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

Cui, J and Stahl, EA and Saevarsdottir, S and Miceli, C and Diogo, D and Trynka, G and Raj, T and Mirkov, MU and Canhao, H and Ikari, K and Terao, C and Okada, Y and Wedrén, S and Askling, J and Yamanaka, H and Momohara, S and Taniguchi, A and Ohmura, K and Matsuda, F and Mimori, T and Gupta, N and Kuchroo, M and Morgan, AW and Isaacs, JD and Wilson, AG and Hyrich, KL and Herenius, M and Doorenspleet, ME and Tak, PP and Crusius, JBA and van der Horst-Bruinsma, IE and Wolbink, GJ and van Riel, PLCM and van de Laar, M and Guchelaar, HJ and Shadick, NA and Allaart, CF and Huizinga, TWJ and Toes, REM and Kimberly, RP and Bridges, SL and Criswell, LA and Moreland, LW and Fonseca, JE and de Vries, N and Stranger, BE and De Jager, PL and Raychaudhuri, S and Weinblatt, ME and Gregersen, PK and Mariette, X and Barton, A and Padyukov, L and Coenen, MJH and Karlson, EW and Plenge, RM (2013) Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis. PLoS Genetics, 9 (3). ISSN 1553-7390

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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. © 2013 Cui et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Cui, J
Stahl, EA
Saevarsdottir, S
Miceli, C
Diogo, D
Trynka, G
Raj, T
Mirkov, MU
Canhao, H
Ikari, K
Terao, C
Okada, Y
Wedrén, S
Askling, J
Yamanaka, H
Momohara, S
Taniguchi, A
Ohmura, K
Matsuda, F
Mimori, T
Gupta, N
Kuchroo, M
Morgan, AW
Isaacs, JD
Wilson, AG
Hyrich, KL
Herenius, M
Doorenspleet, ME
Tak, PP
Crusius, JBA
van der Horst-Bruinsma, IE
Wolbink, GJ
van Riel, PLCM
van de Laar, M
Guchelaar, HJ
Shadick, NA
Allaart, CF
Huizinga, TWJ
Toes, REM
Kimberly, RP
Bridges, SL
Criswell, LA
Moreland, LWlwm5@pitt.eduLWM5
Fonseca, JE
de Vries, N
Stranger, BE
De Jager, PL
Raychaudhuri, S
Weinblatt, ME
Gregersen, PK
Mariette, X
Barton, A
Padyukov, L
Coenen, MJH
Karlson, EW
Plenge, RM
Date: 15 April 2013
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 9
Number: 3
DOI or Unique Handle: 10.1371/journal.pgen.1003394
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
ISSN: 1553-7390
Other ID: NLM PMC3610685
PubMed Central ID: PMC3610685
PubMed ID: 23555300
Date Deposited: 22 Apr 2013 15:59
Last Modified: 22 Jun 2021 15:55


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