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

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 antiTNF 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 (DDAS) in the etanercept subset of patients (P = 8610), but not in the infliximab or adalimumab subsets (P.0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 39 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 = 1610 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 DDAS in a subset of RA patients with gene expression data (n = 31, etanercepttreated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA PLOS Genetics | www.plosgenetics.org 1 March 2013 | Volume 9 | Issue 3 | e1003394 Abstract 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.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. Citation: Cui J, Stahl EA, Saevarsdottir S, Miceli C, Diogo D, et al. (2013) Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis. PLoS Genet 9(3): e1003394. doi:10.1371/journal.pgen.1003394 Editor: Alison Motsinger-Reif, North Carolina State University, United States of America Received August 13, 2012; Accepted January 13, 2013; Published March 28, 2013 Copyright: 2013 Cui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: JC is supported by grants from ACR REF HPNIA award and the NIH (R01-AR059073, P60-AR047782, U01-GM092691, R01-AR049880). RMP is supported by grants from the NIH (R01-AR057108, R01-AR056768, U01-GM092691, R01-AR059648) and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. The American College of Rheumatology Research and Education Foundation provided funding to support this project. The eRA study was supported by R01 AI/AR47487. SS’s work was supported by a clinical research fund from Stockholm County (ALF fund). LP’s work was supported by the Swedish Rheumatism Association and the Swedish Medical Research Council. NdV and MED were sponsored by CTMM, the Center for Translational Molecular Medicine, and the Dutch Arthritis Foundation project TRACER (grant 04I-202). The Swedish studies (EIRA, Karolinska) were supported by grants from the Swedish Medical Research Council, the Stockholm County Council, the Swedish Council for Working Life and Social Research, King Gustaf V’s 80-year foundation, the Swedish Rheumatism Association, the Swedish Foundation for Strategic Research, the Swedish COMBINE project, and the IMI funded BTCure project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: rplenge@partners.org ¤a Current address: Division of Psychiatric Genomics, Mt. Sinai School of Medicine, New York, New York, United States of America ¤b Current address: GlaxoSmithKline, Stevenage, United Kingdom . These authors contributed equally to this work.