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Pharmacogenetic study of long-term response to interferon-β treatment in multiple sclerosis

The Pharmacogenomics Journal volume 17, pages 84–91 (2017)Cite this article

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Abstract

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-β (IFNβ) (4-year follow-up). We performed a genome-wide association study in 337 IFNβ-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNβ-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10−4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNβ stimulation in HC (P=3.1 × 10−9 and 5.6 × 10−10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNβ administration (β=−0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNβ.

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Acknowledgements

We are grateful to all the patients and healthy controls for their participation in this study. We thank the International Multiple Sclerosis Genetic Consortium and the Wellcome Trust Case Control Consortium 2 for sharing genotype data of part of the recruited MS patients.

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Author notes

  1. F Clarelli and G Liberatore: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Neuroscience & INSPE, Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, San Raffaele Scientific Institute, Milan, Italy

    F Clarelli, G Liberatore, M Sorosina, A M Osiceanu, F Esposito, E Mascia, S Santoro & F Martinelli-Boneschi

  2. Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy

    F Esposito, G Pavan, B Colombo, L Moiola, V Martinelli, G Comi & F Martinelli-Boneschi

Authors
  1. F Clarelli
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  2. G Liberatore
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Correspondence to F Martinelli-Boneschi.

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Competing interests

FE received honoraria from Serono Symposia International Foundation. FMB received honoraria for consulting, research grant and travel expenses from TEVA neuroscience, Biogen IDEC, Merck Serono. LM received honoraria for speaking from Sanofi-Aventis, Merck Serono and Biogen Idec. VM received honoraria for speaking, consultancy or support for participation to National and International Congresses from Bayer-Schering, Biogen-Dompè, Merck Serono, Novartis, Sanofi-Aventis and TEVA Pharmaceutical. GC has received consulting fees for participating on advisory boards and lecture fees from Novartis, Teva Pharmaceutical, Sanofi-Aventis, Genzyme, Merck Serono, Biogen, Bayer-Schering, Serono Symposia International Foundation, Excemed, Almirall, Chugai, Receptors. The remaining authors state no conflict of interest.

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Clarelli, F., Liberatore, G., Sorosina, M. et al. Pharmacogenetic study of long-term response to interferon-β treatment in multiple sclerosis. Pharmacogenomics J 17, 84–91 (2017). https://doi.org/10.1038/tpj.2015.85

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