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Eur J Clin Pharmacol. 2008 Nov;64(11):1057-68. doi: 10.1007/s00228-008-0521-7. Epub 2008 Jul 8.

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

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Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.



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.


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


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).


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

[Indexed for MEDLINE]

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