: 03/23/2010] [Indexed: 12/17/2022]
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Hold GL, Untiveros P, Saunders KA, El-Omar EM. Role of host genetics in fibrosis. FIBROGENESIS & TISSUE REPAIR 2009; 2:6. [PMID: 19961576 PMCID: PMC2796989 DOI: 10.1186/1755-1536-2-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2009] [Accepted: 12/04/2009] [Indexed: 01/18/2023]
Abstract
Fibrosis can occur in tissues in response to a variety of stimuli. Following tissue injury, cells undergo transformation or activation from a quiescent to an activated state resulting in tissue remodelling. The fibrogenic process creates a tissue environment that allows inflammatory and matrix-producing cells to invade and proliferate. While this process is important for normal wound healing, chronicity can lead to impaired tissue structure and function. This review examines the major factors involved in transforming or activating tissues towards fibrosis. The role of genetic variation within individuals affected by fibrosis has not been well described and it is in this context that we have examined the mediators of remodelling, including transforming growth factor-beta, T helper 2 cytokines and matrix metalloproteinases. Finally we examine the role of Toll-like receptors in fibrosis. The inflammatory phenotype that precedes fibrosis has been associated with Toll-like receptor activation. This is particularly important when considering gastrointestinal and hepatic disease, where inappropriate Toll-like receptor signalling, in response to the local microbe-rich environment, is thought to play an important role.
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Affiliation(s)
- Georgina L Hold
- Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
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Hung TM, Chang SC, Yu WH, Wang YW, Huang C, Lu SC, Lee PH, Chang MF. A novel nonsynonymous variant of matrix metalloproteinase-7 confers risk of liver cirrhosis. Hepatology 2009; 50:1184-93. [PMID: 19676133 DOI: 10.1002/hep.23137] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
UNLABELLED Liver cirrhosis is characterized by progressive accumulation of extracellular matrix following chronic liver injuries. In the extracellular space, the constant turnover of liver matrix is regulated by the matrix metalloproteinase (MMP) class of enzyme. To assess whether genetic variations in MMP would result in diversity of liver cirrhosis, a case-control study of 320 patients with hepatocellular carcinoma, with or without cirrhosis, was conducted. Ten single-nucleotide polymorphism markers from four potential fibrosis-associated genes were selected for genotyping. Among these genes, a nonsynonymous single-nucleotide polymorphism which generates the variation of Gly-137 and Asp-137 in the MMP-7 gene was found to be strongly associated with the development of liver cirrhosis. In contrast to MMP-7(Gly-137) that predominantly secretes out into the cell culture medium, the cirrhosis-associated MMP-7(Asp-137) variant is preferentially localized on the extracellular membranes where it exerts its proteolytic activity on pericellular substrates. Functional analysis demonstrated an increased ability of the MMP-7(Asp-137) variant to associate with the cell surface CD151 molecule. In wound-healing and Boyden chamber assays, cell motility was specifically enhanced with the expression of MMP-7(Asp-137) as compared to the cells expressing MMP-7(Gly-137). These results demonstrate that the MMP-7(Asp-137) variant confers a gain-of-function phenotype for MMP-7. CONCLUSION We have identified a novel genetic association of MMP-7(Asp-137) variant with liver cirrhosis in patients with hepatocellular carcinoma. Whether the MMP-7 variant can be a new marker for liver cirrhosis will be further studied.
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Affiliation(s)
- Tzu-Min Hung
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan
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An assessment of a TNF polymorphic marker for the risk of HCV infection: meta-analysis and a new clinical study design. INFECTION GENETICS AND EVOLUTION 2009; 9:1356-63. [PMID: 19800032 DOI: 10.1016/j.meegid.2009.09.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2009] [Revised: 09/19/2009] [Accepted: 09/22/2009] [Indexed: 01/22/2023]
Abstract
A number of studies have investigated the association between TNF-alpha -308G/A polymorphism and the risk of HCV infection; the results of these studies are conflict, however. To provide a more definitive conclusion, a meta-analysis combining and summarizing 12 studies was performed. The Mantel-Haenszel and DerSimonian-Laird methods were employed in traditional fixed effects and random effects meta-analysis, respectively. The capability of a Bayesian approach was highlighted in the estimation of a pooled odds ratio and 95% confidence interval, as well as in the calculation of a sample size for the new study design. Heterogeneity and publication bias across the studies were also explored. The results of the meta-analysis (OR=1.179, CI=0.833-1.649) suggest no significant association between TNF-alpha -308G/A polymorphism and susceptibility to HCV infection in the combined populations. However, there was evidence indicating a possible impact of ethnicity (Asian vs. non-Asian populations) on the association evaluated here (beta(ethnicity)=0.293+/-0.271). While the power of existing Asian studies was insufficient to make a statistical statement, the sample size of a new clinical study was estimated (500 subjects with 80% statistical power) for further assessment of an association between TNF-alpha -308G/A polymorphism and risk of HCV infection in Asians.
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Revai K, Patel JA, Grady JJ, Nair S, Matalon R, Chonmaitree T. Association between cytokine gene polymorphisms and risk for upper respiratory tract infection and acute otitis media. Clin Infect Dis 2009; 49:257-61. [PMID: 19522649 DOI: 10.1086/599833] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND We previously reported an association between tumor necrosis factor alpha (TNFalpha)(-308)and interleukin (IL)-6(-174) polymorphisms and otitis susceptibility by history. Acute otitis media occurs most commonly as a complication of upper respiratory tract infection (URI); it is not clear why some children develop acute otitis media after URI and others do not. Our objective was to prospectively evaluate the association of TNFalpha(-308)and IL-6(-174) polymorphisms with URI and with acute otitis media development after URI. METHODS Children aged 6-35 months were prospectively followed for occurrences of URI and acute otitis media. Blood or buccal mucosa samples were collected for DNA extraction to determine cytokine genotypes. Active and passive surveillance was used to capture all URI episodes during the 1-year follow-up period in order to study the rate of acute otitis media following URI. Data were analyzed using SAS software (SAS Institute) and general estimating equations modeling. RESULTS Two hundred forty-two children were followed over 2689 patient-months and had DNA genotyped; 1235 URI episodes occurred, and 392 (32%) were complicated by acute otitis media. Children who had IL-6(-174) polymorphism had a higher susceptibility to URI during the study period (incidence density ratio, 1.24) and were more likely to meet established otitis susceptibility criteria (P < .01). Presence of TNFalpha(-308) polymorphism was associated with increased risk for acute otitis media after an episode of URI (odds ratio, 1.43). CONCLUSIONS TNFalpha(-308) and IL-6(-174) genotypes are associated with increased risk for symptomatic URI and acute otitis media following URI. Future studies may be designed to carefully look at the interaction of these genetic polymorphisms with modifiable environmental risk factors.
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Affiliation(s)
- Krystal Revai
- Department of Pediatrics, University of Texas Medical Branch at Galveston, Texas, USA.
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Minisini R, Fabris C, Toniutto P, Pirisi M. Combinatorial use of single nucleotide polymorphisms to help predict liver fibrosis in patients with hepatitis C infections. ACTA ACUST UNITED AC 2009; 3:355-70. [DOI: 10.1517/17530050902893311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Elsammak MY, Al-Sharkaweey RM, Ragab MS, Amin GM, Kandil MH. In Egyptians, a mutation in the lymphotoxin-alpha gene may increase susceptibility to hepatitis C virus but not that to schistosomal infection. ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY 2009; 102:709-16. [PMID: 19000388 DOI: 10.1179/136485908x337599] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
In Egypt, human schistosomiasis is a chronic endemic disease that can produce portal hypertension and occasionally death. Curiously, most Egyptian cases of the disease are complicated by co-infection with hepatitis C virus (HCV), the co-infection generally resulting in more severe liver disease than seen in those only infected with HCV. The high frequency of co-infection may be the result of transmission of the virus during parental schistosomal therapy or schistosomiasis-related surgery but it also seems possible that certain individuals are particularly susceptible to both schistosome and HCV infection. Lymphotoxin-alpha (LTalpha) participates in inflammatory responses, and single-nucleotide polymorphisms (SNP) in the human LTalpha gene have recently been found to have profound effects on individual susceptibility to various diseases, including some of those caused by parasitic infection. The possibility that the SNP that create an NcoI restriction site in the gene are associated with increased susceptibility to schistosomal and/or HCV infection has now been investigated in the Egyptian city of Alexandria. The subjects investigated were 22 patients infected only with HCV, 44 cases of schistosomal hepatic fibrosis (SHF) who were either co-infected with HCV (22) or HCV-free (22), and 22 apparently healthy, schistosome-free and HCV-free controls. When each of these subjects was tested for the NcoI polymorphism in their LTalpha gene, by PCR-RFLP, those with isolated HCV infection and those co-infected with Schistosoma and HCV (but not those infected with Schistosoma alone) were found significantly more likely to carry the mutation than the control subjects (P<0.05). When the cases of SHF were pooled together (irrespective of HCV-infection status), they were not found significantly more likely to have the mutation than the controls. At least in Egypt, therefore, the LTalpha mutation may have a role in susceptibility to HCV infection (and the subsequent development of clinical manifestations) but appears to have little if any effect on susceptibility to schistosome infection. Larger studies are now needed to confirm these results.
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Affiliation(s)
- M Y Elsammak
- Department of Chemical Pathology, Medical Research Institute Teaching Hospital, Alexandria University, 165 El-Horreya Street, PO Box 21561, Alexandria, Egypt.
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Jonsson JR, Purdie DM, Clouston AD, Powell EE. Recognition of genetic factors influencing the progression of hepatitis C : potential for personalized therapy. Mol Diagn Ther 2008; 12:209-18. [PMID: 18652517 DOI: 10.1007/bf03256286] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Infection with hepatitis C virus (HCV) is a major cause of chronic liver disease. Hepatic fibrosis may develop in subjects with chronic HCV infection, culminating in cirrhosis and an increased risk of hepatocellular carcinoma. The rate of development of fibrosis varies substantially between individuals; while it is influenced by a number of demographic and environmental factors, these account for only a small proportion of the variability. There are no clinical markers or tests that predict the rate of fibrosis progression in an individual subject. Thus, there has been increasing interest in the influence of host genetic factors on the rate of disease progression, and whether a genetic signature can be developed to reliably identify individuals at risk of severe disease. Numerous case-control, candidate gene, allele-association studies have examined the relationship between host single nucleotide polymorphisms or other genetic mutations and fibrosis in patients with chronic HCV infection. However, these studies have generally been irreproducible and disappointing. As seen with genetic studies for other diseases, small study cohorts and poor study design have contributed to limited meaningful findings. The successful determination of genetic signatures for fibrosis progression in chronic HCV will require multicenter collaborations using genome-wide association studies, with large, phenotypically well-defined sample sets. While these studies will require a significant financial commitment, a successful outcome offers the potential for personalized therapy and better patient management.
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Affiliation(s)
- Julie R Jonsson
- School of Medicine, Southern Division, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
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Jiang ZL. Advances in research on genetic predisposition to liver cirrhosis after hepatitis B virus infection. ACTA ACUST UNITED AC 2008; 6:1074-9. [DOI: 10.3736/jcim20081019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Abstract
Human genome variations explain some of the heterogeneity in the immune response to antigenic stimuli. Such differences in response to hepatitis C virus (HCV) antigens can account for the ability of the immune response to clear HCV after an acute infection or to develop more rapidly progressive liver disease. Several studies have examined polymorphisms in several candidate immune-response genes for their relation to these HCV outcomes. Results of some of these studies complement knowledge gained from immunology studies, and others offer new insights into HCV biology. This review summarizes published studies on variation in immune-response genes and HCV outcomes.
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Affiliation(s)
- Chloe L. Thio
- Johns Hopkins University, Department of Medicine, Baltimore, MD
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Abstract
OBJECTIVES Genotype assessment has been suggested to be a tool for predicting disease severity in acute pancreatitis (AP). To study this hypothesis, we performed genotype analysis of tumor necrosis factor (TNF) -308 A/G, CD14 -159C/T, and HSPA1B +1267 A/G polymorphisms. METHODS This is a case-control association study of 397 patients with AP (214 of whom had an alcohol-induced AP) and 300 controls. The control group comprised 218 subjects with detailed data of alcohol consumption, 70 of whom were heavy drinkers (daily alcohol intake >40 g), and 92 blood donors. The severity of AP was determined according to the Atlanta classification. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-assisted genotyping method. RESULTS Major allele frequency in TNF gene was 0.87 for patients with AP and 0.86 for controls. For CD14, the gene major allele frequency was 0.60 for patients and 0.63 for controls. For HSPA1B, the major allele frequencies were 0.52 for patients and 0.49 for controls, respectively. The allele frequencies did not differ significantly between AP patients with organ failure and those with mild disease, patients with alcohol-induced AP, or those with biliary AP. The patients with septic infectious complications (n = 47) had genotype distribution no different from those with mild, uncomplicated disease (n = 245). CONCLUSIONS The TNF, CD14, and HSPA1B polymorphisms studied seem not to play a role in determining the severity of AP or the risk of alcohol-induced AP and thus do not serve as a tool for predicting disease severity.
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Chan HLY, Tse AML, Chim AML, Wong VWS, Choi PCL, Yu J, Zhang M, Sung JJY. Association of cytokine gene polymorphisms and liver fibrosis in chronic hepatitis B. J Gastroenterol Hepatol 2008; 23:783-9. [PMID: 17645476 DOI: 10.1111/j.1440-1746.2007.05110.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM As liver fibrosis is the result of persistent necroinflammation in the liver, pro-inflammatory cytokines secreted in response to cell injury have a central role in the pathogenesis of liver fibrosis. We aimed to investigate the association of cytokine gene polymorphism and liver fibrosis among Chinese patients with chronic hepatitis B. METHODS Polymorphisms at interleukin-10 (IL-10-627, -1117), interleukin-1-beta (IL-1beta-511, -31, -3964), interleukin-1 receptor antagonist (IL-1RN), and tumor necrosis factor-alpha (TNF-alpha-308, -238) among Chinese chronic hepatitis B patients were determined. Severe liver fibrosis was defined as Ishak fibrosis score = 4 (of 6). RESULTS Fifty-nine of 273 (22%) patients had severe fibrosis. The distribution of genotypes for IL-10-627 was CC (11%), CA (41%), and AA (48%). The CC genotype at IL-10-627 was protective against severe fibrosis (odds ratio (OR) 0.11; 95% CI 0.014-0.82; P = 0.032). After adjusted for baseline variables, the adjusted OR of CC genotypes at IL-10-627 for severe fibrosis was 0.063 (95% CI 0.06-0.64; P = 0.063). Other gene polymorphisms at IL-1beta, IL-1RN, TNF-alpha, and IL-10 had no significant association with severe fibrosis. Weak linkage disequilibrium was observed between IL-10-627 and IL-10-1117 with linkage disequilibrium coefficient of 0.12 (P < 0.001). The distribution of haplotypes of IL-10-1117 and IL-10-627 was A-A (69%), A-C (26%), and G-C (5%). High and intermediate IL-10 production (A-C and G-C) haplotypes were protective against severe fibrosis (OR 0.62; 95% CI 0.39-0.99; P = 0.046). CONCLUSIONS High production genotype and haplotypes of IL-10 were associated with less severe liver fibrosis in chronic hepatitis B in Chinese.
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Affiliation(s)
- Henry L-Y Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
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Bouzgarrou N, Hassen E, Schvoerer E, Stoll-Keller F, Bahri O, Gabbouj S, Cheikh I, Maamouri N, Mammi N, Saffar H, Trabelsi A, Triki H, Chouchane L. Association of interleukin-18 polymorphisms and plasma level with the outcome of chronic HCV infection. J Med Virol 2008; 80:607-14. [PMID: 18297714 DOI: 10.1002/jmv.21079] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) infection is the main cause of chronic liver disease throughout the world, and may progress to cirrhosis and hepatocellular carcinoma (HCC). Immunological factors, especially cytokines and some host genetic variations, rather than direct HCV action, seem to play an important role in the pathogenesis of HCV infection. Elevated levels of interleukin-18 (IL-18) were described previously for chronically (HCV)-infected patients. This study is aimed at investigating IL-18 promoter polymorphisms (-607C/A and -137G/C) in HCV-infected patients with different disease severities (chronic hepatitis C, liver cirrhosis and HCC) and establishing an association between these polymorphisms and IL-18 plasma concentration with the outcome of chronic HCV infection. The carriage of at least one C allele at position -607 (CC + CA) was associated with a higher risk of cirrhosis and HCC (P = 0.032). Compared with controls, HCV-infected patients had significantly higher levels of IL-18 (P = 0.0001) that correlate with disease severity (P = 0.01, P = 0.001, P = 0.0006, respectively). In conclusion, we supposed a possible implication of IL-18 promoter polymorphisms in the pathogenesis of chronic HCV infection.
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Affiliation(s)
- N Bouzgarrou
- Laboratory of Molecular Immuno-oncology, Faculty of Medicine, Monastir, Tunisia.
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Goncharova IA, Beloborodova EV, Freidin MB, Beloborodova EI, Chernogoruk GE, Puzyrev VP. Genetic factors predisposing to a chronic course of virus hepatitis and liver fibrosis. Mol Biol 2008. [DOI: 10.1134/s0026893308020052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008; 111:4456-62. [PMID: 18316631 DOI: 10.1182/blood-2007-11-122374] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hereditary hemochromatosis is a genetic disorder of iron metabolism leading to inappropriate iron absorption and iron loading in various organs especially the liver. Despite the genetic mutation being relatively common in those of Anglo Celtic descent, cirrhosis of the liver occurs in only a small proportion of affected individuals. The risk of hepatic fibrosis and cirrhosis relates to the degree of iron loading with threshold hepatic iron concentrations being identified from population studies. However, other environmental and possibly genetic factors appear to modify this risk. Excess alcohol consumption appears to be one of the most important cofactors with steatosis and coexistent viral infection also implicated. Genetic polymorphisms in genes associated with fibrogenesis, antioxidant activity, and inflammation have been investigated in several different forms of chronic liver disease. The variability in the expression of these genes that predispose patients with hemochromatosis to increased risk of severe liver disease is the subject of ongoing investigations. Clearly the progression of iron loading to cirrhosis marks a crucial stage in the natural history of a patient's disease and therefore therapy and prognosis. This review explores recent developments in knowledge of environmental and genetic modifiers of this process.
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Pereira FA, Pinheiro da Silva NN, Rodart IF, Carmo TMA, Lemaire DC, Reis MG. Association of TGF-beta1 codon 25 (G915C) polymorphism with hepatitis C virus infection. J Med Virol 2008; 80:58-64. [PMID: 18041006 DOI: 10.1002/jmv.21011] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Cytokines play a key role in the regulation of immune responses. In hepatitis C virus infection (HCV), the production of abnormal cytokine levels appears to contribute to the progression of the disease, viral persistence, and affects response to therapy. Cytokine genes are polymorphic at specific sites, and certain polymorphisms located within coding/regulatory regions have been shown to affect the overall expression and secretion of cytokines. The aim of the present study was to identify potential markers of cytokines genes associated with the susceptibility to HCV infection. The cohort was composed of 128 individuals infected by HCV and 94 healthy controls. Genotyping was carried out by PCR-SSP. The distributions of the following polymorphisms were compared in these groups: TNF-alpha (-308G/A [rs1800629]), TGF-beta1 (codon 10 T/C [rs1982073], codon 25 G/C [rs1800471]), IL-10 (-1082 A/G [rs 1800896]; -819T/C [rs1800871]; -592A/C [rs 1800872]), IL-6 (-174G/C [rs1800795]), and IFN-gamma (+874T/A [rs2430561]). This study demonstrated a statistically significant difference in the frequency of TGF-beta1 codon 25 polymorphism between healthy subjects and those infected with HCV. No associations were observed between polymorphisms of TNF-alpha, IFN-gamma, IL-10, TGF-beta1 codon 10, and IL-6 and HCV infection. These findings suggest that TGF-beta1 codon 25 polymorphism could be a host genetic factor associated with susceptibility to HCV infection.
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Affiliation(s)
- Fernanda Albuquerque Pereira
- Laboratório de Patologia e Biologia Molecular, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil
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Wu YT, Liao JD, Lin JI, Lu CC. Determination of the optimized conditions for coupling oligonucleotides with 16-mercaptohexadecanoic acid chemically adsorbed upon Au. Bioconjug Chem 2007; 18:1897-904. [PMID: 17970584 DOI: 10.1021/bc700217n] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A specific 5'-modified amino group oligonucleotide (Primer 1), 15-mers in length, is selectively coupled with the carboxyl terminated 16-mercaptohexadecanoic acid (MHDA) chemically adsorbed on Au and subsequently hybridized with Antisense Primer. The amide-coupling process is of significance to create an intermediate structure for the purpose of adding Primer 1, while the hybridization reaction is relevant to various diagnostic purposes to determine the presence in nucleic acids for a target sequence. In this work, the coupling setting was particularly emphasized by varying commonly used temperatures and pH values with a definite concentration of coupling agents (i.e., 10 mM). The recombination with analogous hybridization treatment was investigated using high resolution X-ray photoelectron spectroscopy and a 75 degrees grazing angle Fourier transform infrared spectrometer. On the basis of the spectroscopic studies, the optimized conditions for the coupling process that is also correlated with the molecular density of subsequent hybridization process on MHDA/Au have been proposed at 37 degrees C and a pH value of 4.5. Therefore, it is pertinent to intensify the joining of short-chain DNA strands by complementary base pairing in diagnostic applications such as the identification of single nucleotide polymorphisms.
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Affiliation(s)
- Yi-Te Wu
- Department of Materials Science and Engineering, Center for Micro/Nano Science and Technology, National Cheng Kung University, Tainan, Taiwan
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Knight J. Polymorphisms in tumor necrosis factor and other cytokines as risks for infectious diseases and the septic syndrome. Curr Infect Dis Rep 2007; 3:427-39. [PMID: 24395481 DOI: 10.1007/s11908-007-1010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
An increasing number of genetic association studies have implicated polymorphisms of cytokine genes as host genetic factors influencing susceptibility to infectious disease, primarily using a candidate gene approach based on knowledge of disease pathogenesis. The application and limitations of association studies are reviewed together with the impact of recent advances in single nucleotide polymorphism mapping on strategic approaches to defining genetic susceptibility loci. It often remains unclear whether associated genetic polymorphisms are themselves functionally relevant or acting only as markers within an extended haplotype, and experimental approaches to investigating the functional impact of polymorphisms in noncoding regulatory DNA sequences are discussed. An overview of genetic associations of cytokine genes with infectious disease is presented, together with discussion of recent studies in a number of infectious diseases including hepatitis, HIV, malaria, and sepsis.
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Affiliation(s)
- Julian Knight
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN, Headington, Oxford, UK,
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