Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus

Authors

  • Franziska S. Hoffmann,

    1. Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany
    2. Institute of Clinical Neuroimmunology, Klinikum Groβhadern, University of Munich, Munich, Germany
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    • These authors contributed equally to the study.

  • Andreas Schmidt,

    1. Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany
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    • These authors contributed equally to the study.

  • Meike Dittmann Chevillotte,

    1. Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY, USA
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  • Christian Wisskirchen,

    1. Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany
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  • Johannes Hellmuth,

    1. Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany
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  • Simone Willms,

    1. Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany
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  • Rachel H. Gilmore,

    1. Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY, USA
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  • Jürgen Glas,

    1. Department for Preventive Dentistry and Periodontology, University of Munich, Munich, Germany
    2. Department of Human Genetics, RWTH Aachen, Aachen, Germany
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  • Matthias Folwaczny,

    1. Department for Preventive Dentistry and Periodontology, University of Munich, Munich, Germany
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  • Tobias Müller,

    1. Department of Gastroenterology and Hepatology, Charité University Hospital, Berlin, Germany
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  • Thomas Berg,

    1. Department of Gastroenterology and Rheumatology, Section Hepatology, University Hospital, Leipzig, Germany
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  • Ulrich Spengler,

    1. Department of Internal Medicine, University of Bonn, Bonn, Germany
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  • Karen Fitzmaurice,

    1. Trinity Centre for Health Sciences, St. James' Hospital, Dublin, Ireland
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  • Dermot Kelleher,

    1. Trinity Centre for Health Sciences, St. James' Hospital, Dublin, Ireland
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  • Nicole Reisch,

    1. Section Gastroenterology and Endocrinology, Medizinische Klinik IV, University of Munich, Munich, Germany
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  • Charles M. Rice,

    1. Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY, USA
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  • Stefan Endres,

    1. Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany
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  • Simon Rothenfusser

    Corresponding author
    1. Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany
    • Address reprint requests to: Simon Rothenfusser, M.D., Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Ziemssenstr. 1, D-80336 Munich, Germany. E-mail: Simon.rothenfusser@med.uni-muenchen.de; fax: +49-89-4400-57330.

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  • Potential conflict of interest: Dr. Hoffmann received grants from Novartis.

  • Supported by DFG RO 2525/3-1, Schm 2670/1-1 and RO 2525/5-1 to S.R., DFG GK 1202 to A.S., S.E. and S.R., by LMUexcellent (CIPSM 114, research professorship) and BayImmuNet to S.E., by National Institutes of Health grant AI091707 to C.M.R., and by a Rockefeller University Women and Science grant to M.D.C. T. Berg is supported by the German Competence Network for Viral Hepatitis (Hep-Net) through BMBF Grant No. 01 KI 0437, by the EU-Vigilance network of excellence combating viral resistance (VIRGIL, Project No. LSHM-CT-2004-503359) and by BMBF Grant No. 01KI0787.

  • See Editorial on Page 418

Abstract

Among patients newly infected with hepatitis C virus (HCV), only 20-30% clear the infection spontaneously. In the remaining 70% the infection persists, causing chronic liver inflammation and disease. It is well established that polymorphisms in host genes, especially in components of the innate immune response, contribute to the phenomenon of spontaneous HCV clearance. Retinoic acid inducible gene-I (RIG-I)-like helicases such as melanoma differentiation-associated gene 5 (MDA-5) are cytoplasmic sensors of viral RNA that are critical for triggering innate immune responses after infection with RNA viruses. We analyzed 14 nonsynonymous single-nucleotide polymorphisms in RIG-I-like helicase-pathway-genes comparing European patients who spontaneously cleared HCV (n = 285) or had persistent infection (n = 509). We found that polymorphic haplotypes in the MDA-5 gene IFIH1 encoding histidine at position 843 and threonine at position 946 strongly correlate with the resolution of HCV infection (odds ratio [OR]: 16.23; 95% confidence interval [CI]: 3.67-71.87; P = 1.1 × 10−6). Overexpression of MDA-5 genetic variants in HEK 293 cells and in a tissue culture model of HCV infection revealed that the histidine 843/threonine 946 variant leads to increased baseline and ligand-induced expression of interferon-induced genes and confers an increased ability to suppress HCV replication. Conclusion: These data suggest that MDA-5 plays a significant role in the defense against HCV and that polymorphisms in MDA-5 can influence the outcome of HCV infection. (Hepatology 2015;61:460-470)

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