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European Journal of Clinical Pharmacology

, Volume 64, Issue 11, pp 1057–1068 | Cite as

Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism

  • Petra Bohanec Grabar
  • Dušan Logar
  • Boris Lestan
  • Vita DolžanEmail author
Pharmacogenetics

Abstract

Objective

Methotrexate (MTX) is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (MDR1 G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TS 2R→3R), methionine synthase (MS A2756G) and methionine synthase reductase (MTRR A66G) modify MTX transport and metabolic effects and may influence the treatment response.

Methods

A genotyping approach was used to determine the studied polymorphisms in 213 RA patients.

Results

We observed that 56 (26.3%) patients discontinued MTX treatment due to poor response and/or toxicity. RFC1 A80G and MDR1 C3435T polymorphisms increased the risk for overall MTX toxicity (P = 0.039, OR = 3.574, 95% CI = 1.065–11.993 and P = 0.032, OR = 7.801, 95% CI = 1.194–50.960 respectively), while MTHFR A1298C polymorphism had a protective effect on overall MTX toxicity (P = 0.027, OR = 0.170, 95% CI = 0.035–0.820).

Conclusion

Our results suggest that genetic polymorphisms in the folate metabolic pathway and MTX transporters modify the toxicity but not the efficacy of MTX treatment.

Keywords

Folate metabolic pathway Genetic polymorphism Methotrexate Rheumatoid arthritis 

Notes

Acknowledgements

The authors wish to thank Prof. Emilio Martínez de Victoria Muñoz, PhD, and Prof. Mariano Mañas Almendros, PhD, from Instituto de Nutrición y Tecnología de los Alimentos (INYTA), University of Granada, Spain, for kindly providing the program Alimentación y Salud 2.0. The authors wish to acknowledge Blaž Rozman, MD, PhD, Matija Tomšič, MD, PhD, Mojca Kos-Golja, MD, Sonja Praprotnik, MD, PhD, Aleš Ambrožič, MD, PhD, Alenka Šipek-Dolničar, MD, MSc, Martina Plešivčnik-Novljan, MD, MSc, Cvetka Kastelic-Klasinc, MD, and Nataša Gašperšič MD, MSc, from the Department of Rheumatology, University Medical Centre Ljubljana, Slovenia, for referring the patients. We thank Ms. Milena Pavić-Nikolić for her excellent technical support. We are especially grateful to Snežna Sodin-Šemrl, MS, PhD, for a critical review of the manuscript and the language corrections. This work was financially supported by The Slovenian Research Agency (ARRS Grant No. PO-0503–0381).

Conflict of interest statement

The authors declare no conflict of interest.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Petra Bohanec Grabar
    • 1
  • Dušan Logar
    • 2
  • Boris Lestan
    • 2
  • Vita Dolžan
    • 1
    Email author
  1. 1.Institute of Biochemistry, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
  2. 2.Department of RheumatologyUniversity Medical Centre LjubljanaLjubljanaSlovenia

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