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Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis

Genes & Immunity volume 12, pages 466–472 (2011)Cite this article

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A Corrigendum to this article was published on 19 July 2012

Abstract

Interferon-β (IFNβ) therapy is effective in approximately half of the patients with relapsing-remitting multiple sclerosis (RRMS). Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, we carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNβ treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNβ compared with patients carrying the respective G-alleles (P=0.0006 and P=0.0023, respectively). Moreover, patients with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFNβ treatment (P=0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P=0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFNβ treatment and MRI-based non-responder status was observed (P=0.103 and P=0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P=0.037). These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFNβ therapy that might have relevance as biomarker to predict the response to IFNβ in multiple sclerosis.

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Acknowledgements

We gratefully acknowledge the staff and patients of the departments of Neurology at the VUmc hospital, the Centre d'Esclerosi Múltiple de Catalunya and Brigham and Women's Hospital who participated in this study. The study was supported by the Dutch MS Research Foundation (Grant 04-549 MS).

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Author notes

  1. S Vosslamber and L F van der Voort: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    S Vosslamber, R Heijmans, J B A Crusius & C L Verweij

  2. Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands

    L F van der Voort, B M J Uitdehaag, J Killestein & C H Polman

  3. Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands

    I J van den Elskamp

  4. Broad Institute of Harvard and Massachusetts Institute of Technology, Program in Medical and Population Genetics, Cambridge, MA, USA

    C Aubin, D A Hafler & P L De Jager

  5. Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands

    B M J Uitdehaag

  6. Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands

    T C T M van der PouwKraan

  7. Centre d’Esclerosi Múltiple de Catalunya, CEM-Cat Unitat de Neuroimmunologia Clínica Hospital Universitari Vall d’Hebron, Barcelona, Spain

    M Comabella & X Montalban

  8. Department of Neurology, Program in Translational NeuroPsychiatric Genomics, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

    P L De Jager

  9. Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA

    D A Hafler

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  1. S Vosslamber
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Corresponding author

Correspondence to S Vosslamber.

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Competing interests

Ms Vosslamber MSc, Professors Polman and Verweij are investigators on a patent application on the findings in this paper.

Mr Van den Elskamp MSc, Mr Heijmans, Ms Aubin, Drs Crusius and van der PouwKraan reported no disclosures.

Dr Van der Voort has received research support from Bayer Schering Pharma, Biogen Idec, Merck Serono and Teva Pharmaceutical Industries Ltd.

Professor Uitdehaag is a consultant for Novartis and Merck Serono.

Professor Comabella received honoraria for consultancy from Merck-Serono, Biogen Idec, and Bayer-Schering.

Professor Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering member or participated in advisory boards in corporate-sponsored clinical trials or has had consulting agreements in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals and Almirall.

Professor Hafler was consultant for and gave expert testimony to Allozyne, Inc., EISAI Research Institute and Xceed Molecular Corporation. He received honoraria for consultancy and reimbursed for travel expenses. He received research support from NIH/NINDS (R37 NS024247) (Role: PI), NIH/NINDS (P01 NS038037) (role: Co-Inv), NIH/NINDS R01 NS049477 (role: Co-Inv), NIH (U19 AI070352) (role: PI) and NIH (P01 AI073748) (role: Co-Inc).

Professor De Jager was a consultant for Merck Serono and received honoraria for that and he is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society. He received research support from NIH/Rush University AG030146 (Role: Co-Inv), NMSS Harry Weaver JF2138A1 (Role: PI) Risk Factors, Pathology and Clinical Expressions R01 AG015819 (Role: Co-Inv), Linking NK Antiviral function to genome-wide analysis screens (Role: Co-Inv) and Exploring the Consequences of the TNFRSF1A Susceptibility Allele for MS.

Dr Killestein is a consultant for Novartis, Merck-Serono.

Professor Polman is a consultant for Actelion, Biogen Idec, Bayer Schering, TEVA, Merck-Serono, Novartis, Glaxo SK, UCB, Roche and Antisense Ther and received honoraria for that and gave expert testimony for Biogen Idec. He received research support from Biogen Idec, Bayer Schering, Teva, Merck-Serono, Novartis, Glaxo SK and UCB.

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Vosslamber, S., van der Voort, L., van den Elskamp, I. et al. Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis. Genes Immun 12, 466–472 (2011). https://doi.org/10.1038/gene.2011.18

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