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.
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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).
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Bohanec Grabar, P., Logar, D., Lestan, B. et al. Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur J Clin Pharmacol 64, 1057–1068 (2008). https://doi.org/10.1007/s00228-008-0521-7
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DOI: https://doi.org/10.1007/s00228-008-0521-7