Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis
Year: 2013
Type: review
Study design: Observational Study
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.
Source: PLoS Genetics
Authors: 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
Institutions: Brigham and Women's Hospital, Harvard University, Broad Institute, Karolinska University Hospital, Karolinska Institutet, Université Paris-Sud, Inserm, Assistance Publique – Hôpitaux de Paris, Bicêtre Hospital, Radboud University Medical Center, University of Lisbon, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Instituto de Medicina Molecular João Lobo Antunes, Tokyo Women's Medical University, Kyoto University, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Newcastle University, University of Sheffield, University of Manchester, Arthritis Research UK, Amsterdam UMC Location University of Amsterdam, University of Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Vrije Universiteit Amsterdam, Sanquin, Medisch Spectrum Twente, University of Twente, Leiden University Medical Center, University of Alabama at Birmingham, University of California, San Francisco, Russell/Engleman Rheumatology Research Center, University of Pittsburgh, Manchester Academic Health Science Centre, Northwell Health, Feinstein Institute for Medical Research
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Burroughs Wellcome Fund, American College of Rheumatology Research and Education Foundation, Stiftelsen för Strategisk Forskning, Forskningsrådet för Arbetsliv och Socialvetenskap, Stockholms Läns Landsting, Center for Translational Molecular Medicine, Stiftelsen Konung Gustaf V:s 80-årsfond, Reumatikerförbundet, Versus Arthritis, Dutch Arthritis Association, National Institutes of Health, Medical Research Council, Japan Society for the Promotion of Science, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: NIAMS Multidisciplinary Clinical Research Center, Linking disease-associated variants to transcriptional regulation using ENCODE, G4987136026, G5009335695, Novel Biomarkers and Prediction Models for Rheumatoid Arthritis, Deep Re-Sequencing of Rheumatoid Arthritis Risk Loci, RCT OF PREVENTION OF ACCELERATED ATHEROSCLEROSIS IN SLE, Dissection of two rheumatoid arthritis risk loci from genome-wide studies, Meta-analysis of GWAS data to identify novel rheumatoid arthritis risk loci, G6309256928, Novel Biomarkers and Causal Pathways in RA Susceptbility, Screening of novel anti-citrullinated protein antibodies for rheumatoid arrhtiris by protein array, G7137539107, Predictors of Treatment Response in Early Aggressive RA, Family History, Genes, Environment and G X E Interaction in Predicting RA Risk, Genetic predictors of response to anti-TNF therapy in rheumatoid arthritis, G9000081670
OpenAlex ID: W2127106391