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Abd Alla MDA, Dawood RM, Rashed HAELH, El-Dessouky YM, AbuFarrag GA, Ammar IAE, Mahmoud MMAH, Salum GM, Abu-Amer MZ, Sekeen MAEH, Heggazy MMI, Altanbouly AMA, Abd El-Meguid M, El Awady MK. HCV treatment outcome depends on SNPs of IFNL3-Gene polymorphisms (rs12979860) and cirrhotic changes in liver parenchyma. Heliyon 2023; 9:e21194. [PMID: 37928048 PMCID: PMC10623284 DOI: 10.1016/j.heliyon.2023.e21194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 09/10/2023] [Accepted: 10/18/2023] [Indexed: 11/07/2023] Open
Abstract
The allelic discrimination of IFNL3-(rs12979860 C > T) polymorphism reveals ambiguous associations with the effectiveness of oral HCV treatment. Solitary intra peripheral-blood-mononuclear-cells (PBMCs) HCV-RNA antisense-strands are independently detected in naïve and experienced cases regardless of viremia or hepatic-parenchymal alterations. We examined the frequencies of IFNL3-genetic variants with chronic-HCV-induced liver changes during the sustained virologic response (SVR) by evaluating the PBMCs- HCV-PCR after oral antiviral therapy. Methods: Twelve weeks after finishing oral antiviral therapy, the effects of IFNL3-genetic variants were evaluated in three groups of patients: Group-I (n = 25) showed HCV-RNA negativity in both serum and PBMCs-, group II (n = 52) showed positivity of HCV-RNA in PBMCs, and group-III (n = 25) had positive HCV-RNA in serum. The genetic variants of the IFNL3-gene were estimated for all the enrolled cases and correlated with their hepatic image changes. Results: IFNL3-(rs12979860) genotyping in post-direct acting antivirals (DAAs) SVR and HCV-relapse revealed: a) high frequency of CC-genotype and C-allele in group I compared to group II (P < 0.005) and group III(P ≤ 0.05) when hepatic-parenchyma looks normal by ultrasound b) frequent CT-genotype and T-allele in group II compared with I(P < 0.01) and III(P < 0.05) when liver tissues are bright (early cirrhotic-changes) c) frequent TT-genotype and T-allele in group III relative to I (P < 0.05) and II (P ≤ 0.08) when liver-tissues appear coarse by ultrasound. Conclusion: Outcomes of HCV treatment depend on host IFNL3-gene polymorphism and hepatic-parenchymal changes. A high frequency of wild-CC-genotype and C-allele is observed in patients with normal hepatic parenchyma and that achieved SVR. Solitary relapse in PBMCs occurs on increasing CT-genotype frequency when liver tissues are bright. Serologic relapse is detected when TT-genotype and T-allele are dominant in association with the cirrhotic liver. Therefore, IFNL3-gene-SNP analysis as a genetic predictor in relation to ultra-sonographic hepatic-parenchymal changes could be valuable for selecting the patients with the highest priority for treatment.
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Affiliation(s)
| | - Reham M. Dawood
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
| | - Hassan Abd EL-Hafeth Rashed
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | - Yasser Mohammed El-Dessouky
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | - Galal AbdElhameed AbuFarrag
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | - Islam Abdelmawla Emran Ammar
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | | | - Ghada M. Salum
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
| | - Mohamed Zakaria Abu-Amer
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | | | | | | | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
| | - Mostafa K. El Awady
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
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Galal ASGM, Dawood RM, Awady MKE, El-Dessouky YMM, Mahmoud MMAH, Alla MDAA. Recognition of 7 genes signature (Cirrhosis Risk Score) in the diagnosed non-responders to DAAs therapy by intra-PBMCs nested HCV RNA PCR. J Genet Eng Biotechnol 2023; 21:89. [PMID: 37646837 PMCID: PMC10468448 DOI: 10.1186/s43141-023-00544-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 08/19/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND AND AIMS Predictors of chronic HCV response to oral antiviral therapy (OAT) are related to host genetic variations. Single nucleotide polymorphisms (SNP) and alleles variations of host genes in association with hepatic fibro-cirrhotic changes have a distinct role in OAT outcomes. The current research evaluated the association of Cirrhosis-Risk-Scores (CRS) values, based on the correlation of seven genes signature-SNPs, with sonographic liver parenchymal changes in determining OAT outcomes. METHODS All study subjects (n = 54) were recruited three months after completing OAT and classified into three groups. Group I (n = 21) had negative HCV PCR, group II (n = 17) showed positive solitary intra-PBMCs HCV infection, and group III(n = 16) was serum HCV RNA PCR-positive. All study-population were subjected to examination by hepatic-ultrasound (US), FIB-4-scoring, and screening for 7 gene-signature that addressed CRS values as low, intermediate, and high depending on gene SNPs identification. RESULTS Group I showed a significant association with low CRS values compared to other groups (P < 0.001). Solitary intra- PBMCs HCV infection in group II was significantly combined with intermediate CRS values in comparison to groups I and III (P < 0.001). The high CRS values were significantly found in group III when compared to groups I and II (P < 0.01). On US imaging, low CRS values were common in normally appeared hepatic parenchyma (P < 0.001) and high CRS values were frequent in coarse-liver (P < 0.001), while bright-liver-tissues appearance was mainly detected in the intermediate CRS category (P = 0.09). On FIB-4 scoring, high CRS value were associated with hepatic fibro-cirrhosis compared to intermediate (P < 0.001) and low (P = 0.08) CRS-categories. CONCLUSION The current study concluded the association of (a) high CRS values with coarse liver in viral-RNA serologic relapse, (b) low CRS values with normal liver tissues in sustained virologic response (SVR), (c) intermediate CRS values with bright liver in solitary PBMCs relapse.
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Affiliation(s)
| | - Reham M Dawood
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, National Research Center, Cairo, Egypt
| | | | | | - Mohamed Darwish Ahmed Abd Alla
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
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3
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The role of IFNL4 in liver inflammation and progression of fibrosis. Genes Immun 2022; 23:111-117. [PMID: 35585257 DOI: 10.1038/s41435-022-00173-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/25/2022] [Accepted: 05/05/2022] [Indexed: 11/08/2022]
Abstract
The discovery that genetic variation within the interferon lambda locus has a profound effect on the outcome of hepatitis C virus (HCV) treatment and spontaneous clearance of HCV is one of the great triumphs of genomic medicine. Subsequently, the IFNL4 gene was discovered and proposed as the causal gene underlying this association. However, there has been a lively debate within the field concerning the causality, which has been further complicated by a change in naming. This review summarizes the genetic data available for the IFNL3/IFNl4 loci and provides an in-depth discussion of causality. We also discuss a new series of interesting data suggesting that the genetic variation at the IFNL4 loci influences the evolution of the HCV virus and the implication this relationship between our genetic makeup and virus evolution has upon our understanding of the IFNL4 system. Finally, new data support an influence of the IFNL4 gene upon liver inflammation and fibrosis that is independent of etiology, thereby linking the IFNL4 gene to some of the major liver diseases of today.
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Miri HH, Fazeli P, Ali-Hassanzadeh M, Bemani P, Kabelitz D, Kalantar K. Correlation between IL-28 polymorphism and spontaneous clearance in HCV patients: systematic review and meta-analysis. Arch Virol 2021; 166:2469-2478. [PMID: 34216268 DOI: 10.1007/s00705-021-05141-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/29/2021] [Indexed: 10/20/2022]
Abstract
Hepatitis C virus (HCV) is a serious global health issue. Nearly 20% of HCV patients spontaneously clear the virus. While some studies have shown an association of spontaneous clearance (SC) of the virus with interleukin (IL) 28B single-nucleotide polymorphisms (SNPs), others did not show such a relationship. Thus, the purpose of the present study was to investigate the association of IL28B polymorphisms (12979860 SNP) with SC of HCV infection. Upon initial screening of the databases, a total of 545 articles were retrieved, of which 22 studies that met predefined eligibility criteria were entered into the meta-analysis. Odds ratios (ORs) with confidence intervals (95% CI), heterogeneity, publication bias, and sensitivity analysis were assessed. According to the meta-analysis results, a significant association was observed between the rs12979860 SNP and SC of HCV infection. The results indicated that the ORs of SC from hepatitis C virus infection were 2.75 times higher in those with cytokine gene polymorphisms (95% CI, 2.23 to 3.38). Moreover, it was found that the prevalence of rs12979860 CC was 0.33 with 95 CI 0.28-0.38 in genotype 1 and was 0.40 with 95 CI 0.34-0.47 in other genotypes. Our meta-analysis results suggest that IL28B rs12979860 CC is a strong predictor for SC of hepatitis C infection in PEG IFN-a/RBV-treated patients.
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Affiliation(s)
- Hamid Heidarian Miri
- Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pooria Fazeli
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Peyman Bemani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran.
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Rauff B, Amar A, Chudhary SA, Mahmood S, Tayyab GUN, Hanif R. Interferon-λ rs12979860 genotype association with liver fibrosis in chronic hepatitis C (CHC) patients in the Pakistani population. Arch Virol 2021; 166:1047-1056. [PMID: 33528661 DOI: 10.1007/s00705-020-04901-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/15/2020] [Indexed: 12/18/2022]
Abstract
Risk and progression of liver fibrosis and cirrhosis in chronic hepatitis C (CHC) patients is significantly influenced by host genetic factors in a polygenic manner. The rs12979860 genetic polymorphism in the interferon-λ3-interferon-λ4 (IFNL3-IFNL4) region has been found to be a major determinant of hepatic inflammatory and fibrotic progression in CHC patients of mainly Caucasian origin; however, it is not known if this association applies to other ethnicities, including Pakistani CHC patients. Here, we genotyped IFNL3-IFNL4 rs12979860 genetic variants in a sample set of 502 Pakistani patients with CHC and used logistic regression analysis to determine its association with the risk and progression of HCV-related fibrosis and cirrhosis. We demonstrate that the rs12979860 major (CC) genotype, despite not determining the risk of stage-specific hepatic fibrosis independently, is associated with a marginally significant risk of liver cirrhosis (OR: 1.64, p = 0.049) after an adjustment for age, gender, body mass index, HCV viral load, and liver enzymes. In a subgroup of CHC patients with sustained ALT levels of <60 IU/L, a more pronounced impact of the IFNL3-IFNL4 rs12979860 major (CC) genotype on advanced liver fibrosis (OR: 4.99, p = 0.017) and cirrhosis (OR: 3.34, p = 0.005) was seen. The present study suggests that IFNL3-IFNL4 rs12979860 polymorphism may also be a significant predictor of hepatic fibrosis and cirrhosis in Pakistani CHC patients, especially in those with normal or near-normal liver enzyme levels.
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Affiliation(s)
- Bisma Rauff
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, Australia
- Institute of Biomedical and Allied Health Sciences (IBAHS), University of Health Sciences (UHS), Lahore, Pakistan
| | - Ali Amar
- Department of Human Genetics and Molecular Biology, University of Health Sciences (UHS), Lahore, Pakistan
| | - Shafiq Ahmad Chudhary
- Institute of Biomedical and Allied Health Sciences (IBAHS), University of Health Sciences (UHS), Lahore, Pakistan
| | - Saqib Mahmood
- Institute of Biomedical and Allied Health Sciences (IBAHS), University of Health Sciences (UHS), Lahore, Pakistan
| | | | - Rumeza Hanif
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
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El-Garawani I, Hassab El-Nabi S, Gadallah M, Abdelsameea E. Association between IFN-λ 3 Gene Polymorphisms and Outcome of Treatment with Direct Acting Antivirals in Chronic HCV-Infected Egyptian Patients. Immunol Invest 2021; 50:12-22. [PMID: 32024403 DOI: 10.1080/08820139.2020.1722158] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background: Single nucleotide polymorphisms (SNPs) of the interferon lambda 3 (IFN-λ 3) gene are associated with viral clearance and treatment response in chronic hepatitis C virus (HCV) infection. Aim: to assess whether specific IFN-λ 3 gene SNP, known as rs12979860 (C > T), could predict the outcome of treatment with direct acting antivirals (DAAs) among Egyptian patients with chronic HCV genotype 4 infection. Methods: Tetra-primer (ARMS-PCR) and PCR-RFLP methods were used for SNP genotyping in 100 chronic HCV-infected patients and 50 healthy subjects as control group. Results: The CC (wild type) genotype of rs12979860 was identified in 20 patients, 50% of them achieved sustained virological response (SVR). SNP genotype TT was found in 17 patients and only 2 of them (11.76%) were responders. The frequency of CT genotypes was significantly higher in responders than in non-responders (p= .021). In contrast, the frequency of TT genotypes was significantly higher in non-responders (42.85%, p< .001). On univariate and multivariate logistic regression analyses of the significant predictors of SVR, there were six predictive factors (Age, diabetes mellitus, AST, albumin, type of therapy and IFN-λ 3 genotype). Conclusion: The TT genotype and T allele were significantly associated with failure to achieve SVR. However, CT genotype of IFN-λ 3 (rs12979860) may be considered as a predictor for SVR in patients who received DAAs.
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Affiliation(s)
- Islam El-Garawani
- Zoology Department, Faculty of Science, Menoufia University , Shibin Al Kawm, Egypt
| | - Sobhy Hassab El-Nabi
- Zoology Department, Faculty of Science, Menoufia University , Shibin Al Kawm, Egypt
| | - Marwa Gadallah
- Zoology Department, Faculty of Science, Menoufia University , Shibin Al Kawm, Egypt
| | - Eman Abdelsameea
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University , Shibin Al Kawm, Egypt
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Abstract
Fibrosis is a highly conserved and coordinated wound healing response to injury. In the liver, injury is promoted by immune effector mechanisms that are common across various disease etiologies and even between organs such as lungs, kidneys, heart, and other organs. Thus, the liver represents a useful model to study inflammation and repair, particularly as it is frequently biopsied in clinical contexts. Currently, strong evidence implicates IFNL3/4 polymorphisms and interferon (IFN)-λ3 levels as determinants of the extent of hepatic inflammation and fibrosis in viral and nonviral liver diseases, as well as in governing the severity of nonhepatotropic viral diseases. Interestingly, IFNL3/4 polymorphisms and IFN-λ3 levels correlate with fibrosis extent in other organs such as the lung and kidney. In this review, we discuss the association between IFN-λ and tissue inflammation and fibrosis in human disease and the potential clinical utility of the findings.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia
| | - Golo Ahlenstiel
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia
- Blacktown Medical School, Western Sydney University, Blacktown, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia
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Moghimi M, Tavakoli F, Doosti M, Ahmadi-Vasmehjani A, Akhondi-Meybodi M. Correlation between interleukin-28 gene polymorphism with interleukin-28 cytokine levels and viral genotypes among HCV patients in Yazd, Iran. BMC Res Notes 2019; 12:626. [PMID: 31551080 PMCID: PMC6760063 DOI: 10.1186/s13104-019-4651-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Recent studies using genome-wide association studies (GWAS) have shown the strong association between polymorphisms near the interleukin-28B (IL-28B) gene and spontaneous clearance of hepatitis C virus (HCV). The present study was designed to evaluate the association of interleukin-28 gene polymorphism with interleukin-28 cytokine levels in different viral genotypes among HCV patients in Yazd, Iran. RESULT The most prevalent genotype in chronic cases was genotype 3a, and the lowest one was 2/3a. There were statistically significant differences in genotype frequency between the two studied groups for IL-28B rs12979860C/T. The frequency of CC genotype of IL-28B at rs12979860 SNP was higher in spontaneously cleared patients in comparison with chronic HCV patients. Significant association was found when serum levels of IL28B were compared to various IL-28 genotypes. There was a significant difference between IL-28 polymorphism and HCV genotypes (p = 0.003).
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Affiliation(s)
- Mansour Moghimi
- Department of Pathology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Forough Tavakoli
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Doosti
- Infectious and Tropical Diseases Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Medical Virology, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran
| | - Abbas Ahmadi-Vasmehjani
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Akhondi-Meybodi
- Gastroentrology Department, Shahid Sadoughi Hospital, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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De Re V, Tornesello ML, De Zorzi M, Caggiari L, Pezzuto F, Leone P, Racanelli V, Lauletta G, Gragnani L, Buonadonna A, Vaccher E, Zignego AL, Steffan A, Buonaguro FM. Clinical Significance of Polymorphisms in Immune Response Genes in Hepatitis C-Related Hepatocellular Carcinoma. Front Microbiol 2019; 10:475. [PMID: 30930876 PMCID: PMC6429030 DOI: 10.3389/fmicb.2019.00475] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 02/25/2019] [Indexed: 12/12/2022] Open
Abstract
Background and Aims: Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases. Methods: Selected PDCD1, IFNL3, and TLR2 genes were tested by molecular approaches in 450 HCV-positive patients with increasing severity of underlying liver diseases [including chronic infection (CHC), cirrhosis and hepatocellular carcinoma (HCC)], in 238 HCV-positive patients with lymphoproliferative diseases [such as cryoglobulinemia and non-Hodgkin lymphoma (NHL)] and in 94 blood donors (BD). Results: While the rs12979860 IFNL3 T allele was found a good marker associated with HCV-outcome together with the rs111200466 TLR2 del variant, the rs10204525 PD-1.6 A allele was found to have an insignificant role in patients with HCV-related hepatic disorders. Though in Asian patients the combination of IFNL3 and PD-1.6 markers better define the HCV-related outcomes, in our series of Caucasian patients the PD-1.6 A-allele variant was observed very rarely. Conclusion: Differences in the incidence of HCV-related HCC and clinical response between Asians and Europeans may be partially due to the distribution of PD-1.6 genotype that we found divergent between these two populations. On the other hand, we confirmed in this study that the polymorphic variants within IFNL3 and TLR2 immune response genes are significantly associated with HCV-related disease progression in our cohort of Italian patients.
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Affiliation(s)
- Valli De Re
- Centro di Riferimento Oncologico, Cancer Institute, Aviano, Italy
| | | | | | - Laura Caggiari
- Centro di Riferimento Oncologico, Cancer Institute, Aviano, Italy
| | - Francesca Pezzuto
- Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, Italy
| | - Patrizia Leone
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Gianfranco Lauletta
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Laura Gragnani
- Department of Experimental and Clinical Medicine and Department of Oncology, Interdepartmental Hepatology Center MASVE, Azienda Ospedaliero-Universitaria Careggi (AOUC), Florence, Italy
| | | | - Emanuela Vaccher
- Centro di Riferimento Oncologico, Cancer Institute, Aviano, Italy
| | - Anna Linda Zignego
- Department of Experimental and Clinical Medicine and Department of Oncology, Interdepartmental Hepatology Center MASVE, Azienda Ospedaliero-Universitaria Careggi (AOUC), Florence, Italy
| | - Agostino Steffan
- Centro di Riferimento Oncologico, Cancer Institute, Aviano, Italy
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Attallah AM, Omran D, Omran MM, Abdelrazek MA, Zayed R, Essawey RE, Saif S, Farid A, Hassany M, Yosry A, Omar A. Extracellular Matrix Proteins Substantiate IL-28B T allele Effect on Histological Outcome of Chronic Hepatitis C. Ann Hepatol 2018; 17:569-576. [PMID: 29893697 DOI: 10.5604/01.3001.0012.0918] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM The correlation between interleukin-28B (IL-28B) polymorphisms and chronic hepatitis C (CHC) progression is debatable. Here, we aimed to evaluate the relation between IL-28B C/T genotypes and the development of cirrhotic liver. Extracellular matrix (ECM) proteins, FibroScan and model for end-stage liver disease (MELD) were used to substantiate the severity of liver disease. MATERIAL AND METHODS IL-28B rs12979860, liver stiffness and ECM proteins were assessed in 272 CHC patients. RESULTS Cirrhosis percentage increased to 10%, 52% and 96% with the increasing number of T alleles (CC, CT and TT, respectively). Also, elevated ECM proteins levels were correlated with the increasing number of T alleles. Interestingly, among cirrhotic patients, liver stiffness, MELD and ECM proteins were significantly (P < 0.0001) higher in patients with TT more than CT genotype. FibroScan, hyaluronic acid, Laminin, Collagen IV and the N-terminal pro-peptide of collagen type III have high accuracy to differentiate liver status in CC from TT genotype. Area under receiver-operating characteristic curve (95% CI) were 1.0 (1.0-1.0), 0.97 (0.96- 1.0), 0.93 (0.85-1.0), 0.98 (0.97-1.0) and 0.93 (0.91-0.97), respectively. CONCLUSION This study suggests that IL-28B T allele affects the natural course of CHC type 4 and also suggests that carriage of the IL-28B C allele protects from unfavorable clinical outcomes in CHC as coexistence of C allele with T allele reduced cirrhosis severity.
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Affiliation(s)
- Abdelfattah M Attallah
- Research & Development Department, Biotechnology Research Center, New Damietta City, Egypt
| | - Dalia Omran
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
| | | | - Mohamed A Abdelrazek
- Research & Development Department, Biotechnology Research Center, New Damietta City, Egypt
| | - Rania Zayed
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Egypt
| | - Riham El Essawey
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Egypt
| | - Sameh Saif
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Azza Farid
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Mohamed Hassany
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Ayman Yosry
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
| | - Ashraf Omar
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
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Gutwerk A, Wex T, Stein K, Langner C, Canbay A, Malfertheiner P, Link A. Helicobacter Pylori Serology in Relation to Hepatitis C Virus Infection and IL28B Single Nucleotide Polymorphism. J Clin Med 2018; 7:44. [PMID: 29510558 PMCID: PMC5867570 DOI: 10.3390/jcm7030044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 03/01/2018] [Accepted: 03/02/2018] [Indexed: 12/18/2022] Open
Abstract
The aim of the study was to evaluate the serological rate of Helicobacter pylori (H. pylori) infection in patients with chronic hepatitis C virus (HCV) infection and determine any correlations with liver damage and IL28B single-nucleotide polymorphism (SNP). One hundred eighty-nine patients with chronic HCV infection were included in the study, and H. pylori status was defined based on anti-H. pylori-IgG or anti-CagA-IgG antibodies using enzyme-linked immunosorbent assay (ELISA). Liver damage was assessed using histology or transient elastography. IL28B C/T polymorphism (rs12979860) was evaluated in circulating blood cells using a PCR-based restriction fragment length polymorphism assay. Overall H. pylori serology was positive in 38.1% of our HCV-infected subjects. Among those, the anti-CagA-IgG positivity rate was 43.1% and was within the range of previously described populations of the same region. Highest prevalence of H. pylori was found in patients between 31 and 40 years compared to other age subgroups. The seropositivity rate was higher in the non-cirrhotic group than the cirrhotic one (45.4% vs. 20.0%, p < 0.05). No difference was found in IL28B genotype between H. pylori-positive and -negative cohorts. However, we observed a trend for the lower anti-CagA-IgG expression level in relation to the IL28B T-allele. Our results do not support an association between HCV and H. pylori infection. Whether IL28B SNP has a functional role in modulation of serological response to H. pylori CagA needs further investigation.
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Affiliation(s)
- Alexander Gutwerk
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
- Medical Laboratories for Clinical Chemistry, Microbiology and Infectious Diseases, Department of Molecular Genetics, 39124 Magdeburg, Germany.
| | - Kerstin Stein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Cosima Langner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Ali Canbay
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
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Huang CI, Huang CF, Yeh ML, Lin YH, Liang PC, Liu SYV, Hsieh MH, Lin ZY, Chen SC, Huang JF, Chuang WL, Dai CY, Yu ML. Role of IL-28B genetic variants in HCV-related liver disease severity in patients with different viral genotypes. Medicine (Baltimore) 2018; 97:e9782. [PMID: 29517696 PMCID: PMC5882450 DOI: 10.1097/md.0000000000009782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 12/04/2017] [Accepted: 01/10/2018] [Indexed: 12/25/2022] Open
Abstract
Reports of the role of host interleukin 28B (IL-28B) genetic variants in liver disease severity in patients with chronic hepatitis C (CHC) have obtained conflicting results. The impact of IL-28B in Asian patients with different viral genotypes remains elusive.We try to elucidate the effect of IL-28B genetic variants in a large Asian cohort with different viral genotypes.The association between the IL-28B rs8099917 genotype and liver fibrosis was investigated in 1288 patients with biopsy-proven CHC.Patients with hepatitis C virus genotype 1 (HCV-1) infection comprised 59.4% of the population. The remaining 40.6% (518 patients) did not have HCV-1 infection. Of the 1084 patients with the IL-28 genotype, 85.6% (928 patients) had the TT genotype. Univariate analysis revealed that, compared to patients without advanced liver fibrosis, patients with advanced liver fibrosis (Metavir fibrosis score 3-4) had an older age, a lower platelet count, a higher α-fetoprotein level, a higher alanine aminotransferase level, a higher incidence of diabetes, and a higher frequency of rs8099917 non-TT genotype carriage.Logistic regression analysis revealed that factors significantly associated with advanced liver fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 1.023/1.009-1.037, P = .001), diabetes (OR/CI: 1.736/1.187-2.539, P = .004), α-fetoprotein (OR/CI: 1.007/1.002-1.012, P = .009), platelet count (OR/CI: 0.991/0.988-0.993, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.585/0.400-0.856, P = .006). When patients were classified by viral genotype, factors that had significant independent associations with advanced liver fibrosis in patients with HCV-1 infection included diabetes (OR/CI: 2.379/1.452-3.896, P = .001), α-fetoprotein (OR/CI: 1.023/1.012-1.035, P < .001), platelet count (OR/CI: 0.99/0.987-0.994, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.529/0.328-0.854, P = .009). In patients who had advanced liver fibrosis but not HCV-1 infection, factors that had significant independent associations with advanced liver fibrosis included age (OR/CI: 1.039/1.016-1.063, P = .001) and platelet count (OR/CI: 0.99/0.986-0.995, P < .001); additionally, IL-28B genetic variants were not associated with liver disease severity.Unfavorable IL-28B genetic variants were associated with advanced liver disease. The genetic effect is limited to patients with HCV-1 infection.
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Affiliation(s)
- Ching-I Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
| | - Chung-Feng Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital
| | - Shang-Yin Vanson Liu
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University
| | - Meng-Hsuan Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Jee-Fu Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Wan-Long Chuang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
| | - Chia-Yen Dai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University
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Baharlou R, Romani B, Kiani SJ, Sadeghi K, Shadmand E, Fazel H, Jalilian FA, Kord E, Yaghoubi S, Nikmanesh Y, Ahmadi Vasmehjani A. Genotype-related variations in proinflammatory and regulatory cytokine levels in treated and treatment-naive HCV-infected patients. Med Microbiol Immunol 2018; 207:65-74. [PMID: 29147974 DOI: 10.1007/s00430-017-0527-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 11/09/2017] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) modulates immune-related inflammatory responses to induce milder reactions leading to virus persistence. In this regard, the present study aimed to investigate the link between the HCV genotypes and the proinflammatory and regulatory cytokine levels. Ninety patients with hepatitis C infection (68 treatment-naive and 22 treated patients) and 76 healthy blood donors were studied. The serum levels of IFN-γ, IL-10, IL-17A, and IL-21 were measured by ELISA in the patients and healthy controls. IL-10, IL-17A, and IL-21 levels were significantly higher in HCV patients than in the healthy controls. The same cytokines were also higher in genotype 3a-infected patients compared with genotype 1a-infected patients. Interestingly, in treated patients, lower serum levels of IL-17A and IL-21 were detected in G3a-infected individuals, but not in those infected with G1a. G3a viral load displayed a significant correlation with IL-21 and IL-17A levels. In addition, G1a viral load correlated with IL-10 levels. In G3a-infected patients, a significant association was found between IL-17A serum levels and ALT. We found differences in IL-21 and IL-17A serum levels among HCV-infected patients which were genotype dependent. Since Th17-associated cytokines are associated with the progression of liver disease in HCV patients, IL-17A and IL-21 can be used as important biological markers for evaluating the immunopathogenesis of chronic hepatitis. Our results suggest that HCV G3a along with immune responses such as cytokines in HCV patients should be taken into account when interpreting clinical data and IFN-based therapeutic response.
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Affiliation(s)
- Rasoul Baharlou
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, School of Medicine, Motahari Blvd, Jahrom, Iran
| | - Bizhan Romani
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
- Cellular & Molecular Research Center (CMRC), Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences (AJUMS), Ahvaz, Iran
| | - Seyed Jalal Kiani
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Kaveh Sadeghi
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Enayatollah Shadmand
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, School of Medicine, Motahari Blvd, Jahrom, Iran
| | - Hadi Fazel
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Farid Azizi Jalilian
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ebrahim Kord
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajad Yaghoubi
- Division of Microbiology, Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Yousef Nikmanesh
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Ahmadi Vasmehjani
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, School of Medicine, Motahari Blvd, Jahrom, Iran.
- Department of Microbiology and Immunology, Jahrom University of Medical Sciences, Jahrom, Iran.
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Machicote A, Flichmann D, Arana E, Paz S, Fainboim H, Fainboim L, Fernández PM. IL28B SNPs rs12979860 and rs8099917 Are Associated with Inflammatory Response in Argentine Chronic HCV Patients. ACTA ACUST UNITED AC 2018. [DOI: 10.4236/ijcm.2018.92009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Li Y, Wei T, Yan L, Yang Z, Huang Q, Shi Y, Wang L. Association of interleukin-28B polymorphisms with platelet count and liver function recovery after liver transplant. Medicine (Baltimore) 2017; 96:e8219. [PMID: 29095252 PMCID: PMC5682771 DOI: 10.1097/md.0000000000008219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 09/10/2017] [Accepted: 09/13/2017] [Indexed: 02/05/2023] Open
Abstract
The present genome-wide association study investigated the relationship of interleukin 28B (IL-28B) genetic variants with HBV susceptibility and prognosis of HBV-infected patients. This study aims to examine the role of IL-28B polymorphisms on transplant etiologies and the liver function recovery in Chinese liver transplant recipients.A total of 231 liver transplant recipients were enrolled in the study. The transplant etiologies included progressive HBV hepatitis, HBV-related liver cirrhosis (LC), HBV-related hepatocellular carcinoma (HCC), and non-HBV-related disease. All recipients were in stable condition before transplantation. Three single nucleotide polymorphisms (SNPs) of IL-28B (rs12979860, rs12980275, rs8099917) of recipients were analyzed by high-resolution melting (HRM) curve analysis. Liver function, blood cell count, and coagulation function were regularly tested before and for next 5 years after transplantation.No significant association was found between IL-28B gene polymorphisms and transplant etiologies. Peripheral platelet count in the third and fourth days after transplantation were significantly higher in recipients carrying IL-28B rs12979860 T allele, or rs8099917 C allele (P < .016666667), while there were no significant differences between these variants and International Normalized Ratio (INR) levels. In addition, gamma-glutamyltransferase (GGT) levels in recipients with rs12980275 G allele were higher than those in the wide-type recipients before transplantation (P < .016666667, respectively); nevertheless, no influence of these variants on GGT recovery was observed after transplantation.Genetic variations of IL-28B might impact on liver function recovery by influencing peripheral platelet counts and reducing liver inflammation, but have weak association with transplant etiologies.
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Affiliation(s)
- Yi Li
- Department of Laboratory Medicine
| | - Tiantian Wei
- Kidney Research Institute, Division of Nephrology, West China Hospital
| | - Lin Yan
- Department of Laboratory Medicine
| | - Zhiqiang Yang
- West China Medical School, Sichuan University, Chengdu, China
| | - Qian Huang
- West China Medical School, Sichuan University, Chengdu, China
| | - Yunying Shi
- Kidney Research Institute, Division of Nephrology, West China Hospital
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Boglione L, Cusato J, Cariti G, Di Perri G, D'Avolio A. Role of IL28B genotype in the liver stiffness increase in untreated patients with chronic hepatitis C. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2017; 53:195-198. [PMID: 28579527 DOI: 10.1016/j.meegid.2017.05.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 05/17/2017] [Accepted: 05/31/2017] [Indexed: 01/01/2023]
Abstract
The role of interleukin (IL)28B has been deepened in the treatment response to pegylated-interferon in patients affected by chronic hepatitis C (CHC). However, recently the IL28B genotypes were also related to hepatic fibrosis progression in untreated patients, using the liver biopsy. The aim of this prospective and longitudinal study was to assess the role of different IL28B genotypes in the liver stiffness progression in a cohort of untreated subjects affected by CHC. We included in this analysis all untreated patients affected by CHC and followed for at least 5years with the annual evaluation of liver stiffness using Fibroscan®. All enrolled subjects were genotyped for rs8099917 and rs12979860 IL28B polymorphisms. In the study period, 266 patients were considered. After 5years we observed the following median stiffness increases: 6.7kPa [5.1-7.8] in TT/CC, 4.9kPa [4.1-5.0] in TT/TC, 3.4kPa [3.2-3.8] in TG/TC and 1.7kPa [1.2-1.9] in GG/TT. These values were statistically significant in all groups (p<0.001). In the multivariate analysis resulted as predictive factors of liver stiffness progression the following: IL28B TT/CC genotype (OR=4.571; 95%IC=2.381-12.994; p<0.001) and IL28B GG/TT genotype (OR=0.510; 95%IC=0.289-0.712; p=0.007). In this study we evidenced that IL28B genotypes were associated with a different level of liver stiffness increase after 5years and could be used to select the patients who should be treated with priority.
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Affiliation(s)
- Lucio Boglione
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
| | - Jessica Cusato
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giuseppe Cariti
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
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Shaker OG, Senousy MA. Serum microRNAs as predictors for liver fibrosis staging in hepatitis C virus-associated chronic liver disease patients. J Viral Hepat 2017; 24:636-644. [PMID: 28211229 DOI: 10.1111/jvh.12696] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 02/03/2017] [Indexed: 12/21/2022]
Abstract
Accurate staging of liver fibrosis is important for clinical decision making and personalized management. Liver fibrosis is influenced by patients' genomics, including IFNL3 genotype and microRNA expression. However, incorporating microRNAs into fibrosis prediction algorithms has not been investigated. We examined the potential of eight selected serum microRNAs; miR-122, miR-126, miR-129, miR-199a, miR-155, miR-203a, miR-221, and miR-223 as non-invasive biomarkers to stage liver fibrosis in HCV-associated chronic liver disease (HCV-CLD). 145 Egyptian HCV-CLD patients were divided according to Metavir fibrosis scores. MicroRNAs and IFNL3 rs12979860 genotype were assayed by RT-qPCR and allelic discrimination techniques, respectively. Serum miR-122 was downregulated, whereas miR-203a and miR-223 were upregulated in significant fibrosis (≥F2) compared with no/mild fibrosis (F0-F1). Serum miR-126, miR-129, miR-203a, and miR-223 were upregulated in severe fibrosis (≥F3) and cirrhosis (F4) compared with F0-F2 and F0-F3, respectively. miR-221 was upregulated in ≥F3, but unchanged in F4. miR-155, miR-199a, and IFNL3 rs12979860 genotype were not significantly different in all comparisons. Differentially expressed serum microRNAs discriminated ≥F2, ≥F3, and F4 by receiver-operating-characteristic analysis. Multivariate logistic analysis revealed a model combining miR-129, miR-223, AST, and platelet count with high diagnostic accuracy for ≥F3 (AUC=0.91). The model also discriminated F4 (AUC=0.96) and ≥F2 (AUC=0.783), and was superior to APRI and FIB-4 in discriminating ≥F3 and F4, but not ≥F2. In conclusion, combining serum microRNAs with baseline predictors could serve as a new non-invasive algorithm for staging HCV-associated liver fibrosis. Additional studies are required to confirm this model and test its significance in liver fibrosis of other etiologies.
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Affiliation(s)
- O G Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - M A Senousy
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Association of Genotype and Haplotype of IL-28B Gene with Hepatitis C Infection Outcome in Iran: Spontaneous Clearance Versus Chronic Infection. HEPATITIS MONTHLY 2017. [DOI: 10.5812/hepatmon.45745] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Mangia A, De Ledinghen V, Bailly F, Brahm J, Keiss J, Valantinas J, Rasmann N, Messinger D, Tatsch F, Bakalos G, Foster GR. IL28B genotype is associated with cirrhosis or transition to cirrhosis in treatment-naive patients with chronic HCV genotype 1 infection: the international observational Gen-C study. SPRINGERPLUS 2016; 5:1990. [PMID: 27917361 PMCID: PMC5116020 DOI: 10.1186/s40064-016-3663-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 11/07/2016] [Indexed: 02/07/2023]
Abstract
Background and purpose Contradictory data exist on the association between host interleukin-28B (IL28B) rs12979860 genotype and liver fibrosis in patients with chronic hepatitis C (CHC). This large, international, observational study (NCT01675427/MV25600) investigated relationships between IL28B rs12979860 genotype and liver fibrosis stage in CHC patients. Methods A total of 3003 adult, treatment-naive CHC patients were enrolled into the study. Patients made one study visit to provide a blood sample for genotyping; other data were obtained from medical records. Results 2916 patients comprised the analysis population; the majority were enrolled in Europe (n = 2119), were Caucasian (n = 2582) and had hepatitis C virus (HCV) genotype (G)1 infection (n = 1702) (G2 = 323, G3 = 574, G4 = 260). Distribution of IL28B genotypes varied according to region of enrolment, patient ethnicity and HCV genotype. A significant association was observed between increasing number of IL28B T alleles and the prevalence of cirrhosis/transition to cirrhosis (based on biopsy or non-invasive assessments) in G1-infected patients (CC = 22.2% [111/499], CT = 27.5% [255/928], TT = 32.3% [87/269]; p = 0.0018). The association was significant in the large subgroup of European Caucasian G1 patients (n = 1245) but not in the smaller Asian (n = 25), Latin American (n = 137) or Middle Eastern (n = 289) G1 subgroups. IL28B genotype was not associated with liver fibrosis stage in patients with HCV G2, G3 or G4 infection. Conclusion This large, international study found that IL28B rs12979860 genotype is significantly associated with liver fibrosis stage in CHC patients with HCV G1 infection. This association was evident in European Caucasians but not in G1-infected patients from Asia, Latin America or the Middle East. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-3663-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, 71013 Italy
| | | | - François Bailly
- Hepatology Unit, Groupe Hospitalier Nord, CHU Lyon, 69004 Lyon, France
| | - Javier Brahm
- Gastroenterology Department, University of Chile Clinical Hospital, Santiago, 8380456 Chile
| | - Jazeps Keiss
- Latvian Centre of Infectious Diseases, LLC Riga East University Hospital, Riga, 1006 Latvia
| | - Jonas Valantinas
- Centre of Hepatology, Gastroenterology and Dietetics, Vilnius University, 08661 Vilnius, Lithuania
| | - Nele Rasmann
- Center for Infectious Diseases, West Tallinn Central Hospital, 10617 Tallinn, Estonia
| | | | - Fernando Tatsch
- Global Medical Affairs, F. Hoffmann-La Roche Ltd, 4074 Basel, Switzerland ; AbbVie, North Chicago, IL USA
| | - Georgios Bakalos
- Global Product Development Medical Affairs, F. Hoffmann-La Roche Ltd, 4074 Basel, Switzerland
| | - Graham R Foster
- Institute of Cellular and Molecular Sciences, Queen Mary University of London, London, E1 2AT UK
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Mah YH, Liu CH, Chen CL, Tseng TC, Liu CJ, Chen PJ, Chen DS, Kao JH. Prevalence and clinical implications of IL28B genotypes in Taiwanese patients with chronic hepatitis C. J Formos Med Assoc 2016; 115:953-960. [PMID: 27751759 DOI: 10.1016/j.jfma.2016.07.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 06/23/2016] [Accepted: 07/05/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/PURPOSE Clinical implications of IL28B gene in Taiwanese chronic hepatitis C (CHC) patients remain unknown. We thus investigated the prevalence and clinical implications of IL28B rs8099917 genotypes in CHC patients with different hepatitis C virus (HCV) genotypes and healthy controls. METHODS A total of 200 HCV genotype 1 patients and 200 HCV genotype 2 patients who received liver biopsy, as well as 197 healthy controls were enrolled to determine the frequencies of IL28B rs8099917 genotypes. In addition, the association of IL28B rs8099917 genotype with baseline data, including HCV RNA level, HCV genotype, histological activity grade, fibrosis stage, and body mass index, were evaluated and further stratified by covariant factors. RESULTS Compared with healthy controls, CHC patients had a lower prevalence rate of favorable IL28B rs8099917 TT genotype (81.0% vs. 89.3%, p = 0.025). In addition, the prevalence rates of favorable TT genotype in patients with HCV genotypes 1 and 2 were 76.0% and 86.0%, respectively (p = 0.007). Using ordered logistic regression analysis, higher fibrosis stages were found to be associated with a lower prevalence of TT genotype (p = 0.033), but not histological activity grades (p = 0.748). The association with fibrosis stages was more pronounced in female patients (p = 0.024). CONCLUSION In Taiwan, CHC patients have a lower frequency of favorable IL28B TT genotype than healthy controls. Among patients with CHC, the frequency of TT genotype is higher in HCV genotype 2 patients than in HCV genotype 1 patients. In addition, CHC patients with TT genotype, particularly females, have a lower likelihood of advanced fibrosis.
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Affiliation(s)
- Yone-Han Mah
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, Lotung St Mary's Hospital, I-Lan, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei City, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
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Mehta M, Hetta HF, Abdel-Hameed EA, Rouster SD, Hossain M, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, El-Mokhtar MA, Abdelwahab SF, Medhat A, Sherman KE, Shata MTM. Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients. Arch Virol 2016; 161:3161-3169. [PMID: 27544760 PMCID: PMC5035222 DOI: 10.1007/s00705-016-3015-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 08/11/2016] [Indexed: 02/08/2023]
Abstract
The IL28B gene is associated with spontaneous or treatment-induced HCV viral clearance. However, the mechanism by which the IL28B single nucleotide polymorphism (SNP) affects the extra-hepatic HCV immune responses and its relationship to HCV pathogenesis have not been thoroughly investigated. To examine the mechanism by which IL28B affects HCV clearance. Forty Egyptian patients with chronic HCV infection receiving an Interferon/ribavirin treatment regimen were enrolled into this study. There were two groups: non-responders (NR; n = 20) and sustained virologic responders (SVR; n = 20). The initial plasma HCV viral loads prior to treatment and IL28B genotypes were determined by quantitative RT-PCR and sequencing, respectively. Liver biopsies were examined to determine the inflammatory score and the stage of fibrosis. Colonic regulatory T cell (Treg) frequency was estimated by immunohistochemistry. No significant association between IL28B genotypes and response to therapy was identified, despite an odds ratio of 3.4 to have the TT genotype in NR compared to SVR (95 % confidence interval 0.3-35.3, p = 0.3). Patients with the TT-IL28Brs12979860 genotype (unfavorable genotype) have significantly higher frequencies of colonic Treg compared to the CT (p = 0.04) and CC (p = 0.03) genotypes. The frequency of colonic Treg cells in HCV-infected patients had a strong association with the IL-28B genotype and may have a significant impact on HCV clearance.
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Affiliation(s)
- Minesh Mehta
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Helal F Hetta
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enass A Abdel-Hameed
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Susan D Rouster
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - MdMonir Hossain
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Mohamed A Mekky
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nasr K Khalil
- Assiut Liver Institute for Treatment of Hepatitis C, Assiut, Egypt
| | - Wegdan A Mohamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Feky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shabaan H Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enas A Daef
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Sayed F Abdelwahab
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minya, Egypt
| | - Ahmed Medhat
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Kenneth E Sherman
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Mohamed Tarek M Shata
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH, 45267-0595, USA.
- Department of Microbiology, Saint James School of Medicine, Saint Vincent, Arnos Vale, Saint Vincent and the Grenadines.
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22
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Nguyen LT, Gray E, O'Leary A, Carr M, De Gascun CF, Irish Hepatitis C Outcomes Research Network. The Role of Hepatitis C Virus Core Antigen Testing in the Era of Direct Acting Antiviral Therapies: What We Can Learn from the Protease Inhibitors. PLoS One 2016; 11:e0163900. [PMID: 27711230 PMCID: PMC5053597 DOI: 10.1371/journal.pone.0163900] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 09/18/2016] [Indexed: 12/16/2022] Open
Abstract
Direct-acting antiviral (DAA) therapies have revolutionised the treatment of hepatitis C virus (HCV). The financial cost of DAAs however is significant, and first generation protease inhibitors (PIs) also require frequent monitoring of viral RNA levels to guide treatment. In this context, we examined the relevance of HCV antigen testing to evaluate the potential role in monitoring virological response to HCV antiviral treatment with the PI-based triple therapies, telaprevir (TVR) and boceprevir (BOC). Chronic HCV-infected individuals (n = 152) enrolled in the Irish Hepatitis C Outcomes Research Network (ICORN) study were prospectively analysed for baseline markers and the early viral kinetics associated with SVR. The sustained virological response (SVR) rates in the cohort receiving TVR and BOC were 87.3% and 73.8%, respectively. Baseline factors associated with successful outcome in TVR therapy were age (P = 0.0098), IFNL3 genotype (P = 0.0330) and viral load (P = 0.0456). RNA level at week 4 (P = 0.0068) and viral antigen negativity at week 2 (P = 0.0359) were predictive of SVR for TVR-based therapy. In BOC therapy, prior interferon treatment (P = 0.0209) and IFNL3 genotype (P = 0.0410) were baseline predictors of SVR. Evidence of viraemia based either on viral RNA or antigen at week 4 predicted SVR in these patients. Our data showed that rapid decline of HCV antigen to negative level at week 2 in TVR treatment and <0.96 log fmol/l in BOC treatment after commencement of PI triple therapy were associated with SVR. HCV antigen measurement should be considered as a potential alternative for monitoring treatment response during DAA-based regimens.
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Affiliation(s)
- Linh Thuy Nguyen
- National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
- Ireland Vietnam Blood-Borne Virus Initiative (IVVI), Dublin, Ireland and Hanoi, Vietnam
- * E-mail:
| | - Emma Gray
- National Centre for Pharmacoeconomics in Ireland, St James’s Hospital, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics in Ireland, St James’s Hospital, Dublin, Ireland
| | - Michael Carr
- National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
| | - Cillian F. De Gascun
- National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
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23
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The Effect of IL28B Gene Polymorphism on Treatment Response in Iranian Patients with Hepatitis C Virus Infection. Jundishapur J Microbiol 2016. [DOI: 10.5812/jjm.31501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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24
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Teama SH, Agwa SH, El Sayed OA, Sayed MM, Abd El Samee A, El Nakeep S. Assessment of interleukin-28B (interferon λ3) rs12979860 C/T gene polymorphism and the risk for hepatocellular carcinoma in chronic hepatitis C cirrhotic patients. EGYPTIAN LIVER JOURNAL 2016. [DOI: 10.1097/01.elx.0000515930.52529.6c] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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25
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De Re V, De Zorzi M, Caggiari L, Lauletta G, Tornesello ML, Fognani E, Miorin M, Racanelli V, Quartuccio L, Gragnani L, Russi S, Pavone F, Ghersetti M, Costa EG, Casarin P, Bomben R, Mazzaro C, Basaglia G, Berretta M, Vaccher E, Izzo F, Buonaguro FM, De Vita S, Zignego AL, De Paoli P, Dolcetti R. HCV-related liver and lymphoproliferative diseases: association with polymorphisms of IL28B and TLR2. Oncotarget 2016; 7:37487-37497. [PMID: 27183918 PMCID: PMC5122326 DOI: 10.18632/oncotarget.9303] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 04/19/2016] [Indexed: 12/29/2022] Open
Abstract
To explore the relationship between innate immunity and hepatitis C Virus (HCV) in determining the risk of cirrhosis (CIR), hepatocellular carcinoma (HCC), mixed cryoglobulinemia syndrome (MCS) and non-Hodgkin lymphoma (NHL), we investigated the impact of the toll-like receptor-2 (TLR2) and interleukin-28B (IL28B) genetic variants. TLR2 -174 del variant was associated with TLR2 expression and with specific downstream molecules that drive the expression of different interleukins; rs12979860 Il28B was important in response to interferon-treatment and in spontaneous clearance of HCV. The risk for liver and lymphoproliferative diseases in HCV progression was clarified by stratifying 862 HCV-positive patients into groups based on liver (CIR, HCC) and lymphoproliferative HCV-related diseases (MCS, NHL) and compared with chronic HCV (CHC) infection. Analysis of TLR2-IL28B haplotypes showed an association of wild type haplotype with the lymphoproliferative diseases (OR 1.77, p = 0.029) and a slight increase in HCV viral load (HR 1.38, p = 0.054). Wild type haplotype (TLR2 ins/ins- IL28B C/C) was also found associated with older age in patients with an hepatic diseases (in CIR and in HCC p = 0.038 and p = 0.020, respectively) supporting an effect of innate immunity in the liver disease progression. TLR2 and IL28B polymorphisms in combination showed a role in the control of HCV viral load and different HCV disease progression.
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Affiliation(s)
- Valli De Re
- Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Mariangela De Zorzi
- Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Laura Caggiari
- Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Gianfranco Lauletta
- Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Elisa Fognani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Marta Miorin
- Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Vito Racanelli
- Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Luca Quartuccio
- Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital “Santa Maria della Misericordia”, Udine, Italy
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Sabino Russi
- Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Fabio Pavone
- Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Michela Ghersetti
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Elena Garlatti Costa
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Pietro Casarin
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy
| | - Riccardo Bomben
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Cesare Mazzaro
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Giancarlo Basaglia
- Microbiology-Immunology and Virology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Massimiliano Berretta
- Medical Oncology, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Emanuela Vaccher
- Medical Oncology, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Francesco Izzo
- Hepatobiliary Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Salvatore De Vita
- Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital “Santa Maria della Misericordia”, Udine, Italy
| | - Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Paolo De Paoli
- Scientific Directorate, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
| | - Riccardo Dolcetti
- Cancer Bio-Immunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy
- University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
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26
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Mueller JL, King LY, Johnson KB, Gao T, Nephew LD, Kothari D, Simpson MA, Zheng H, Wei L, Corey KE, Misdraji J, Lee JH, Lin MV, Gogela NA, Fuchs BC, Tanabe KK, Gordon FD, Curry MP, Chung RT. Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study. Clin Transplant 2016; 30:452-460. [PMID: 26854475 PMCID: PMC4868041 DOI: 10.1111/ctr.12710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2016] [Indexed: 01/03/2023]
Abstract
Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.
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Affiliation(s)
- Jessica L. Mueller
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Lindsay Y. King
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Kara B. Johnson
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Tian Gao
- Division of Gastroenterology, Department of Medicine, Boston Medical Center, Boston, MA
| | - Lauren D. Nephew
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Health System, Philadelphia, PA
| | - Darshan Kothari
- Harvard Medical School, Boston, MA
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconness Medical Center, Boston
| | - Mary Ann Simpson
- Division of Gastroenterology, Department of Medicine, Lahey Hospital & Medical Center, Burlington
| | - Hui Zheng
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Lan Wei
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Kathleen E. Corey
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Joon Hyoek Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - M. Valerie Lin
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Neliswa A. Gogela
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Bryan C. Fuchs
- Harvard Medical School, Boston, MA
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Kenneth K. Tanabe
- Harvard Medical School, Boston, MA
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Fredric D. Gordon
- Harvard Medical School, Boston, MA
- Division of Gastroenterology, Department of Medicine, Lahey Hospital & Medical Center, Burlington
| | - Michael P. Curry
- Harvard Medical School, Boston, MA
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconness Medical Center, Boston
| | - Raymond T. Chung
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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27
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Sarkar M, Aouzierat B, Bacchetti P, Prokunina-Olsson L, French A, Seaberg E, O'Brien TR, Kuniholm MH, Minkoff H, Plankey M, Strickler HD, Peters MG. Association of IFNL3 and IFNL4 polymorphisms with liver-related mortality in a multiracial cohort of HIV/HCV-coinfected women. J Viral Hepat 2015; 22:1055-60. [PMID: 26115445 PMCID: PMC4618098 DOI: 10.1111/jvh.12431] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 05/08/2015] [Indexed: 12/22/2022]
Abstract
African Americans coinfected with HIV and hepatitis C virus (HCV) have lower liver-related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV-related outcomes, the impact of these variants on liver-related mortality has not been investigated. We conducted a cohort study of HIV/HCV-coinfected women followed in the multicentre, NIH-funded Women's Interagency HIV Study (WIHS) to investigate whether 10 polymorphisms spanning the IFN-λ region were associated with liver-related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver-related death by race/ethnicity (ascertained by self-report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver-related deaths during up to 18 years of follow-up. On adjusted analysis, rs12980275 GG genotype compared to AG+AA hazards ratios [(HR) 0.36, 95% CI 0.14-0.90, P = 0.029] and rs8109886 AA genotype compared to CC+AC (HR 0.67, 95% CI 0.45-0.99, P = 0.047) were most strongly associated with liver-related death although these associations were no longer significant after adjusting for race/ethnicity (HR 0.41, 95% CI 0.16-1.04, P = 0.060 and HR 0.78, 95% CI 0.51-1.19, P = 0.25, respectively). African American women had persistently lower liver-related death independent of IFN-λ variants (HRs ≤ 0.44, P values ≤ 0.04). The lower risk of death among African American HIV/HCV-coinfected women is not explained by genetic variation in the IFN-λ region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality.
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Affiliation(s)
- M Sarkar
- Division of Gastroenterology and Hepatology, Medicine, University of California San Francisco, San Francisco, CA, USA
| | - B Aouzierat
- Nursing, University of California San Francisco, San Francisco, CA, USA
| | - P Bacchetti
- Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - L Prokunina-Olsson
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - A French
- Medicine, CORE Center/Stroger Hospital of Cook County, Chicago, IL, USA
| | - E Seaberg
- Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - T R O'Brien
- Division of Cancer Epidemiology and Genetics, Infections and Immunoepidemiology Branch, National Cancer Institute, Bethesda, MD, USA
| | - M H Kuniholm
- Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - H Minkoff
- Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NY, USA
| | - M Plankey
- Division of Infectious Diseases, Georgetown University, Washington D.C., USA
| | - H D Strickler
- Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - M G Peters
- Division of Gastroenterology and Hepatology, Medicine, University of California San Francisco, San Francisco, CA, USA
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28
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Lemoine M, Chevaliez S, Bastard JP, Fartoux L, Chazouillères O, Capeau J, Pawlotsky JM, Serfaty L. Association between IL28B polymorphism, TNFα and biomarkers of insulin resistance in chronic hepatitis C-related insulin resistance. J Viral Hepat 2015; 22:890-6. [PMID: 25818002 DOI: 10.1111/jvh.12408] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 01/31/2015] [Indexed: 12/31/2022]
Abstract
TNFα has been shown to play a role in hepatitis C virus (HCV)-induced insulin resistance (IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNFα. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNFα activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNFα (sTNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA-IR was positively correlated with serum levels of leptin (r = 0.35, P < 0.0001) and sTNFR1 (r = 0.35, P < 0.0001) but not with IL-6 or adiponectin. IL28B rs12979860 CC genotype was observed in 35% patients. Genotype CC and nongenotype CC patients were similar in terms of HOMA-IR (means 1.6 ± 0.9 vs 1.7 ± 1.4) and had similar circulating levels of sTNFR1 and adipokines. Independent factors associated with IR were ferritin (OR = 1.002, P = 0.02), leptin (OR = 1.06, P = 0.02) and sTNFR1 (OR = 7.9, P = 0.04). This study suggests that in nondiabetic, noncirrhotic, HCV genotype 1-infected patients, there is no relationship between IL28B rs12979860 genotype and HOMA-IR or sTNFR1 level. HCV-related IR may be mediated through TNFα independent of IL28B genotype.
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Affiliation(s)
- M Lemoine
- Service d'Hépatologie, APHP, Hôpital Saint-Antoine, Paris, France
- UPMC Université Paris 06, UMR_S938, Paris, France
| | - S Chevaliez
- APHP, Laboratoire de Virologie, Hopital Henri Mondor, Créteil, France
- INSERM U955, Université Paris-Est Créteil, Créteil, France
| | - J P Bastard
- UPMC Université Paris 06, UMR_S938, Paris, France
- Service de biochimie et hormonologie, APHP, Hôpital Tenon, Paris, France
| | - L Fartoux
- Service d'Hépatologie, APHP, Hôpital Saint-Antoine, Paris, France
| | - O Chazouillères
- Service d'Hépatologie, APHP, Hôpital Saint-Antoine, Paris, France
| | - J Capeau
- UPMC Université Paris 06, UMR_S938, Paris, France
- Service de biochimie et hormonologie, APHP, Hôpital Tenon, Paris, France
| | - J M Pawlotsky
- APHP, Laboratoire de Virologie, Hopital Henri Mondor, Créteil, France
- INSERM U955, Université Paris-Est Créteil, Créteil, France
| | - L Serfaty
- Service d'Hépatologie, APHP, Hôpital Saint-Antoine, Paris, France
- UPMC Université Paris 06, UMR_S938, Paris, France
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29
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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Chang KC, Tseng PL, Wu YY, Hung HC, Huang CM, Lu SN, Wang JH, Lee CM, Chen CH, Tsai MC, Yen YH, Lin MT, Wu CK, Huang CC, Chen HH, Hu TH. A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection. Clin Gastroenterol Hepatol 2015; 13:1017-24. [PMID: 25460552 DOI: 10.1016/j.cgh.2014.10.035] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 10/12/2014] [Accepted: 10/17/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin. METHODS In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC. RESULTS The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC. CONCLUSIONS Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.
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Affiliation(s)
- Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Ying Wu
- Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Hung-Chao Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Min Huang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsiu-Hsi Chen
- Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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Impact of rs12979860 polymorphism on liver morphology in chronic HCV infection. Clin Exp Hepatol 2015; 1:12-16. [PMID: 28856250 PMCID: PMC5421166 DOI: 10.5114/ceh.2015.51374] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 04/07/2015] [Indexed: 11/17/2022] Open
Abstract
AIM OF THE STUDY To determine distribution of rs12979860 genotypes, their correlations with viral load as well as inflammatory activity and stage of liver fibrosis in patients infected with HCV genotype 1. MATERIAL AND METHODS The study included 132 patients infected with HCV genotype 1b. Serum viral loads were obtained with the PCR method. Rs12979860 polymorphisms were determined by sequencing of PCR products. Liver biopsy was performed in all patients. RESULTS CT, TT and CC alleles of rs12979860 polymorphism were detected in 58%, 20% and 22% of patients respectively. The highest viral load was observed in the TT and the lowest in the CC group (72.0 × 106 IU/ml vs. 2.1 × 106 IU/ml, p < 0.005). A significant correlation was demonstrated between patient's age and inflammatory activity as well as degree of liver fibrosis. No association was found between liver histopathology and HCV viral load or rs12979860 genotypes. CONCLUSIONS There is an association between HCV viral load and rs12979860 polymorphism. Inflammatory activity and stage of liver fibrosis depend on age, but there is no relationship with rs12979860 genotypes and HCV viral load.
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Taheri S, Aygen B, Korkmaz K, Yıldız O, Zararsız G, Canatan H. Characterization of the Interleukin-28B Gene rs12979860 C/T Polymorphism in Turkish Chronic Hepatitis C Patients and Healthy Individuals. Balkan Med J 2015; 32:147-55. [PMID: 26167338 DOI: 10.5152/balkanmedj.2015.15156] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Accepted: 12/10/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Host genetic factors can affect the progress of hepatitis-C virus (HCV) infection. Interleukin-28B (IL28B) single nucleotide polymorphisms may play an important role in the clearance of HCV spontaneously or with treatment. AIMS The aim of our study was to evaluate the rate of IL28B genotypes in patients with Chronic Hepatitis-C (CHC) and healthy control subjects and to examine the characteristics of patients in each IL28B subgroup. STUDY DESIGN Case-control study. METHODS IL28B polymorphisms were genotyped by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP) in all subjects. RESULTS The mean age was 52.3±10.9 years (33% female) in the CHC patients and 52.5±11.5 years (39.1% female) in the healthy controls. The percentage of patients with a high baseline viral load (≥400,000 IU/mL) was higher in the CT group (69.8%) compared to the C/C (44.4%) and T/T (50%) groups (p=0.021). There was no significant difference in liver fibrosis and liver necroinflammation distribution among the CC, CT and TT genotypes with mild, moderate and severe groups (p=0.058 and p=0.791, respectively). Mean age, gender ratio, body mass index, viral load at baseline, rate of HCV genotypes, baseline ALT levels were not significantly different among the three IL28B subgroups (p>0.05). A significant increase was observed in the frequencies of IL28B rs12979860 TT genotypes in the CHC patients (20.6%) compared to the healthy control group (8.7%) (p=0.033). CONCLUSION In the patients with chronic HCV-genotype 1b and 4 infections, the IL28B rs12979860 (C>T) gene polymorphism frequency of the TT genotype and T allele was higher than in healthy control subjects. This result indicates that the TT genotype may be more effective in the progression of HCV infection than other genotypes.
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Affiliation(s)
- Serpil Taheri
- Department of Medical Biology, Erciyes University Faculty of Medicine, Kayseri, Turkey ; Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Bilgehan Aygen
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Keziban Korkmaz
- Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Orhan Yıldız
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Gökmen Zararsız
- Department of Biostatistics, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Halit Canatan
- Department of Medical Biology, Erciyes University Faculty of Medicine, Kayseri, Turkey
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Eslam M, Hashem AM, Leung R, Romero-Gomez M, Berg T, Dore GJ, Chan HL, Irving WL, Sheridan D, Abate ML, Adams LA, Mangia A, Weltman M, Bugianesi E, Spengler U, Shaker O, Fischer J, Mollison L, Cheng W, Powell E, Nattermann J, Riordan S, McLeod D, Armstrong NJ, Douglas MW, Liddle C, Booth DR, George J, Ahlenstiel G. Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat Commun 2015; 6:6422. [PMID: 25740255 PMCID: PMC4366528 DOI: 10.1038/ncomms7422] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Accepted: 01/28/2015] [Indexed: 12/11/2022] Open
Abstract
Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Ahmed M. Hashem
- Faculty of Engineering, Department of Systems and Biomedical Engineering, Minia University, Minia 6111, Egypt
| | - Reynold Leung
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
- Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Manuel Romero-Gomez
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla 41014, Spain
| | - Thomas Berg
- Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin 04103, Germany
- Department of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig 04103, Germany
| | - Gregory J. Dore
- Kirby Institute, The University of New South Wales, Sydney, New South Wales 2052, Australia
- St Vincent’s Hospital, Sydney, New South Wales 2052, Australia
| | - Henry L.K. Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - William L. Irving
- NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham NG7 2UH, UK
| | - David Sheridan
- Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL4 8AA, UK
| | - Maria L. Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin 10126, Italy
| | - Leon A. Adams
- School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, Western Australia 6009, Australia
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo 71013, Italy
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales 2747, Australia
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin 10126, Italy
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn 53105, Germany
| | - Olfat Shaker
- Faculty of Medicine, Medical Biochemistry and Molecular Biology Department, Cairo University, Cairo 11562, Egypt
| | - Janett Fischer
- Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin 04103, Germany
| | - Lindsay Mollison
- Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia 6160, Australia
| | - Wendy Cheng
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia 6000, Australia
| | - Elizabeth Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia
- The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland 4072, Australia
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn 53105, Germany
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales 2031, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales 2145, Australia
| | - Nicola J. Armstrong
- School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Mark W. Douglas
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Christopher Liddle
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - David R. Booth
- Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Jacob George
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Golo Ahlenstiel
- Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
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Fateh A, Aghasadeghi MR, Keyvani H, Mollaie HR, Yari S, Hadizade Tasbiti AR, Ghazanfari M, Monavari SHR. High resolution melting curve assay for detecting rs12979860 IL28B polymorphisms involved in response of Iranian patients to chronic hepatitis C treatment. Asian Pac J Cancer Prev 2015; 16:1873-1880. [PMID: 25773839 DOI: 10.7314/apjcp.2015.16.5.1873] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND A recent genome-wide association study (GWAS) on patients with chronic hepatitis C (CHC) treated with peginterferon and ribavirin (pegIFN-α/RBV) identified a single nucleotide polymorphism (SNP) on chromosome 19 (rs12979860) which was strongly associated with a sustained virological response (SVR). The aim of this study was twofold: to study the relationship between IL28B rs12979860 and sustained virological response (SVR) to pegIFN-α/RVB therapy among CHC patients and to detect the rs12979860 polymorphism by high resolution melting curve (HRM) assay as a simple, fast, sensitive, and inexpensive method. MATERIALS AND METHODS The study examined outcomes in 100 patients with chronic hepatitis C in 2 provinces of Iran from December 2011 to June 2013. Two methods were applied to detect IL28B polymorphisms: PCR-sequencing as a gold standard method and HRM as a simple, fast, sensitive, and inexpensive method. RESULTS The frequencies of IL28B rs12979860 CC, CT, and TT alleles in chronic hepatitis C genotype 1a patients were 10% (10/100), 35% (35/100), and 6% (6/100) and in genotype 3a were 13% (13/100), 31% (31/100), and 5% (5/100), respectively. In genotype 3a infected patients, rs12979860 (CC and CT alleles) and in genotype 1a infected patients (CC allele) were significantly associated with a sustained virological response (SVR). The SVR rates for CC, CT and TT (IL28B rs12979860) were 18%, 34% and 4%, respectively. Multiple logistic regression analysis identified two independent factors that were significantly associated with SVR: IL-28B genotype (rs 12979860 CC vs TT and CT; odds ratio [ORs], 7.86 and 4.084, respectively), and HCV subtype 1a (OR, 7.46). In the present study, an association between SVR rates and IL28B polymorphisms was observed. CONCLUSIONS The HRM assay described herein is rapid, inexpensive, sensitive and accurate for detecting rs12979860 alleles in CHC patients. This method can be readily adopted by any molecular diagnostic laboratory with HRM capability and will be clinically beneficial in predicting treatment response in HCV genotype 1 and 3 infected patients. In addition, it was demonstrated that CC and CT alleles in HCV-3a and the CC allele in HCV-1a were significantly associated with response to pegIFN-α/RBV treatment. The present results may help identify subjects for whom the therapy might be successful.
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Affiliation(s)
- Abolfazl Fateh
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran E-mail :
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Aygen B, Yildiz O, Akhan S, Gunal O, Taheri S, Zararsiz G, Sayan M, Rustemoglu A, Altinok ES. Impact of Interleukin 28B Genotype on the Virological Responses in Chronic Hepatitis C Treatment. Gastroenterology Res 2014; 7:123-130. [PMID: 27785282 PMCID: PMC5040535 DOI: 10.14740/gr629e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/30/2014] [Indexed: 12/24/2022] Open
Abstract
Background Interleukin (IL) 28B single nucleotide polymorphisms may play a role in the clearance of hepatitis C virus (HCV). We aimed to evaluate the treatment response of chronic HCV infection patients to pegile interferon (pegIFN) and ribavirin treatment with regard to IL28B rs12979860 C/T polymorphism. Methods A total of 186 patients (mean age, 55.6 ± 10 years; 65.1% female) who underwent pegIFN and ribavirin treatment for chronic HCV infection were studied. We analyzed demographics, HCV genotype, baseline alanine aminotransferase (ALT) levels, histopathological data, viral load before treatment and at 4, 12, 24, 48, and 72 weeks from the treatment start, and IL28B genotype. IL28B polymorphism was genotyped using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) in all the subjects. Results One hundred forty-five (86.8%) patients were infected with viral genotype 1b, and 13.2% were infected with viral genotype 4. The rates of C/C, C/T, and T/T genotypes were 22.6%, 52.7%, and 24.7% respectively. The percentage of patients with a viral load over 400,000 IU/mL was higher in the C/T group (P = 0.020). Of the patients, 44.6% provided sustained virological response (SVR) to pegIFN and ribavirin combination treatment. The frequency of T allele was 41% in patients with SVR, whereas 59% patients provided no response (P < 0.001). SVR was obtained in 66.7%, 42.9%, and 28.3% of CC, CT, and TT groups (P = 0.001). The rates of rapid virological response (RVR), early virological response (EVR), end-of-treatment response (ETR), and SVR were higher in the CC group than other groups (P = 0.216, P < 0.001, P = 0.001, P = 0.001, respectively). The relapse and null response (NR) rates were higher in TT group and partial response rate (PR) was higher in CT group. Conclusions IL28B rs12979860 C/T gene polymorphism affects the response to antiviral treatment in the patients with chronic HCV genotypes 1b and 4 infections.
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Affiliation(s)
- Bilgehan Aygen
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Erciyes University, Kayseri, Turkey
| | - Orhan Yildiz
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Erciyes University, Kayseri, Turkey
| | - Sila Akhan
- Kocaeli University Medical Faculty Infectious Diseases and Clinical Microbiology, Kocaeli, Turkey
| | - Ozgur Gunal
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Gaziosmanpasa University, Tokat, Turkey
| | - Serpil Taheri
- Erciyes University Betul Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey
| | - Gokmen Zararsiz
- Department of Biostatistics, Medical School of Erciyes University, Kayseri, Turkey
| | - Murat Sayan
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Kocaeli University, Kocaeli, Turkey
| | - Aydin Rustemoglu
- Gaziosmanpasa University Medical Faculty, Department of Medical Biology, Tokat, Turkey
| | - Elif Sargin Altinok
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Kocaeli University, Kocaeli, Turkey
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King LY, Johnson KB, Zheng H, Wei L, Gudewicz T, Hoshida Y, Corey KE, Ajayi T, Ufere N, Baumert TF, Chan AT, Tanabe KK, Fuchs BC, Chung RT. Host genetics predict clinical deterioration in HCV-related cirrhosis. PLoS One 2014; 9:e114747. [PMID: 25504078 PMCID: PMC4264769 DOI: 10.1371/journal.pone.0114747] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 11/13/2014] [Indexed: 01/27/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, and IL28B from liver tissue from 169 patients with biopsy-proven HCV cirrhosis. We estimated risk of clinical deterioration, defined as development of ascites, encephalopathy, variceal hemorrhage, HCC, or liver-related death using Cox proportional hazards modeling. During a median follow-up of 6.6 years, 66 of 169 patients experienced clinical deterioration. EGF non-AA, PNPLA3 non-CC, and IL28B non-CC genotypes were each associated with increased risk of clinical deterioration in age, sex, and race-adjusted analysis. Only EGF non-AA genotype was independently associated with increased risk of clinical deterioration (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.31-6.25) after additionally adjusting for bilirubin, albumin, and platelets. Compared to subjects who had 0-1 unfavorable genotypes, the HR for clinical deterioration was 1.79 (95%CI 0.96-3.35) for 2 unfavorable genotypes and 4.03 (95%CI 2.13-7.62) for unfavorable genotypes for all three loci (Ptrend<0.0001). In conclusion, among HCV cirrhotics, EGF non-AA genotype is independently associated with increased risk for clinical deterioration. Specific PNPLA3 and IL28B genotypes also appear to be associated with clinical deterioration. These SNPs have potential to identify patients with HCV-related cirrhosis who require more intensive monitoring for decompensation or future therapies preventing disease progression.
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Affiliation(s)
- Lindsay Y. King
- Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kara B. Johnson
- Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hui Zheng
- Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Lan Wei
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Thomas Gudewicz
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yujin Hoshida
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Kathleen E. Corey
- Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Tokunbo Ajayi
- Department of Medicine, North Shore Medical Center, Salem, Massachusetts, United States of America
| | - Nneka Ufere
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Thomas F. Baumert
- Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- Inserm U1110, University of Strasbourg, Strasbourg, France
| | - Andrew T. Chan
- Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kenneth K. Tanabe
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Bryan C. Fuchs
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Raymond T. Chung
- Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
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He J, Yu G, Li Z, Liang H. Influence of interleukin-28B polymorphism on progression to hepatitis virus-induced hepatocellular carcinoma. Tumour Biol 2014; 35:8757-63. [PMID: 24874053 DOI: 10.1007/s13277-014-2142-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 05/22/2014] [Indexed: 12/11/2022] Open
Abstract
Genetic variation of interleukin-28B (IL-28B) rs12979860 T/C polymorphism is associated with the immune response to interferon (IFN) therapy, which is applied in the treatment of chronic viral hepatitis induced by hepatitis B virus (HBV) and hepatitis C virus (HCV). These chronic liver diseases could progress to end-stage liver diseases, such as hepatocellular carcinoma (HCC). The aim of this study was to clarify whether there exists a causal association between IL-28B rs12979860 T/C polymorphism and development of HCC. In a meta-analysis of six studies with 850 cases and 811 controls, we summarized the data on the association between IL-28B rs12979860 T/C polymorphism and HCC risk and calculated ORs and 95 % CIs to estimate the association strength. We observed that IL-28B rs12979860 T/C polymorphism was positively associated with overall HCC risk (TT vs. CC: OR = 2.38; 95 %, 1.60-3.55; TT vs CT + CC: OR = 1.79; 95 %, 1.23-2.60). In the stratified analysis by ethnicity, the robust association retained in Caucasians with higher risk among TT carriers relative to the CC carriers. A similar trend was found in the studies of healthy controls when data were stratified by source of controls. The combined data suggest that IL-28B rs12979860 T/C polymorphism seems to augment the risk of developing HCC, especially in Caucasians.
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Affiliation(s)
- Jinxia He
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
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Wu RR, Liu FQ, Zhu SS, Han J. Association of Hepatitis C Virus Infection and Interleukin-28B Gene Polymorphism in Chinese Children. Pak J Med Sci 2014; 30:519-24. [PMID: 24948971 PMCID: PMC4048498 DOI: 10.12669/pjms.303.4267] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 02/10/2014] [Accepted: 02/12/2014] [Indexed: 12/17/2022] Open
Abstract
Objective: To preliminarily explore the association of rs12979860 and rs8099917 SNPs with chronic HCV infection in Chinese Han children. Methods: Chronic HCV infection patients (n=277; 1-17 years old, 4.5 years old in average) and healthy subjects (n=150, children; 2-17 years old, 5.2 years old in average) were recruited and tested by PCR combining direct sequencing. The differences between the rs12979860 and rs8099917 genotypes in patients and healthy subjects were compared. Results: The genetic variations at rs12979860 and rs8099917 in chronic hepatitis C (CHC) children and healthy subjects did not differ significantly. The frequency of spontaneous clearance in CHC children was higher (47%), which is related to the genetic variations. The histological changes of patients were more significant compared to their clinical and biochemical indices, but they did not correlate with the genetic mutations at rs12979860 and rs8099917 significantly. Conclusion: The rs12979860 and rs8099917 SNPs are independent factors predicting the spontaneous clearance of Chinese CHC children patients. The correlation between diseases outcomes are in need of further study.
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Affiliation(s)
- Rong-Rong Wu
- Rong-Rong Wu, Department of Pharmacy, Beijing 302 Hospital, Beijing China
| | - Feng-Qun Liu
- Feng-Qun Liu, Department of Pharmacy, Beijing 302 Hospital, Beijing China
| | - Shi-Shu Zhu
- Shi-Shu Zhu, Department of Pediatric Hepatology, Beijing 302 Hospital, Beijing China
| | - Jin Han
- Jin Han, Department of Pharmacy, Beijing 302 Hospital, Beijing China
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Mancuso ME, Linari S, Aghemo A, Bartolozzi D, Santagostino E, Rumi MG, Fognani E, Fasulo MR, Gragnani L, Bruno R, Morfini M, Zignego AL, Colombo M. Interferon lambda 3 rs12979860 polymorphism in patients with haemophilia and HCV infection: a predictor of spontaneous viral clearance and sustained virological response. Thromb Haemost 2014; 111:1067-76. [PMID: 24522196 DOI: 10.1160/th13-11-897] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Accepted: 12/19/2013] [Indexed: 12/19/2022]
Abstract
Chronic hepatitis C is the main cause of morbidity and mortality in adult haemophilic patients who received non-virally inactivated plasma-derived clotting factor concentrates. Overall, spontaneous viral clearance rate is 10-25% and the only approach that can halt disease progression is hepatitis C virus (HCV) eradication by means of antiviral therapy. In non-haemophilic patients a single nucleotide polymorphism located upstream the gene of interferon lambda 3 (IFNλ3) has been associated with both spontaneous viral clearance and sustained virological response after antiviral treatment. The aim of this study was to assess whether the rs12979860 polymorphism was a predictor of spontaneous viral clearance and of sustained virological response after antiviral therapy in a large cohort of haemophilic patients with HCV infection. The rs12979860 polymorphism, defined as CC genotype or T allele, was tested in a cohort of 342 haemophilic patients and evaluated as predictor of spontaneous clearance or response to antiviral therapy. By multivariate regression analysis the IFNλ3 CC genotype was an independent predictor of spontaneous viral clearance (odds ratio: 3.7, 95% confidence interval: 2.0-6.8). Sustained virological response rates were doubled in patients with the CC genotype than in those with the T allele (78% vs 44%; p<0.001), especially in patients with HCV type 1 (67% vs 32%; p<0.001) and higher sustained response rates were observed in patients with the CC genotype who did not achieve rapid virological response (61% vs 30% in T allele patients; p=0.006).
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Affiliation(s)
- Maria Elisa Mancuso
- Maria Elisa Mancuso, MD, PhD, Angelo Bianchi Bonomi Haemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy, Tel.: +39 02 5503 4072, Fax: +39 02 5503 2072, E-mail:
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Sato M, Kondo M, Tateishi R, Fujiwara N, Kato N, Yoshida H, Taguri M, Koike K. Impact of IL28B genetic variation on HCV-induced liver fibrosis, inflammation, and steatosis: a meta-analysis. PLoS One 2014; 9:e91822. [PMID: 24637774 PMCID: PMC3956722 DOI: 10.1371/journal.pone.0091822] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 02/15/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND & AIMS IL28B polymorphisms were shown to be strongly associated with the response to interferon therapy in chronic hepatitis C (CHC) and spontaneous viral clearance. However, little is known about how these polymorphisms affect the natural course of the disease. Thus, we conducted the present meta-analysis to assess the impact of IL28B polymorphisms on disease progression. METHODS A literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library. Integrated odds ratios (OR) were calculated with a fixed-effects or random-effects model based on heterogeneity analyses. RESULTS We identified 28 studies that included 10,024 patients. The pooled results indicated that the rs12979860 genotype CC was significantly associated (vs. genotype CT/TT; OR, 1.122; 95%CI, 1.003-1.254; P = 0.044), and that the rs8099917 genotype TT tended to be (vs. genotype TG/GG; OR, 1.126; 95%CI, 0.988-1.284; P = 0.076) associated, with an increased possibility of severe fibrosis. Both rs12979860 CC (vs. CT/TT; OR, 1.288; 95%CI, 1.050-1.581; P = 0.015) and rs8099917 TT (vs. TG/GG; OR, 1.324; 95%CI, 1.110-1.579; P = 0.002) were significantly associated with a higher possibility of severe inflammation activity. Rs8099917 TT was also significantly associated with a lower possibility of severe steatosis (vs. TG/GG; OR, 0.580; 95%CI, 0.351-0.959; P = 0.034), whereas rs12979860 CC was not associated with hepatic steatosis (vs. CT/TT; OR, 1.062; 95%CI, 0.415-2.717; P = 0.901). CONCLUSIONS IL28B polymorphisms appeared to modify the natural course of disease in patients with CHC. Disease progression seems to be promoted in patients with the rs12979860 CC and rs8099917 TT genotypes.
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Affiliation(s)
- Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Mayuko Kondo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Naoto Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Naoya Kato
- Unit of Disease Control Genome Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Haruhiko Yoshida
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Masataka Taguri
- Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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Aalaei-Andabili SH, Behnava B, Salimi S, Sharafi H, Alavian SM. Mysterious Linkages Between Hepatitis C Virus Genotypes, Interleukin-28B Genotypes and Viral Clearance- A Meta-Analysis. HEPATITIS MONTHLY 2014; 14:e15895. [PMID: 24734092 PMCID: PMC3984474 DOI: 10.5812/hepatmon.15895] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 11/02/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent genome wide association studies (GWAS) have shown important roles of single nucleotide polymorphisms (SNP) near region of interleukin B 28 (IL28B) gene in spontaneous and drug-induced clearance of hepatitis C virus (HCV) in genotype 1 HCV infection. OBJECTIVES This meta-analysis was designed to determine the world-wide distribution patterns of IL28B genotypes and alleles, and to find possible linkages between IL28B and HCV genotypes. PATIENTS AND METHODS Manual and electronic databases were searched. Critical appraisal was performed. According to the results of heterogeneity tests, we used fix/random model for the analysis. The data concerning patients' ethnicity and HCV genotypes were analyzed by using statistical analysis software. RESULTS A total of 255 articles were found. After article review and quality assessment, 50 studies, including 18662 patients and 1313 healthy subjects, were analyzed. Presence of HCV genotype 3 versus genotype 1 was significantly associated with a higher frequency of CC genotype and C allele, with an odds ratio (OR) of 1.68 (95% CI: 1.44-1.99) and 1.49 (95% CI: 1.33-1.67), respectively. Prevalence of the rs12979860 CC genotype among genotype 1 HCV infected patients of Asian ethnicity was 69.48% (95% CI: 65.20-73.77), which was significantly higher than its prevalence [33.27% (95% CI: 28.88-37.67)] in the Caucasian genotype 1 HCV infected patients. Prevalence of rs12979860 TT genotype in the African-American genotype 1 HCV infected patients was the highest [36.20% (95% CI: 32.91-39.49)], and significantly different compared to all other ethnicities. CONCLUSIONS There were significant linkages between HCV genotypes and IL28B genotypes/alleles. Patients with a favorable IL28B and genotypes 1 and 4 HCV infection stand a better chance to clear HCV in the acute phase.
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Affiliation(s)
- Seyed Hossein Aalaei-Andabili
- Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Bita Behnava
- Middle East Liver Disease Center, Tehran, IR Iran ; Baqiyatallah Research Center for Gastroenterology and Liver Disease (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Shima Salimi
- Middle East Liver Disease Center, Tehran, IR Iran ; Baqiyatallah Research Center for Gastroenterology and Liver Disease (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Heidar Sharafi
- Middle East Liver Disease Center, Tehran, IR Iran ; Baqiyatallah Research Center for Gastroenterology and Liver Disease (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Middle East Liver Disease Center, Tehran, IR Iran ; Iran Hepatitis Network (IHN), Tehran, IR Iran
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De Re V, Gragnani L, Fognani E, Piluso A, Izzo F, Mangia A, Crovatto M, Gava G, Casarin P, Sansonno D, Racanelli V, De Vita S, Pioltelli P, Caggiari L, De Zorzi M, Berretta M, Gini A, Zucchetto A, Buonaguro FM, De Paoli P, Zignego AL. Impact of immunogenetic IL28B polymorphism on natural outcome of HCV infection. BIOMED RESEARCH INTERNATIONAL 2014; 2014:710642. [PMID: 24707497 PMCID: PMC3955679 DOI: 10.1155/2014/710642] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/19/2013] [Accepted: 11/20/2013] [Indexed: 01/20/2023]
Abstract
With the aim of investigating whether interleukin 28B gene (IL28B) rs1297860 polymorphism is associated with different hepatitis C (HCV) infection statuses, we compared IL28B allelic distribution in an Italian case series of 1050 patients with chronic infection and different outcomes, 47 individuals who spontaneously cleared HCV, and 178 blood donors. Furthermore, we compared IL28B variants among 3882 Caucasian patients with chronic infection, 397 with spontaneous clearance, and 1366 blood donors reported in PubMed. Overall data confirmed a relation between IL28B C allele and HCV spontaneous clearance. Furthermore, we found that IL28B T allele had a weak relation with chronic HCV progression to hepatocellular carcinoma. Study findings are in accordance with the hepatocellular carcinogenic model where IL28B TT genotype, by promoting a persistent chronic hepatitis which leads to both hepatocyte injury and chronic inflammation, could facilitate HCC development. Conversely, patients with lymphoproliferative disorders had not any significantly different IL28B rs1297860 allelic distribution than those with chronic HCV, but, like all chronic HCV-related diseases, they showed a lower CC frequency than patients who spontaneously cleared HCV. Study results confirmed the model of persistent HCV infection as a risk factor for the pathogenesis of both liver and lymphoproliferative disorders.
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Affiliation(s)
- Valli De Re
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
| | - Elisa Fognani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
| | - Alessia Piluso
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
| | - Francesco Izzo
- Hepatobiliary Unit, National Cancer Institute “Fondazione Pascale”, 80138 Naples, Italy
| | - Alessandra Mangia
- Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, Italy
| | - Marina Crovatto
- Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, 33170 Pordenone, Italy
| | - Graziella Gava
- Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, 33170 Pordenone, Italy
| | - Pietro Casarin
- Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, 33170 Pordenone, Italy
| | - Domenico Sansonno
- Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70121 Bari, Italy
| | - Vito Racanelli
- Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70121 Bari, Italy
| | - Salvatore De Vita
- Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital Santa Maria della Misericordia, 33100 Udine, Italy
| | - Pietro Pioltelli
- Hematology and Transplant Unit, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Laura Caggiari
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | - Mariangela De Zorzi
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | | | - Andrea Gini
- Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, 33081 Aviano, Italy
| | - Antonella Zucchetto
- Epidemiology and Biostatistics, Centro di Riferimento Oncologico, IRCCS, 33081 Aviano, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology, National Cancer Institute “Fondazione Pascale”, 80138 Naples, Italy
| | - Paolo De Paoli
- Bio-Proteomics Facility, Department of Translational Research, CRO, National Cancer Institute, 33081 Aviano, Italy
| | - Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
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Muir AJ, Gong L, Johnson SG, Lee MTM, Williams MS, Klein TE, Caudle KE, Nelson DR. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-α-based regimens. Clin Pharmacol Ther 2014; 95:141-6. [PMID: 24096968 PMCID: PMC3904555 DOI: 10.1038/clpt.2013.203] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 09/24/2013] [Indexed: 01/09/2023]
Abstract
Pegylated interferon-α (PEG-IFN-α or PEG-IFN 2a and 2b)- and ribavirin (RBV)-based regimens are the mainstay for treatment of hepatitis C virus (HCV) genotype 1. IFNL3 (IL28B) genotype is the strongest baseline predictor of response to PEG-IFN-α and RBV therapy in previously untreated patients and can be used by patients and clinicians as part of the shared decision-making process for initiating treatment for HCV infection. We provide information regarding the clinical use of PEG-IFN-α- and RBV-containing regimens based on IFNL3 genotype.
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Affiliation(s)
- A J Muir
- Division of Gastroenterology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - L Gong
- Department of Genetics, Stanford University, Palo Alto, California, USA
| | - S G Johnson
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, Colorado, USA
- Clinical Pharmacy Services, Kaiser Permanente Colorado, Denver, Colorado, USA
| | - M T M Lee
- Laboratory for International Alliance on Genomic Research, RIKEN Center for Genomic Medicine, Yokohama, Japan
- National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - M S Williams
- Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA
| | - T E Klein
- Department of Genetics, Stanford University, Palo Alto, California, USA
| | - K E Caudle
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - D R Nelson
- Department of Medicine, University of Florida, Gainesville, Florida, USA
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Zekri ARN, Salama H, Medhat E, Bahnassy AA, Morsy HM, Lotfy MM, Ahmed R, Darwish T, Marei MS. IL28B rs12979860 gene polymorphism in Egyptian patients with chronic liver disease infected with HCV. Asian Pac J Cancer Prev 2014; 15:7213-8. [PMID: 25227816 DOI: 10.7314/apjcp.2014.15.17.7213] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Egypt has one of the highest prevalences of hepatitis C virus (HCV) infection worldwide. Although the IL28B gene polymorphism has been shown to modify the course of chronic HCV infection, this has not been properly assessed in the Egyptian population. MATERIALS AND METHODS The IL28B rs12979860 single nucleotide polymorphism (SNP) was therefore examined in 256 HCV-infected Egyptian patients (group II) at different stages of disease progression and in 48 healthy volunteers (group I). Group II was subdivided into GII-A (chronic hepatitis patients, n=119), GII-B (post hepatitis cirrhosis, n=66) and GII-C (HCC on top of cirrhosis, n=71). RESULTS The C/T genotype was the commonest in all groups. It was more frequent in GI (52%) than in GII (48%). There was no significant difference in the frequency of C/T and C/C or T/T genotypes between groups and subgroups (p=0.82). Within the subgroups; the C/C genotype was more common in GII-B while C/T and T/T genotypes were more common in GII-C, though with no significant difference (p=0.59 and p=0.80). There was no significant association between IL28B rs12979860 SNP and viral load, ALT, AFP level, METAVIR scores for necro-inflammation and fibrosis, and Child-Pugh classification. CONCLUSIONS 1) IL28Brs12979860 C/T genotype is the commonest genotype in HCV-associated CH and HCC in Egypt. 2) IL28Brs12979860 polymorphisms are not associated with disease progression or aggression (histological staging, severity of fibrosis in CH or the incidence of post-HCV HCC). 3) Differences in IL28Brs12979860 genotypes could be a consequence of environmental or ethnic variation.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, Faculty of Medicine, National Cancer Institute, Cairo University, Cairo, Egypt E-mail :
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Youssef SS, Abbas EAER, Mostafa A, el Zanaty T, Seif SM. Association of IL28B polymorphism with fibrosis, liver inflammation, gender respective natural history of hepatitis C virus in Egyptian patients with genotype 4. J Interferon Cytokine Res 2014; 34:22-7. [PMID: 23981065 DOI: 10.1089/jir.2013.0036] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The polymorphism of interleukin 28B (IL28B) rs12979860 is associated with spontaneous and treatment-induced clearance in hepatitis C virus (HCV) genotype 4 (G4). However, there is no information on its interaction with gender, moreover its association with intrahepatic inflammation in North Africans is not studied and its association with fibrosis in North Africans (especially Egyptians) is controversial. This study aims to explore the association between the minor allele of the IL28B rs12979860 polymorphism with gender, fibrosis and necroinflammation in Egyptian G4 HCV patients. IL28B rs12979860 was genotyped in 224 individuals, including 100 healthy controls and 124 consecutive patients with chronic HCV. Results showed (1) IL28B rs12979860 minor alleles associated with susceptibity to chronic HCV mainly in men not women, (2) no association between IL28B rs12979860 with fibrosis and necroinflammation activity, (3) the IL28B rs12979860 TT genotype associated with severe fibrosis in women only and with the necroinflammation activity in men using a recessive model. In conclusion, the IL28B rs12979860 polymorphism is not associated with fibrosis and liver inflammation in Egyptian HCV G4. Nonetheless, the TT genotype of IL28B rs12979860 polymorphism affects the natural history of each gender independently.
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Affiliation(s)
- Samar Samir Youssef
- 1 Microbial Biotechnology Department, National Research Center , Cairo, Egypt
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Noureddin M, Wright EC, Alter HJ, Clark S, Thomas E, Chen R, Zhao X, Conry-Cantilena C, Kleiner DE, Liang TJ, Ghany MG. Association of IL28B genotype with fibrosis progression and clinical outcomes in patients with chronic hepatitis C: a longitudinal analysis. Hepatology 2013; 58:1548-57. [PMID: 23703931 PMCID: PMC3758382 DOI: 10.1002/hep.26506] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 04/26/2013] [Indexed: 12/31/2022]
Abstract
UNLABELLED Interleukin (IL)28B polymorphisms are associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to therapy. Whether IL28B genotype affects fibrosis progression or clinical outcome is unclear. Our aim was to study the relationship between IL28B genotype and both histological and clinical outcomes in patients with chronic hepatitis C (CHC). Hepatic fibrosis was scored using the Ishak (0-6) scale; progression was defined as a 2-point increase in Ishak score between biopsies. Multiple logistic and Cox regressions were used to identify variables associated with fibrosis progression. In all, 1,483 patients were included in a baseline cross-sectional analysis, from which 276 were eligible for a paired biopsy analysis (median time between biopsies 4 years), and 400 for a clinical outcome analysis. At baseline biopsy, patients with IL28B CC genotype had significantly higher portal inflammation (2.4 versus 2.2) and alanine aminotransferase (ALT) levels (133 versus 105 U/L; P < 0.05 for all). In the paired biopsy analysis, there was no difference in the frequency of fibrosis progression between patients with IL28B CC and non-CC genotypes (17% versus 23%). In logistic regression, only higher baseline alkaline phosphatase, lower platelets, and greater hepatic steatosis were associated with fibrosis progression. Patients with IL28B CC were twice as likely to develop adverse clinical outcomes compared to non-CC (32% versus 16%; P = 0.007). CONCLUSION IL28B CC genotype was associated with greater hepatic necroinflammation, higher ALT, and worse clinical outcomes in CHC patients. This suggests that IL28B CC is associated with a state of enhanced immunity that, on the one hand, can promote viral clearance, but alternately can increase necroinflammation and hepatic decompensation without enhancing fibrosis progression.
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Affiliation(s)
- Mazen Noureddin
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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Liu CH, Kao JH. IL28B Genotype on HCV Infection in Asia. CURRENT HEPATITIS REPORTS 2013; 12:149-156. [DOI: 10.1007/s11901-013-0176-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Petta S, Rosso C, Leung R, Abate ML, Booth D, Salomone F, Gambino R, Rizzetto M, Caviglia P, Smedile A, Grimaudo S, Cammà C, Craxì A, George J, Bugianesi E. Effects of IL28B rs12979860 CC genotype on metabolic profile and sustained virologic response in patients with genotype 1 chronic hepatitis C. Clin Gastroenterol Hepatol 2013; 11:311-7.e1. [PMID: 23220171 DOI: 10.1016/j.cgh.2012.11.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 11/01/2012] [Accepted: 11/21/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with genotype 1 chronic hepatitis C (G1 CHC) frequently develop steatosis and insulin resistance (IR), caused by metabolic and viral factors. These accelerate the progression of liver disease and reduce the response to therapy. A sustained virologic response (SVR) to therapy in patients with G1 CHC is associated strongly with polymorphisms near the interleukin-28B (IL28B) gene, but the interaction between IL28B genotype and IR, and their combined effects on SVR, have not been defined. We tested the association between the IL28B rs12979860 single-nucleotide polymorphism and metabolic features, including IR, and evaluated their effects on SVR. METHODS We performed genotype analysis of IL28B rs12979860 for 434 white G1 CHC patients who underwent consecutive biopsy analysis at 3 tertiary centers. Metabolic profile analyses included assessments of lipid levels and IR by the homeostasis model assessment. RESULTS Patients with the CC polymorphism in IL28B had higher levels of total and low-density lipoprotein cholesterol, lower levels of triglycerides, and a lower prevalence of IR and moderate-severe steatosis (P < .05) than patients without this genotype. By multiple logistic regression analysis, body mass index (odds ratio [OR], 1.223; P < .001), level of triglycerides (OR, 1.007; P = .006), the CC polymorphism in IL28B (OR, 0.378; P = .001), and levels of HCV RNA greater than 850,000 IU/mL (OR, 1.803; P = .01) were associated with IR. The CC polymorphism in IL28B (OR, 8.350; P < .001) and IR (OR, 0.432; P = .005), but not steatosis (OR, 0.582; P = 0.25), was associated with an SVR. CONCLUSIONS In white patients with G1 CHC, the IL28B rs12979860 CC genotype is associated with reduced IR. IL28B rs12979860 genotype and IR by the homeostasis model assessment strongly affect the outcome of antiviral therapy.
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Affiliation(s)
- Salvatore Petta
- Division of Gastroenterology, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy.
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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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Sharafi H, Pouryasin A, Alavian SM, Behnava B, Keshvari M, Salimi S, Mehrnoush L, Fatemi A. Distribution of IL28B Genotypes in Iranian Patients with Chronic Hepatitis C and Healthy Individuals. HEPATITIS MONTHLY 2012; 12:e8387. [PMID: 23550102 PMCID: PMC3580886 DOI: 10.5812/hepatmon.8387] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 08/10/2012] [Accepted: 10/02/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND IL28B polymorphism is recognized as one of the most prominent predictors of hepatitis C spontaneous and treatment-induced clearance. Interestingly, the favorable genotypes of IL28B are found to be more frequent in Asian ethnicity than Caucasian and African populations, respectively. A few studies reported that there is a mysterious association between the IL28B polymorphism and the hepatitis C virus (HCV) genotype in patients with chronic hepatitis C but they did not give any reason for this phenomenon. OBJECTIVES The foremost purpose of this study was to compare the distribution of IL28B genotypes between Iranian healthy individuals and patients with chronic hepatitis C. PATIENTS AND METHODS In this study, 921 patients with chronic hepatitis C and 142 healthy individuals were included. The IL28B rs12979860 and rs8099917 polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS The frequency of IL28B rs12979860 CC, CT, and TT genotypes in chronic hepatitis C patients was 38%, 48.8%, and 13.2% and in healthy individuals was 43.7%, 48.6%, and 7.7%. Also, the frequency of IL28B rs8099917 TT, GT, and GG genotypes in chronic hepatitis C patients was 58.3%, 37.1%, and 4.6% and in healthy individuals was 64.1%, 32.4% and 3.5%. The differences in the distribution of IL28B rs12979860 and rs8099917 genotypes between patients with chronic hepatitis C and healthy individuals were not statistically significant. When we compared the distribution of IL28B genotypes between the healthy group and the HCV infected patients by HCV genotype, we found 9.8% higher frequency of rs12979860 CC genotype in the healthy individuals than HCV genotype 1 infected patients (P = 0.03) however there was no significant difference in the distribution of rs12979860 genotypes between the healthy and HCV genotype 3 infected groups (P = 0.46). CONCLUSIONS It seems that the impact of IL28B polymorphism on the spontaneous clearance of HCV genotype 1 is more prominent than HCV genotype 3 which results in the observation of higher rs12979860 C allele frequency in chronic hepatitis C patients with HCV genotype 3 than HCV genotype 1.
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Affiliation(s)
- Heidar Sharafi
- Armin Pathobiology Laboratory, Tehran, Iran
- Tehran Hepatitis Cohort (THC) Study Center, Tehran, Iran
| | - Ali Pouryasin
- Armin Pathobiology Laboratory, Tehran, Iran
- Tehran Hepatitis Cohort (THC) Study Center, Tehran, Iran
- Department of Genetics, Islamic Azad University of Arsanjan, Arsanjan, Iran
- Corresponding author: Ali Pouryasin, Department of Genetics, Islamic Azad University of Arsanjan, Arsanjan, Iran. Tel.: +98-2188732773, Fax: +98-2188735835, E-mail:
| | - Seyed Moayed Alavian
- Tehran Hepatitis Cohort (THC) Study Center, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Bita Behnava
- Tehran Hepatitis Cohort (THC) Study Center, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Maryam Keshvari
- Tehran Hepatitis Cohort (THC) Study Center, Tehran, Iran
- Iranian Blood Transfusion Organization, Tehran, Iran
| | - Shima Salimi
- Tehran Hepatitis Cohort (THC) Study Center, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Leila Mehrnoush
- Tehran Hepatitis Cohort (THC) Study Center, Tehran, Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ahmad Fatemi
- Department of Hematology, Tehran University of Medical Sciences, Tehran, Iran
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