Journal Article

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

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

2019

Overview

ObjectivesWe 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.MethodsWe studied the relation of TNFi response, quantified by change in swollen joint counts ( Δ SJC) and erythrocyte sedimentation rate ( Δ 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.ResultsWe detected a statistically significant association between Δ SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between Δ 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.ConclusionsThe 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.

• Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism,Elsevier Limited,BMJ Publishing Group
• Subject: Adult / Aged / anti-tnf / Antigens, CD - genetics / Antirheumatic Agents - therapeutic use / Apyrase - genetics / Arthritis, Rheumatoid - diagnosis / Arthritis, Rheumatoid - drug therapy / Arthritis, Rheumatoid - genetics / Biological Products - therapeutic use / Biomarkers / CD4 antigen / CD40 antigen / CD40 Antigens - genetics / Cell culture / Cohort Studies / Crowdsourcing / Disease / DNA methylation / Drug therapy / Erythrocyte sedimentation rate / Female / Gene Expression Regulation / Gene loci / Genetics / Genome-Wide Association Study / Genomes / Genomics / Health risk assessment / Health sciences / Humans / Immunoregulation / Informatics / Lymphocytes T / Male / Methotrexate / Middle Aged / Molecular Targeted Therapy - methods / Multivariate Analysis / pharmacogenetics / Phenotypic variations / Predictive Value of Tests / Prognosis / Quantitative trait loci / Quantitative Trait Loci - genetics / Regression Analysis / Rheumatoid Arthritis / Statistical analysis / Studies / TNF inhibitors / Transcription / Treatment Outcome / Tumor necrosis factor / Tumor Necrosis Factor Inhibitors - therapeutic use / Tumor necrosis factor-TNF