The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients

Arthritis Rheum. 2001 Nov;44(11):2525-30. doi: 10.1002/1529-0131(200111)44:11<2525::aid-art432>;2-b.


Objective: To study the possible relationship between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the toxicity and efficacy of treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA).

Methods: Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of MTX treatment because of elevated liver enzyme levels, and the total occurrence of elevated liver enzyme levels during the study. Multivariate logistic regression analysis was used to study the relationship between the presence of the MTHFR C677T mutation and toxicity outcomes of MTX treatment.

Results: Forty-eight percent of the patients showed the homozygous (T/T) or heterozygous (T/C) mutation. The presence of the C677CT or C677TT genotypes was associated with an increased risk of discontinuing MTX treatment because of adverse events (relative risk 2.01; 95% confidence interval 1.09, 3.70), mainly due to an increased risk of elevated liver enzyme levels (relative risk 2.38; 95% confidence interval 1.06, 5.34). Efficacy parameters were not significantly different between the patients with and those without the mutation.

Conclusion: The C677T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patients with RA. We postulate that the incidence of clinically important elevation of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism. Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / metabolism
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / physiopathology
  • Double-Blind Method
  • Female
  • Folic Acid / administration & dosage
  • Genetic Predisposition to Disease*
  • Genotype
  • Hematinics / administration & dosage
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Middle Aged
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Point Mutation*
  • Severity of Illness Index
  • Treatment Outcome


  • Antirheumatic Agents
  • Hematinics
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Alanine Transaminase
  • Methotrexate