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Chung Y, Tsou HLP, Heneghan MA, Chokshi S, Riva A. Soluble Herpes Virus Entry Mediator and Type II/III Interferons Are Upregulated in Primary Biliary Cholangitis. Int J Mol Sci 2025; 26:605. [PMID: 39859319 PMCID: PMC11765339 DOI: 10.3390/ijms26020605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/06/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Bacterial translocation-induced inflammation and immune dysfunction are recognised factors contributing to the pathogenesis of primary biliary cholangitis (PBC). However, the specific involvement of interferons (IFNs) and soluble checkpoints (sol-CRs) in shaping the immune landscape in PBC patients remains unexplored. Furthermore, the influence of ursodeoxycholic acid (UDC) on these immune mediators is unknown. Twenty-eight cytokines and 14 sol-CRs were quantified by Luminex assays in plasma samples from 64 PBC patients and 10 healthy controls (HCs). D-lactate was measured as a marker of bacterial translocation. The PBC subgroups were: 24 UDC responders (UDCRs), 18 UDC non-responders (UDCNRs) and 22 patients with end-stage cirrhotic PBC (ESPBC). Soluble herpes virus entry mediator (HVEM) was upregulated in the UDCR subgroup compared to the HC group (p = 0.0404), with increased significance in the ESPBC subgroup (p < 0.0001). There was a progressive increase in several sol-CRs, particularly soluble CD80, LAG3 and CD137 in ESPBC patients. IFN-gamma was higher in the ESPBC subgroup compared to the UDCR subgroup. Elevated IFN-gamma in the UDCNR subgroup compared to UDCR was more significant on excluding patients with cirrhosis (p = 0.0056). Patients with ESPBC expressed several pro-inflammatory cytokines including IL-6, TNF-alpha and CXCL10 compared to the HC group. IFN-lambda-3, but not IFN-lambda-2, was elevated in the ESPBC subgroup compared to all other subgroups. D-lactate levels were equally elevated in all PBC subgroups compared to the HC group. This study provides valuable insights into the immune landscape of PBC, highlighting potential biomarkers and cytokine signatures associated with disease severity and treatment response. Further investigation into the mechanistic roles may pave the way for more targeted therapeutic interventions in PBC management.
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Affiliation(s)
- Yooyun Chung
- The Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London & Foundation for Liver Research, London SE5 9NT, UK
- King’s College Hospital, London SE5 9RS, UK
| | - Hio Lam Phoebe Tsou
- The Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London & Foundation for Liver Research, London SE5 9NT, UK
| | - Michael A. Heneghan
- The Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London & Foundation for Liver Research, London SE5 9NT, UK
- King’s College Hospital, London SE5 9RS, UK
| | - Shilpa Chokshi
- The Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London & Foundation for Liver Research, London SE5 9NT, UK
- Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
| | - Antonio Riva
- The Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London & Foundation for Liver Research, London SE5 9NT, UK
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Pan Z, Alharthi J, Bayoumi A, George J, Eslam M. A Cell Specific Effect of MBOAT7 MAFLD-risk Variant on Immune Cells. FRONT BIOSCI-LANDMRK 2024; 29:148. [PMID: 38682204 DOI: 10.31083/j.fbl2904148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 02/19/2024] [Accepted: 03/11/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Disease risk variants are likely to affect gene expression in a context- and cell-type specific manner. The membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs8736 metabolic-dysfunction-associated fatty liver disease (MAFLD)-risk variant was recently reported to be a negative regulator of toll-like receptors (TLRs) signalling in macrophages. Whether this effect is generic or cell-type specific in immune cells is unknown. METHODS We investigated the impact of modulating TLR signaling on MBOAT7 expression in peripheral blood mononuclear cells (PBMCs). We also examined whether the rs8736 polymorphism in MBOAT7 regulates this effect. Furthermore, we measured the allele-specific expression of MBOAT7 in various immune cell populations under both unstimulated and stimulated conditions. RESULTS We show that MBOAT7 is down-regulated by TLRs in PBMCs. This effect is modulated by the MBOAT7 rs8736 polymorphism. Additionally, we provide evidence that MBOAT7 acts primarily as a modulator of TLR signalling in mononuclear phagocytes. CONCLUSION Our results highlight the importance of studying Genome-Wide Association Studies (GWAS) signals in the specific cell types in which alterations of gene expression are found.
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Affiliation(s)
- Ziyan Pan
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW 2145, Australia
| | - Jawaher Alharthi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW 2145, Australia
- Department of Biotechnology, Faculty of Science, Taif University, 21944 Taif, Saudi Arabia
| | - Ali Bayoumi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW 2145, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW 2145, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW 2145, Australia
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Ouladlahsen A, Bensghir R, Baba H, Haddaji A, Abbadi I, Zaidane I, Badi H, Sodqi M, Marih L, Wakrim L, Marhoum El Filali K, Benjelloun S, Ezzikouri S. Lack of Association between IFNL3 Polymorphism and Human Papillomavirus Infection and Their Progression in HIV-Infected Women Receiving Antiretroviral Treatment. Pathobiology 2020; 87:262-267. [PMID: 32428907 DOI: 10.1159/000507763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 03/18/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND It has been reported that interferon-λ3 (IFNL3)might influence the pathogenesis and clearance of human papillomavirus (HPV) infection. The impact of IFNL3 single-nucleotide polymorphism (SNP) on HPV infection is currently unknown. The aim of this study was to investigate the association between variants in the IFNL3 region and HPV infection in women with human immunodeficiency virus (HIV) infection. METHODS A total of 236 HIV patients, including 65 HPV-negative and 171 HPV DNA-positive women, were enrolled into this study. The IFNL3 rs12979860 polymorphism was genotyped using a predesigned TaqMan SNP genotyping assay. RESULTS Data showed no significant differences in genotypes or allele frequencies between the HPV DNA-positive and the HPV-negative women (p > 0.05). After dividing the HPV-positive women according to cytology results into patients with abnormal and normal lesions, the genotype and allele distribution of the SNP did not significantly differ between the 2 groups (p > 0.05). CONCLUSIONS Our results showed that the IFNL3 rs12979860 polymorphism is not a major determinant of the susceptibility to HPV infection and their progression to abnormal cervical lesions in women living with HIV.
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Affiliation(s)
- Ahd Ouladlahsen
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Rajaa Bensghir
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Hanâ Baba
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Asmaa Haddaji
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Islam Abbadi
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Hanan Badi
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Mustapha Sodqi
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Latifa Marih
- Service des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Lahcen Wakrim
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | | | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco,
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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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Sharkawy RE, Bayoumi A, Metwally M, Mangia A, Berg T, Romero-Gomez M, Abate ML, Irving WL, Sheridan D, Dore GJ, Spengler U, Lampertico P, Bugianesi E, Weltman M, Mollison L, Cheng W, Riordan S, Santoro R, Gallego-Durán R, Fischer J, Nattermann J, D'Ambrosio R, McLeod D, Powell E, Latchoumanin O, Thabet K, Najim MAM, Douglas MW, Liddle C, Qiao L, George J, Eslam M. A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms. Sci Rep 2019; 9:1439. [PMID: 30723271 PMCID: PMC6363805 DOI: 10.1038/s41598-018-35736-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 11/09/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms.
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Affiliation(s)
- Rasha El Sharkawy
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
| | - Ali Bayoumi
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
| | - Mayada Metwally
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Manuel Romero-Gomez
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario Virgen del Rocío, University of Seville, Sevilla, Spain
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - William L Irving
- NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, United Kingdom
| | - David Sheridan
- Institute of Translational and Stratified Medicine, Plymouth University, Plymouth, United Kingdom
| | - Gregory J Dore
- Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Pietro Lampertico
- Università degli Studi di Milano Centro A.M. e A. Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation Milan Italy, Milan, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia
| | - Lindsay Mollison
- Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, WA, Australia
| | - Wendy Cheng
- Department of Gastroenterology & Hepatology, Royal Perth Hospital, Wellington, WA, Australia
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia
| | - Rosanna Santoro
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Rocío Gallego-Durán
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario Virgen del Rocío, University of Seville, Sevilla, Spain
| | - Janett Fischer
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Roberta D'Ambrosio
- Università degli Studi di Milano Centro A.M. e A. Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation Milan Italy, Milan, Italy
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia
| | - Elizabeth Powell
- The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Olivier Latchoumanin
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
| | - Khaled Thabet
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Mustafa A M Najim
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
- Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
| | - Christopher Liddle
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
| | - Liang Qiao
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia.
| | - Mohammed Eslam
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia
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Bhushan A, Chinnaswamy S. Identifying causal variants at the interferon lambda locus in case-control studies: Utilizing non-synonymous variant rs117648444 to probe the role of IFN-λ4. Gene 2018; 664:168-180. [PMID: 29705128 DOI: 10.1016/j.gene.2018.04.076] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 04/19/2018] [Accepted: 04/25/2018] [Indexed: 02/08/2023]
Abstract
Genetic variants at the interferon lambda (IFNL) locus have been associated with several human phenotypes in both disease and health. In chronic hepatitis C virus (HCV) infections, where the IFNL variants were first identified to be associated with response to interferon-α-ribavirin therapy, the available data clearly suggests that the causal variant could be the dinucleotide polymorphism rs368234815 that causes an open reading frame-shift in the IFNL4 gene resulting in expression of a functional IFN-λ4, a new type III IFN. In other human diseases/phenotypes where IFNL variants have been recently associated with, the causal mechanism remains unclear. In vitro evidence has shown that other IFNL variants (rs28416813, rs4803217) may regulate expression of another type III IFN, IFN-λ3. Therefore, expression of a functional IFN-λ4 and quantitative differences in IFN-λ3 expression are two potential causal mechanisms behind the observed phenotypes. Since these two potential causal mechanisms involve features of mutual exclusivity and overlapping functions, it is difficult to differentiate one from the other, in vivo, in absence of other implicating evidences. In addition, the strong linkage disequilibrium (LD) observed in many populations at the IFNL locus makes it difficult to tease out the actual functional/causal variants responsible for the phenotypes. The non-synonymous single nucleotide polymorphism rs117648444 that alters the activity of IFN-λ4 and the LD structure in the IFNL region which leads to a confounding effect of rs117648444 on other IFNL variants, provide us with additional tools in case-control studies to probe the role of IFN-λ4.
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Affiliation(s)
- Anand Bhushan
- National Institute of Biomedical Genomics, P.O.:N.S.S., Kalyani, West Bengal 741251, India
| | - Sreedhar Chinnaswamy
- National Institute of Biomedical Genomics, P.O.:N.S.S., Kalyani, West Bengal 741251, India.
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7
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de Souza SL, Vidal LL, Ramos J, Cardoso CC, Coelho HSM, Villela-Nogueira CA, Perez RDM, Soares MA, Santos AF. Hepatitis C Virus-Infected Responders and Relapsers to Treatment Show Similar Genetic Profiles of IL28B and IL10 Single Nucleotide Polymorphisms. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2931486. [PMID: 29888255 PMCID: PMC5985065 DOI: 10.1155/2018/2931486] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/26/2018] [Accepted: 04/12/2018] [Indexed: 12/13/2022]
Abstract
Genotype 1 of hepatitis C virus (HCV) is the most prevalent worldwide. Pegylated-interferon and ribavirin therapy is still used in the developing world but has less efficiency in this genotype. Single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 (IL28B) and rs1800896, rs1800871, and rs1800872 (IL10) are related to treatment outcome, but previous studies clustered nonresponse and relapse patients. The aim of this study is to analyze the frequency of those SNPs in HCV genotype 1 for response, nonresponse, or relapse. Patients were classified according to treatment outcome. Genomic DNA was extracted by blood samples and SNPs were defined by PCR and sequencing. Data analysis was performed with R project. The frequency of rs12979860 CC was similar among responders (0.48) and relapsers (0.46) and lower among nonresponders (0.18). The same trend was observed for rs8099917 TT. rs12979860 CC showed a protective effect for relapsers compared to nonresponders (OR = 0.25) as it occurs with responders (OR = 0.17). Haplotypes 12979860/C rs8099917/T were associated with protection against the nonresponder phenotype compared to responders (OR = 0.27) or relapsers (OR = 0.37). Frequency of rs12979860 and rs8099917 is different between relapsers and nonresponders, but similar between relapsers and responders.
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Affiliation(s)
| | | | - Juliene Ramos
- Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | | | | | | | - Renata de Mello Perez
- Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil
| | - Marcelo Alves Soares
- Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Instituto Nacional do Câncer, Rio de Janeiro, RJ, Brazil
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Nosotti L, Petrelli A, Genovese D, Catone S, Argentini C, Vella S, Rossi A, Costanzo G, Fortino A, Chessa L, Miglioresi L, Mirisola C. Distribution of IL28B Polymorphism in a Cohort of Italians and Immigrants with HCV Infection: Association with Viraemia, Stage of Fibrosis and Response to Treatment. J Immigr Minor Health 2017; 19:876-882. [PMID: 27271956 DOI: 10.1007/s10903-016-0444-9] [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] [Indexed: 11/29/2022]
Abstract
Aims of the study are to investigate, in a cohort of patients affected by HCV chronic hepatitis with genotypes 1 and 4, the prevalence of interleukin 28B (IL28B) genotypes, the possible association between IL28B polymorphism and severity of liver damage, the role of IL28B CC as a predictor of outcome. 365 patients with HCV infection were observed between 2013 and 2014. Demographic, virological, biochemical, and genetic characteristics of each patient were investigated. Liver fibrosis was assessed by transient elastometry. Mean age of the patients (72.9 % males, 27.1 % females) is 50 years. 91.5 % % of patients are Caucasian, 8.5 % African. In the patients with HCV1 and HCV4 a higher frequency of IL28B CT is observed with a prevalence of 52.1 and 61.8 % respectively. As regards ethnic group, African people have a prevalence of 35.5 % for CC, while Caucasians have a prevalence of 23.8 % for CC. In our cohort, IL28B polymorphism does not show significant differences among ethnic groups and in HCV1 and HCV4 genotypes. As described in literature, IL28B CC genotype is confirmed as predictor of sustained virological response in both Caucasians and Africans. A significant correlation between liver fibrosis and IL28B polymorphism emerges.
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Affiliation(s)
- L Nosotti
- National Institute for Health, Migration and Poverty (NIHMP), Via San Gallicano 25/a, 00153, Rome, Italy.
| | - A Petrelli
- National Institute for Health, Migration and Poverty (NIHMP), Via San Gallicano 25/a, 00153, Rome, Italy
| | - D Genovese
- National Institute for Health (NIH), Rome, Italy
| | - S Catone
- National Institute for Health (NIH), Rome, Italy
| | - C Argentini
- National Institute for Health (NIH), Rome, Italy
| | - S Vella
- National Institute for Health (NIH), Rome, Italy
| | - A Rossi
- National Institute for Health, Migration and Poverty (NIHMP), Via San Gallicano 25/a, 00153, Rome, Italy
| | - G Costanzo
- National Institute for Health, Migration and Poverty (NIHMP), Via San Gallicano 25/a, 00153, Rome, Italy
| | - A Fortino
- National Institute for Health, Migration and Poverty (NIHMP), Via San Gallicano 25/a, 00153, Rome, Italy
| | - L Chessa
- Center for the Study of Liver Diseases, University of Cagliari, Cagliari, Italy
| | - L Miglioresi
- National Institute for Health, Migration and Poverty (NIHMP), Via San Gallicano 25/a, 00153, Rome, Italy
| | - C Mirisola
- National Institute for Health, Migration and Poverty (NIHMP), Via San Gallicano 25/a, 00153, Rome, Italy
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9
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Thabet K, Chan HLY, Petta S, Mangia A, Berg T, Boonstra A, Brouwer WP, Abate ML, Wong VWS, Nazmy M, Fischer J, Liddle C, George J, Eslam M. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology 2017; 65:1840-1850. [PMID: 28109005 DOI: 10.1002/hep.29064] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 12/18/2016] [Accepted: 01/13/2017] [Indexed: 12/24/2022]
Abstract
UNLABELLED Chronic hepatitis B (CHB) is characterized by hepatic inflammation that promotes progression to cirrhosis and predisposes to the development of hepatocellular carcinoma (HCC). Subtle interindividual genetic variation as well as viral and environmental factors interact to determine disease progression between individuals. Recently, the rs641738 membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) polymorphism was demonstrated to influence histological liver damage in alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C, but no data are available for CHB. We evaluated rs641738 influence on disease severity in a cohort of 1,101 patients with CHB. Forty-two patients underwent gene expression analysis to assess the functional consequences of rs641738 on hepatic MBOAT7 expression. The minor allele (T) of rs641738 was associated with greater inflammation (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.06-1.95; P = 0.001) and fibrosis (OR = 1.31; 95% CI, 1.19-1.92; P = 0.01). Risk allele frequency in whites (0.43) was greater than in Chinese (0.24), translating to a larger size effect in the former. The rs641738 (T) allele was associated with lower hepatic MBOAT7 expression (P = 0.008), and the latter was associated with serum liver enzymes and inflammation. Neither patatin-like phospholipase domain-containing protein 3 rs738409 nor transmembrane 6 superfamily member 2 rs58542926 polymorphisms influenced disease severity. CONCLUSION In patients with CHB, MBOAT7 rs641738 influences hepatic inflammation and fibrosis stage. (Hepatology 2017;65:1840-1850).
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Affiliation(s)
- Khaled Thabet
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Henry Lik Yuen Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, the Chinese University of Hong Kong
| | - Salvatore Petta
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Willem P Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, the Chinese University of Hong Kong
| | - Maiiada Nazmy
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Janett Fischer
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
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10
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Eslam M, McLeod D, Kelaeng KS, Mangia A, Berg T, Thabet K, Irving WL, Dore GJ, Sheridan D, Grønbæk H, Abate ML, Hartmann R, Bugianesi E, Spengler U, Rojas A, Booth DR, Weltman M, Mollison L, Cheng W, Riordan S, Mahajan H, Fischer J, Nattermann J, Douglas MW, Liddle C, Powell E, Romero-Gomez M, George J. IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis. Nat Genet 2017; 49:795-800. [PMID: 28394349 DOI: 10.1038/ng.3836] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 03/13/2017] [Indexed: 12/15/2022]
Abstract
Genetic variation in the IFNL3-IFNL4 (interferon-λ3-interferon-λ4) region is associated with hepatic inflammation and fibrosis. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3-IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4-Ser70) and those encoding fully active IFN-λ4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales, Australia
| | - Kebitsaone Simon Kelaeng
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Khaled Thabet
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - William L Irving
- NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, UK
| | - Gregory J Dore
- Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - David Sheridan
- Institute of Translational and Stratified Medicine, Plymouth University, Plymouth, UK
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Rune Hartmann
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Angela Rojas
- UCM IC Digestive Diseases and ciberehd. University Hospital Virgen del Rocio, Institute of Biomedicine of Seville, Seville, Spain
| | - David R Booth
- Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales, Australia
| | - Lindsay Mollison
- Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia, Australia
| | - Wendy Cheng
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales, Australia
| | - Hema Mahajan
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales, Australia
| | - Janett Fischer
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Mark W Douglas
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
| | - Elizabeth Powell
- University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Manuel Romero-Gomez
- UCM IC Digestive Diseases and ciberehd. University Hospital Virgen del Rocio, Institute of Biomedicine of Seville, Seville, Spain
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
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11
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Abstract
Type-III interferons (IFN-λ), the most recently discovered family of IFNs, shares common features with other family members, but also has many distinctive activities. IFN-λ uniquely has a different receptor complex, and a more focused pattern of tissue expression and signaling effects, from other classes of IFNs. Multiple genome-wide association studies (GWAS) and subsequent validation reports suggest a pivotal role for polymorphisms near the IFNL3 gene in hepatitis C clearance and control, as also for several other epithelial cell tropic viruses. Apart from its antiviral activity, IFN-λ possesses anti-tumor, immune-inflammatory and homeostatic functions. The overlapping effects of IFN-λ with type I IFN, with a restricted tissue expression pattern renders IFN-λ an attractive therapeutic target for viral infection, cancer and autoimmune diseases, with limited side effects. Areas covered: This review will summarize the current and future therapeutic opportunities offered by this most recently discovered family of interferons. Expert opinion: Our knowledge on IFN-λ is rapidly expanding. Though there are many remaining questions and challenges that require elucidation, the unique characteristics of IFN-λ increases enthusiasm that multiple therapeutic options will emerge.
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Affiliation(s)
- Mohammed Eslam
- a Storr Liver Centre, Westmead Institute for Medical Research , Westmead Hospital and University of Sydney , Sydney , Australia
| | - Jacob George
- a Storr Liver Centre, Westmead Institute for Medical Research , Westmead Hospital and University of Sydney , Sydney , Australia
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12
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Aiken T, Garber A, Thomas D, Hamon N, Lopez R, Konjeti R, McCullough A, Zein N, Fung J, Askar M, John BV. Donor IFNL4 Genotype Is Associated with Early Post-Transplant Fibrosis in Recipients with Hepatitis C. PLoS One 2016; 11:e0166998. [PMID: 27875564 PMCID: PMC5119817 DOI: 10.1371/journal.pone.0166998] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 11/07/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND AIMS Early post-transplant hepatic fibrosis is associated with poor outcomes and may be influenced by donor/recipient genetic factors. The rs368234815 IFNL4 polymorphism is related to the previously described IL28B polymorphism, which predicts etiology-independent hepatic fibrosis. The aim of this study was to identify the impact of donor and/or recipient IFNL4 genotype on early fibrosis among patients transplanted for hepatitis C (HCV). METHODS Clinical data were collected for 302 consecutive patients transplanted for HCV. 116 patients who had available liver biopsies and donor/recipient DNA were included. 28% of these patients with stage 2 fibrosis or greater were compared to patients without significant post-transplant fibrosis with respect to clinical features as well as donor/recipient IFNL4 genotype. RESULTS The IFNL4 TT/TT genotype was found in 26.0% of recipients and 38.6% of donors. Patients who developed early post-transplant fibrosis had a 3.45 adjusted odds of having donor IFNL4 TT/TT genotype (p = 0.012). Donor IFNL4 TT/TT genotype also predicted decreased overall survival compared to non-TT/TT genotypes (p = 0.016). CONCLUSIONS Donor IFNL4 TT/TT genotype, a favorable predictor of spontaneous HCV clearance pre-transplant, is associated with increased early post-transplant fibrosis and decreased survival.
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Affiliation(s)
- Taylor Aiken
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Ari Garber
- Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Dawn Thomas
- Allogen Laboratories, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Nicole Hamon
- Allogen Laboratories, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Rocio Lopez
- Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Rajesh Konjeti
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Arthur McCullough
- Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Nizar Zein
- Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - John Fung
- Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Medhat Askar
- Transplant Immunology, Baylor University Medical Center, Dallas, Texas, United States of America
| | - Binu V. John
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
- Gastroenterology and Hepatology, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia, United States of America
- * E-mail:
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13
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Thabet K, Asimakopoulos A, Shojaei M, Romero-Gomez M, Mangia A, Irving WL, Berg T, Dore GJ, Grønbæk H, Sheridan D, Abate ML, Bugianesi E, Weltman M, Mollison L, Cheng W, Riordan S, Fischer J, Spengler U, Nattermann J, Wahid A, Rojas A, White R, Douglas MW, McLeod D, Powell E, Liddle C, van der Poorten D, George J, Eslam M. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat Commun 2016; 7:12757. [PMID: 27630043 PMCID: PMC5027609 DOI: 10.1038/ncomms12757] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/29/2016] [Indexed: 02/08/2023] Open
Abstract
Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.
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Affiliation(s)
- Khaled Thabet
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 6111, Egypt
| | - Anastasia Asimakopoulos
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Maryam Shojaei
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, New South Wales 2145, Australia
- Nepean Genomic Research Group, ICU, Nepean Hospital, Kingswood, New South Wales 2747, Australia
| | - Manuel Romero-Gomez
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, 41014 Sevilla, Spain
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, 71013 San Giovanni Rotondo, Italy
| | - William L. Irving
- NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham NG7 2UH, UK
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, 04103 Leipzig, Germany
| | - Gregory J. Dore
- Kirby Institute, The University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus, Denmark
| | - David Sheridan
- Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL4 8AA, UK
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, 10126 Turin, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, 10126 Turin, Italy
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales 2747, Australia
| | - Lindsay Mollison
- Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia 6160, Australia
| | - Wendy Cheng
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Western Australia 6000, Australia
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales 2031, Australia
| | - Janett Fischer
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, 04103 Leipzig, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany
| | - Ahmed Wahid
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 6111, Egypt
| | - Angela Rojas
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, 41014 Sevilla, Spain
| | - Rose White
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Mark W. Douglas
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales 2145, Australia
| | - Elizabeth Powell
- Princess Alexandra Hospital, School of Medicine, The University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - David van der Poorten
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia
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14
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Kuntzen T, Kuhn S, Kuntzen D, Seifert B, Müllhaupt B, Geier A. Influence of Ribavirin Serum Levels on Outcome of Antiviral Treatment and Anemia in Hepatitis C Virus Infection. PLoS One 2016; 11:e0158512. [PMID: 27388623 PMCID: PMC4936744 DOI: 10.1371/journal.pone.0158512] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 06/16/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Ribavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered. METHODS The impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1-4 infection, including 88 patients with available IL28b genotyping. RESULTS Mean ribavirin levels varied between 0.68-5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia. CONCLUSION While data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon.
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Affiliation(s)
- Thomas Kuntzen
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Sereina Kuhn
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Daniela Kuntzen
- Department of Internal Medicine, Kantonsspital Baden, Baden, Switzerland
| | - Burkhardt Seifert
- Epidemiology, Biostatistics and Prevention Institute, University Zürich, Zürich, Switzerland
| | - Beat Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Andreas Geier
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
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15
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Eslam M, Mangia A, Berg T, Chan HLY, Irving WL, Dore GJ, Abate ML, Bugianesi E, Adams LA, Najim MAM, Miele L, Weltman M, Mollison L, Cheng W, Riordan S, Fischer J, Romero-Gomez M, Spengler U, Nattermann J, Rahme A, Sheridan D, Booth DR, McLeod D, Powell E, Liddle C, Douglas MW, van der Poorten D, George J. Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology 2016; 64:34-46. [PMID: 26822232 DOI: 10.1002/hep.28475] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 01/27/2016] [Indexed: 01/03/2023]
Abstract
UNLABELLED A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). The roles of this variant across a spectrum of liver diseases and pathologies and on serum lipids comparing viral hepatitis to NAFLD and viral load in chronic viral hepatitis, as well as its intrahepatic molecular signature, have not been well characterized. We undertook detailed analyses in 3260 subjects with viral and nonviral liver diseases and in healthy controls. Serum inflammatory markers and hepatic expression of TM6SF2 and genes regulating lipid metabolism were assessed in a subset with chronic hepatitis C (CHC). The rs58542926 T allele was more prevalent in 502 NAFLD patients than controls (P = 0.02) but not different in cohorts with CHC (n = 2023) and chronic hepatitis B (n = 507). The T allele was associated with alterations in serum lipids and hepatic steatosis in all diseases and with reduced hepatic TM6SF2 and microsomal triglyceride transfer protein expression. Interestingly, the substitution was associated with reduced CHC viral load but increased hepatitis B virus DNA. The rs58542926 T allele had no effect on inflammation, impacted ≥F2 fibrosis in CHC and NAFLD assessed cross-sectionally (odds ratio = 1.39, 95% confidence interval 1.04-1.87, and odds ratio = 1.62, 95% confidence interval 1.03-2.52, respectively; P < 0.03 for both), but had no effect on fibrosis progression in 1174 patients with CHC and a known duration of infection. CONCLUSION The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (Hepatology 2016;64:34-46).
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Henry Lik Yuen 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, UK
| | - Gregory J Dore
- Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
- St. Vincent's Hospital, Sydney, NSW, Australia
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Leon A Adams
- School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia
| | - Mustafa A M Najim
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia
- Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia
| | - Luca Miele
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia
| | - Lindsay Mollison
- Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, WA, Australia
| | - Wendy Cheng
- Department of Gastroenterology & Hepatology, Royal Perth Hospital, WA, Australia
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia
| | - Janett Fischer
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Manuel Romero-Gomez
- Unit for the Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Antony Rahme
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia
| | - David Sheridan
- Institute of Translational and Stratified Medicine, Plymouth University, UK
| | - David R Booth
- Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, NSW, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, Australia
| | - Elizabeth Powell
- The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Christopher Liddle
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia
| | - Mark W Douglas
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
| | - David van der Poorten
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia
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16
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Eslam M, Hashem AM, Romero-Gomez M, Berg T, Dore GJ, Mangia A, Chan HLY, Irving WL, Sheridan D, Abate ML, Adams LA, Weltman M, Bugianesi E, Spengler U, Shaker O, Fischer J, Mollison L, Cheng W, Nattermann J, Riordan S, Miele L, Kelaeng KS, Ampuero J, Ahlenstiel G, McLeod D, Powell E, Liddle C, Douglas MW, Booth DR, George J. FibroGENE: A gene-based model for staging liver fibrosis. J Hepatol 2016; 64:390-398. [PMID: 26592354 DOI: 10.1016/j.jhep.2015.11.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 11/02/2015] [Accepted: 11/09/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The extent of liver fibrosis predicts long-term outcomes, and hence impacts management and therapy. We developed a non-invasive algorithm to stage fibrosis using non-parametric, machine learning methods designed for predictive modeling, and incorporated an invariant genetic marker of liver fibrosis risk. METHODS Of 4277 patients with chronic liver disease, 1992 with chronic hepatitis C (derivation cohort) were analyzed to develop the model, and subsequently validated in an independent cohort of 1242 patients. The model was assessed in cohorts with chronic hepatitis B (CHB) (n=555) and non-alcoholic fatty liver disease (NAFLD) (n=488). Model performance was compared to FIB-4 and APRI, and also to the NAFLD fibrosis score (NFS) and Forns' index, in those with NAFLD. RESULTS Significant fibrosis (⩾F2) was similar in the derivation (48.4%) and validation (47.4%) cohorts. The FibroGENE-DT yielded the area under the receiver operating characteristic curve (AUROCs) of 0.87, 0.85 and 0.804 for the prediction of fast fibrosis progression, cirrhosis and significant fibrosis risk, respectively, with comparable results in the validation cohort. The model performed well in NAFLD and CHB with AUROCs of 0.791, and 0.726, respectively. The negative predictive value to exclude cirrhosis was>0.96 in all three liver diseases. The AUROC of the FibroGENE-DT performed better than FIB-4, APRI, and NFS and Forns' index in most comparisons. CONCLUSION A non-invasive decision tree model can predict liver fibrosis risk and aid decision making.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Ahmed M Hashem
- Department of Systems and Biomedical Engineering, Faculty of Engineering, Minia University, Minia, Egypt
| | - Manuel Romero-Gomez
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
| | - Thomas Berg
- Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Germany; Department of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Gregory J Dore
- Kirby Institute, The University of New South Wales, Sydney, NSW, Australia; St Vincent's Hospital, Sydney, NSW, Australia
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy
| | - Henry Lik Yuen 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, United Kingdom
| | - David Sheridan
- Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Translational and Stratified Medicine, Plymouth University, United Kingdom
| | - Maria Lorena Abate
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Leon A Adams
- School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Olfat Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Janett Fischer
- Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Germany
| | - Lindsay Mollison
- School of Medicine and Pharmacology, Fremantle Hospital, UWA, Fremantle, WA, Australia
| | - Wendy Cheng
- Department of Gastroenterology & Hepatology, Royal Perth Hospital, WA, Australia
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia
| | - Luca Miele
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Kebitsaone Simon Kelaeng
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Javier Ampuero
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
| | - Golo Ahlenstiel
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia
| | - Elizabeth Powell
- Princess Alexandra Hospital, Department of Gastroenterology and Hepatology, Woolloongabba, QLD, Australia; The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Christopher Liddle
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia
| | - David R Booth
- Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia.
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Wu R, Chi X, Wang X, Sun H, Lv J, Gao X, Yu G, Kong F, Xu H, Hua R, Jiang J, Sun B, Zhong J, Pan Y, Niu J. IFNL4 ss469415590 polymorphism contributes to treatment decisions in patients with chronic hepatitis C virus genotype 1b, but not 2a, infection. INFECTION GENETICS AND EVOLUTION 2016; 39:132-140. [PMID: 26820907 DOI: 10.1016/j.meegid.2016.01.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 01/17/2016] [Accepted: 01/23/2016] [Indexed: 12/11/2022]
Abstract
Recently, the dinucleotide variant ss469415590 (TT/ΔG) in a novel gene, interferon lambda 4 (IFNL4), was identified as a stronger predictor of hepatitis C virus (HCV) clearance in individuals of African ancestry compared with rs12979860. We aimed to determine whether this variant contributes to treatment decisions in a Chinese population. A total of 447 chronic hepatitis C (CHC) patients (including 328 treated with interferon alpha-2b and ribavirin), 129 individuals who had spontaneously cleared HCV (SHC), and 169 healthy controls were retrospectively investigated. ss469415590 genotyping was performed using a mass spectrometry method (SEQUENOM). A higher proportion of SHC individuals carried the TT/TT genotype compared with CHC patients (95.3% vs. 88.8%, P=0.027). In patients with HCV genotype 1b, the ss469415590 variant was independently associated with sustained virologic response (SVR) (odds ratio [OR]=3.247, 95% confidence interval [CI]=1.038-10.159, P=0.043) and on-treatment virological responses, including rapid (RVR), complete early (cEVR), early (EVR), and end-of-treatment (ETVR), with a minimal OR of 3.73. Especially for patients with high viral load (≥4×10(5) IU/ml), ΔG allele carriers had a lower chance of achieving SVR compared with those carrying the TT/TT genotype (7.1% vs. 36.0%, P=0.034, OR [95% CI]=7.24 [1.02-318.45], negative predictive value=92.9%). In patients with HCV genotype 2a, no significant association between the ss154949590 variant and the virological response was identified (P>0.05). Additionally, we found that ss154949590 was in complete linkage disequilibrium with rs12979860. In conclusion, the IFNL4 ss154949590 TT/TT genotype favors spontaneous clearance of HCV. This same variant is associated with treatment-induced clearance in patients with genotype 1b, but not 2a. ss469415590 (or rs12979860) genotyping should be considered for patients with HCV genotype 1b and high viral load when making a choice between standard dual therapy and an IFN-free direct-acting antiviral regimen.
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Affiliation(s)
- Ruihong Wu
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Xiumei Chi
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Xiaomei Wang
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Haibo Sun
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Juan Lv
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Xiuzhu Gao
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Ge Yu
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Fei Kong
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Hongqin Xu
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Rui Hua
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Jing Jiang
- Department of Clinical Epidemiology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China
| | - Bing Sun
- Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Street, Shanghai 200031, China
| | - Jin Zhong
- Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Street, Shanghai 200031, China
| | - Yu Pan
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun, Jilin Province 130021, China.
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18
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Peiffer KH, Sommer L, Susser S, Vermehren J, Herrmann E, Döring M, Dietz J, Perner D, Berkowski C, Zeuzem S, Sarrazin C. Interferon lambda 4 genotypes and resistance-associated variants in patients infected with hepatitis C virus genotypes 1 and 3. Hepatology 2016; 63:63-73. [PMID: 26406534 DOI: 10.1002/hep.28255] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 09/23/2015] [Indexed: 12/25/2022]
Abstract
UNLABELLED Single-nucleotide polymorphisms (SNPs) in the interferon lambda 4 (IFNL4) gene are predictors for treatment success in patients with hepatitis C virus (HCV) infection. For direct-acting antiviral combinations only weak association with IFNL4 SNPs was observed. Little is known about potential selections of resistance-associated variants (RAVs) by the IFNL4 genotype. This study analyzed the prevalence of RAVs to currently approved direct-acting antivirals in a large European population in correlation to SNPs in IFNL4. Samples of 633 patients chronically infected with HCV genotypes 1a (n = 259), 1b (n = 323), and 3 (n = 51) were genotyped for rs12979860 (formerly known as IL28B) and rs368234815. RAVs in NS3, NS5A, and NS5B were detected by population-based sequencing. In addition, IFNL4 SNPs and NS5A RAVs were analyzed including deep sequencing (n = 109) in an independent replication cohort of HCV genotype 1-infected patients (n = 201). No significant correlation was found between IFNL4 SNPs and rare and common RAVs within NS3 and NS5B. In contrast, the NS5A RAV Y93H was detected frequently in HCV genotype 1b (14%) and significantly associated with the beneficial IFNL4 SNPs (P < 0.001 and P = 0.002, respectively). Moreover, the presence of Y93H in HCV genotype 1b patients was significantly associated with the second site variant T83M (P < 0.001). Independent factors significantly associated with the presence of Y93H were IFNL4 genotype and high baseline viral load. CONCLUSION The NS5A RAV Y93H is significantly associated with the presence of beneficial IFNL4 SNPs and a high baseline viral load in HCV genotype 1-infected patients, which may explain a lack of correlation or even an inverse correlation of treatment response with IFNL4 genotype in some NS5A inhibitor containing IFN-free regimens.
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Affiliation(s)
| | - Lisa Sommer
- Department of Gastroenterology and Hepatology
| | | | | | - Eva Herrmann
- Department of Medicine, Institute of Biostatistics and Mathematical Modeling, J.W. Goethe University, Frankfurt, Germany
| | - Matthias Döring
- Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarbrücken, Germany.,Graduate School of Computer Science, Saarbrücken, Germany
| | - Julia Dietz
- Department of Gastroenterology and Hepatology
| | - Dany Perner
- Department of Gastroenterology and Hepatology
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19
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Wiegand SB, Heidrich B, Susser S, Rogalska-Taranta M, Petersen J, Böker KHW, Grigorian N, Link R, Naumann U, John C, Lueth S, Malfertheiner P, Manns MP, Wedemeyer H, Sarrazin C, Cornberg M. Performance and Value of IFN-Lambda3 and IFN-Lambda4 Genotyping in Patients with Chronic Hepatitis C (CHC) Genotype 2/3 in a Real World Setting. PLoS One 2015; 10:e0145622. [PMID: 26699619 PMCID: PMC4689517 DOI: 10.1371/journal.pone.0145622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/06/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. METHODS We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). RESULTS Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). CONCLUSION IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.
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Affiliation(s)
- Steffen B. Wiegand
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Liver Foundation, HepNet Study-House, Hannover and Frankfurt, Germany
- German Center for Infectious Diesease (DZIF), Hannover-Braunschweig, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Liver Foundation, HepNet Study-House, Hannover and Frankfurt, Germany
- German Center for Infectious Diesease (DZIF), Hannover-Braunschweig, Germany
| | - Simone Susser
- Department of Internal Medicine I, University of Frankfurt, Frankfurt, Germany
| | - Magdalena Rogalska-Taranta
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jörg Petersen
- IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | | | - Natalia Grigorian
- Department of Internal Medicine II, University of Saarland, Saarland, Germany
| | - Ralph Link
- Department of Internal Medicine, Clinic for Internal Medicine St. Josefs hospital, Offenburg, Germany
| | - Uwe Naumann
- Center for Addiction-Medicine, Hepatology and HIV, Praxiszentrum Kaiserdamm, Berlin, Germany
| | | | - Stefan Lueth
- Department of Internal Medicine, University of Hamburg, Hamburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Endocrinology, University of Magdeburg, Magdeburg, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Liver Foundation, HepNet Study-House, Hannover and Frankfurt, Germany
- German Center for Infectious Diesease (DZIF), Hannover-Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Liver Foundation, HepNet Study-House, Hannover and Frankfurt, Germany
- German Center for Infectious Diesease (DZIF), Hannover-Braunschweig, Germany
| | - Christoph Sarrazin
- German Liver Foundation, HepNet Study-House, Hannover and Frankfurt, Germany
- Department of Internal Medicine I, University of Frankfurt, Frankfurt, Germany
- German Center for Infectious Diesease (DZIF), Hannover-Braunschweig, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Liver Foundation, HepNet Study-House, Hannover and Frankfurt, Germany
- German Center for Infectious Diesease (DZIF), Hannover-Braunschweig, Germany
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20
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Ampuero J, Romero-Gómez M. Hepatitis C Virus: Current and Evolving Treatments for Genotypes 2 and 3. Gastroenterol Clin North Am 2015; 44:845-57. [PMID: 26600223 DOI: 10.1016/j.gtc.2015.07.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) genotypes 2 and 3 have previously been classified as easy-to-treat genotypes, because sustained virologic responses (SVRs) up to 80% have been achieved with 24-week peginterferon and ribavirin. More detailed studies have shown differences between HCV genotypes 2 and 3, indicating that genotype 3 has become the most difficult-to-treat genotype. With new drugs, new challenges are emerging regarding relapse rates, the role of ribavirin, and optimal duration of therapy. Sofosbuvir remains the backbone of genotype 3 therapy, whereas this drug is not an option in patients with creatinine clearance lower than 30 mL/min.
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Affiliation(s)
- Javier Ampuero
- Unit for the Clinical Management of Digestive Diseases & CIBERehd, Virgen Macarena - Virgen del Rocio University Hospitals, Avenida Manuel Siurot, s/n, Sevilla 41017, Spain
| | - Manuel Romero-Gómez
- Unit for the Clinical Management of Digestive Diseases & CIBERehd, Virgen Macarena - Virgen del Rocio University Hospitals, Avenida Manuel Siurot, s/n, Sevilla 41017, Spain.
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21
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Abstract
Despite advances in therapy, hepatitis C virus infection remains a major global health issue with 3 to 4 million incident cases and 170 million prevalent chronic infections. Complex, partially understood, host-virus interactions determine whether an acute infection with hepatitis C resolves, as occurs in approximately 30% of cases, or generates a persistent hepatic infection, as occurs in the remainder. Once chronic infection is established, the velocity of hepatocyte injury and resultant fibrosis is significantly modulated by immunologic as well as environmental factors. Immunomodulation has been the backbone of antiviral therapy despite poor understanding of its mechanism of action.
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Affiliation(s)
- David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
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22
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Lee MH, Yang HI, Lu SN, Lin YJ, Jen CL, Wong KH, Chan SY, Chen LC, Wang LY, L’Italien G, Yuan Y, Chen CJ. Polymorphisms near the IFNL3 Gene Associated with HCV RNA Spontaneous Clearance and Hepatocellular Carcinoma Risk. Sci Rep 2015; 5:17030. [PMID: 26602024 PMCID: PMC4658500 DOI: 10.1038/srep17030] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 10/22/2015] [Indexed: 12/14/2022] Open
Abstract
The aims of this study were to investigate associations between single nucleotide polymorphisms (SNPs) near the genes IFNL2, IFNL3, and IFNL4 and spontaneous clearance of hepatitis C virus (HCV) and to evaluate variants for their risk of hepatocellular carcinoma (HCC) among subjects in whom spontaneous HCV RNA clearance did not occur. In the first study, 889 untreated anti-HCV-seropositive patients without HCC symptoms were followed from 1991 to 2005. The spontaneous HCV clearance rate was found to be 33.1%. The TT variant of rs8099917 near IFNL3 was associated with increased spontaneous HCV RNA clearance, with an adjusted odds ratio (95% CI) of 2.78 (1.43-5.39), as was the newly-identified TT/TT dinucleotide variant rs368234815 near IFNL4 (adjusted odds ratio 2.68, 95% CI: 1.42-5.05). In the second study, associations between SNPs and HCC risk were examined in 483 HCC cases with detectable HCV RNA and 516 controls. In participants with HCV genotype 1, unfavorable genotypes for HCV clearance near IFNL3 were associated with increased HCC risk, the adjusted odds ratio (95% CI) for rs12979860 and rs8099917 being 1.73 (1.00-2.99) and 1.84 (1.02-3.33), respectively. Host characteristics should be considered to identify high-risk patients to prioritize the use of new antiviral agents and intensive screening.
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Affiliation(s)
- Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Sheng-Nan Lu
- Division of Hepato-Gastroenterology, (Department of Internal Medicine), Kaohsiung Chang Gung Memorial Hospital, KaohsiungChang Gung University School of Medicine, Kaohsiung, Taiwan
| | - Yu-Ju Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Chin-Lan Jen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Kang-Hsuan Wong
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Soa-Yu Chan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Liang-Chun Chen
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | | | - Gilbert L’Italien
- Global Health Economics and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, United States
- Yale University School of Medicine, New Haven, CT, United States
| | - Yong Yuan
- Global Health Economics and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, United States
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei , Taiwan
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23
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Hydes TJ, Moesker B, Traherne JA, Ashraf S, Alexander GJ, Dimitrov BD, Woelk CH, Trowsdale J, Khakoo SI. The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways. TISSUE ANTIGENS 2015; 86:267-75. [PMID: 26381047 PMCID: PMC4858811 DOI: 10.1111/tan.12650] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 08/05/2015] [Accepted: 08/10/2015] [Indexed: 12/15/2022]
Abstract
Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)-λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ(2) test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA-B (TapG:HLA-B(114D) ) (P = 0.007) and HLA-DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ(2) test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA-C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non-interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.
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Affiliation(s)
- T J Hydes
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - B Moesker
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - J A Traherne
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - S Ashraf
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - G J Alexander
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - B D Dimitrov
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Academic Unit of Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - C H Woelk
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - J Trowsdale
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - S I Khakoo
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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Coppola N, Pisaturo M, Sagnelli C, Onorato L, Sagnelli E. Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases 2015; 3:807-822. [PMID: 26380828 PMCID: PMC4568530 DOI: 10.12998/wjcc.v3.i9.807] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 12/09/2014] [Accepted: 06/08/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C (CHC).
METHODS: We conducted an electronic search on the PubMed and MEDLINE (2000-2014) databases and Cochrane library (2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.
RESULTS: Several studies associated polymorphisms in the interleukin 28B gene on chromosome 19 (19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon (Peg-IFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation.
CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
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Bellanti F, Lauletta G, Villani R, Lipsi MR, Natalicchio MI, Sansonno D, Vendemiale G, Serviddio G. Combined Effects of 2 Interleukin 28B Polymorphisms on the Therapeutic Outcome of Hepatitis C Patients With Circulating Cryoglobulins. Medicine (Baltimore) 2015; 94:e1409. [PMID: 26334898 PMCID: PMC4616511 DOI: 10.1097/md.0000000000001409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 07/24/2015] [Accepted: 07/24/2015] [Indexed: 02/05/2023] Open
Abstract
Chronic hepatitis C is commonly associated with extrahepatic manifestations. Cryoglobulins are observed in 40% to 60% of such patients and their presence seems to modify response to therapy. The new antivirals are greatly improving the sustained virological response (SVR); however, their high cost limits the use, leaving pegylated interferon plus ribavirin (PR) still the standard-of-care therapy worldwide. Since PR therapy is burdened with several side effects, pretreatment predictions of patients who are unlikely to respond to this regimen may avoid ineffective treatment. Variants of the interleukin-28B (IL28B) gene correlate with an SVR to PR, and combined IL28B polymorphisms may improve the prediction of treatment outcome.The potential role of both rs8099917 and rs12979860 IL28B single nucleotide polymorphisms (SNPs) combined with presence of cryoglobulins in predicting SVR to PR in hepatitis C virus (HCV)-chronically infected patients was analyzed in the present study.Single and combined IL28B SNPs (rs12979860 and rs8099917) were analyzed in 64 chronic HCV patients treated with PR showing circulating cryoglobulins and compared to 108 noncryoglobulinemic subjects to verify the predictive value on the SVR.The association of rs12979860CC or rs8099917TT with SVR was confirmed in the noncryoglobulinemic group but not in cryoglobulinemic patients. Moreover, the combined determination of both SNPs improved the prediction of SVR in noncryoglobulinemic patients but not in the cryoglobulinemic subgroup.We report that both single and combined determination of IL28B rs12979860 and rs8099917 SNPs in chronic HCV patients with circulating cryoglobulins treated with PR may have a reduced predictive value of SVR.
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Affiliation(s)
- Francesco Bellanti
- From the Department of Medical and Surgical Sciences, C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, University of Foggia, Foggia, Italy (FB, RV, GV, GS); Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy (GL, DS); and Department of Clinical Pathology, II Laboratory, Section of Cytogenetic and Molecular Biology, University Hospital "Ospedali Riuniti", Foggia, Italy (MRL, MIN)
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Holmes JA, Congiu M, Bonanzinga S, Sandhu MK, Kia YH, Bell SJ, Nguyen T, Iser DM, Visvanathan K, Sievert W, Bowden DS, Desmond PV, Thompson AJ. The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3. Aliment Pharmacol Ther 2015; 42:296-306. [PMID: 26032235 DOI: 10.1111/apt.13263] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 02/02/2015] [Accepted: 05/09/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.
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Affiliation(s)
- J A Holmes
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - M Congiu
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - S Bonanzinga
- Victorian Infectious Diseases Reference Laboratory, The Doherty Institute, Melbourne, Vic., Australia
| | - M K Sandhu
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - Y H Kia
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - S J Bell
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - T Nguyen
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - D M Iser
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - K Visvanathan
- Immunology Research Centre, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - W Sievert
- Department of Gastroenterology, Monash Medical Centre, Monash University, Clayton, Vic., Australia
| | - D S Bowden
- Victorian Infectious Diseases Reference Laboratory, The Doherty Institute, Melbourne, Vic., Australia
| | - P V Desmond
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
| | - A J Thompson
- Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia
- Victorian Infectious Diseases Reference Laboratory, The Doherty Institute, Melbourne, Vic., Australia
- Department of Gastroenterology, Duke University Medical Centre, Duke Clinical Research Institute, Durham, NC, USA
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Heidrich B, Cordes HJ, Klinker H, Möller B, Naumann U, Rössle M, Kraus MR, Böker KH, Roggel C, Schuchmann M, Stoehr A, Trein A, Hardtke S, Gonnermann A, Koch A, Wedemeyer H, Manns MP, Cornberg M. Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial. PLoS One 2015; 10:e0128069. [PMID: 26057627 PMCID: PMC4461366 DOI: 10.1371/journal.pone.0128069] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 04/18/2015] [Indexed: 12/21/2022] Open
Abstract
Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 μg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group.
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Affiliation(s)
- Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- HepNet Study-House, German Liver Foundation, Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | | | - Hartwig Klinker
- Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
| | | | - Uwe Naumann
- Center for Addiction-Medicine, Hepatology and HIV, Praxiszentrum Kaiserdamm, Berlin, Germany
| | | | - Michael R. Kraus
- Department of Internal Medicine, Hospital Altötting-Burghausen, Germany
| | | | | | | | - Albrecht Stoehr
- IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | | | - Svenja Hardtke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- HepNet Study-House, German Liver Foundation, Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | - Andrea Gonnermann
- Institute of Biostatistics, Hannover Medical School, Hannover, Germany
| | - Armin Koch
- Institute of Biostatistics, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- HepNet Study-House, German Liver Foundation, Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- HepNet Study-House, German Liver Foundation, Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- HepNet Study-House, German Liver Foundation, Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
- * E-mail: (MC)
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Wang M, Li JS, Ping Y, Li ZQ, Wang LP, Guo Q, Zhang Z, Yue DL, Wang F, Zhang TF, Islam MS, Zhang Y. The host HLA-A*02 allele is associated with the response to pegylated interferon and ribavirin in patients with chronic hepatitis C virus infection. Arch Virol 2015; 160:1043-1054. [PMID: 25666200 DOI: 10.1007/s00705-015-2361-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 01/31/2015] [Indexed: 12/16/2022]
Abstract
Human leukocyte antigen (HLA) alleles are associated with both the progression of chronic hepatitis C (CHC) and the sustained virological response (SVR) to antiviral therapy. HLA-A*02 is the most common HLA allele in people of European/Caucasian descent and the Chinese and Japanese population. Therefore, we investigated whether HLA-A*02 expression is associated with disease outcome in Chinese CHC patients. Three hundred thirty-one treatment-naïve CHC patients were recruited in this study. The expression of HLA-A*02 was tested by FACS and LABType SSO assays. All patients were treated weekly with pegylated interferon plus ribavirin (PEG-IFN/RBV) according to a standard protocol. Virological response was assessed by TaqMan assay at the 4th, 12th, 24th, and 48th week of therapy, and again at the 24th week post-therapy. By the end of the study, 293 CHC patients, including 144 HLA-A*02-positive patients and 149 HLA-A*02-negative patients, were evaluable for analysis. There were no statistical differences in clinicopathological parameters between HLA-A*02-positive and negative patients before antiviral therapy (P > 0.05). The HLA-A*02-positive patients had a higher rapid virological response (RVR, 74.3 % versus 62.4 %, P = 0.03) and SVR (78.5 % versus 64.4 %, P = 0.01) and a lower relapse rate (4.2 % versus 11.9 %, P = 0.03) than HLA-A*02-negative patients. Multivariable logistic regression analysis showed that HLA-A*02 expression, liver fibrosis stages
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Affiliation(s)
- Meng Wang
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Buchanan R, Hydes T, Khakoo SI. Innate and adaptive genetic pathways in HCV infection. TISSUE ANTIGENS 2015; 85:231-40. [PMID: 25708172 DOI: 10.1111/tan.12540] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes.
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Affiliation(s)
- R Buchanan
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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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: 148] [Impact Index Per Article: 14.8] [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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Mottola L, Cenderello G, Piazzolla VA, Forte P, Carretta V, Mecenate F, Brancaccio G, Minisini R, Zuin M, Terreni N, Monti M, Colombo AE, Nosotti L, Minerva N, Luzzitelli I, Kostandini A, Cuccorese G, Russello M, Santoro R, Mangia A. Interleukin-28B genetic variants in untreated Italian HCV-infected patients: a multicentre study. Liver Int 2015; 35:482-8. [PMID: 25039676 DOI: 10.1111/liv.12630] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 06/26/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Different prevalence of favourable IL28BCC genotype have been reported in studies performed in different countries around the world. Data on distribution of IL28B genotypes in healthy Italian subjects are lacking. METHODS Studies on prospectively collected untreated chronic HCV-infected Italian patients led to conflicting results. To investigate the prevalence of IL28B genotypes in untreated HCV-infected patients and in subjects able to clear HCV, and to compare them to the prevalence registered in healthy Italian controls. To evaluate IL28B prevalence across different HCV genotypes. RESULTS IL28BCC was observed in 30.9% of chronic HCV patients, in 71.0% of subjects able to clear HCV infection and in 41.6% of the Italian controls. The frequency of IL28BCC was higher in HCV genotype 2 and 3 than in 1 (38.3 vs. 28.2) (P = 0.02). Levels of ALT higher in IL28BCC than in non-CC were observed regardless of HCV genotypes (P = 0.0014). CONCLUSIONS IL28BCC frequencies progressively decline from subjects with spontaneous HCV clearance to normal non-infected subjects and to chronically infected. This study suggests that patients with IL28BCC, if genotype 1, are able to clear HCV more often than if genotype 2 and 3 infected, and that CC genotype is associated with higher grade of necro-inflammation.
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Affiliation(s)
- Leonardo Mottola
- Liver Unit, Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
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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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Eslam M, George J. Is hepatitis C subtyping still relevant in the era of direct-acting antiviral therapy? Hepatol Int 2015; 9:5-8. [PMID: 25788373 DOI: 10.1007/s12072-014-9600-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 12/03/2014] [Indexed: 02/07/2023]
Affiliation(s)
- Mohammed Eslam
- Storr Liver Unit, Westmead Millennium Institute, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
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O’Connor KS, George J, Booth D, Ahlenstiel G. Dendritic cells in hepatitis C virus infection: key players in the IFNL3-genotype response. World J Gastroenterol 2014; 20:17830-8. [PMID: 25548481 PMCID: PMC4273133 DOI: 10.3748/wjg.v20.i47.17830] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/14/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, single nucleotide polymorphisms, in the vicinity of the interferon lambda 3 (IFNL3) gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus (HCV) infection. Since then, increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect. Dendritic cells (DCs) are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging. Reports have identified subclasses of DCs, particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection. Given the complexities of dendritic cell biology and the conflicting current available data, this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to place it into context of what is know about lambda interferons and dendritic cells in general.
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