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

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..