Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

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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.

Original languageEnglish
Pages (from-to)528-538
Number of pages11
JournalPharmacogenomics Journal
Volume18
Issue number4
DOIs
StatePublished - Jul 1 2018

Bibliographical note

Funding Information:
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 Pharma-cogenomics 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).

Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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