Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Abstract

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10−8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10−11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases

“…The DANBIO (Danish Biologics Database) register also suggested that older age and use of oral prednisolone are predictors of poor response (Hetland et al, 2010), but this was not seen in other registry data ). An increasing number of single nucleotide polymorphisms associated with clinical response to TNF inhibitors are being identified (Cui et al, 2013;DavilaFajardo et al, 2014). These require extensive further validation and are not currently of clinical utility.…”

Integration of Known DNA, RNA and Protein Biomarkers Provides Prediction of Anti-TNF Response in Rheumatoid Arthritis: Results from the COMBINE Study

“…We identified three published studies that identified SNPs associated with anti-TNF-response (11)(12)(13), as well as the results from the winning algorithm at the recent Rheumatoid Arthritis Responder Challenge, developed by team GuanLab, University of Michigan (https://www.synapse.org/#!Synapse:syn2504648). Altogether 52 potentially anti-TNF-response associated Figure S2).…”

“…Integration of known DnA, rnA and Protein Biomarkers Provides Prediction of Anti-TnF response in rheumatoid Arthritis: results from the CoMBIne study Lasse Folkersen,1,2 Boel Brynedal, 3 Lina Marcela Diaz-Gallo, 2 Daniel Ramsköld, 2 Klementy Shchetynsky, 2 Helga Westerlind, 3 Yvonne Sundström, 2 Danika Schepis, 2 Aase Hensvold, 2 Nancy Vivar, 2 Maija-Leena Eloranta, 4 Lars Rönnblom, 4 Søren Brunak, 1 (11)(12)(13) and proteomics (14), as well as better use of clinical data (15) to predict treatment response, particularly for TNF blockade. Success has been limited with virtually no findings validated in independent material, and no biomarker for prediction of response is currently used in clinical practice (11).…”

“…Success has been limited with virtually no findings validated in independent material, and no biomarker for prediction of response is currently used in clinical practice (11). In any such study the collection of relevant biological samples is of key importance, and independent validation of results is necessary for further research.…”

Genotyping in rheumatoid arthritis: a game changer in clinical management?

“…Studies that address this at the level of genetic variation have proved challenging to perform, tending to suffer as a result of insufficient power, differing definitions of therapeutic efficacy, confounding factors or a combination thereof [13]. A few seemingly robust findings include association between the reduced folate carrier 1 variant and methotrexate efficacy [14] and between the 1q23 locus and etanercept efficacy (with the CD84 gene being functionally implicated) [15]. Moving forward concerted efforts must be made to collate large cohorts of RA patients, better characterized for multiple clinical covariates, in order that high-powered and optimally controlled GWASs might identify robust predictors of therapeutic efficacy.…”