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      The Role of Interferon-λ Locus Polymorphisms in Hepatitis C and Other Infectious Diseases

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          Abstract

          Since its discovery in 2003, the type III interferon-λ (IFN-λ) family has been found to contribute significantly to the host response to infection. Whilst IFN-λ shares many features with type I IFN induction and signalling pathways, the tissue-specific restricted expression of its receptor, IL28RA, makes IFN-λ a major mediator of host innate immunity in tissues and organs with a high epithelial cell content. Host susceptibility and responses to infection are known to be heterogeneous, and the identification of common genetic variants linked to disease outcome by genome-wide association studies (GWAS) has underscored the significance of host polymorphisms in responses to infection. Several such GWAS have highlighted the IFN-λ locus on chromosome 19q13 as an area of genetic variation significantly associated with hepatitis C virus (HCV) infection, and the rs12979860 genotype can be used in clinical practice as a biomarker for predicting a successful response to treatment with pegylated IFN and ribavarin. Here, we discuss IFN-λ genetic polymorphisms and their role in HCV and other infectious diseases as well as their potential impact on clinical diagnostics, patient stratification and therapy. Finally, the broader role of IFN-λ in the immunopathogenesis of non-infectious inflammatory diseases is considered.

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          Most cited references98

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          IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.

          We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The expression of IFN-lambda mRNAs was inducible by viral infection in several cell lines. We identified a distinct receptor complex that is utilized by all three IFN-lambda proteins for signaling and is composed of two subunits, a receptor designated CRF2-12 (also designated as IFN-lambdaR1) and a second subunit, CRF2-4 (also known as IL-10R2). Both receptor chains are constitutively expressed on a wide variety of human cell lines and tissues and signal through the Jak-STAT (Janus kinases-signal transducers and activators of transcription) pathway. This receptor-ligand system may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.
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            Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.

            The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).
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              IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.

              Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-alpha/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNlambda3; rs8099917 combined P = 9.25 x 10(-9), OR = 1.98, 95% CI = 1.57-2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-alpha.
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                Author and article information

                Journal
                JIN
                JIN
                J Innate Immun
                10.1159/issn.1662-811X
                Journal of Innate Immunity
                S. Karger AG
                1662-811X
                1662-8128
                2015
                April 2015
                23 January 2015
                : 7
                : 3
                : 231-242
                Affiliations
                Division of Infection and Pathway Medicine, University of Edinburgh Medical School, Edinburgh, UK
                Author notes
                *Dr. Samantha J. Griffiths or Dr. Jürgen G. Haas, Division of Infection and Pathway Medicine, University of Edinburgh Medical School, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB (UK), E-Mail samantha.griffiths@ed.ac.uk or juergen.haas@ed.ac.uk
                Author information
                https://orcid.org/0000-0002-6782-4675
                Article
                369902 J Innate Immun 2015;7:231-242
                10.1159/000369902
                25634147
                bebf180b-3a8d-4401-8618-c7d0a7cccfa3
                © 2015 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 07 October 2014
                : 15 November 2014
                Page count
                Figures: 3, Tables: 1, References: 105, Pages: 12
                Categories
                Review

                Internal medicine,Respiratory medicine,Clinical Psychology & Psychiatry,Microbiology & Virology,Infectious disease & Microbiology
                Epithelium,Polymorphism,IL28B,Interferon-λ,Autoimmunity,Host defence,Single-nucleotide polymorphism,Immune response,Cytokines,Virology,Hepatitis C virus

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