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

doi:10.1371/journal.pgen.1003394

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 MimoriNamrata 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

Research output: Contribution to journal › Article › Academic › peer-review

151 Citations (Scopus)

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

Original language	English
Article number	e1003394
Pages (from-to)	e1003394
Journal	PLoS genetics
Volume	9
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1003394
Publication status	Published - 2013

Access to Document

10.1371/journal.pgen.1003394

Cite this

Cui, J., Stahl, E. A., Saevarsdottir, S., Miceli, C., Diogo, D., Trynka, G., Raj, T., Mirkov, M. U., Canhao, H., Ikari, K., Terao, C., Okada, Y., Wedrén, S., Askling, J., Yamanaka, H., Momohara, S., Taniguchi, A., Ohmura, K., Matsuda, F., ... Plenge, R. M. (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), e1003394. Article e1003394. https://doi.org/10.1371/journal.pgen.1003394

@article{2c57a55d76c14062ae084425091b323d,

title = "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",

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

year = "2013",

doi = "10.1371/journal.pgen.1003394",

language = "English",

volume = "9",

pages = "e1003394",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "3",

}

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, P-P, Crusius, JBA, van der Horst-Bruinsma, IE , Wolbink, GJ, van Riel, PLCM, van de Laar, M, Guchelaar, H-J, Shadick, NA, Allaart, CF, Huizinga, TWJ, Toes, REM, Kimberly, RP, Bridges, SL, Criswell, LA, Moreland, LW, 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 2013, 'Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis', PLoS genetics, vol. 9, no. 3, e1003394, pp. e1003394. https://doi.org/10.1371/journal.pgen.1003394

TY - JOUR

T1 - Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis

AU - Cui, Jing

AU - Stahl, Eli A.

AU - Saevarsdottir, Saedis

AU - Miceli, Corinne

AU - Diogo, Dorothee

AU - Trynka, Gosia

AU - Raj, Towfique

AU - Mirkov, Maša Umiċeviċ

AU - Canhao, Helena

AU - Ikari, Katsunori

AU - Terao, Chikashi

AU - Okada, Yukinori

AU - Wedrén, Sara

AU - Askling, Johan

AU - Yamanaka, Hisashi

AU - Momohara, Shigeki

AU - Taniguchi, Atsuo

AU - Ohmura, Koichiro

AU - Matsuda, Fumihiko

AU - Mimori, Tsuneyo

AU - Gupta, Namrata

AU - Kuchroo, Manik

AU - Morgan, Ann W.

AU - Isaacs, John D.

AU - Wilson, Anthony G.

AU - Hyrich, Kimme L.

AU - Herenius, Marieke

AU - Doorenspleet, Marieke E.

AU - Tak, Paul-Peter

AU - Crusius, J. Bart A.

AU - van der Horst-Bruinsma, Irene E.

AU - Wolbink, Gert Jan

AU - van Riel, Piet L. C. M.

AU - van de Laar, Mart

AU - Guchelaar, Henk-Jan

AU - Shadick, Nancy A.

AU - Allaart, Cornelia F.

AU - Huizinga, Tom W. J.

AU - Toes, Rene E. M.

AU - Kimberly, Robert P.

AU - Bridges, S. Louis

AU - Criswell, Lindsey A.

AU - Moreland, Larry W.

AU - Fonseca, João Eurico

AU - de Vries, Niek

AU - Stranger, Barbara E.

AU - de Jager, Philip L.

AU - Raychaudhuri, Soumya

AU - Weinblatt, Michael E.

AU - Gregersen, Peter K.

AU - Mariette, Xavier

AU - Barton, Anne

AU - Padyukov, Leonid

AU - Coenen, Marieke J. H.

AU - Karlson, Elizabeth W.

AU - Plenge, Robert M.

PY - 2013

Y1 - 2013

N2 - 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

AB - 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

U2 - 10.1371/journal.pgen.1003394

DO - 10.1371/journal.pgen.1003394

M3 - Article

C2 - 23555300

SN - 1553-7390

VL - 9

SP - e1003394

JO - PLoS genetics

JF - PLoS genetics

IS - 3

M1 - e1003394

ER -