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

Jing Cui, Eli A. Stahl, Saedis Saevarsdottir, Corinne Miceli, Dorothee Diogo, Gosia Trynka, Towfique Raj, Maša Umiċeviċ Mirkov, Helena Canhao, Katsunori Ikari, Chikashi Terao, Yukinori Okada, Sara Wedrén, Johan Askling, Hisashi Yamanaka, Shigeki Momohara, Atsuo Taniguchi, Koichiro Ohmura, Fumihiko Matsuda, Tsuneyo Mimori, Namrata Gupta, Manik Kuchroo, Ann W. Morgan, John D. Isaacs, Anthony G. Wilson, Kimme L. Hyrich, Marieke Herenius, Marieke E. Doorenspleet, Paul-Peter Tak, J. Bart A. Crusius, Irene E. van der Horst-Bruinsma, Gert Jan Wolbink, Piet L. C. M. van Riel, Mart van de Laar, Henk-Jan Guchelaar, Nancy A. Shadick, Cornelia F. Allaart, Tom W. J. Huizinga, Rene E. M. Toes, Robert P. Kimberly, S. Louis Bridges, Lindsey A. Criswell, Larry W. Moreland, João Eurico Fonseca, Niek de Vries, Barbara E. Stranger, Philip L. De Jager, Soumya Raychaudhuri, Michael E. Weinblatt, Peter K. Gregersen, Xavier Mariette, Anne Barton, Leonid Padyukov, Marieke J. H. Coenen, Elizabeth W. Karlson, Robert M. Plenge

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.