Abstract

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

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Acknowledgements

We thank all the patients who have contributed to this research, clinical staff who supported patient recruitment and laboratory staff who undertook sample processing. We thank the Medical Research Council (MRC) and Arthritis Research UK (ARUK) for their joint funding of PEAC and MATURA (grant codes 36661 and MR/K015346/1 and 20670 & 20022 (Experimental Arthritis Treatment Centre), respectively). The RAMS cohort was part funded by ARUK (grant code 20385) and the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit (BRU). The YEAR and IACON studies were part funded by program grants from ARUK (grant codes 18475 and 18387), the NIHR Leeds Musculoskeletal BRU and Diagnostic Evaluation Co-operative, the British Medical Association (Doris Hillier Award) and the Ann Wilks Charitable Foundation. The IDEA study was supported by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Limited. Pfizer provided study drug and unrestricted grant funding for the EMPIRE study. The authors had the sole responsibility for data analysis and manuscript preparation. ARUK paid for the genotyping of CARDERA-1 and 2 (grant reference 19739). The SERA cohort was funded by Pfizer and the Scottish Government (ETM40), and the SERA genomic analysis was funded by the Stratified Medicine Scotland Innovation Centre (SMS-IC007). Research in the Newcastle University Musculoskeletal Research Group is supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. I.C.S. and ST held Academic Clinical Lectureships funded by the NIHR. This article presents independent research partly funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in the study design, data collection and analysis, data interpretation, the writing of the manuscript or the decision to submit the manuscript for publication. B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. Part of this project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure (grant code MR/L016311/1) and the MRC Leeds Medical Bioinformatics infrastructure (grant code MR/L01629X/1). PAMERA was supported by the US NIH Pharmacogenomics Research Network (PGRN) funded by NIGMS (U19 GM61388) and the RIKEN Center for Integrative Medical Sciences. It was funded in part by the Biobank Japan Project, funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Acquisition and analysis of genetic and treatment response data from the TEAR Trial were supported in part by NIH R01 AR052658 (SLB, Jr., PI) Predictors of Treatment Response in Early Aggressive RA. The Synoviomics study was supported by the Dutch Arthritis Foundation (grant NR06/1/303).

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Author notes

  1. These authors contributed equally: Ann W Morgan, Jennifer H Barrett.

Affiliations

  1. Leeds Institute of Cancer and Pathology, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK

    • John C. Taylor
    • , Jenna L. Strathdee
    •  & Jennifer H. Barrett
  2. Vanderbilt University, Nashville, TN, USA

    • Tim Bongartz
  3. Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

    • Jonathan Massey
    • , Darren Plant
    • , Suzanne M. M. Verstappen
    •  & Anne Barton
  4. NIHR Manchester BRC, Central Manchester Foundation Trust, Manchester, UK

    • Jonathan Massey
    • , Darren Plant
    • , Suzanne M. M. Verstappen
    •  & Anne Barton
  5. Clinical Pharmacology, William Harvey Research Institute, Queen Mary University, London, UK

    • Borbala Mifsud
  6. Centre for Population Health Sciences, Usher Institute, University of Edinburgh Old Medical School, Teviot Place, Edinburgh, UK

    • Athina Spiliopoulou
    • , Marco Colombo
    •  & Paul McKeigue
  7. Pharmatics Ltd., 9, Little France Road, Edinburgh, UK

    • Athina Spiliopoulou
    • , Peter Orchard
    •  & Felix Agakov
  8. Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University and Department of Rheumatology, Haywood Hospital, High Lane, Burslem, Staffordshire, UK

    • Ian C. Scott
  9. Department of Medical and Molecular Genetics, King’s College London, London, UK

    • Ian C. Scott
  10. Roche Products, Welwyn Garden City, UK

    • Jianmei Wang
  11. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK

    • Michael Morgan
    • , Sarah Twigg
    • , Jane E. Freeston
    • , Jackie L. Nam
    • , Paul Emery
    •  & Ann W. Morgan
  12. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK

    • Michael Morgan
  13. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK

    • Iain B. McInnes
    •  & Duncan Porter
  14. Institute of Genetic Medicine, Newcastle University, Newcastle, UK

    • Heather J. Cordell
  15. Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University and NIHR Newcastle Biomedical Research Centre in Ageing and Long Term Conditions, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

    • John D. Isaacs
  16. University of Kentucky College of Public Health, Lexington, KY, 40536, USA

    • Donna Arnett
  17. University Medical Center Utrecht, Utrecht, The Netherlands

    • Maria J. H. de Hair
  18. Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

    • Paul P. Tak
  19. GlaxoSmithKline, Stevenage, UK

    • Paul P. Tak
  20. Cambridge University, Cambridge, UK

    • Paul P. Tak
  21. Ghent University, Ghent, Belgium

    • Paul P. Tak
  22. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA

    • Stella Aslibekyan
    •  & S. Louis Bridges
  23. Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    • Ronald F. van Vollenhoven
    •  & Leonid Padyukov
  24. Barts and The London School of Medicine & Dentistry, William Harvey Research Institute, Queen Mary University, London, UK

    • Costantino Pitzalis
    •  & Michael R. Barnes
  25. Academic Department of Rheumatology, Faculty of Life Sciences and Medicine, King’s College London, London, UK

    • Andrew P. Cope
  26. RIKEN Center for Integrative Medical Sciences, Tokyo, Japan

    • Taisei Mushiroda
    •  & Michiaki Kubo
  27. Mayo Clinic, Rochester, MN, USA

    • Richard Weinshilboum

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  1. on behalf of the MATURA

    1. and PAMERA

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        Conflict of interest

        Paul P Tak is an employee and shareholder of GlaxoSmithKline; GSK has not been involved in this study. Jianmei Wang is an employee of Roche Products and Felix Agakov is an employee of Pharmatics Ltd., UK. Dr. Weinshilboum is a co-founder and stockholder in OneOme LLC, a Pharmacogenomics Decision Support Company. Paul Emery has undertaken clinical trials and provided expert advice to Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz and Lilly. The authors declare no conflict of interest with the content contained in this manuscript.

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        Correspondence to Ann W. Morgan.

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        DOI

        https://doi.org/10.1038/s41397-018-0025-5

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