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Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study

The Pharmacogenomics Journal volume 17, pages 312–318 (2017)Cite this article

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Abstract

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-β) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-β treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-β-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10−6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10−5) and near ZNF697 (combined P-value 8.15 × 10−5).

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Acknowledgements

The members of the ANZgene Consortium are: Alan Baxter (James Cook University, Townsville, Australia), Allan G Kermode (Sir Charles Gairdner Hospital, Perth, Australia), Bruce Taylor (Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia), David R Booth (ANZgene Consortium Chair) (Westmead Millennium Institute, University of Sydney, Sydney, Australia) david.booth@sydney.edu.au, Deborah Mason (Canterbury District Health Board, Christchurch, New Zealand), Graeme J Stewart (Westmead Millennium Institute, University of Sydney, Sydney, Australia), Helmut Butzkueven (University of Melbourne, Melbourne, Australia), Jac Charlesworth (Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia), James Wiley (Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia), Jeannette Lechner- Scott (Hunter Medical Research Institute, Newcastle, Australia), Judith Field (Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia), Lotti Tajouri (Bond University, Gold Coast, Australia), Lyn Griffiths (Griffith Institute of Health and Medical Research, Griffith University, Gold Coast, Australia), Mark Slee (School of Medicine, Flinders University of South Australia, Adelaide, Australia), Matthew A Brown (University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia), Pablo Moscato (Hunter Medical Research Institute, Newcastle, Australia), Rodney J Scott (Hunter Medical Research Institute, Newcastle, Australia), Simon Broadley (School of Medicine, Griffith University, Gold Coast, Australia), Steve Vucic (Westmead Millennium Institute, University of Sydney, Sydney, Australia), Trevor Kilpatrick (University of Melbourne, Melbourne, Australia), William M Carroll (Sir Charles Gairdner Hospital, Perth, Australia). We thank individuals with MS in Australia for supporting this research and all investigators of the study who have contributed to the recruitment of MS patients. This work was supported by a University of South Australia, Division of Health Sciences Research Development Grant.

Membership of the ANZgene Consortium

We would like to thank the Welcome Trust Case Control Consortium 2 for access to genotype data for a number of Australian patients included in the discovery stage of the current study. We also thank the Australian Genome Research Facility forassisting with genotyping of the samples in the validation study.

Author information

Author notes

  1. Membership of the ANZgene Consortium appears before References.

Authors and Affiliations

  1. School of Pharmacy and Medical Sciences and Sansom Institute for Health Research, University of South Australia, Frome Road, Adelaide, South Australia, Australia

    S Mahurkar, V Suppiah & C King

  2. South Australian Health & Medical Research Institute and Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

    M Moldovan

  3. Australian Institute of Health Innovation, University of New South Wales, Sydney, Australia

    M Moldovan

  4. Division of Neuroscience, Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy

    M Sorosina, F Clarelli, G Liberatore, V Martinelli, G Comi & F M Boneschi

  5. Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy

    G Liberatore, G Comi & F M Boneschi

  6. Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona,, Barcelona, Spain

    S Malhotra, X Montalban & M Comabella

  7. Servicio de Neurología, Basurto Hospital, Bilbao, Spain

    A Antigüedad

  8. Flinders University and Medical Centre, Adelaide, South Australia, Australia

    M Krupa & M Slee

  9. Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia

    V G Jokubaitis

  10. Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia

    F C McKay & P N Gatt

  11. Western Australian Neuroscience Research Institute, Centre for Neuromuscular and Neurological Disorders, University of WA, Nedlands, Western Australia, Australia

    M J Fabis-Pedrini & A G Kermode

  12. Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia

    J Lechner-Scott

  13. Institute of Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia

    A G Kermode

  14. Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia

    B V Taylor

  15. Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain

    K Vandenbroeck

  16. Achucarro Basque Center for Neuroscience, Zamudio, Spain

    K Vandenbroeck

  17. Ikerbasque, Basque Foundation of Science, Bilbao, Spain

    K Vandenbroeck

Authors
  1. S Mahurkar
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  15. V Martinelli
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  16. G Comi
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  19. M Slee
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  20. B V Taylor
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  22. M Comabella
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  23. F M Boneschi
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  24. C King
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The Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene)

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Correspondence to V Suppiah.

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Competing interests

G Comi has received honoraria for consultancy and/or speaking activities in the past 12 months from Biogen, Novartis, Teva, Sanofi, Genzyme, Merck Serono, Bayer, Serono Symposia International Foundation, Roche, Almirall, Chugai, Receptos. V Martinelli has received honoraria and travel reimbursement for lectures at Meetings and Congresses from Teva Pharma, Bayer, Genzyme, Biogen Idec, Novartis and Merck Serono; he has received research support from Merck Serono and has served as a member in Advisory Board for Bayer, Genzyme, Biogen Idec, Novartis and Merck Serono.

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Mahurkar, S., Moldovan, M., Suppiah, V. et al. Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study. Pharmacogenomics J 17, 312–318 (2017). https://doi.org/10.1038/tpj.2016.20

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