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Author (up) 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.; Wedren, S.; Askling, J.; Yamanaka, H.; Momohara, S.; Taniguchi, A.; Ohmura, K.; Matsuda, F.; Mimori, T.; Gupta, N.; Kuchroo, M.; Morgan, A.W.; Isaacs, J.D.; Wilson, A.G.; Hyrich, K.L.; Herenius, M.; Doorenspleet, M.E.; Tak, P.-P.; Crusius, J.B.A.; van der Horst-Bruinsma, I.E.; Wolbink, G.J.; van Riel, P.L.C.M.; van de Laar, M.; Guchelaar, H.-J.; Shadick, N.A.; Allaart, C.F.; Huizinga, T.W.J.; Toes, R.E.M.; Kimberly, R.P.; Bridges, S.L.J.; Criswell, L.A.; Moreland, L.W.; Fonseca, J.E.; de Vries, N.; Stranger, B.E.; De Jager, P.L.; Raychaudhuri, S.; Weinblatt, M.E.; Gregersen, P.K.; Mariette, X.; Barton, A.; Padyukov, L.; Coenen, M.J.H.; Karlson, E.W.; Plenge, R.M. url  doi
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  Title Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis Type Journal Article
  Year 2013 Publication PLoS Genetics Abbreviated Journal PLoS Genet  
  Volume 9 Issue 3 Pages e1003394  
  Keywords Adult; Aged; Alleles; *Antigens, CD/genetics/metabolism; Antirheumatic Agents/administration & dosage; *Arthritis, Rheumatoid/drug therapy/physiopathology; Asian Continental Ancestry Group/genetics; *Biomarkers, Pharmacological/metabolism; European Continental Ancestry Group/genetics; Female; Gene Expression Regulation; *Genome-Wide Association Study; Humans; Immunoglobulin G/administration & dosage; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Tumor Necrosis Factor/administration & dosage; Tumor Necrosis Factor-alpha  
  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 (DeltaDAS) in the etanercept subset of patients (P = 8 x 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 x 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 DeltaDAS 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.  
  Address Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1553-7390 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23555300 Approved no  
  Call Number ref @ user @ Serial 74245  
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