Skip to main content
SpringerLink
Log in

TYMS polymorphisms and responsiveness to or toxicity of methotrexate in rheumatoid arthritis

TYMS-Polymorphismen und Empfindlichkeit gegenüber oder Toxizität von Methotrexat bei rheumatoider Arthritis

  • Originalien
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Abstract

Objective

The aim of this study was to investigate whether the thymidylate synthase (TYMS) 2R/3R and 6 bp I/D polymorphisms can predict the response to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA).

Methods

We conducted a meta-analysis of studies on the association between the TYMS 2R/3R and 6 bp I/D polymorphisms and non-responsiveness to or toxicity of MTX in RA patients.

Results

A total of 11 studies involving 1613 patients were considered. Meta-analysis showed no association between the TYMS 2R/3R 3R allele and non-responsiveness to MTX therapy (odds ratio [OR] = 1.087, confidence interval [CI] = 0.682–1.731, p = 0.726). The meta-analysis indicated that there was no association between the TYMS 6 bp I/D D allele and non-responsiveness to MTX therapy (OR = 0.688, 95% CI = 0.281–1.683, p = 0.413). Meta-analysis revealed that the TYMS 2R/3R polymorphism was not associated with MTX toxicity, except for in a co-dominant model, and the TYMS 6 bp I/D polymorphism was not associated with MTX toxicity in all genetic models.

Conclusions

This meta-analysis demonstrates that the TYMS 2R/3R and 6 bp I/D polymorphisms may not be associated with non-responsiveness to or toxicity of MTX therapy in RA patients.

Zusammenfassung

Ziel

Ziel der vorliegenden Studie war es zu untersuchen, ob sich anhand von Thymidylatsynthase(TYMS)-2R/3R- und TYMS-6bp-I/D-Polymorphismen die Reaktion auf oder die Toxizität von Methotrexat (MTX) bei Patienten mit rheumatoider Arthritis (RA) vorhersagen lassen.

Methoden

Die Autoren erhoben eine Metaanalyse von Studien zur Assoziation zwischen TYMS-2R/3R- und TYMS-6bp-I/D-Polymorphismen und dem Nichtansprechen auf oder der Toxizität von MTX bei Patienten mit RA.

Ergebnisse

Insgesamt wurden 11 Studien mit 1613 Patienten ausgewertet. Die Metaanalyse ergab keine Assoziation zwischen dem TYMS-2R/3R-3R-Allel und dem Nichtansprechen auf eine MTX-Therapie (Odds Ratio [OR] = 1,087; 95% Konfidenzintervall [KI] = 0,682–1,731; p = 0,726). Anhand der Metaanalyse zeigte sich ebenfalls, dass keine Assoziation zwischen dem TYMS-6-bp-I/D-D-Allel und dem Nichtansprechen auf eine MTX-Therapie vorlag (OR = 0,688; 95%-KI = 0,281–1,683; p = 0,413). Außerdem ergab sich aus der Metaanalyse, dass der TYMS-2R/3R-Polymorphismus nicht mit der MTX-Toxizität assoziiert war – außer in einem kodominanten Modell – und dass auch der TYMS-6-bp-I/D-Polymorphismus in sämtlichen genetischen Modellen nicht mit der MTX-Toxizität assoziiert war.

Schlussfolgerung

Die vorliegende Metaanalyse zeigt, dass der TYMS-2R/3R- und -6bp-I/D-Polymorphismus möglicherweise mit dem Nichtansprechen auf oder der Toxizität von MTX als Therapie bei RA-Patienten assoziiert sind.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Aletaha D, Smolen JS (2002) The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses. Rheumatology (Oxford) 41(12):1367–1374

    Article  CAS  Google Scholar 

  2. Banerjee D, Mayer-Kuckuk P, Capiaux G et al (2002) Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. Biochim Biophys Acta 1587(2–3):164–173

    Article  CAS  Google Scholar 

  3. Bohanec Grabar P, Logar D, Lestan B et al (2008) Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur J Clin Pharmacol 64(11):1057–1068

    Article  CAS  Google Scholar 

  4. Borman P, Tasbas O, Karabulut H et al (2015) Thymidylate synthase genetic polymorphism and plasma total homocysteine level in a group of Turkish patients with rheumatoid arthritis: relationship with disease activity and methotrexate toxicity. Rev Bras Reumatol. https://doi.org/10.1016/j.rbr.2014.12.001

    Article  PubMed  Google Scholar 

  5. Chaabane S, Marzouk S, Akrout R et al (2015) Genetic Determinants of Methotrexate Toxicity in Tunisian Patients with Rheumatoid Arthritis: A Study of Polymorphisms Involved in the MTX Metabolic Pathway. Eur J Drug Metab Pharmacokinet. https://doi.org/10.1007/s13318-015-0288-z

    Article  Google Scholar 

  6. Chen Y, Zou K, Sun J et al (2017) Are gene polymorphisms related to treatment outcomes of methotrexate in patients with rheumatoid arthritis? A systematic review and meta-analysis. Pharmacogenomics 18(2):175–195

    Article  Google Scholar 

  7. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  Google Scholar 

  8. Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  Google Scholar 

  9. Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315(7121):1533–1537

    Article  CAS  Google Scholar 

  10. Felson DT, Anderson JJ, Meenan RF (1990) The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 33(10):1449–1461

    Article  CAS  Google Scholar 

  11. Ghodke Y, Chopra A, Joshi K et al (2008) Are Thymidylate synthase and Methylene tetrahydrofolate reductase genes linked with methotrexate response (efficacy, toxicity) in Indian (Asian) rheumatoid arthritis patients? Clin Rheumatol 27(6):787–789

    Article  Google Scholar 

  12. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    Article  Google Scholar 

  13. Horie N, Aiba H, Oguro K et al (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5’-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20(3):191–197

    Article  CAS  Google Scholar 

  14. James HM, Gillis D, Hissaria P et al (2008) Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis. J Rheumatol 35(4):562–571

    CAS  PubMed  Google Scholar 

  15. Jekic B, Lukovic L, Bunjevacki V et al (2013) Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients. Eur J Clin Pharmacol 69(3):377–383

    Article  CAS  Google Scholar 

  16. Johnston PG, Drake JC, Trepel J et al (1992) Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5‑fluorouracil-sensitive and -resistant human cancer cell lines. Cancer Res 52(16):4306–4312

    CAS  PubMed  Google Scholar 

  17. Kremer JM (2004) Toward a better understanding of methotrexate. Arthritis Rheum 50(5):1370–1382

    Article  CAS  Google Scholar 

  18. Kumagai K, Hiyama K, Oyama T et al (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int J Mol Med 11(5):593–600

    CAS  PubMed  Google Scholar 

  19. Lee YH, Bae SC, Choi SJ et al (2011) Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 38(6):3643–3651

    Article  CAS  Google Scholar 

  20. Lee YH, Rho YH, Choi SJ et al (2007) PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Rheumatol Int 27(9):827–833

    Article  CAS  Google Scholar 

  21. Lee YH, Woo JH (2009) Choi SJ et al Associations between osteoprotegerin polymorphisms and bone mineral density: a meta-analysis. Mol Biol Rep 37(1):227–234

    Article  Google Scholar 

  22. Lima A, Seabra V, Bernardes M et al (2014) Role of key TYMS polymorphisms on methotrexate therapeutic outcome in portuguese rheumatoid arthritis patients. PLoS ONE 9(10):e108165

    Article  Google Scholar 

  23. Mandola MV, Stoehlmacher J, Muller-Weeks S et al (2003) A novel single nucleotide polymorphism within the 5’ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63(11):2898–2904

    CAS  PubMed  Google Scholar 

  24. Mandola MV, Stoehlmacher J, Zhang W et al (2004) A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14(5):319–327

    Article  CAS  Google Scholar 

  25. Muralidharan N, Misra DP, Jain VK et al (2017) Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis. Clin Rheumatol 36:1253–1259

    Article  Google Scholar 

  26. Qiu Q, Huang J, Lin Y et al (2017) Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis: A systematic review and meta-analysis. Medicine (Baltimore) 96(11):e6337

    Article  CAS  Google Scholar 

  27. Qiu Q, Huang J, Shu X et al (2017) Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis. Sci Rep 7:44015

    Article  Google Scholar 

  28. Scott DL, Wolfe F, Huizinga TW (2010) Rheumatoid arthritis. Lancet 376(9746):1094–1108

    Article  Google Scholar 

  29. Swierkot J, Slezak R, Karpinski P et al (2015) Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR , TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis. Pol Arch Med Wewn 125(3):152–161

    PubMed  Google Scholar 

  30. Swierkot J, Szechiński J (2006) Methotrexate in rheumatoid arthritis. Pharmacol Rep 58(4):473–492

    CAS  PubMed  Google Scholar 

  31. Takatori R, Takahashi KA, Tokunaga D et al (2006) ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin Exp Rheumatol 24(5):546–554

    CAS  PubMed  Google Scholar 

  32. Ulrich CM, Bigler J, Velicer CM et al (2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 9(12):1381–1385

    CAS  PubMed  Google Scholar 

  33. Wells G, Shea B, O’connell D et al (2000) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

    Google Scholar 

Download references

Acknowledgements

This study was supported in part by a grant of the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI15C2958).

Author information

Authors and Affiliations

  1. Department of Rheumatology, Hospital for Rheumatic Diseases, Division of Rheumatology, Hanyang University, Hanyang, Korea (Republic of)

    Sang-Cheol Bae

  2. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Inchon-ro, 136-705, Seoul, Seongbuk-gu, Korea (Republic of)

    Young Ho Lee MD, PhD

Authors
  1. Sang-Cheol Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young Ho Lee MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young Ho Lee MD, PhD.

Ethics declarations

Conflict of interest

S.-C. Bae and Y.H. Lee declare that they have no competing interests.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Additional information

Redaktion

U. Müller-Ladner, Bad Nauheim

U. Lange, Bad Nauheim

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bae, SC., Lee, Y.H. TYMS polymorphisms and responsiveness to or toxicity of methotrexate in rheumatoid arthritis. Z Rheumatol 77, 824–832 (2018). https://doi.org/10.1007/s00393-018-0419-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-018-0419-4

Keywords

Schlüsselwörter

Search

Navigation