Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.
Subscribe to Journal
Get full journal access for 1 year
only $83.17 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Taylor PC, Feldmann M . Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 578–582.
Mease P, Genovese MC, Gladstein G, Kivitz AJ, Ritchlin C, Tak PP et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum 2011; 63: 939–948.
Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008; 67: 1516–1523.
Potter C, Hyrich KL, Tracey A, Lunt M, Plant D, Symmons DP et al. Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis. Ann Rheum Dis 2009; 68: 69–74.
Plant D, Wilson AG, Barton A . Genetic and epigenetic predictors of responsiveness to treatment in RA. Nat Rev Rheumatol 2014; 10: 329–337.
Julia A, Erra A, Palacio C, Tomas C, Sans X, Barcelo P et al. An eight-gene blood expression profile predicts the response to infliximab in rheumatoid arthritis. PLoS One 2009; 4: e7556.
Kapoor SR, Filer A, Fitzpatrick MA, Fisher BA, Taylor PC, Buckley CD et al. Metabolic profiling predicts response to anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis. Arthritis Rheum 2013; 65: 1448–1456.
Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014; 506: 376–381.
Julia A, Marsal S . The genetic architecture of rheumatoid arthritis: from susceptibility to clinical subphenotype associations. Curr Top Med Chem 2013; 13: 720–731.
Liu C, Batliwalla F, Li W, Lee A, Roubenoff R, Beckman E et al. Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med 2008; 14: 575–581.
Plant D, Bowes J, Potter C, Hyrich KL, Morgan AW, Wilson AG et al. Genome-wide association study of genetic predictors of anti-tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci. Arthritis Rheum 2011; 63: 645–653.
Krintel SB, Palermo G, Johansen JS, Germer S, Essioux L, Benayed R et al. Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFalpha inhibitors in patients with rheumatoid arthritis. Pharmacogenet Genomics 2012; 22: 577–589.
Cui J, Stahl EA, Saevarsdottir S, Miceli C, Diogo D, Trynka G et al. Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet 2013; 9: e1003394.
Umicevic Mirkov M, Cui J, Vermeulen SH, Stahl EA, Toonen EJ, Makkinje RR et al. Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis. Ann Rheum Dis 2012; 72: 1375–1381.
Acosta-Colman I, Palau N, Tornero J, Fernandez-Nebro A, Blanco F, Gonzalez-Alvaro I et al. GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis. Pharmacogenomics 2013; 14: 727–734.
Marquez A, Ferreiro-Iglesias A, Davila-Fajardo CL, Montes A, Pascual-Salcedo D, Perez-Pampin E et al. Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis. Arthritis Res Ther 2014; 16: R66.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.
Julia A, Domenech E, Ricart E, Tortosa R, Garcia-Sanchez V, Gisbert JP et al. A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300. Gut 2012; 62: 1440–1445.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.
Alonso A, Marsal S, Tortosa R, Canela-Xandri O, Julia A . GStream: improving SNP and CNV coverage on genome-wide association studies. PLoS One 2013; 8: e68822.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Fransen J, van Riel PL . The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005 Suppl 5 23: S93–S99.
Montes A, Perez-Pampin E, Narvaez J, Canete JD, Navarro-Sarabia F, Moreira V et al. Association of FCGR2A with the response to infliximab treatment of patients with rheumatoid arthritis. Pharmacogenet Genomics 2014; 24: 238–245.
Qiu W, Lazarus R Power Calculation for Testing If Disease is Associated with Marker in a Case-Control Study Using the GeneticsDesign Package: Cambridge 2010.
Delaneau O, Marchini J, Zagury JF . A linear complexity phasing method for thousands of genomes. Nat Methods 2012; 9: 179–181.
Howie BN, Donnelly P, Marchini J . A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 2009; 5: e1000529.
Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE et al. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491: 56–65.
Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010; 26: 2336–2337.
Naar AM, Beaurang PA, Zhou S, Abraham S, Solomon W, Tjian R . Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 1999; 398: 828–832.
Kato Y, Habas R, Katsuyama Y, Naar AM, He X . A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Nature 2002; 418: 641–646.
Jawad AF, McDonald-Mcginn DM, Zackai E, Sullivan KE . Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr 2001; 139: 715–723.
Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM . A census of human transcription factors: function, expression and evolution. Nat Rev Genet 2009; 10: 252–263.
Firestein GS . Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–361.
McInnes IB . Leukotrienes, mast cells, and T cells. Arthritis Res Ther 2003; 5: 288–289.
Ortiz AM, Laffon A, Gonzalez-Alvaro I . CD69 expression on lymphocytes and interleukin-15 levels in synovial fluids from different inflammatory arthropathies. Rheumatol Int 2002; 21: 182–188.
Kang YM, Zhang X, Wagner UG, Yang H, Beckenbaugh RD, Kurtin PJ et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med 2002; 195: 1325–1336.
Gemelli C, Montanari M, Tenedini E, Zanocco Marani T, Vignudelli T, Siena M et al. Virally mediated MafB transduction induces the monocyte commitment of human CD34+ hematopoietic stem/progenitor cells. Cell Death Differ 2006; 13: 1686–1696.
This work was supported by the Spanish Ministry of Economy and Competitiveness Strategic Project grants (PSE-010000-2006-6 and IPT-010000-2010-36). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
About this article
Cite this article
Julià, A., Fernandez-Nebro, A., Blanco, F. et al. A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis. Pharmacogenomics J 16, 147–150 (2016). https://doi.org/10.1038/tpj.2015.31
Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response
International Journal of Molecular Sciences (2020)
Annals of the Rheumatic Diseases (2019)
Introducing Patterns of Variability for Overcoming Compensatory Adaptation of the Immune System to Immunomodulatory Agents: A Novel Method for Improving Clinical Response to Anti-TNF Therapies
Frontiers in Immunology (2019)
Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept
PLOS ONE (2019)
A Combined Transcriptomic and Genomic Analysis Identifies a Gene Signature Associated With the Response to Anti-TNF Therapy in Rheumatoid Arthritis
Frontiers in Immunology (2019)