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

Athina Spiliopoulou, Marco Colombo, Darren Plant, Nisha Nair, Jing Cui, Marieke J. H. Coenen, Katsunori Ikari, Hisashi Yamanaka, Saedis Saevarsdottir, Leonid Padyukov, S. Louis Bridges, Robert P. Kimberly, Yukinori Okada, Piet L. C. M. van Riel, Gertjan Wolbink, Irene E. van der Horst-Bruinsma, Niek de Vries, Paul P. Tak, Koichiro Ohmura, Helena CanhãoHenk-Jan Guchelaar, Tom W. J. Huizinga, Lindsey A. Criswell, Soumya Raychaudhuri, Michael E. Weinblatt, Anthony G. Wilson, Xavier Mariette, John D. Isaacs, Ann W. Morgan, Costantino Pitzalis, Anne Barton, Paul McKeigue

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 (ΔSJC) and erythrocyte sedimentation rate (ΔESR) 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 ΔSJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between ΔSJC 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.

Original languageEnglish
Pages (from-to)1055-1061
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume78
Issue number8
DOIs
Publication statusPublished - 1 Aug 2019

Cite this