Lookup NU author(s): Professor John Isaacs
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. Objectives: We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response. Methods: We studied the relation of TNFi response, quantified by change in swollen joint counts ("SJC) and erythrocyte sedimentation rate ("ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation. Results: We detected a statistically significant association between "SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between "SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance. Conclusions: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.
Author(s): Spiliopoulou A, Colombo M, Plant D, Nair N, Cui J, Coenen MJH, Ikari K, Yamanaka H, Saevarsdottir S, Padyukov L, Bridges SL, Kimberly RP, Okada Y, Van Riel PLCM, Wolbink G, Van Der Horst-Bruinsma IE, De Vries N, Tak PP, Ohmura K, Canhao H, Guchelaar H-J, Huizinga TWJ, Criswell LA, Raychaudhuri S, Weinblatt ME, Wilson AG, Mariette X, Isaacs JD, Morgan AW, Pitzalis C, Barton A, McKeigue P
Publication type: Article
Publication status: Published
Journal: Annals of the Rheumatic Diseases
Pages: ePub ahead of print
Online publication date: 29/04/2019
Acceptance date: 11/04/2019
Date deposited: 13/05/2019
ISSN (print): 0003-4967
ISSN (electronic): 1468-2060
Publisher: BMJ Publishing Group
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