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

被引：142

作者：

Cui, Jing ^{[1
]}

Stahl, Eli A. ^{[1
,2
,3
]}

Saevarsdottir, Saedis ^{[4
,5
,6
]}

Miceli, Corinne ^{[7
,8
]}

Diogo, Dorothee ^{[1
,2
,3
]}

Trynka, Gosia ^{[1
,2
,3
]}

Raj, Towfique ^{[2
,3
,9
]}

Mirkov, Masa Umicevic ^{[10
]}

Canhao, Helena ^{[1
,11
,12
]}

Ikari, Katsunori ^{[13
]}

Terao, Chikashi ^{[14
,15
]}

Okada, Yukinori ^{[1
,2
,3
]}

Wedren, Sara ^{[4
,5
,6
]}

Askling, Johan ^{[4
,5
,16
]}

Yamanaka, Hisashi ^{[13
]}

Momohara, Shigeki ^{[13
]}

Taniguchi, Atsuo ^{[13
]}

Ohmura, Koichiro ^{[14
]}

Matsuda, Fumihiko ^{[15
]}

Mimori, Tsuneyo ^{[14
]}

Gupta, Namrata ^{[3
]}

Kuchroo, Manik ^{[3
,9
]}

Morgan, Ann W. ^{[17
,18
]}

Isaacs, John D. ^{[19
]}

Wilson, Anthony G. ^{[20
]}

Hyrich, Kimme L. ^{[21
]}

Herenius, Marieke ^{[22
]}

Doorenspleet, Marieke E. ^{[22
]}

Tak, Paul-Peter ^{[22
]}

Crusius, J. Bart A. ^{[23
]}

van der Horst-Bruinsma, Irene E. ^{[24
]}

Wolbink, Gert Jan ^{[25
,26
,27
]}

van Riel, Piet L. C. M. ^{[10
]}

van de Laar, Mart ^{[28
,29
]}

Guchelaar, Henk-Jan ^{[30
]}

Shadick, Nancy A. ^{[1
]}

Allaart, Cornelia F. ^{[31
]}

Huizinga, Tom W. J. ^{[31
]}

Toes, Rene E. M. ^{[31
]}

Kimberly, Robert P. ^{[32
]}

Bridges, S. Louis, Jr. ^{[32
]}

Criswell, Lindsey A. ^{[33
]}

Moreland, Larry W. ^{[34
]}

Fonseca, Joao Eurico ^{[11
,12
]}

de Vries, Niek ^{[22
]}

Stranger, Barbara E. ^{[2
,3
]}

De Jager, Philip L. ^{[2
,3
,8
]}

Raychaudhuri, Soumya ^{[1
,2
,3
,35
]}

Weinblatt, Michael E. ^{[1
]}

Gregersen, Peter K. ^{[36
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA

[3] Broad Inst, Chem Biol Program, Med & Populat Genet Program, Cambridge, MA USA

[4] Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden

[5] Karolinska Univ Hosp Solna, Stockholm, Sweden

[6] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden

[7] Univ Paris 11, Orsay, France

[8] Hop Bicetre, AP HP, INSERM, U1012, Paris, France

[9] Brigham & Womens Hosp, Dept Neurol, Inst Neurosci, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA

[10] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[11] Univ Lisbon, Fac Med, Inst Med Mol, Rheumatol Res Unit, P-1699 Lisbon, Portugal

[12] Santa Maria Hospital CHLN, Dept Rheumatol, Lisbon, Portugal

[13] Tokyo Womens Med Univ, Inst Rheumatol, Tokyo, Japan

[14] Kyoto Univ, Grad Sch Med, Dept Rheumatol & Clin Immunol, Kyoto, Japan

[15] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan

[16] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden

[17] Univ Leeds, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England

[18] Univ Leeds, Leeds Inst Mol Med, Leeds, W Yorkshire, England

[19] Inst Cellular Med, Musculoskeletal Res Grp, Newcastle Upon Tyne, Tyne & Wear, England

[20] Univ Sheffield, Sch Med, Rheumatol Unit, Sheffield, S Yorkshire, England

[21] Univ Manchester, Sch Translat Med, Arthrit Res UK Epidemiol Unit, Manchester, Lancs, England

[22] Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands

[23] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Immunogenet Lab, Amsterdam, Netherlands

[24] Vrije Univ Amsterdam, Med Ctr, Dept Rheumatol, Amsterdam, Netherlands

[25] Univ Amsterdam, Acad Med Ctr, Sanquin Res Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands

[26] Univ Sheffield, Sch Med & Biomed Sci, Sheffield, S Yorkshire, England

[27] Jan van Breemen Inst, Amsterdam, Netherlands

[28] Univ Twente, Arthrit Ctr Twente, NL-7500 AE Enschede, Netherlands

[29] Med Spectrum Twente, Enschede, Netherlands

[30] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands

[31] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands

[32] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[33] Univ Calif San Francisco, Dept Med, Div Rheumatol, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA USA

[34] Univ Pittsburgh, Div Rheumatol & Clin Immunol, Pittsburgh, PA USA

[35] Cent Manchester NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, NIHR Manchester Musculoskeletal Biomed Res Unit, Manchester, Lancs, England

[36] North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA

[37] Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Epidemiol Unit, Musculoskeletal Res Grp, Manchester, Lancs, England

来源：

PLOS GENETICS | 2013年 / 9卷 / 03期

基金：

英国医学研究理事会;

关键词：

NECROSIS-FACTOR-ALPHA; TNF-ALPHA; DISEASE; METAANALYSIS; INFLIXIMAB; LYMPHOCYTES; ADALIMUMAB; IMPUTATION; GAMMA; LOCI;

D O I：

10.1371/journal.pgen.1003394

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 (Delta DAS) in the etanercept subset of patients (P = 8x10(-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 = 1x10(-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 DDAS 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 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.

引用

页数：11

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