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.
OBJECTIVE:Methotrexate (MTX) is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1A80G), P-glycoprotein (MDR1G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase (MTHFRC677T 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 RApatients. RESULTS: We observed that 56 (26.3%) patients discontinued MTX treatment due to poor response and/or toxicity. RFC1A80G and MDR1C3435T polymorphisms increased the risk for overall MTXtoxicity (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 MTHFRA1298C polymorphism had a protective effect on overall MTXtoxicity (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.
Authors: R Takatori; K A Takahashi; D Tokunaga; T Hojo; M Fujioka; T Asano; T Hirata; Y Kawahito; Y Satomi; H Nishino; T Tanaka; Y Hirota; T Kubo Journal: Clin Exp Rheumatol Date: 2006 Sep-Oct Impact factor: 4.473
Authors: N M van der Put; F Gabreëls; E M Stevens; J A Smeitink; F J Trijbels; T K Eskes; L P van den Heuvel; H J Blom Journal: Am J Hum Genet Date: 1998-05 Impact factor: 11.025
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Authors: L A Davis; B Polk; A Mann; R K Wolff; G S Kerr; A M Reimold; G W Cannon; T R Mikuls; L Caplan Journal: Clin Exp Rheumatol Date: 2014-01-20 Impact factor: 4.473