Genome-wide Association Study of Response to Methotrexate in Early Rheumatoid Arthritis Patients

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.

Metadata

Item Type:	Article
Authors/Creators:	Taylor, JC https://orcid.org/0000-0002-2518-5799 Bongartz, T Massey, J Mifsud, B Spiliopoulou, A Scott, IC Wang, J Morgan, M Plant, D Colombo, M Orchard, P Twigg, S McInnes, IB Porter, D Freeston, JE https://orcid.org/0000-0003-0358-338X Nam, JL Cordell, HJ Isaacs, JD Strathdee, JL Arnett, D de Hair, MJH Tak, PP Aslibekyan, S van Vollenhoven, RS Padyukov, L Bridges, SL Pitzalis, C Cope, AP Verstappen, SMM Emery, P https://orcid.org/0000-0002-7429-8482 Barnes, MR Agakov, F McKeigue, P Mushiroda, T Kubo, M Weinshilboum, R Barton, A Morgan, AW https://orcid.org/0000-0003-1109-624X Barrett, JH https://orcid.org/0000-0002-1720-7724 on behalf of the MATURA and PAMERA consortia
Copyright, Publisher and Additional Information:	(c) 2018, Macmillan Publishers Limited, part of Springer Nature. This is an author produced version of a paper published in the Pharmacogenomics Journal. Uploaded in accordance with the publisher's self-archiving policy.
Dates:	Published: July 2018 Published (online): 25 May 2018 Accepted: 9 February 2018
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Clinical Musculoskeletal Medicine (LIRMM) (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds)
Funding Information:	Funder Grant number MRC (Medical Research Council) R116825
Depositing User:	Symplectic Publications
Date Deposited:	02 Mar 2018 16:46
Last Modified:	29 Jan 2021 12:35
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s41397-018-0025-5
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:128128