Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis

The Pharmacogenomics Journal volume 16, pages 147–150 (2016)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Taylor PC, Feldmann M . Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 578–582.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Plant D, Wilson AG, Barton A . Genetic and epigenetic predictors of responsiveness to treatment in RA. Nat Rev Rheumatol 2014; 10: 329–337.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. Julia A, Marsal S . The genetic architecture of rheumatoid arthritis: from susceptibility to clinical subphenotype associations. Curr Top Med Chem 2013; 13: 720–731.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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.

    Article  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fransen J, van Riel PL . The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005 Suppl 5 23: S93–S99.

    CAS  PubMed  Google Scholar 

  23. 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.

    CAS  PubMed  Google Scholar 

  24. 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.

  25. Delaneau O, Marchini J, Zagury JF . A linear complexity phasing method for thousands of genomes. Nat Methods 2012; 9: 179–181.

    Article  CAS  Google Scholar 

  26. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Article  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Firestein GS . Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–361.

    Article  CAS  PubMed  Google Scholar 

  34. McInnes IB . Leukotrienes, mast cells, and T cells. Arthritis Res Ther 2003; 5: 288–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain

    A Julià, I Acosta-Colman, A Alonso, M López-Lasanta, R Tortosa & S Marsal

  2. UGC Reumatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain

    A Fernandez-Nebro

  3. Rheumatology Service, INIBIC-Hospital Universitario A Coruña, A Coruña, Spain

    F Blanco

  4. Rheumatology Service, Hospital Universitario La Princesa, IIS Princesa, IIS La Princesa, Madrid, Spain

    A Ortiz

  5. Rheumatology Service, Hospital Clínic de Barcelona, Barcelona, Spain

    J D Cañete

  6. Rheumatology Service, Hospital del Mar, Barcelona, Spain

    J Maymó

  7. Rheumatology Service, Hospital Universitario Central de Asturias, Oviedo, Spain

    M Alperi-López

  8. Rheumatology Service, Hospital Clínico San Carlos, Madrid, Spain

    B Fernández-Gutierrez

  9. Rheumatology Service, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain

    A Olivè

  10. Rheumatology Service, Hospital Moisès Broggi, Barcelona, Spain,

    H Corominas

  11. Rheumatology Service, Hospital Sant Rafael, Barcelona, Spain

    A Erra

  12. Rheumatology Service, Hospital Universitario De Guadalajara, Guadalajara, Spain

    J Tornero

Authors
  1. A Julià
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Fernandez-Nebro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Blanco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Ortiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J D Cañete
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Maymó
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Alperi-López
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Fernández-Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Olivè
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H Corominas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Erra
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. I Acosta-Colman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M López-Lasanta
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. R Tortosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J Tornero
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. S Marsal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Marsal.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.31

This article is cited by

Search

Advanced search

Quick links