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.

  • Original Article
  • Published:

TNF-α −308 G/A polymorphism and responsiveness to TNF-α blockade therapy in moderate to severe rheumatoid arthritis: a systematic review and meta-analysis

The Pharmacogenomics Journal volume 9, pages 161–167 (2009)Cite this article

Abstract

Although tumor necrosis factor-α (TNF-α) blockade is a very effective therapy for rheumatoid arthritis (RA), not all patients achieve a favorable outcome. The objective of this study was to determine if the common TNF-α variant −308(A) predicts poor response to TNF-α inhibitors in RA patients using meta-analysis. Studies were identified using MEDLINE and EMBASE. Data were extracted based on DAS28 or achieving at least American College of Rheumatology 20 response. A total of nine studies met the inclusion criteria representing a total of 692 RA patients. There was no significant heterogeneity among study effect sizes (P=0.36). The frequency of the A allele was 22% (119/531) in responders and 37% (60/161) in non-responders. The odds of having the A allele was lower in responders versus non-responders (odds ratio (OR)=0.43, 95% confidence intervals (CI): 0.28−0.68, P=0.000245), irrespective of the TNF-α inhibitor prescribed, indicating that the −308(A) variant predicts poor response to TNF-α inhibitors. The clinical utility of prospectively genotyping for this variant when initiating anti-TNF-α therapy for RA should now be formally assessed.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Lee DM, Weinblatt ME . Rheumatoid arthritis. Lancet 2001; 358: 903–911.

    Article  CAS  PubMed  Google Scholar 

  2. Feldmann M, Brennan FM, Maini RN . Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14: 397–440.

    Article  CAS  Google Scholar 

  3. Feldmann M, Brennan FM, Foxwell BM, Maini RN . The role of TNF alpha and IL-1 in rheumatoid arthritis. Curr Dir Autoimmun 2001; 3: 188–199.

    Article  CAS  PubMed  Google Scholar 

  4. Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW et al. Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2005. Ann Rheum Dis 2005; 64: iv2–iv14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Keystone EC . Safety of biologic therapies—an update. J Rheumatol Suppl 2005; 74: 8–12.

    Article  PubMed  Google Scholar 

  6. Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 1998; 113: 401–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nemec P, Pavkova-Goldbergova M, Stouracova M, Vasku A, Soucek M, Gatterova J . Polymorphism in the tumor necrosis factor-alpha gene promoter is associated with severity of rheumatoid arthritis in the Czech population. Clin Rheumatol 2008; 27: 59–65.

    Article  PubMed  Google Scholar 

  8. Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D . Polymorphism at position −308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 2003; 48: 1849–1852.

    Article  CAS  PubMed  Google Scholar 

  9. Padyukov L, Lampa J, Heimbürger M, Ernestam S, Cederholm T, Lundkvist I et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 2003; 62: 526–529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cuchacovich M, Ferreira L, Aliste M, Soto L, Cuenca J, Cruzat A et al. Tumour necrosis factor-alpha (TNF-alpha) levels and influence of −308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol 2004; 33: 228–232.

    Article  CAS  PubMed  Google Scholar 

  11. Fonseca JE, Carvalho T, Cruz M, Nero P, Sobral M, Mourão AF et al. Polymorphism at position −308 of the tumour necrosis factor alpha gene and rheumatoid arthritis pharmacogenetics. Ann Rheum Dis 2005; 64: 793–794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kang CP, Lee KW, Yoo DH, Kang C, Bae SC . The influence of a polymorphism at position −857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology (Oxford) 2005; 44: 547–552.

    Article  CAS  Google Scholar 

  13. Cuchacovich M, Soto L, Edwardes M, Gutierrez M, Llanos C, Pacheco D et al. Tumour necrosis factor (TNF)alpha −308 G/G promoter polymorphism and TNFalpha levels correlate with a better response to adalimumab in patients with rheumatoid arthritis. Scand J Rheumatol 2006; 35: 435–440.

    Article  CAS  PubMed  Google Scholar 

  14. Seitz M, Wirthmüller U, Möller B, Villiger PM . The −308 tumour necrosis factor-alpha gene polymorphism predicts therapeutic response to TNFalpha-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxford) 2007; 46: 93–96.

    Article  CAS  Google Scholar 

  15. Guis S, Balandraud N, Bouvenot J, Auger I, Toussirot E, Wendling D et al. Influence of −308 A/G polymorphism in the tumor necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis. Arthritis Rheum 2007; 57: 1426–1430.

    Article  PubMed  Google Scholar 

  16. Marotte H, Arnaud B, Diasparra J, Zrioual S, Miossec P . Association between the level of circulating bioactive tumor necrosis factor alpha and the tumor necrosis factor alpha gene polymorphism at −308 in patients with rheumatoid arthritis treated with a tumor necrosis factor alpha inhibitor. Arthritis Rheum 2008; 58: 1258–1263.

    Article  CAS  PubMed  Google Scholar 

  17. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG . Association of TNF-alpha −308 G/A polymorphism with responsiveness to TNF-alpha-blockers in rheumatoid arthritis: a meta-analysis. Rheumatol Int 2006; 27: 157–161.

    Article  CAS  PubMed  Google Scholar 

  18. Balog A, Klausz G, Gál J, Molnár T, Nagy F, Ocsovszky I et al. Investigation of the prognostic value of TNF-alpha gene polymorphism among patients treated with infliximab, and the effects of infliximab therapy on TNF-alpha production and apoptosis. Pathobiology 2004; 71: 274–280.

    Article  CAS  PubMed  Google Scholar 

  19. Kooloos WM, de Jong DJ, Huizinga TW, Guchelaar HJ . Potential role of pharmacogenetics in anti-TNF treatment of rheumatoid arthritis and Crohn′s disease. Drug Discov Today 2007; 12: 125–131.

    Article  CAS  PubMed  Google Scholar 

  20. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

    CAS  PubMed  Google Scholar 

  21. Hardy RJ, Thompson SG . Detecting and describing heterogeneity in meta-analysis. Stat Med 1998; 17: 841–856.

    Article  CAS  PubMed  Google Scholar 

  22. Higgins JP, Thompson SG, Deeks JJ, Altman DG . Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sutton AJ, Duval SJ, Tweedie RL . Empirical assessment of effect of publication bias on meta-analyses. BMJ 2000; 320: 1574–1577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

JB would like to acknowledge funding from the Canadian Institute of Health Research, CIHR (Grant. no. 84392) and PR was supported by grants from CIHR and the Arthritis Society of Canada.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Memorial University of Newfoundland, Newfoundland, Canada

    D D O'Rielly & P Rahman

  2. The Hospital for Sick Children Research Institute, Ontario, Canada

    N M Roslin & J Beyene

  3. Department of Statistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    J Beyene

  4. Newfound Genomics, St John's, Newfoundland, Canada

    A Pope

Authors
  1. D D O'Rielly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N M Roslin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Beyene
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Pope
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

O'Rielly, D., Roslin, N., Beyene, J. et al. TNF-α −308 G/A polymorphism and responsiveness to TNF-α blockade therapy in moderate to severe rheumatoid arthritis: a systematic review and meta-analysis. Pharmacogenomics J 9, 161–167 (2009). https://doi.org/10.1038/tpj.2009.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2009.7

Keywords

This article is cited by

Search

Advanced search

Quick links