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1
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Lv X, Zhang PB, Zhang EL, Yang S. Predictive factors and prognostic models for Hepatic arterial infusion chemotherapy in Hepatocellular carcinoma: a comprehensive review. World J Surg Oncol 2025; 23:166. [PMID: 40287734 PMCID: PMC12034129 DOI: 10.1186/s12957-025-03765-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/23/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and lethal cancer, often diagnosed at advanced stages where traditional treatments such as surgical resection, liver transplantation, and locoregional therapies provide limited benefits. Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment modality for advanced HCC, enhancing anti-tumor efficacy through targeted drug delivery while minimizing systemic side effects. However, the heterogeneous nature of HCC leads to variable responses to HAIC, highlighting the necessity for reliable predictive indicators to tailor personalized treatment strategies. This review explores the factors influencing HAIC success, including patient demographics, tumor characteristics, biomarkers, genomic profiles, and advanced imaging techniques such as radiomics and deep learning models. Additionally, the synergistic potential of HAIC combined with immunotherapy and molecular targeted therapies is examined, demonstrating improved survival outcomes. Prognostic scoring systems and nomograms that integrate clinical, molecular, and imaging data are discussed as superior tools for individualized prognostication compared to traditional staging systems. Understanding these predictors is essential for optimizing HAIC efficacy and enhancing survival and quality of life for patients with advanced HCC. Future research directions include large-scale prospective studies, integration of multi-omics data, and advancements in artificial intelligence to refine predictive models and further personalize treatment approaches.
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Affiliation(s)
- Xing Lv
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Peng-Bo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Er-Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - S Yang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
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2
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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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3
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Kim KS, Iwamoto M, Kitagawa K, Park H, Hayashi S, Tsukuda S, Matsui T, Atsukawa M, Matsuura K, Chuaypen N, Tangkijvanich P, Allweiss L, Nishiyama T, Nakamura N, Fujita Y, Kawakami E, Nakaoka S, Muramatsu M, Aihara K, Wakita T, Perelson AS, Dandri M, Watashi K, Iwami S, Tanaka Y. Prediction of cccDNA dynamics in hepatitis B patients by a combination of serum surrogate markers. PLoS Comput Biol 2025; 21:e1012615. [PMID: 39787253 PMCID: PMC11753647 DOI: 10.1371/journal.pcbi.1012615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 01/22/2025] [Accepted: 11/04/2024] [Indexed: 01/12/2025] Open
Abstract
Quantification of intrahepatic covalently closed circular DNA (cccDNA) is a key for evaluating an elimination of hepatitis B virus (HBV) in infected patients. However, quantifying cccDNA requires invasive methods such as a liver biopsy, which makes it impractical to access the dynamics of cccDNA in patients. Although HBV RNA and HBV core-related antigens (HBcrAg) have been proposed as surrogate markers for evaluating cccDNA activity, they do not necessarily estimate the amount of cccDNA. Here, we employed a recently developed multiscale mathematical model describing intra- and intercellular viral propagation and applied it in HBV-infected patients under treatment. We developed a model that can predict intracellular HBV dynamics by use of extracellular viral markers, including HBsAg, HBV DNA, and HBcrAg in peripheral blood. Importantly, the model prediction of the amount of cccDNA in patients over time was confirmed to be well correlated with the data for quantified cccDNA by paired liver biopsy. Thus, our method combining classic and emerging surrogate markers enables us to predict the decay dynamics of cccDNA in patients undergoing treatment.
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Affiliation(s)
- Kwang Su Kim
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- Department of Scientific Computing, Pukyong National University, Busan, South Korea
| | - Masashi Iwamoto
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kosaku Kitagawa
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Hyeongki Park
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Sanae Hayashi
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Senko Tsukuda
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Masanori Atsukawa
- Department of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Lena Allweiss
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner sites, Germany
| | - Takara Nishiyama
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Naotoshi Nakamura
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Yasuhisa Fujita
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Eiryo Kawakami
- Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
- Medical Sciences Innovation Hub Program; RIKEN, Yokohama, Kanagawa, Japan
| | - Shinji Nakaoka
- Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kazuyuki Aihara
- International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Alan S. Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Maura Dandri
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba, Japan
| | - Shingo Iwami
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan
- Institute of Mathematics for Industry, Kyushu University,; Fukuoka, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
- NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Interdisciplinary Theoretical and Mathematical Sciences (iTHEMS), RIKEN, Wako, Japan
- Science Groove Inc., Fukuoka, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Roy DG, De M, Bharatiya S, Khedekar DA, Datta K, Bhattacharjee S, Chinnaswamy S. Evidence for a sex-dependent effect modification in the association between IFN-λ DNA polymorphisms and expression of IFN-λ and interferon-stimulated genes in human PBMCs. Cytokine 2024; 184:156779. [PMID: 39423653 DOI: 10.1016/j.cyto.2024.156779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 09/16/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024]
Abstract
Human interferon (IFN) lambda (IFNL, IFN-L or IFN-λ) locus has several functional genetic variants but their role in regulating in vivo gene expression, and whether they associate with antiviral states in healthy individuals, is not clear. In this study, we recruited ∼550 healthy individuals belonging to both sexes, genotyped them for several IFNL genetic variants and measured, by qPCR, the expression of IFNL2/3, IFNL4 and four IFN-stimulated genes (ISGs) (MX1, OAS1, ISG15 and RSAD2) from their peripheral blood mononuclear cells (PBMC) both before and after stimulation with a viral mimic, poly I: C. We also measured secreted levels of several cytokines including IFN-λ1 and IFN-λ3 in poly I:C stimulated PBMCs. We found that males secrete higher levels of IFN-λs than females. The IFNL3/4 genetic variants significantly associated with secreted levels of both IFN-λ1 and IFN-λ3 in opposite directions, only in males. While the IFNL3/4 variants significantly associated with ISG expression either in basal or poly I:C induced or in both states, the direction of effect was opposite for the two sexes, suggesting that sex was a strong effect modifier. We did not see this trend in the association of ISG expression with the IFNL1 polymorphism, rs7247086, whose association with ISG expression and secreted IFN-λ3 levels was seen in females but not in males. Further, expression of several genes was associated with the IFN-λ4 activity-modifying variant rs117648444. However, we neither saw any strong correlation between levels of IFN-λ1/3 and ISG expression, nor did we see any strong evidence of IFNL4 expression that could be responsible for the association between ISG expression and IFNL genetic variants. These results suggest that there are complex interactions involving gender, IFN-λs, IFN-λ genetic variants and antiviral states in humans.
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Affiliation(s)
- Debarati Guha Roy
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Regional Centre for Biotechnology, Faridabad, India
| | - Manjarika De
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India
| | - Seema Bharatiya
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Regional Centre for Biotechnology, Faridabad, India
| | - Dhanashree A Khedekar
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Regional Centre for Biotechnology, Faridabad, India
| | - Kallol Datta
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Regional Centre for Biotechnology, Faridabad, India
| | - Samsiddhi Bhattacharjee
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Regional Centre for Biotechnology, Faridabad, India
| | - Sreedhar Chinnaswamy
- Biotechnology Research Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India; Regional Centre for Biotechnology, Faridabad, India; Biotechnology Research Innovation Council-National Institute of Animal Biotechnology (BRIC-NIAB), Hyderabad, India.
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5
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Woods E, Mena A, Sierpinska S, Carr E, STTAR Bioresource, Hagan R, Crowley J, Bergin C, Clark D, Brophy C, Macallan D, Gardiner CM. Reduced IFNL1 and/or IFNL2, but not IFNL3 is associated with worse outcome in patients with COVID-19. Clin Exp Immunol 2024; 218:300-307. [PMID: 38953458 PMCID: PMC11557148 DOI: 10.1093/cei/uxae047] [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: 09/13/2023] [Revised: 04/05/2024] [Accepted: 06/28/2024] [Indexed: 07/04/2024] Open
Abstract
The recent pandemic was caused by the emergence of a new human pathogen, SARS-CoV-2. While the rapid development of many vaccines provided an end to the immediate crisis, there remains an urgent need to understand more about this new virus and what constitutes a beneficial immune response in terms of successful resolution of infection. Indeed, this is key for development of vaccines that provide long lasting protective immunity. The interferon lambda (IFNL) family of cytokines are produced early in response to infection and are generally considered anti-viral and beneficial. However, data regarding production of IFNL cytokines in coronavirus disease 2019 (COVID-19) patients is highly variable, and generally from underpowered studies. In this study, we measured all three IFNL1, IFNL2, and IFNL3 cytokines in plasma from a well characterized, large COVID-19 cohort (n = 399) that included good representation from patients with a more indolent disease progression, and hence a beneficial immune response. While all three cytokines were produced, they differed in both the frequency of expression in patients, and the levels produced. IFNL3 was produced in almost all patients but neither protein level nor IFNL3/IFNL4 single nucleotide polymorphisms were associated with clinical outcome. In contrast, both IFNL1 and IFNL2 levels were significantly lower, or absent, in plasma of patients that had a more severe disease outcome. These data are consistent with the concept that early IFNL1 and IFNL2 cytokine production is protective against SARS-CoV-2 infection.
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Affiliation(s)
- Elena Woods
- School of Biochemistry and Immunology, Trinity Biomedical Research Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Adriana Mena
- School of Biochemistry and Immunology, Trinity Biomedical Research Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Sophie Sierpinska
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
| | - Emily Carr
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
| | | | - Richard Hagan
- National Histocompatibility and Immunogenetics Reference Laboratory, National Blood Centre, Dublin, Ireland
| | - John Crowley
- National Histocompatibility and Immunogenetics Reference Laboratory, National Blood Centre, Dublin, Ireland
| | - Colm Bergin
- Department of Infectious Diseases, St. James’s Hospital, Dublin, Ireland
| | - David Clark
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
| | - Caroline Brophy
- School of Computer Science and Statistics, Trinity College Dublin, Dublin 2, Ireland
| | - Derek Macallan
- Institute for Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, UK
- Infection and Immunity Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Clair M Gardiner
- School of Biochemistry and Immunology, Trinity Biomedical Research Institute, Trinity College Dublin, Dublin 2, Ireland
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6
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Yamauchi K, Maekawa S, Osawa L, Komiyama Y, Nakakuki N, Takada H, Muraoka M, Suzuki Y, Sato M, Takano S, Enomoto N. Single-molecule sequencing of the whole HCV genome revealed envelope deletions in decompensated cirrhosis associated with NS2 and NS5A mutations. J Gastroenterol 2024; 59:1021-1036. [PMID: 39225750 DOI: 10.1007/s00535-024-02146-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Defective hepatitis C virus (HCV) genomes with deletion of the envelope region have been occasionally reported by short-read sequencing analyses. However, the clinical and virological details of such deletion HCV have not been fully elucidated. METHODS We developed a highly accurate single-molecule sequencing system for full-length HCV genes by combining the third-generation nanopore sequencing with rolling circle amplification (RCA) and investigated the characteristics of deletion HCV through the analysis of 21 patients chronically infected with genotype-1b HCV. RESULT In 5 of the 21 patients, a defective HCV genome with approximately 2000 bp deletion from the E1 to NS2 region was detected, with the read frequencies of 34-77%, suggesting the trans-complementation of the co-infecting complete HCV. Deletion HCV was found exclusively in decompensated cirrhosis (5/12 patients), and no deletion HCV was observed in nine compensated patients. Comparing the amino acid substitutions between the deletion and complete HCV (DAS, deletion-associated substitutions), the deletion HCV showed higher amino acid mutations in the ISDR (interferon sensitivity-determining region) in NS5A, and also in the TMS (transmembrane segment) 3 to H (helix) 2 region of NS2. CONCLUSIONS Defective HCV genome with deletion of envelope genes is associated with decompensated cirrhosis. The deletion HCV seems susceptible to innate immunity, such as endogenous interferon with NS5A mutations, escaping from acquired immunity with deletion of envelope proteins with potential modulation of replication capabilities with NS2 mutations. The relationship between these mutations and liver damage caused by HCV deletion is worth investigating.
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Affiliation(s)
- Kozue Yamauchi
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Shinya Maekawa
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Yasuyuki Komiyama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Natsuko Nakakuki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Hitomi Takada
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Masaru Muraoka
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Yuichiro Suzuki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Mitsuaki Sato
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Shinichi Takano
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Nobuyuki Enomoto
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
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7
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John S, Klumsathian S, Own‐eium P, Charoenyingwattana A, Eu‐ahsunthornwattana J, Sura T, Dejsuphong D, Sritara P, Vathesatogkit P, Thongchompoo N, Thabthimthong W, Teerakulkittipong N, Chantratita W, Sukasem C. Thai pharmacogenomics database -2 (TPGxD-2) sequel to TPGxD-1, analyzing genetic variants in 26 non-VIPGx genes within the Thai population. Clin Transl Sci 2024; 17:e70019. [PMID: 39449569 PMCID: PMC11502937 DOI: 10.1111/cts.70019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/20/2024] [Accepted: 07/11/2024] [Indexed: 10/26/2024] Open
Abstract
Next-generation sequencing (NGS) has transformed pharmacogenomics (PGx), enabling thorough profiling of pharmacogenes using computational methods and advancing personalized medicine. The Thai Pharmacogenomic Database-2 (TPGxD-2) analyzed 948 whole genome sequences, primarily from the Electricity Generating Authority of Thailand (EGAT) cohort. This study is an extension of the previous Thai Pharmacogenomic Database (TPGxD-1) and specifically focused on 26 non-very important pharmacogenes (VIPGx) genes. Variant calling was conducted using Sentieon (version 201808.08) following GATK's best workflow practices. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0. Star allele analysis was performed with Stargazer v2.0.2, which called star alleles for 22 of 26 non-VIPGx genes. The variant analysis revealed a total of 14,529 variants in 26 non-VIPGx genes, with TBXAS1 had the highest number of variants (27%). Among the 14,529 variants, 2328 were novel (without rsID), with 87 identified as clinically relevant. We also found 56 known PGx variants among the known variants (n = 12,201), with UGT2B7 (19.64%), CYP1B1 (8.9%), SLCO2B1 (8.9%), and POR (8.9%) being the most common. We reported a high frequency of intermediate metabolizers (IMs) in CYP2F1 (34.6%) and CYP4A11 (8.6%), and a high frequency of decreased functional alleles in POR (53.9%) and SLCO1B3 (34.9%) genes. This study enhances our understanding of pharmacogenomic profiling of 26 non-VIPGx genes of notable clinical importance in the Thai population. However, further validation with additional computational and reference genotyping methods is necessary, and novel alleles identified in this study should undergo further orthogonal validation.
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Affiliation(s)
- Shobana John
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC)Ramathibodi HospitalBangkokThailand
| | - Sommon Klumsathian
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Paravee Own‐eium
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | | | | | - Thanyachai Sura
- Division of Medical Genetics and Molecular Medicine, Department of Internal Medicine, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Donniphat Dejsuphong
- Program in Translational Medicine, Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathobodi HospitalMahidol UniversityBang PhliSamutprakarnThailand
| | - Piyamitr Sritara
- Department of Medicine, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Prin Vathesatogkit
- Department of Medicine, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Nartthawee Thongchompoo
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Wiphaporn Thabthimthong
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Nuttinee Teerakulkittipong
- Department of Pharmacology and Biopharmaceutical Sciences, Faculty of Pharmaceutical SciencesBurapha UniversityChonburiThailand
| | - Wasun Chantratita
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC)Ramathibodi HospitalBangkokThailand
- Department of Pharmacology and Biopharmaceutical Sciences, Faculty of Pharmaceutical SciencesBurapha UniversityChonburiThailand
- Department of Pharmacology and Therapeutics, MRC Centre for Drug Safety ScienceInstitute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUK
- Pharmacogenomics and Precision Medicine, The Preventive Genomics & Family Check‐up Services CenterBumrungrad International HospitalBangkokThailand
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8
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Abdelaziz AI, Abdelsameea E, Abdel-Samiee M, Ghanem SE, Wahdan SA, Elsherbiny DA, Zakaria Z, Azab SS. Effect of immunogenetics polymorphism and expression on direct-acting antiviral drug response in chronic hepatitis C. Clin Exp Med 2024; 24:184. [PMID: 39117877 PMCID: PMC11310263 DOI: 10.1007/s10238-024-01432-x] [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: 04/10/2024] [Accepted: 07/09/2024] [Indexed: 08/10/2024]
Abstract
The prevalence of HCV infection in Egypt has decreased following the introduction of direct-acting antiviral therapy. However, treatment response is influenced by various factors, particularly host immunogenetics such as IL-28B and FOXP3 polymorphisms. The current study examined the impact of SNPs in the FOXP3 gene promoter region on HCV-infected Egyptian patients, along with SNPs in the IL28B gene.This study involved 99 HCV patients who achieved SVR12 after a 12 week DAA treatment while 63 HCV patients experienced treatment failure. IL28B rs12979860 SNP was identified using real-time PCR, while IL28B rs8099917, FOXP3 rs3761548, and rs2232365 SNPs were analyzed using RFLP-PCR. Serum levels of IL28B and FOXP3 were quantified using ELISA technique in representative samples from both groups. The IL28B rs12979860 T > C (P = 0.013) and FOXP3 rs2232365 A > G polymorphisms (P = 0.008) were found to significantly increase the risk of non-response. Responders had higher IL28B serum levels (P = 0.046) and lower FOXP3 levels (P < 0.001) compared to non-responders. Regression analysis showed an association between IL28B rs12979860 and FOXP3 rs2232365 with treatment response, independent of age and gender. A predictive model was developed with 76.2% sensitivity and 91.9% specificity for estimating DAAs response in HCV patients.Our findings confirmed the IL28B rs12979860 T > C and FOXP3 rs2232365 A > G polymorphisms significantly affect DAA treatment response in HCV Egyptian patients. Lower levels of IL-28B along with higher levels of FOXP3 are linked to poor response. Our results may lead to new insights into DAA responsiveness contributing to personalized medicine and improving therapeutic decision-making for HCV patients.
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Affiliation(s)
- Aya Ismail Abdelaziz
- Department of Research and Development, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Samar E Ghanem
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Sara A Wahdan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Doaa A Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Zeinab Zakaria
- Department of Research and Development, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Samar S Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
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9
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Miura M, Nishino M, Kawaguchi K, Li S, Shimakami T, Tamai T, Nakagawa H, Terashima T, Iida N, Takatori H, Arai K, Sakai Y, Yamashita T, Honda M, Kaneko S, Mizukoshi E, Yamashita T. Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy. PLoS One 2024; 19:e0299424. [PMID: 38781172 PMCID: PMC11115325 DOI: 10.1371/journal.pone.0299424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 02/11/2024] [Indexed: 05/25/2024] Open
Abstract
Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.
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Affiliation(s)
- Miyabi Miura
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Michiko Nishino
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Shihui Li
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Toshikatsu Tamai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hidetoshi Nakagawa
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Information-Based Medicine Development, Kanazawa University Graduate School of Medicine, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
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10
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Sallam M, Khalil R. Contemporary Insights into Hepatitis C Virus: A Comprehensive Review. Microorganisms 2024; 12:1035. [PMID: 38930417 PMCID: PMC11205832 DOI: 10.3390/microorganisms12061035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge. Approximately 50 million people were living with chronic hepatitis C based on the World Health Organization as of 2024, contributing extensively to global morbidity and mortality. The advent and approval of several direct-acting antiviral (DAA) regimens significantly improved HCV treatment, offering potentially high rates of cure for chronic hepatitis C. However, the promising aim of eventual HCV eradication remains challenging. Key challenges include the variability in DAA access across different regions, slightly variable response rates to DAAs across diverse patient populations and HCV genotypes/subtypes, and the emergence of resistance-associated substitutions (RASs), potentially conferring resistance to DAAs. Therefore, periodic reassessment of current HCV knowledge is needed. An up-to-date review on HCV is also necessitated based on the observed shifts in HCV epidemiological trends, continuous development and approval of therapeutic strategies, and changes in public health policies. Thus, the current comprehensive review aimed to integrate the latest knowledge on the epidemiology, pathophysiology, diagnostic approaches, treatment options and preventive strategies for HCV, with a particular focus on the current challenges associated with RASs and ongoing efforts in vaccine development. This review sought to provide healthcare professionals, researchers, and policymakers with the necessary insights to address the HCV burden more effectively. We aimed to highlight the progress made in managing and preventing HCV infection and to highlight the persistent barriers challenging the prevention of HCV infection. The overarching goal was to align with global health objectives towards reducing the burden of chronic hepatitis, aiming for its eventual elimination as a public health threat by 2030.
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Affiliation(s)
- Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Roaa Khalil
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
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11
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Azamor T, Cunha DP, Nobre Pires KS, Lira Tanabe EL, Melgaço JG, Vieira da Silva AM, Ribeiro-Alves M, Calvo TL, Tubarão LN, da Silva J, Fernandes CB, Fonseca de Souza A, Torrentes de Carvalho A, Avvad-Portari E, da Cunha Guida L, Gomes L, Lopes Moreira ME, Dinis Ano Bom AP, Cristina da Costa Neves P, Missailidis S, Vasconcelos Z, Borbely AU, Moraes MO. Decidual production of interferon lambda in response to ZIKV persistence: Clinical evidence and in vitro modelling. Heliyon 2024; 10:e30613. [PMID: 38737240 PMCID: PMC11087979 DOI: 10.1016/j.heliyon.2024.e30613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 05/14/2024] Open
Abstract
Zika virus (ZIKV) infections during pregnancy can result in Congenital Zika Syndrome (CZS), a range of severe neurological outcomes in fetuses that primarily occur during early gestational stages possibly due to placental damage. Although some placentas can maintain ZIKV persistence for weeks or months after the initial infection and diagnosis, the impact of this viral persistence is still unknown. Here, we aimed to investigate the immunological repercussion of ZIKV persistence in term placentas. As such, term placentas from 64 pregnant women diagnosed with Zika in different gestational periods were analyzed by ZIKV RT-qPCR, examination of decidua and placental villous histopathology, and expression of inflammation-related genes and IFNL1-4. Subsequently, we explored primary cultures of term decidual Extravillous Trophoblasts (EVTs) and Term Chorionic Villi (TCV) explants, as in vitro models to access the immunological consequences of placental ZIKV infection. Placenta from CZS cases presented low IFNL1-4 expression, evidencing the critical protective role of theses cytokines in the clinical outcome. Term placentas cleared for ZIKV showed increased levels of IFNL1, 3, and 4, whether viral persistence was related with a proinflammatory profile. Conversely, upon ZIKV persistence placentas with decidual inflammation showed high IFNL1-4 levels. In vitro experiments showed that term EVTs are more permissive, and secreted higher levels of IFN-α2 and IFN-λ1 compared to TCV explants. The results suggest that, upon ZIKV persistence, the maternal-skewed decidua contributes to placental inflammatory and antiviral signature, through chronic deciduitis and IFNL upregulation. Although further studies are needed to elucidate the mechanisms underlying the decidual responses against ZIKV. Hence, this study presents unique insights and valuable in vitro models for evaluating the immunological landscape of placentas upon ZIKV persistence.
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12
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Zhang Q, Kisand K, Feng Y, Rinchai D, Jouanguy E, Cobat A, Casanova JL, Zhang SY. In search of a function for human type III interferons: insights from inherited and acquired deficits. Curr Opin Immunol 2024; 87:102427. [PMID: 38781720 PMCID: PMC11209856 DOI: 10.1016/j.coi.2024.102427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 03/19/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024]
Abstract
The essential and redundant functions of human type I and II interferons (IFNs) have been delineated over the last three decades by studies of patients with inborn errors of immunity or their autoimmune phenocopies, but much less is known about type III IFNs. Patients with cells that do not respond to type III IFNs due to inherited IL10RB deficiency display no overt viral disease, and their inflammatory disease phenotypes can be explained by defective signaling via other interleukine10RB-dependent pathways. Moreover, patients with inherited deficiencies of interferon-stimulated gene factor 3 (ISGF-3) (STAT1, STAT2, IRF9) present viral diseases also seen in patients with inherited deficiencies of the type I IFN receptor (IFNAR1/2). Finally, patients with autoantibodies neutralizing type III IFNs have no obvious predisposition to viral disease. Current findings thus suggest that type III IFNs are largely redundant in humans. The essential functions of human type III IFNs, particularly in antiviral defenses, remain to be discovered.
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Affiliation(s)
- Qian Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France.
| | - Kai Kisand
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Yi Feng
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA
| | - Darawan Rinchai
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA
| | - Emmanuelle Jouanguy
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France
| | - Aurélie Cobat
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France; Howard Hughes Medical Institute, New York, USA
| | - Shen-Ying Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France
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13
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Plaza J, Mínguez A, Bastida G, Marqués R, Nos P, Poveda JL, Moret-Tatay I. Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review. Int J Mol Sci 2024; 25:3717. [PMID: 38612528 PMCID: PMC11012229 DOI: 10.3390/ijms25073717] [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: 01/16/2024] [Revised: 03/05/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn's disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual's drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.
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Affiliation(s)
- Javier Plaza
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain
| | - Alejandro Mínguez
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Guillermo Bastida
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Remedios Marqués
- Pharmacy Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (R.M.); (J.L.P.)
| | - Pilar Nos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Jose Luis Poveda
- Pharmacy Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (R.M.); (J.L.P.)
| | - Inés Moret-Tatay
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- General Directorate of Public Health, Council of Healthcare, 46021 Valencia, Spain
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14
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Roy DG, Singh L, Chaturvedi HK, Chinnaswamy S. Gender-dependent multiple cross-phenotype association of interferon lambda genetic variants with peripheral blood profiles in healthy individuals. Mol Genet Genomic Med 2024; 12:e2292. [PMID: 37795763 PMCID: PMC10767428 DOI: 10.1002/mgg3.2292] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 09/08/2023] [Accepted: 09/19/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Type III interferons (IFN), also called as lambda IFNs (IFN-λs), are antiviral and immunomodulatory cytokines that are evolutionarily important in humans. Given their central roles in innate immunity, they could be influencing other aspects of human biology. This study aimed to examine the association of genetic variants that control the expression and/or activity of IFN-λ3 and IFN-λ4 with multiple phenotypes in blood profiles of healthy individuals. METHODS In a cohort of about 550 self-declared healthy individuals, after applying several exclusion criteria to determine their health status, we measured 30 blood parameters, including cellular, biochemical, and metabolic profiles. We genotyped them at rs12979860 and rs28416813 using competitive allele-specific PCR assays and tested their association with the blood profiles under dominant and recessive models for the minor allele. IFN-λ4 variants rs368234815 and rs117648444 were also genotyped or inferred. RESULTS We saw no association in the combined cohort under either of the models for any of the phenotypes. When we stratified the cohort based on gender, we saw a significant association only in males with monocyte (p = 1 × 10-3 ) and SGOT (p = 7 × 10-3 ) levels under the dominant model and with uric acid levels (p = 0.01) under the recessive model. When we tested the IFN-λ4 activity modifying variant within groupings based on absence or presence of one or two copies of IFN-λ4 and on different activity levels of IFN-λ4, we found significant (p < 0.05) association with several phenotypes like monocyte, triglyceride, VLDL, ALP, and uric acid levels, only in males. All the above significant associations did not show any confounding when we tested for the same with up to ten different demographic and lifestyle variables. CONCLUSIONS These results show that lambda interferons can have pleiotropic effects. However, gender seems to be an effect modifier, with males being more sensitive than females to the effect.
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Affiliation(s)
- Debarati Guha Roy
- Infectious Disease GeneticsNational Institute of Biomedical GenomicsKalyaniIndia
- Regional Centre for BiotechnologyFaridabadIndia
| | - Lucky Singh
- ICMR‐National Institute of Medical StatisticsNew DelhiIndia
| | | | - Sreedhar Chinnaswamy
- Infectious Disease GeneticsNational Institute of Biomedical GenomicsKalyaniIndia
- Regional Centre for BiotechnologyFaridabadIndia
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15
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Abd Alla MDA, Dawood RM, Rashed HAELH, El-Dessouky YM, AbuFarrag GA, Ammar IAE, Mahmoud MMAH, Salum GM, Abu-Amer MZ, Sekeen MAEH, Heggazy MMI, Altanbouly AMA, Abd El-Meguid M, El Awady MK. HCV treatment outcome depends on SNPs of IFNL3-Gene polymorphisms (rs12979860) and cirrhotic changes in liver parenchyma. Heliyon 2023; 9:e21194. [PMID: 37928048 PMCID: PMC10623284 DOI: 10.1016/j.heliyon.2023.e21194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 09/10/2023] [Accepted: 10/18/2023] [Indexed: 11/07/2023] Open
Abstract
The allelic discrimination of IFNL3-(rs12979860 C > T) polymorphism reveals ambiguous associations with the effectiveness of oral HCV treatment. Solitary intra peripheral-blood-mononuclear-cells (PBMCs) HCV-RNA antisense-strands are independently detected in naïve and experienced cases regardless of viremia or hepatic-parenchymal alterations. We examined the frequencies of IFNL3-genetic variants with chronic-HCV-induced liver changes during the sustained virologic response (SVR) by evaluating the PBMCs- HCV-PCR after oral antiviral therapy. Methods: Twelve weeks after finishing oral antiviral therapy, the effects of IFNL3-genetic variants were evaluated in three groups of patients: Group-I (n = 25) showed HCV-RNA negativity in both serum and PBMCs-, group II (n = 52) showed positivity of HCV-RNA in PBMCs, and group-III (n = 25) had positive HCV-RNA in serum. The genetic variants of the IFNL3-gene were estimated for all the enrolled cases and correlated with their hepatic image changes. Results: IFNL3-(rs12979860) genotyping in post-direct acting antivirals (DAAs) SVR and HCV-relapse revealed: a) high frequency of CC-genotype and C-allele in group I compared to group II (P < 0.005) and group III(P ≤ 0.05) when hepatic-parenchyma looks normal by ultrasound b) frequent CT-genotype and T-allele in group II compared with I(P < 0.01) and III(P < 0.05) when liver tissues are bright (early cirrhotic-changes) c) frequent TT-genotype and T-allele in group III relative to I (P < 0.05) and II (P ≤ 0.08) when liver-tissues appear coarse by ultrasound. Conclusion: Outcomes of HCV treatment depend on host IFNL3-gene polymorphism and hepatic-parenchymal changes. A high frequency of wild-CC-genotype and C-allele is observed in patients with normal hepatic parenchyma and that achieved SVR. Solitary relapse in PBMCs occurs on increasing CT-genotype frequency when liver tissues are bright. Serologic relapse is detected when TT-genotype and T-allele are dominant in association with the cirrhotic liver. Therefore, IFNL3-gene-SNP analysis as a genetic predictor in relation to ultra-sonographic hepatic-parenchymal changes could be valuable for selecting the patients with the highest priority for treatment.
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Affiliation(s)
| | - Reham M. Dawood
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
| | - Hassan Abd EL-Hafeth Rashed
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | - Yasser Mohammed El-Dessouky
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | - Galal AbdElhameed AbuFarrag
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | - Islam Abdelmawla Emran Ammar
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | | | - Ghada M. Salum
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
| | - Mohamed Zakaria Abu-Amer
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Egypt
| | | | | | | | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
| | - Mostafa K. El Awady
- Department of Microbial Biotechnology, National Research Centre, Cairo, Egypt
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16
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Medina C, García AH, Crespo FI, Toro FI, Mayora SJ, De Sanctis JB. A Synopsis of Hepatitis C Virus Treatments and Future Perspectives. Curr Issues Mol Biol 2023; 45:8255-8276. [PMID: 37886964 PMCID: PMC10605161 DOI: 10.3390/cimb45100521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.
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Affiliation(s)
- Christian Medina
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Alexis Hipólito García
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Francis Isamarg Crespo
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Félix Isidro Toro
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Soriuska José Mayora
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Juan Bautista De Sanctis
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, 779 00 Olomouc, Czech Republic
- The Czech Advanced Technology and Research Institute (Catrin), Palacky University, 779 00 Olomouc, Czech Republic
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17
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O'Brien TR, Lee MH, Wilson E, Kottilil S. IFNL4 Genotype Frequencies in Asian Populations Support Shorter Duration Therapy with Sofosbuvir-Based Hepatitis C Virus Regimens to Increase the Number Cured. J Interferon Cytokine Res 2023; 43:435-438. [PMID: 37347978 PMCID: PMC10517314 DOI: 10.1089/jir.2023.0022] [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: 02/16/2023] [Accepted: 03/25/2023] [Indexed: 06/24/2023] Open
Abstract
Globally, ∼56.8 million people are chronically infected with hepatitis C virus (HCV), with about half residing in Asia. The cost and efficiency of delivering regimens based on direct-acting antiviral agents for HCV are important considerations in implementing these curative treatments. For sofosbuvir-based regimens, most patients are treated for 12 weeks; however, treatment for 8 weeks has been shown to cure HCV infection in 95% of patients without cirrhosis. Furthermore, virological failure after 8-week treatment occurs in only 1%-2% of individuals without cirrhosis, who have a favorable IFNL4 genotype, which is present in >50% of South Asians and >80% of East Asians. We propose that sofosbuvir-based treatment for 8 weeks, or perhaps shorter, would yield high response rate regimens in Asian countries and markedly increase the number of patients who could be cured for a given cost of the medication. We propose that a noninferiority trial in an East Asian population be conducted to test this hypothesis.
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Affiliation(s)
- Thomas R. O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Eleanor Wilson
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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18
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Kanai M, Sugiyama M, Kondo M, Yamada K, Nishimura M, Mano S. Fusing the 3'UTR of seed storage protein genes leads to massive recombinant protein accumulation in seeds. Sci Rep 2023; 13:12217. [PMID: 37500719 PMCID: PMC10374616 DOI: 10.1038/s41598-023-39356-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023] Open
Abstract
The demand for recombinant proteins is rising dramatically, and effective production systems are currently being developed. The production of recombinant proteins in plants is a promising approach due to its low cost and low risk of contamination of the proteins with endotoxins or infectious agents from the culture serum. Plant seeds primarily accumulate seed storage proteins (SSPs), which are transcribed and translated from a few genes; therefore, the mechanism underlying SSP accumulation has been studied to help devise ways to increase recombinant protein production. We found that the 3'UTR of SSP genes are essential for SSP accumulation and can be used in the production of recombinant proteins in Arabidopsis. Fusion of the 3'UTR of SSP genes to the 3' ends of DNA sequences encoding recombinant proteins enables massive accumulation of recombinant proteins with enzymatic activity in Arabidopsis seeds. This method is also applicable to the production of human Interferon Lambda-3 (IFN-lambda 3), a candidate biopharmaceutical compound against hepatitis C infection. Considering the low cost and ease of protein production in Arabidopsis, as well as the rapid growth of this plant, our method is useful for large-scale preparation of recombinant proteins for both academic research and biopharmaceutical production.
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Affiliation(s)
- Masatake Kanai
- Laboratory of Organelle Regulation, National Institute for Basic Biology, Okazaki, 444-8585, Japan.
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Ichikawa, 272-8516, Japan
| | - Maki Kondo
- Department of Cell Biology, National Institute for Basic Biology, Okazaki, 444-8585, Japan
| | - Kenji Yamada
- Malopolska Centre of Biotechnology, Jagiellonian University, 30-387, Krakow, Poland
| | - Mikio Nishimura
- Department of Cell Biology, National Institute for Basic Biology, Okazaki, 444-8585, Japan
- Faculty of Science and Engineering, Konan University, Kobe, 658-8501, Japan
| | - Shoji Mano
- Laboratory of Organelle Regulation, National Institute for Basic Biology, Okazaki, 444-8585, Japan
- Basic Biology Program, Graduate Institute for Advanced Studies, The Graduate University for Advanced Studies, SOKENDAI, Okazaki, 444-8585, Japan
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19
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Mohamed Abdelnajid D, Elmowafy AY, Rostaing L, Elrakaiby MT. Prediction of response to sofosbuvir-based therapy using serum interleukin-12 and single nucleotide polymorphism of the interleukin 28B gene as predictive factors in HCV positive genotype-4 patients. Medicine (Baltimore) 2023; 102:e34125. [PMID: 37443472 PMCID: PMC10344568 DOI: 10.1097/md.0000000000034125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Some hepatitis-C virus patients have resistance to direct-acting-antivirals (DAAs). Genetic polymorphisms have been associated with drug resistance. This study aimed to evaluate the role of interleukin (IL)-28B gene polymorphism and IL-12 levels as predictors for a response to sofosbuvir/ribavirin (SOF/RBV) with (triple-therapy) or without (dual-therapy) Peg-alpha-interferon. 92 hepatitis C virus (HCV)/RNA (+)-patients treated with dual (n = 72) or triple (n = 20) therapy. IL28B genetic polymorphism and IL-12 level assessments. 30.4% of the patients were IL28B C/C genotype, 56.5% C/T-genotype, and 13% T/T-genotype. Mean baseline IL-12 levels were 27.5 ± 3.0 pg/mL. Rapid viral response was achieved in 86/92 patients. All patients achieved end-of-treatment virologic response. The 12- and 24-week sustained virologic responses (SVR) were achieved in 76 patients (82.6%), that is, a relapse was found in 16 patients (17.4%). 8 and 12-weeks after antiviral therapy, IL-12 levels decreased significantly, and became comparable to those of the control-group. That drop in IL-12 levels was similar across the dual- and triple-therapy patients. Finally, logistic regression analysis showed that the increase in baseline aspartate aminotransferase (AST) and T/T genotyping had an independent effect on increasing the probability a SVR failing in both dual- and triple-therapy groups (P = .0007 and P = .02, respectively). Single-nucleotide polymorphism (SNP) in IL-28B and IL-12 levels play roles as predictors in DAAs resistance.
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Affiliation(s)
- Doaa Mohamed Abdelnajid
- Department of Microbiology and Immunology, Military Medical Academy, Cairo, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr Al-Aini, Cairo, Egypt
| | | | - Lionel Rostaing
- Department of Nephrology, Hemodialysis, Apheresis, and Kidney Transplantation, CHU Grenoble-Alpes, France
- Grenoble Alpes University, Grenoble, France
| | - Marwa T. Elrakaiby
- Department of Microbiology and Immunology, Military Medical Academy, Cairo, Egypt
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20
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Mertowska P, Smolak K, Mertowski S, Grywalska E. Immunomodulatory Role of Interferons in Viral and Bacterial Infections. Int J Mol Sci 2023; 24:10115. [PMID: 37373262 DOI: 10.3390/ijms241210115] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/02/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Interferons are a group of immunomodulatory substances produced by the human immune system in response to the presence of pathogens, especially during viral and bacterial infections. Their remarkably diverse mechanisms of action help the immune system fight infections by activating hundreds of genes involved in signal transduction pathways. In this review, we focus on discussing the interplay between the IFN system and seven medically important and challenging viruses (herpes simplex virus (HSV), influenza, hepatitis C virus (HCV), lymphocytic choriomeningitis virus (LCMV), human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and SARS-CoV coronavirus) to highlight the diversity of viral strategies. In addition, the available data also suggest that IFNs play an important role in the course of bacterial infections. Research is currently underway to identify and elucidate the exact role of specific genes and effector pathways in generating the antimicrobial response mediated by IFNs. Despite the numerous studies on the role of interferons in antimicrobial responses, many interdisciplinary studies are still needed to understand and optimize their use in personalized therapeutics.
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Affiliation(s)
- Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Konrad Smolak
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
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21
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Oleinik LA, Madonov PG, Pykhtina MB. Potential of Interferon Lambda as an Inhibitor of SARS-CoV-2. Mol Biol 2023; 57:291-298. [PMID: 37128210 PMCID: PMC10131541 DOI: 10.1134/s0026893323020152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/06/2022] [Accepted: 10/06/2022] [Indexed: 05/03/2023]
Abstract
This study provides an overview of scientific results on the feasibility of using type III interferons against SARS-CoV-2. We have analyzed data obtained from the PubMed electronic database for the period 2020‒2022. The results of our own studies of pharmacological substances based on recombinant IFN-λ1 and its pegylated form are also presented. Completed and ongoing investigations allow us to position IFN-λ as an effective therapeutic agent against SARS-CoV-2.
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Affiliation(s)
- L. A. Oleinik
- Research Institute of Clinical and Experimental Lymрhology—Branch of Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - P. G. Madonov
- Research Institute of Clinical and Experimental Lymрhology—Branch of Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - M. B. Pykhtina
- Research Institute of Clinical and Experimental Lymрhology—Branch of Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
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22
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Murata K, Mizokami M. Possible biological mechanisms of entecavir versus tenofovir disoproxil fumarate on reducing the risk of hepatocellular carcinoma. J Gastroenterol Hepatol 2023; 38:683-691. [PMID: 36918402 DOI: 10.1111/jgh.16178] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023]
Abstract
Hepatitis B virus (HBV) is a life-threatening infectious virus associated with the risk of liver failure and hepatocellular carcinoma (HCC). Regarding HBV treatment, the recent development of nucleoside/nucleotide analogs (NUC), HBV reverse transcriptase inhibitors, enabled favorable viral control as well as improved prognosis in patients with chronic hepatitis B. However, NUC fails to clear HBV because the formation of covalently closed circular DNA or HBV surface antigen occurs upstream of the point of action of NUC. Recently, we found that acyclic nucleoside phosphonates (ANP) such as adefovir or tenofovir, but not lamivudine or entecavir, induced IFN-λ3 productions in the gastrointestinal tract and modulated lipopolysaccharide (LPS)-mediated cytokine profiles in peripheral blood mononuclear cells, such as interleukin (IL)-12p70 induction and IL-10 inhibition, which are immunologically favorable cytokine profiles for HBV elimination. Furthermore, IFN-α, in combination with ANP, showed additional and synergistic effects on IFN-λ3 and IL-12p70 production, respectively, while not affecting IL-10 levels. Mechanistic analyses of the cytokine modulation by ANP revealed that ANP blocked the mammalian target of the rapamycin (mTOR) pathway by inhibiting Akt translocation to the plasma membrane, thereby inhibiting Akt phosphorylation. As it has been reported that IFN-λ inhibits tumor growth directly or indirectly and the mTOR pathway is generally activated in most cancer cells, ANP might have potential anti-HCC effects. Our in vitro and ex vivo findings might stir the debate on whether types of NUC affect the risk of HBV-related HCC incidence.
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Affiliation(s)
- Kazumoto Murata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Japan
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
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23
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Yamagiwa Y, Tanaka K, Matsuo K, Wada K, Lin Y, Sugawara Y, Mizoue T, Sawada N, Takimoto H, Ito H, Kitamura T, Sakata R, Kimura T, Tanaka S, Inoue M. Response to antiviral therapy for chronic hepatitis C and risk of hepatocellular carcinoma occurrence in Japan: a systematic review and meta-analysis of observational studies. Sci Rep 2023; 13:3445. [PMID: 36859564 PMCID: PMC9977913 DOI: 10.1038/s41598-023-30467-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/23/2023] [Indexed: 03/03/2023] Open
Abstract
In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33-0.43) for sustained virologic response (SVR) and 1.70 (1.61-1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19-0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19-0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence.
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Affiliation(s)
- Yoko Yamagiwa
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Clinical Research Centers for Medicine, International University of Health and Welfare, Tokyo, Japan
| | - Keitaro Tanaka
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Keiko Wada
- Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Aichi, Japan
| | - Yumi Sugawara
- Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Mizoue
- Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Hidemi Takimoto
- Department of Nutritional Epidemiology, National Institute of Health and Nutrition, National Institute of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Tetsuhisa Kitamura
- Department of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ritsu Sakata
- Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Takashi Kimura
- Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shiori Tanaka
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Manami Inoue
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
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24
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Genetic Susceptibility to Hepatocellular Carcinoma in Patients with Chronic Hepatitis Virus Infection. Viruses 2023; 15:v15020559. [PMID: 36851773 PMCID: PMC9964813 DOI: 10.3390/v15020559] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The risk factors for HCC include chronic hepatitis B and C virus infections, excessive alcohol consumption, obesity, metabolic disease, and aflatoxin exposure. In addition to these viral and environmental risk factors, individual genetic predisposition is a major determinant of HCC risk. Familial clustering of HCC has been observed, and a hereditary factor likely contributes to the risk of HCC development. The familial aggregation may depend on a shared environment and genetic background as well as the interactions of environmental and genetic factors. Genome-wide association studies (GWASs) are one of the most practical tools for mapping the patterns of inheritance for the most common form of genomic variation, single nucleotide polymorphisms. This approach is practical for investigating genetic variants across the human genome, which is affected by thousands of common genetic variants that do not follow Mendelian inheritance. This review article summarizes the academic knowledge of GWAS-identified genetic loci and their association with HCC. We summarize the GWASs in accordance with various chronic hepatitis virus infection statuses. This genetic profiling could be used to identify candidate biomarkers to refine HCC screening and management by enabling individual risk-based personalization and stratification. A more comprehensive understanding of the genetic mechanisms underlying individual predisposition to HCC may lead to improvements in the prevention and early diagnosis of HCC and the development of effective treatment strategies.
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25
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Hitomi Y, Nakamura M. The Genetics of Primary Biliary Cholangitis: A GWAS and Post-GWAS Update. Genes (Basel) 2023; 14:405. [PMID: 36833332 PMCID: PMC9957238 DOI: 10.3390/genes14020405] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which the small intrahepatic bile ducts are destroyed by autoimmune reactions. Among autoimmune diseases, which are polygenic complex traits caused by the combined contribution of genetic and environmental factors, PBC exhibits the strongest involvement of genetic heritability in disease development. As at December 2022, genome-wide association studies (GWASs) and associated meta-analyses identified approximately 70 PBC susceptibility gene loci in various populations, including those of European and East Asian descent. However, the molecular mechanisms through which these susceptibility loci affect the pathogenesis of PBC are not fully understood. This study provides an overview of current data regarding the genetic factors of PBC as well as post-GWAS approaches to identifying primary functional variants and effector genes in disease-susceptibility loci. Possible mechanisms of these genetic factors in the development of PBC are also discussed, focusing on four major disease pathways identified by in silico gene set analyses, namely, (1) antigen presentation by human leukocyte antigens, (2) interleukin-12-related pathways, (3) cellular responses to tumor necrosis factor, and (4) B cell activation, maturation, and differentiation pathways.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Omura 856-8562, Japan
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
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26
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Hayes CN, Imamura M, Tanaka J, Chayama K. Road to elimination of HCV: Clinical challenges in HCV management. Liver Int 2022; 42:1935-1944. [PMID: 34967486 DOI: 10.1111/liv.15150] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/29/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022]
Abstract
Since its discovery in 1989, the road to a cure for hepatitis C virus (HCV) has been slow, but most patients can now expect to achieve a sustained virological response (SVR). With direct-acting antiviral (DAA) combination therapies such as glecaprevir/pibrentasvir and velpatasvir/sofosbuvir, 98% of patients successfully eradicate the virus, even if previous treatments failed or if resistance-associated substitutions (RASs) are present. Adverse events are rare or mild, and patients with compensated cirrhosis and other co-morbidities are often eligible for treatment. However, a small number of patients fail to eradicate the virus even after retreatment. The cause of failure is mainly due to emergence of NS5A P32 deletion mutants after initial DAA therapy in genotype 1b patients, although the reason is unknown for some patients. Alternative therapies that do not rely on NS5A inhibitors, such as sofosbuvir plus ribavirin, can be attempted in these patients. While scaled-up treatment efforts present a challenge, another problem is that many carriers are unaware of their infection. Long-term damage to the liver becomes irreversible, and patients who are not diagnosed in time can develop liver cancer or liver failure even after eliminating the virus. The long-term costs of treatment of advanced liver disease in undiagnosed patients relative to the immediate costs of DAA therapy should be considered. As no vaccine is yet available, eventual elimination of the virus requires identifying and treating undiagnosed cases and screening of high-risk populations such as injection drug users and men who have sex with men and female sex workers.
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Affiliation(s)
- C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Junko Tanaka
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Department of Epidemiology, Infectious Disease Control and Prevention, Graduate school of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Collaborative Research Laboratory of Medical Innovation, Hiroshima University, Hiroshima, Japan.,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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27
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The presence of interferon affects the progression of non-alcoholic fatty liver disease. Genes Immun 2022; 23:157-165. [PMID: 35725929 DOI: 10.1038/s41435-022-00176-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 11/08/2022]
Abstract
Inflammation and metabolic dysfunction are hallmarks of the progression of non-alcoholic fatty liver disease (NAFLD), which is the fastest-growing liver disease worldwide. Emerging evidence indicates that innate immune mechanisms are essential drivers of fibrosis development in chronic inflammatory liver diseases, including NAFLD. In this study, 142 NAFLD patients were genotyped for three IFNL4 single-nucleotide variants in order to investigate the genetic relationship between IFNL4 and fibrosis in NAFLD patients. We observed an overrepresentation of the non-functional IFNL4 allele in patients with significant fibrosis (>F2). Next, we investigated the potential protective role of interferon (IFN) in relation to the development of liver fibrosis in an animal model of non-alcoholic steatohepatitis (NASH). In contradiction to our hypothesis, the results showed an increase in fibrosis in IFN treated animals. Our study clearly indicates that IFN is able to affect the development of liver fibrosis, although our clinical and experimental data are conflicting.
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28
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The role of IFNL4 in liver inflammation and progression of fibrosis. Genes Immun 2022; 23:111-117. [PMID: 35585257 DOI: 10.1038/s41435-022-00173-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/25/2022] [Accepted: 05/05/2022] [Indexed: 11/08/2022]
Abstract
The discovery that genetic variation within the interferon lambda locus has a profound effect on the outcome of hepatitis C virus (HCV) treatment and spontaneous clearance of HCV is one of the great triumphs of genomic medicine. Subsequently, the IFNL4 gene was discovered and proposed as the causal gene underlying this association. However, there has been a lively debate within the field concerning the causality, which has been further complicated by a change in naming. This review summarizes the genetic data available for the IFNL3/IFNl4 loci and provides an in-depth discussion of causality. We also discuss a new series of interesting data suggesting that the genetic variation at the IFNL4 loci influences the evolution of the HCV virus and the implication this relationship between our genetic makeup and virus evolution has upon our understanding of the IFNL4 system. Finally, new data support an influence of the IFNL4 gene upon liver inflammation and fibrosis that is independent of etiology, thereby linking the IFNL4 gene to some of the major liver diseases of today.
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Qi X, Li F, Zhang Y, Zhu H, Yang F, Li X, Jiang X, Chen L, Huang Y, Zhang J. STAT4 genetic polymorphism significantly affected HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients receiving Peginterferon-α therapy: A prospective cohort study in China Running title: STAT4 variation affecting response to PegIFN-α therapy. J Med Virol 2022; 94:4449-4458. [PMID: 35610746 DOI: 10.1002/jmv.27880] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 11/11/2022]
Abstract
AIM Variant in STAT4 was reported to correlate with response of IFN-α in a retrospective study in HBeAg-positive chronic hepatitis B (CHB) patients. Here we conducted a prospective study to analyze the effect of STAT4 genetic polymorphism on response of PegIFN-α-2a in HBeAg-positive patients. METHOD A prospective, multi-center, open-label, paralleled cohort study was performed. 150 treat-naïve and 156 nucleos(t)ide analogues (NAs)-experienced HBeAg-positive CHB patients were enrolled respectively. All patients received PegIFN-α-2a treatment for 48 weeks and 24-week follow-up post PegIFN-α-2a treatment. Before treatment, STAT4 genetic polymorphism were determined by PCR and DNA sequencing. Serological markers, serum HBV DNA level and adverse events were collected at each visit point. RESULT We observed a larger reduction of HBV DNA load and significant higher HBeAg seroconversion rate in GT/TT than in GG group at week 72 (P = 0.002 and P = 0.023) in treat-naïve patients. In NAs-experienced patients, the HBeAg seroconversion rate in GT/TT group was higher than in GG group at week 72 (P = 0.005). STAT4 rs7574865 gene polymorphism was the strongest independent predictor for HBeAg seroconversion in both two paralleled cohorts. Also, patients in GT/TT group had higher HBsAg loss rate than in GG group in the study. There was no significant difference in adverse events between GG and GT/TT groups. CONCLUSION This prospective cohort study confirmed that STAT4 rs7574865 polymorphism is associated with HBeAg seroconversion and HBsAg loss irrespective of naïve and NAs-experienced HBeAg-positive CHB patients treated with PegIFN-α-2a. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Xun Qi
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China.,Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Xinyan Li
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xuhua Jiang
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Liang Chen
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China.,Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China.,Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China.,Department of Infectious Diseases, Jing'An Branch of Huashan Hospital, Fudan University, Shanghai, China
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Meza G, Galián F, Jaimes-Bernal C, Márquez FJ, Sinangil F, Scagnolari C, Real LM, Forthal D, Caruz A. IFNL4 genotype influences the rate of HIV-1 seroconversion in men who have sex with men. Virulence 2022; 13:757-763. [PMID: 35481423 PMCID: PMC9067526 DOI: 10.1080/21505594.2022.2066612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Individuals lacking interferon lambda 4 (IFNL4) protein due to a common null mutation (rs368234815) in the IFNL4 gene display higher resistance against several infections. The influence of IFNL4 on HIV-1 infection is still under discussion and conflicting results have been reported. This study intended to corroborate or refute the association of the null allele of IFNL4 and HIV-1 predisposition in a cohort of men who have sex with men (MSM). IFNL4 null genotype was assessed on 619 HIV-1-seronegative MSM who were followed for 36 months during a trial of a prophylactic vaccine against HIV-1. Of those, 257 individuals seroconverted during this period. A logistic regression model was constructed including demographic and IFNL4 genotype. In addition, a meta-analysis using data from the current study and other European populations was conducted. The null IFNL4 genotypes were correlated with lower HIV-1 seroconversion (Adjusted OR = 0.4 [95%CI: 0.2–0.8], P = 0.008) and longer time to seroconversion (889 vs. 938 days, P= 0.01). These results were validated by a meta-analysis incorporating data from other European populations and the result yielded a significant association of the IFNL4 null genotype under a dominant model with a lower probability of HIV-1 infection (OR=0.4 [95% CI: 0.3-0.6]; P= 1.3 x 10E-5).
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Affiliation(s)
- Giovanna Meza
- Departamento de Biología Experimental, Unidad de Inmunogenetica, Universidad de Jaén, Jaén, Spain.,Universidad de Ciencias Aplicadas y Ambientales, Facultad de Ciencia y Tecnología, Bogotá, Colombia
| | - Fátima Galián
- Departamento de Biología Experimental, Unidad de Inmunogenetica, Universidad de Jaén, Jaén, Spain
| | - Claudia Jaimes-Bernal
- Departamento de Biología Experimental, Unidad de Inmunogenetica, Universidad de Jaén, Jaén, Spain.,Universidad de Boyaca, Facultad de Ciencias de la Salud, Tunja, Colombia
| | - Francisco J Márquez
- Departamento de Biología Experimental, Unidad de Inmunogenetica, Universidad de Jaén, Jaén, Spain
| | - Faruk Sinangil
- Global Solutions for Infectious Diseases, Lafayette, CA, USA
| | - Carolina Scagnolari
- Department of Molecular Medicine, Laboratory of Virology, Institut Pasteur Italia, SApienza University of Rome, Rome, Italy
| | - Luis Miguel Real
- de Enfermedades Infecciosas y Microbiología Clínica, Hospital Universitario de Valme, Sevilla, Spain.,Inmunología, Universidad de MálagaDepartamento de Especialidades Quirúrgicas, Bioquímica e , Málaga Spain
| | - Donald Forthal
- Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, USA
| | - Antonio Caruz
- Departamento de Biología Experimental, Unidad de Inmunogenetica, Universidad de Jaén, Jaén, Spain
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Auwerx C, Sadler MC, Reymond A, Kutalik Z. From pharmacogenetics to pharmaco-omics: Milestones and future directions. HGG ADVANCES 2022; 3:100100. [PMID: 35373152 PMCID: PMC8971318 DOI: 10.1016/j.xhgg.2022.100100] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The origins of pharmacogenetics date back to the 1950s, when it was established that inter-individual differences in drug response are partially determined by genetic factors. Since then, pharmacogenetics has grown into its own field, motivated by the translation of identified gene-drug interactions into therapeutic applications. Despite numerous challenges ahead, our understanding of the human pharmacogenetic landscape has greatly improved thanks to the integration of tools originating from disciplines as diverse as biochemistry, molecular biology, statistics, and computer sciences. In this review, we discuss past, present, and future developments of pharmacogenetics methodology, focusing on three milestones: how early research established the genetic basis of drug responses, how technological progress made it possible to assess the full extent of pharmacological variants, and how multi-dimensional omics datasets can improve the identification, functional validation, and mechanistic understanding of the interplay between genes and drugs. We outline novel strategies to repurpose and integrate molecular and clinical data originating from biobanks to gain insights analogous to those obtained from randomized controlled trials. Emphasizing the importance of increased diversity, we envision future directions for the field that should pave the way to the clinical implementation of pharmacogenetics.
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Affiliation(s)
- Chiara Auwerx
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
| | - Marie C. Sadler
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
| | - Alexandre Reymond
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Zoltán Kutalik
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
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Youssef SS, Abbas EAER, Youness RA, Elemeery MN, Nasr AS, Seif S. PNPLA3 and IL 28B signature for predicting susceptibility to chronic hepatitis C infection and fibrosis progression. Arch Physiol Biochem 2022; 128:483-489. [PMID: 31793339 DOI: 10.1080/13813455.2019.1694039] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Association studies identified genetic polymorphisms as predictive risk factors of rapid fibrosis progression in chronic hepatitis C (CHC). This study aims to assess the impact of IL28B rs8099917 polymorphism on CHC genotype 4 (G4) susceptibility and liver fibrosis progression individually; and in combination with PNPLA3 rs738409. PATIENTS AND METHODS IL28B rs8099917 and PNPLA3 rs738409 were genotyped in 150 Egyptian CHC patients and 175 healthy controls using real-time PCR. RESULTS IL28B rs8099917 genotype distribution significantly differs in healthy individuals versus CHC patients (p = .018); and in low versus advanced fibrosis IL28B (p = .013). The haplotype CC -GG (PNPLA3-IL28B) is considered a high-risk signature for susceptibility to CHC infection. Similarly, GG-GG (PNPLA3-IL28B) is considered a high-risk signature for higher degree of fibrosis. CONCLUSION IL28B rs8099917 and PNPLA3 rs738409 introduce genetic signature to identify patients at higher risk for CHC susceptibility and fibrosis progression in CHC G4.
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Affiliation(s)
- Samar Samir Youssef
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
| | - Eman Abd El Razek Abbas
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
| | - Rana Ahmed Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Moustafa Nouh Elemeery
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
- Département de Neurosciences, CRCHUM, Université de Montréal, Montréal, Quebec, Canada
| | - Amal Soliman Nasr
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Sameh Seif
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
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Schmidt A, M. Groh A, S. Frick J, Vehreschild MJGT, U. Ludwig K. Genetic Predisposition and the Variable Course of Infectious Diseases. DEUTSCHES ARZTEBLATT INTERNATIONAL 2022; 119:117-123. [PMID: 35101171 PMCID: PMC9160423 DOI: 10.3238/arztebl.m2022.0105] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 08/31/2021] [Accepted: 01/11/2022] [Indexed: 05/07/2023]
Abstract
BACKGROUND Contact with a pathogen is followed by variable courses of infectious disease, which are only partly explicable by classical risk factors. The susceptibility to infection is variable, as is the course of disease after infection. In this review, we discuss the extent to which this variation is due to genetic factors of the affected individual (the host). METHODS Selective review of the literature on host genetics in infectious disease, with special attention to the pathogens SARSCoV- 2, influenza viruses, Mycobacterium tuberculosis, and human immunodeficiency virus (HIV). RESULTS Genetic variants of the host contribute to the pathogenesis of infectious diseases. For example, in HIV infection, a relatively common variant leading to a loss of function of the HIV co-receptor CCR5 affects the course of the disease, as do variants in genes of the major histocompatibility complex (MHC) region. Rare monogenic variants of the interferon immune response system contribute to severe disease courses in COVID-19 and influenza (type I interferon in these two cases) and in tuberculosis (type II interferon). An estimated 1.8% of life-threatening courses of COVID-19 in men under age 60 are caused by a deficiency of toll-like receptor 7. The scientific understanding of host genetic factors has already been beneficial to the development of effective drugs. In a small number of cases, genetic information has also been used for individual therapeutic decision-making and for the identification of persons at elevated risk. CONCLUSION A comprehensive understanding of host genetics can improve the care of patients with infectious diseases. Until the present, the clinical utility of host genetics has been limited to rare cases; in the future, polygenic risk scores summarizing the relevant genetic variants in each patient will enable a wider benefit. To make this possible, multicenter studies are needed that will systematically integrate clinical and genetic data.
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Affiliation(s)
- Axel Schmidt
- Institute of Human Genetics, Medical Faculty of the University of Bonn & Bonn University Hospital
| | - Ana M. Groh
- Medical Department II, Infectiology, University HospitalFrankfurt, Goethe University Frankfurt
| | - Julia S. Frick
- Interfaculty Institute for Microbiology and Infection Medicine, University Hospital and Faculty of Medicine Tübingen
- MVZ Laboratory Ludwigsburg GbR
| | | | - Kerstin U. Ludwig
- Institute of Human Genetics, Medical Faculty of the University of Bonn & Bonn University Hospital
- * Institut für Humangenetik, Department of Genomics Universitätsklinikum Bonn Venusberg-Campus 1, Gebäude 76 53127 Bonn, Germany
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Matsumoto K, Miyaaki H, Fukushima M, Sasaki R, Haraguchi M, Miuma S, Nakao K. The impact of single-nucleotide polymorphisms on liver stiffness and controlled attenuation parameter in patients treated with direct-acting antiviral drugs for hepatitis C infection. Biomed Rep 2022; 16:9. [PMID: 34987793 PMCID: PMC8719319 DOI: 10.3892/br.2021.1492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/18/2021] [Indexed: 11/18/2022] Open
Abstract
Single-nucleotide polymorphisms (SNPs) of patatin-like phospholipase domain-containing 3 (PNPLA3), tolloid-like protein 1 (TLL1) and interleukin-28 (IL28) have been identified as susceptibility factors for liver steatosis, inflammation and fibrosis in patients with hepatitis C virus (HCV) infection. Here, whether these polymorphisms affected predispositions to changes in liver stiffness (LS) and controlled attenuation parameter (CAP) following direct-acting antiviral (DAA) therapy was assessed. The changes in LS and steatosis in 77 HCV-infected patients receiving DAA therapy were compared with PNPLA3, TLL1 and IL28 genotypes, using CAP, FibroScan and Virtual Touch tissue quantification (VTTQ) before treatment and 12 weeks after the end of the treatment. VTTQ results showed that LS significantly decreased in PNPLA3 CC (P=0.035), TLL1 AA (P=0.011) and IL28B TT (P=0.005) genotypes; no significant differences were observed in PNPLA3 CG/GG, TLL1 AT/TT and IL28B TG/GG. FibroScan results showed that LS significantly decreased in TLL1 AA (P=0.028) and IL28B TT (P=0.032), with no significant difference in PNPLA3 CC. No significant differences were observed in PNPLA3 CG/GG, TLL1 AT/TT and IL28B TG/GG groups. CAP was significantly increased in PNPLA3 CG/GG (P=0.039 and P<0.05) and IL28B TT (P=0.014); no significant difference was observed in PNPLA3 CC and all genotypes of TLL1 and IL28B TG/GG. Therefore, these results indicated that SNPs could predict changes in LS and steatosis after DAA therapy.
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Affiliation(s)
- Kosuke Matsumoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Masanori Fukushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
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Luna-Cuadros MA, Chen HW, Hanif H, Ali MJ, Khan MM, Lau DTY. Risk of hepatocellular carcinoma after hepatitis C virus cure. World J Gastroenterol 2022; 28:96-107. [PMID: 35125821 PMCID: PMC8793019 DOI: 10.3748/wjg.v28.i1.96] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/12/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a significant cause of hepatocellular carcinoma (HCC). The direct-acting antivirals marked a new era of HCV therapy and are associated with greater than 95% cure rate. Successful treatment of chronic hepatitis C greatly reduces the risk of HCC. A proportion of patients, especially those with pre-existing cirrhosis, remain at risk for HCC despite sustained virologic response (SVR). Diabetes mellitus, hepatic steatosis, alcohol consumption and lack of fibrosis regression are associated with risks of HCC after HCV cure. Noninvasive modalities such as aspartate aminotransferase to platelet ratio index and fibrosis-4 index and transient elastography have been used to monitor hepatic fibrosis. More recently, various fibrosis scores have been combined with clinical parameters and other novel biomarkers to predict risks of HCC for patients who achieved SVR. These models still need to be validated and standardized prior to applying to routine clinical care.
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Affiliation(s)
- Maria Alejandra Luna-Cuadros
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Hao-Wei Chen
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Hira Hanif
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Mukarram Jamat Ali
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Muzammil Muhammad Khan
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Daryl Tan-Yeung Lau
- Liver Center, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
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Villamil FG, Massenzio NE, Baré PC, Cocco PA, Cairo FM, Picchio GR. Twenty-year follow-up of an outbreak of hepatitis C in a small rural town of Argentina: The O'Brien Project. Ann Hepatol 2022; 27 Suppl 1:100577. [PMID: 34740846 DOI: 10.1016/j.aohep.2021.100577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/08/2021] [Accepted: 04/08/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES In 1999, a population-based survey showed a 5.6 % (102/1832) prevalence of HCV infection in O'Brien, a small rural town of Argentina. The aim of this study was to assess the impact of screening, clinical evaluation and antiviral therapy on elimination of HCV after 20 years of follow-up. PATIENTS AND METHODS HCV+ subjects (n=102) underwent clinical, biochemical and histological evaluation to assess the presence and severity of liver disease. Antiviral therapy included pegylated interferon + ribavirin in 2005 and direct antiviral agents from 2017. RESULTS All viremic subjects (n=84) had genotype 1b with 90%-97.5% sequence homology scores, suggesting the existence of a common source of infection (use of unsafe injections administered by the same health professional). Liver biopsy (n=55) showed chronic hepatitis in all patients. The prevalence of cirrhosis was 28% overall (29/102) and 34.5% among viremic patients. Sustained virological response (SVR) was obtained in 20/34 (59%) patients treated with interferon. From 2005 to 2017, when oral antivirals became available 37/50 untreated patients died. Median age of this group in 2005 was 67 years. Six interferon non-responders and five naive subjects received direct antiviral agents and all developed SVR. Only 1/31 patient (3.2%) with SVR died and none developed decompensated cirrhosis or HCC. In 2019, a new population-based study showed that the prevalence of HCV in O'Brien decreased 20-fold, from 5.6% to 0.28% (3/1070). CONCLUSIONS Despite the high mortality rate precluding timely access to direct antiviral agents, the O'Brien Project is a good example of HCV micro-elimination studies.
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Affiliation(s)
- Federico Guillermo Villamil
- Liver Transplantation Unit, British Hospital, Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplantation Unit, Hospital El Cruce, Florencio Varela, Provincia Buenos Aires, Argentina.
| | | | - Patricia Cristina Baré
- Instituto de Investigaciones Hematológicas, Instituto de Medicina Experimental CONICET, Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires, Argentina
| | - Paula Andrea Cocco
- Unidad Sanitaria "Martín Espinel Bavio", O'Brien, Provincia Buenos Aires, Argentina
| | - Fernando Mario Cairo
- Liver Transplantation Unit, British Hospital, Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplantation Unit, Hospital El Cruce, Florencio Varela, Provincia Buenos Aires, Argentina
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Xu T, Peng B, Liu M, Liu Q, Yang J, Qu M, Liu N, Lin L, Wu J. Favorable Genotypes of Type III Interferon Confer Risk of Dyslipidemia in the Population With Obesity. Front Endocrinol (Lausanne) 2022; 13:871352. [PMID: 35784542 PMCID: PMC9243353 DOI: 10.3389/fendo.2022.871352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/28/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Studies have indicated that the chronic state of inflammation caused by obesity leads to dyslipidemia. However, how the polymorphisms involved in these inflammatory pathways affect the lipid metabolism in people with obesity is poorly understood. We investigated the associations of inflammation-related gene polymorphisms with dyslipidemia in individuals with obesity living in China. METHODS This case-control study in a population with obesity involved 194 individuals with dyslipidemia and 103 individuals without dyslipidemia. Anthropometric indices of obesity, fasting plasma glucose, blood pressure, blood lipids, and C-reactive protein were evaluated. The genes we tested were IL6 (interleukin 6), IL6R (interleukin 6 receptor), FOXP3 (forkhead box P3), TLR2 (toll-like receptor 2), TLR4 (toll-like receptor 4), IFNL3 (interferon lambda 3, formerly known as IL28B), and IFNL4 (interferon lambda 4, formerly known as IL29). Polymorphisms were genotyped using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. RESULTS There were significant differences in the allelic and genotype frequencies of IFNL3 (IL28B) rs12971396, rs8099917, rs11882871, rs12979860, rs4803217 between non-dyslipidemia and dyslipidemia groups in people with obesity. These single nucleotide polymorphisms (SNPs) of IFNL3 were highly linked (D' and r > 0.90), so the result of one SNP could represent the result of other SNPs. For IFNL3 rs12971396, people with the homozygous genotype (the major group) carried a higher risk of dyslipidemia than people with the heterozygous genotype (P < 0.001, OR = 4.46, 95%CI, 1.95-10.22). CONCLUSIONS The favorable genotypes of type III interferon, which have a beneficial role in anti-virus function, were associated with dyslipidemia in a Chinese population with obesity. Type III interferon could have a pathologic role and confer risk of dyslipidemia in people with obesity and chronic inflammation.
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Affiliation(s)
- Tiantian Xu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Bo Peng
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Mengmeng Liu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qingjing Liu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Junya Yang
- School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom
| | - Minli Qu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Na Liu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lizhen Lin
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Wu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Jing Wu,
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38
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Öksüz Z, Üçbilek E, Serin MS, Yaraş S, Temel GÖ, Sezgin O. Possible relationship between IL28B rs12979860 and TLR2 -196 to -174 del/ins polymorphisms and the liver fibrosis stage in hepatitis C patients. Arch Virol 2022; 167:153-161. [PMID: 34817649 DOI: 10.1007/s00705-021-05302-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/01/2021] [Indexed: 10/19/2022]
Abstract
It has been shown that host factors play an important role in the progression of hepatitis C virus (HCV) infection. Toll-like receptor 2 (TLR2) del and interleukin 28B (IL28B) T alleles can mediate liver inflammation and pathogenesis of hepatocellular carcinoma. In the present study, the possible relationship between the IL28B rs12979860 C/T and TLR2 -196 to -174 del/ins gene variants and different fibrosis stages and host factors in hepatitis C patients was investigated. IL28B and TLR2 polymorphisms in the blood of 50 hepatitis C patients at different stages of fibrosis (24 mild/moderate, 26 advanced) and 24 healthy controls were examined by RT-qPCR. The highest frequency of the TLR2 del (26.9%) and IL28B T (46.2%) alleles was found in hepatitis C patients with the most advanced fibrosis, and the lowest frequency was found in healthy controls. There was a statistically significant difference between hepatitis C patients with advanced fibrosis and healthy controls in terms of the TLR2 del (p = 0.0062) and IL28B T (p = 0.0017) allele frequencies. However, no statistically significant difference was found between the mild/moderate fibrosis and severe fibrosis patient groups in terms of genotype or IL28B and TLR2 polymorphisms (p > 0.05). In addition, there was a significant difference between patients with mild/moderate or advanced fibrosis who carried the TLR2 del allele together with the IL28B CT genotype and healthy controls. The present study emphasizes that the TLR2 and IL28B gene variants cannot be single biomarkers for the determination of fibrosis stage in hepatitis C infection but together can play an important role in predicting severe disease.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Mersin University Faculty of Pharmacy, Mersin, Turkey.
| | - Enver Üçbilek
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Mersin University Faculty of Pharmacy, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Gülhan Örekici Temel
- Department of Biostatistics, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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40
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Ibrahim MK, AbdElrahman M, Bader El Din NG, Tawfik S, Abd-Elsalam S, Omran D, Barakat AZ, Farouk S, Elbatae H, El Awady MK. The impact of genetic variations in sofosbuvir metabolizing enzymes and innate immunity mediators on treatment outcome in HCV-infected patients. Microb Pathog 2022; 162:105311. [PMID: 34843922 DOI: 10.1016/j.micpath.2021.105311] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) is the leading cause of liver diseases worldwide. At present, combinations of different classes of direct-acting antiviral agents (DAAs) are used as treatment options for HCV, in which sofosbuvir (SOF) is the common DAA among different therapeutic regimes. In Egypt, SOF plus daclatasvir (DCV) is the widely used anti-HCV treatment protocol. Herein, we aimed to assess the association between 3 single-nucleotide polymorphisms (SNPs) at the genes coding for 2 SOF metabolizing enzymes: histidine triad nucleotide-binding protein 1 (HINT1) rs4696/rs7728773 and nucleoside diphosphate kinase 1 (NME1) rs3760468, together with the most potent anti-HCV innate molecule, i.e., interferon lambda 3 (IFNL3) rs12979860 and the response to SOF/DCV in Egyptian patients chronically infected with genotype 4 (GT4). SNPs were genotyped using real-time PCR in DNA from patients who achieved sustained virological response (SVR) at 12 weeks post-SOF/DCV treatment (i.e., responders; n = 188), patients who failed to achieve SVR12 (i.e., non-responders; n = 109), and healthy controls (n = 62). Our results demonstrated that patients bearing HINT1 rs7728773 CT/TT (odds ratio 2.119, 95% CI 1.263-3.559, p = 0.005) and IFNL3 rs12979860 CC (odds ratio 3.995, 95% CI 2.126-7.740, p = 0.0001) were more likely to achieve SVR12. However, neither HINT1 rs4696 nor NME1 rs3760468 seems to contribute to the responsiveness to SOF/DCV. Binary regression analysis defined 5 predictor factors independently associated with SVR12: age, bilirubin, hemoglobin, early stages of fibrosis, and combined HINT1 rs7728773 and IFNL3 rs12979860 favorable and mixed genotypes (odds ratio 3.134, 95% CI 1.518-6.47, p = 0.002), and that was confirmed by the combined ROC curve for the 5 predictor factors (AUC = 0.91, 95% CI 0.869-0.95, P = 0.0001). In conclusion, these data suggest that the two SNPs have the potential in predicting the response rate to SOF/DCV treatment in patients infected with HCV GT4. This study is the first to investigate the pharmacogenetics of SOF metabolizing enzyme and introduce HINT1 rs7728773 as a novel SNP that predicts the treatment efficacy.
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Affiliation(s)
- Marwa K Ibrahim
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth St. (formerly El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt.
| | - Mohamed AbdElrahman
- Department of Pharmacy, Al-Mustaqbal University College, Babylon, Iraq; Clinical Pharmacy Unit, Badr University Hospital, Faculty of Medicine, Helwan University, Egypt
| | - Noha G Bader El Din
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth St. (formerly El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Salwa Tawfik
- Department of Internal Medicine, National Research Center, 33 EL Bohouth St. (formerly El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Sherief Abd-Elsalam
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dalia Omran
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
| | - Amal Z Barakat
- Department of Molecular Biology, Biotechnology Research Institute, National Research Center, 33 EL Bohouth St. (formerly El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Sally Farouk
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth St. (formerly El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
| | - Hassan Elbatae
- Department of Tropical Medicine, Faculty of Medicine, Kafer Elshiek University, Kafer Elshiek, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth St. (formerly El Tahrir St.), Dokki, Giza, P.O. 12622, Egypt
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Kawaratani H, Sawai H, Onishi M, Kogiso T, Shimada N, Uojima H, Nakajima T, Matsumoto N, Ikejima K, Ishikawa T, Terai S, Motoyama H, Komori A, Hirashima N, Saito S, Eguchi Y, Nojima M, Kawai Y, Tateyama M, Yoshiji H, Tanaka Y. A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites. Liver Int 2021; 41:2944-2953. [PMID: 34309184 DOI: 10.1111/liv.15022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/03/2021] [Accepted: 07/15/2021] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. METHODS From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study. RESULTS Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. CONCLUSION SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.
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Affiliation(s)
- Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Hiromi Sawai
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaya Onishi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tomomi Kogiso
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Kashiwa, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Tomoaki Nakajima
- Department of Hepatology, Sapporo Kosei General Hospital, Hokkaido, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kenichi Ikejima
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroyuki Motoyama
- Department of Hepatology, Graduate School of Medicine, Osaka City University Osaka, Japan
| | - Atsumasa Komori
- Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan
| | - Noboru Hirashima
- Department of Gastroenterology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
| | - Satoru Saito
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | - Masanori Nojima
- Center for Translational Research, The Institute of Medical Science, the University of Tokyo, Tokyo, Japan
| | - Yosuke Kawai
- Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan
| | - Masakuni Tateyama
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
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42
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Møhlenberg M, Monrad I, Vibholm LK, Nielsen SSF, Frattari GS, Schleimann MH, Olesen R, Kjolby M, Gunst JD, Søgaard OS, O'Brien TR, Tolstrup M, Hartmann R. The Impact of IFNλ4 on the Adaptive Immune Response to SARS-CoV-2 Infection. J Interferon Cytokine Res 2021; 41:407-414. [PMID: 34788130 DOI: 10.1089/jir.2021.0106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Genetic polymorphisms at the IFNL4 loci are known to influence the clinical outcome of several different infectious diseases. Best described is the association between the IFNL4 genotype and hepatitis C virus clearance. However, an influence of the IFNL4 genotype on the adaptive immune system was suggested by several studies but never investigated in humans. In this cross-sectional study, we have genotyped 201 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive participants for 3 IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) and stratified them according to the IFNλ4 activity. Based on this stratification, we investigated the association between the IFNL4 genotype and the antibody as well as the CD8+ T cell response in the acute phase of the SARS-CoV-2 infection. We observed no differences in the genotype distribution compared with a Danish reference cohort or the 1,000 Genome Project, and we were not able to link the IFNL4 genotype to changes in either the antibody or CD8+ T cell responses of these patients.
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Affiliation(s)
- Michelle Møhlenberg
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark
| | - Ida Monrad
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark
| | - Line K Vibholm
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark
| | - Stine S F Nielsen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark
| | | | | | - Rikke Olesen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark
| | - Mads Kjolby
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark.,DANDRITE, Deptarment of Biomedicine, Aarhus University, Aarhus, Denmark.,Steno Diabetes Center Aarhus, Aarhus University Hospital, Aalborg, Denmark.,University of Dundee, Scotland, United Kingdom
| | | | - Ole Schmeltz Søgaard
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Martin Tolstrup
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Rune Hartmann
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark
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43
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Rossi ÁD, Faucz FR, Melo A, de Azevedo GS, Pezzuto P, Bezerra OCDL, Manta FSDN, Azamor T, Schamber-Reis BLF, Tanuri A, Moraes MO, Aguiar RS, Stratakis CA, Cardoso CC. Association between Maternal Non-Coding Interferon-λ Polymorphisms and Congenital Zika Syndrome in a Cohort from Brazilian Northeast. Viruses 2021; 13:2253. [PMID: 34835060 PMCID: PMC8622836 DOI: 10.3390/v13112253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 11/16/2022] Open
Abstract
Congenital Zika syndrome (CZS) is characterized by a diverse group of congenital malformations induced by ZIKV infection during pregnancy. Type III interferons have been associated with placental immunity against ZIKV and restriction of vertical transmission in mice, and non-coding single-nucleotide polymorphisms (SNPs) on these genes are well known to influence susceptibility to other viral infections. However, their effect on ZIKV pathogenesis has not yet been explored. To investigate whether maternal non-coding SNPs at IFNL genes are associated with CZS, 52 women infected with ZIKV during pregnancy were enrolled in a case-control association study. A total of 28 women were classified as cases and 24 as controls based on the presence or absence of CZS in their infants, and seven Interferon-λ non-coding SNPs (rs12980275, rs8099917, rs4803217, rs4803219, rs8119886, rs368234815, rs12979860) were genotyped. The results of logistic regression analyses show an association between the G allele at rs8099917 and increased susceptibility to CZS under a log-additive model (adjustedOR = 2.80; 95%CI = 1.14-6.91; p = 0.02), after adjustment for trimester of infection and genetic ancestry. These results provide evidence of an association between Interferon-λ SNPs and CZS, suggesting rs8099917 as a promising candidate for further studies on larger cohorts.
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Affiliation(s)
- Átila Duque Rossi
- Laboratório de Virologia Molecular, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (Á.D.R.); (P.P.); (A.T.); (R.S.A.)
| | - Fabio Rueda Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA; (F.R.F.); (C.A.S.)
| | - Adriana Melo
- Instituto de Pesquisa Professor Joaquim Amorim Neto (IPESQ), Campina Grande 58406-115, Brazil; (A.M.); (G.S.d.A.)
| | - Girlene Souza de Azevedo
- Instituto de Pesquisa Professor Joaquim Amorim Neto (IPESQ), Campina Grande 58406-115, Brazil; (A.M.); (G.S.d.A.)
| | - Paula Pezzuto
- Laboratório de Virologia Molecular, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (Á.D.R.); (P.P.); (A.T.); (R.S.A.)
| | - Ohanna Cavalcanti de Lima Bezerra
- Laboratório de Hanseníase, Instituto Oswaldo Cruz Fiocruz, Rio de Janeiro 21040-900, Brazil; (O.C.d.L.B.); (F.S.d.N.M.); (T.A.); (M.O.M.)
| | - Fernanda Saloum de Neves Manta
- Laboratório de Hanseníase, Instituto Oswaldo Cruz Fiocruz, Rio de Janeiro 21040-900, Brazil; (O.C.d.L.B.); (F.S.d.N.M.); (T.A.); (M.O.M.)
| | - Tamiris Azamor
- Laboratório de Hanseníase, Instituto Oswaldo Cruz Fiocruz, Rio de Janeiro 21040-900, Brazil; (O.C.d.L.B.); (F.S.d.N.M.); (T.A.); (M.O.M.)
| | - Bruno Luiz Fonseca Schamber-Reis
- Faculdade de Ciências Médicas de Campina Grande, Núcleo de Genética Médica, Centro Universitário UniFacisa, Campina Grande 58408-326, Brazil;
| | - Amilcar Tanuri
- Laboratório de Virologia Molecular, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (Á.D.R.); (P.P.); (A.T.); (R.S.A.)
| | - Milton Ozório Moraes
- Laboratório de Hanseníase, Instituto Oswaldo Cruz Fiocruz, Rio de Janeiro 21040-900, Brazil; (O.C.d.L.B.); (F.S.d.N.M.); (T.A.); (M.O.M.)
| | - Renato Santana Aguiar
- Laboratório de Virologia Molecular, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (Á.D.R.); (P.P.); (A.T.); (R.S.A.)
- Laboratório de Biologia Integrativa, Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA; (F.R.F.); (C.A.S.)
| | - Cynthia Chester Cardoso
- Laboratório de Virologia Molecular, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (Á.D.R.); (P.P.); (A.T.); (R.S.A.)
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Tahata Y, Sakamori R, Takehara T. Treatment progress and expansion in Japan: From interferon to direct-acting antiviral. Glob Health Med 2021; 3:321-334. [PMID: 34782876 DOI: 10.35772/ghm.2021.01083] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) was first discovered in 1989, and patients infected with HCV were initially treated with interferon (IFN) monotherapy. In the 2000s, pegylated IFN combined with ribavirin was the mainstay of therapy for infected patients, but the sustained virologic response (SVR) rate was less than 50% for patients with HCV genotype 1. To further improve the therapeutic effect, direct-acting antiviral (DAA) was developed, and combination therapy with DAA and IFN has been available since 2011. In addition, IFN-free DAA therapy became available in 2014, and SVR was achieved in more than 95% of patients with chronic hepatitis and compensated cirrhosis. Thus, in just 30 years since the discovery of HCV, we aim to eliminate HCV in almost all patients. However, there are remaining issues to be addressed. Many of the patients who achieved SVR with DAA therapy had advanced liver fibrosis, and it is necessary to verify to what extent DAA therapy improves their prognosis in terms of liver function, hepatocellular carcinoma occurrence, and mortality. Resistance-associated substitutions can cause failure of DAA therapy, and the search for an effective therapy for high-level resistant viruses such as P32 deletion is particularly important. DAA therapy was approved for use in patients with decompensated cirrhosis in Japan in 2019, which is an unmet need so far. It is also important to verify the efficacy and safety in real-world settings. The World Health Organization aims to eliminate HCV by 2030, and Japan must tackle its remaining issues to achieve this goal.
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Affiliation(s)
- Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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45
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Minemura M, Tajiri K, Hayashi Y, Takahashi N, Watanabe K, Hanaoka T, Araki Y, Takahashi K, Takahara T, Kojima S, Yasuda I. Discrepant Diagnostic Results of Nested Polymerase Chain Reaction-based Genotyping in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection. Intern Med 2021; 60:3239-3243. [PMID: 33896867 PMCID: PMC8580760 DOI: 10.2169/internalmedicine.7132-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/15/2021] [Indexed: 02/05/2023] Open
Abstract
Accurate genotyping is important to improve the treatment of hepatitis C virus (HCV) infection. We herein report a 44-year-old Japanese man with hemophilia A and coinfection of HCV and human immunodeficiency virus (HIV) who was diagnosed with HCV genotype 4 by direct sequencing. Two genotyping tests based on the nested polymerase chain reaction method that we used misdiagnosed his genotype as 2b and 1b. Although several HCV genotyping tests are available in Japan, it is important to recognize that some cannot detect genotype 4. Care should be taken when genotyping HCV patients who have received non-heated coagulation factor preparations or were infected abroad.
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Affiliation(s)
- Masami Minemura
- Department of Gastroenterology, Toyama University Hospital, Japan
- Department of Community Medical Support, Toyama University Hospital, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Yuka Hayashi
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Kasumi Watanabe
- Department of Gastroenterology, Toyama University Hospital, Japan
| | | | - Yasuhiro Araki
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Kosuke Takahashi
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Terumi Takahara
- Department of Gastroenterology, Toyama University Hospital, Japan
| | | | - Ichiro Yasuda
- Department of Gastroenterology, Toyama University Hospital, Japan
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46
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Gatselis NK, Azariadis K, Lyberopoulou A, Dalekos GN. Programmed cell death-1 rs11568821 and interleukin-28B rs12979860 polymorphisms in autoimmune hepatitis. J Transl Autoimmun 2021; 4:100126. [PMID: 34632357 PMCID: PMC8488593 DOI: 10.1016/j.jtauto.2021.100126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a relatively rare chronic liver disease of unknown etiology. The genetic background affects susceptibility, clinical phenotype, and prognosis. The programmed cell death-1 rs11568821 polymorphism (PD1.3) has been associated with susceptibility to autoimmune diseases. The interleukin-28B (IL28B) rs12979860 polymorphism has been associated with steatosis, inflammation, and fibrosis in liver diseases. AIM Our aim was to investigate for the first time the incidence and clinical significance of PD1.3 and IL28B rs12979860 in AIH. METHODS Two hundred patients with AIH were evaluated, while 100 healthy subjects were used as controls. Genotyping was performed with in-house allelic discrimination End-Point PCR. RESULTS The SNP PD1.3/A was present in 36/200 (18%) AIH patients compared to 28/100 (28%) healthy controls (p = 0.065). The AA/GA genotypes were not associated with the mode of presentation of AIH, the histological grade or stage, the presence of cirrhosis, risk of disease progression, response to treatment and survival. The IL28B rs12979860 genotype distribution was CC 79/200 (39.5%), TT 36/200 (18%) and CT 85/200 (42.5%), in similar rates with healthy controls (p = 0.878). Inflammatory activity and fibrosis stage did not differ between CC homozygotes and CT/TT carriers. LDL cholesterol was significantly higher in CC than CT/TT patients (P = 0.027), though no differences was found regarding the presence of steatosis or steatohepatitis. On-treatment response to immunosuppressive treatment was not affected by the IL28B rs12979860 polymorphism. However, CC homozygotes AIH patients achieved treatment withdrawal in significantly higher rates (OR 2.3, 95%CI: 1.1-4.7, P = 0.02) irrespective of the presence of steatosis or steatohepatitis. CONCLUSIONS The PD1.3 and IL28B rs12979860 variants are unlikely to contribute to AIH susceptibility, disease presentation and prognosis. The IL28B rs12979860 is not associated with the presence of concurrent steatosis or steatohepatitis. However, although on-treatment response rates to immunosuppression were not affected by the IL28B rs12979860 polymorphism, AIH patients with CC homozygosity were more likely to achieve complete treatment withdrawal. This novel finding needs validation and further clarification from larger multicenter studies.
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Key Words
- AIH, Autoimmune hepatitis.
- ANA, Antinuclear antibodies.
- Anti-LC1, Liver cytosol type-1 antibodies.
- Anti-LKM1, Liver kidney microsomal type-1 antibodies
- Anti-SLA/LP, Soluble liver antigen/liver pancreas antibodies.
- Autoimmune hepatitis
- CR, Complete response.
- HCC, Hepatocellular carcinoma.
- HCV, Hepatis C virus.
- HDL, High density lipoprotein.
- HLA, Human leukocyte antigen.
- HWE, Hardy-weinberg equilibrium.
- IL28B, Interleukin 28B.
- INR, International normalized ratio.
- IQR, Interquartile range.
- IgG, Immunoglobulin class G.
- Interleukin-28B
- LDL, Low density lipoprotein
- MetS, Metabolic syndrome.
- NAFLD, Non-alcoholic fatty liver disease.
- PCR, Polymerase chain reaction.
- PD1, Programmed cell death-1.
- Polymorphisms
- Programmed cell death-1
- SD, Standard deviation.
- SLE, Systemic lupus erythematosus.
- SMA, Smooth muscle antibodies.
- SNP, Single nucleotide polymorphism.
- ULN, Upper limit of normal.
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Affiliation(s)
- Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
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Ferraris P, Wichit S, Cordel N, Missé D. Human host genetics and susceptibility to ZIKV infection. INFECTION GENETICS AND EVOLUTION 2021; 95:105066. [PMID: 34487865 DOI: 10.1016/j.meegid.2021.105066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 12/26/2022]
Abstract
Managing emerging infectious diseases is a current challenge in the fields of microbiology and epidemiology. Indeed, among other environmental and human-related factors, climate change and global warming favor the emergence of new pathogens. The recent Zika virus (ZIKV) epidemic, of which the large and rapid spread surprised the scientific community, is a reminder of the importance to study viruses currently responsible for sporadic infections. Increasing our knowledge of key factors involved in emerging infections is essential to implement specific monitoring that can be oriented according to the pathogen, targeted population, or at-risk environment. Recent technological developments, such as high-throughput sequencing, genome-wide association studies and CRISPR screenings have allowed the identification of human single nucleotide polymorphisms (SNPs) involved in infectious disease outcome. This review focuses on the human genetic host factors that have been identified and shown to be associated with the pathogenesis of ZIKV infection and candidate SNP targets.
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Affiliation(s)
- Pauline Ferraris
- MIVEGEC, Univ. Montpellier, IRD, CNRS, 34394 Montpellier, France.
| | - Sineewanlaya Wichit
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Nadège Cordel
- Guadeloupe University Hospital, Department of Dermatology and Clinical Immunology, Pointe-à-Pitre, Guadeloupe and Normandie University, UNIROUEN, IRIB, Inserm, U1234, Rouen, France
| | - Dorothée Missé
- MIVEGEC, Univ. Montpellier, IRD, CNRS, 34394 Montpellier, France
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Miri HH, Fazeli P, Ali-Hassanzadeh M, Bemani P, Kabelitz D, Kalantar K. Correlation between IL-28 polymorphism and spontaneous clearance in HCV patients: systematic review and meta-analysis. Arch Virol 2021; 166:2469-2478. [PMID: 34216268 DOI: 10.1007/s00705-021-05141-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/29/2021] [Indexed: 10/20/2022]
Abstract
Hepatitis C virus (HCV) is a serious global health issue. Nearly 20% of HCV patients spontaneously clear the virus. While some studies have shown an association of spontaneous clearance (SC) of the virus with interleukin (IL) 28B single-nucleotide polymorphisms (SNPs), others did not show such a relationship. Thus, the purpose of the present study was to investigate the association of IL28B polymorphisms (12979860 SNP) with SC of HCV infection. Upon initial screening of the databases, a total of 545 articles were retrieved, of which 22 studies that met predefined eligibility criteria were entered into the meta-analysis. Odds ratios (ORs) with confidence intervals (95% CI), heterogeneity, publication bias, and sensitivity analysis were assessed. According to the meta-analysis results, a significant association was observed between the rs12979860 SNP and SC of HCV infection. The results indicated that the ORs of SC from hepatitis C virus infection were 2.75 times higher in those with cytokine gene polymorphisms (95% CI, 2.23 to 3.38). Moreover, it was found that the prevalence of rs12979860 CC was 0.33 with 95 CI 0.28-0.38 in genotype 1 and was 0.40 with 95 CI 0.34-0.47 in other genotypes. Our meta-analysis results suggest that IL28B rs12979860 CC is a strong predictor for SC of hepatitis C infection in PEG IFN-a/RBV-treated patients.
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Affiliation(s)
- Hamid Heidarian Miri
- Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pooria Fazeli
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Peyman Bemani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran.
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Kumar N, Prabhu SS, Monga I, Banerjee I. Influence of IL28B gene polymorphisms on PegINF-RBV-mediated HCV clearance in HIV-HCV co-infected patients: A meta-analysis. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Gul N, Khan SU, Ali I, Khan FU. Transmission dynamic of stochastic hepatitis C model by spectral collocation method. Comput Methods Biomech Biomed Engin 2021; 25:578-592. [PMID: 34459684 DOI: 10.1080/10255842.2021.1970143] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
In this research work, we present an exciting mathematical analysis of a stochastic model, using a standard incidence function, for infectious disease hepatitis C transmission dynamics. In this model, we divided the infected population into three different classes with two different infection stages known as chronic class and acute class while the third is an isolation class. We also presents briefly the Legendre spectral method for the numerical solution to the proposed model. It is observed that the disease-free equilibrium is asymptotically stable, when basic reproduction number R0<1. It is also shown that the proposed model has a stable endemic equilibrium when the reproduction number R0>1. Also, sensitivity analysis is carried out to study and identify the effect of parameters on R0. Moreover, we have performed numerical simulations to study the influence of disease free equilibrium and endemic equilibrium. Legendre polynomial and Legendre weight function are used to solve the proposed stochastic system numerically. Numerical results are compared against the basic reproduction number.
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Affiliation(s)
- Naseeb Gul
- Department of Mathematics, City University of Science and Information Technology Peshawar, KP, Pakistan
| | - Sami Ullah Khan
- Department of Mathematics, City University of Science and Information Technology Peshawar, KP, Pakistan
| | - Ishtiaq Ali
- Department of Mathematics and Statistics, College of Science, King Faisal University, Al-Hasa, KSA
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