Toggle Main Menu Toggle Search

Open Access padlockePrints

Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39

Lookup NU author(s): Professor John Isaacs

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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

Year: 2019

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

URL: https://doi.org/10.1136/annrheumdis-2018-214877

DOI: 10.1136/annrheumdis-2018-214877


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share