Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: a meta-analysis

Pharmacogenet Genomics. 2012 Feb;22(2):117-33. doi: 10.1097/FPC.0b013e32834ded2a.


Objective: A systematic review and a meta-analysis were conducted, to investigate the possible association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms with adverse effects related to methotrexate (MTX).

Methods: A systematic literature search in PubMed retrieved a total of 44 studies (42 unique articles). Two polymorphisms were included in the meta-analysis: C677T and A1298C. Random effect models were used in the analysis. Odds ratios along with their 95% confidence intervals were computed to compare the distribution of alleles and genotypes between cases and controls.

Results: The analysis highlighted a significant association of C677T polymorphism with overall MTX toxicity, hepatotoxicity, hematological toxicity, and neurotoxicity. It also revealed an association with MTX toxicity in patients with rheumatoid arthritis. In contrast, a protective effect of C677T MTHFR polymorphism on acute graft-versus-host disease and on patients treated with hematopoietic cell transplantation was found. As for the A1298C polymorphism, a statistically significant association with overall MTX toxicity and a protective role of the polymorphism in rheumatoid arthritis patients was detected.

Conclusion: These results indicate the association of MTHFR polymorphisms with MTX toxicity. However, further studies are needed to reveal the underlying biological mechanism of the association.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Alleles
  • Antimetabolites, Antineoplastic / toxicity
  • Antirheumatic Agents / toxicity
  • Genotype
  • Humans
  • Methotrexate / toxicity*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Polymorphism, Genetic


  • Antimetabolites, Antineoplastic
  • Antirheumatic Agents
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Methotrexate