Association Between MTHFR C677T Polymorphism and Methotrexate Treatment Outcome in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis

Genet Test Mol Biomarkers. 2017 May;21(5):275-285. doi: 10.1089/gtmb.2016.0326. Epub 2017 Mar 9.


Purpose: Methotrexate (MTX) is one of the most widely used disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis (RA). However, its efficacy in RA patients is variable and unpredictable. Methylene tetrahydrofolate reductase (MTHFR) is an important enzyme in the MTX pathway and is involved in folate metabolism and DNA synthesis. Several studies have examined the association between the MTHFR C677T polymorphism and MTX toxicity and efficacy in RA, but their conclusions remain controversial.

Materials and methods: We conducted a comprehensive literature search of the PubMed, Embase, and Cochrane Library databases to identify studies reporting an association between the MTHFR C677T single nucleotide polymorphism and MTX response in RA patients.

Results: We identified 16 studies reporting MTX efficacy in 2373 RA cases, and 25 studies reporting MTX toxicity in 4063 RA cases. The pooled data analysis indicated that the MTHFR C677T polymorphism was associated with increased toxicity, but not efficacy, of MTX in RA patients. Further stratification based on ethnicity revealed an association between the MTHFR 677TT genotype and overall MTX toxicity in East Asian and Caucasian patient populations. In addition, RA patients with the MTHFR C677T polymorphism who were supplemented with folic acid displayed significantly elevated risk for MTX toxicity.

Conclusion: Our study indicated that the MTHFR C677T polymorphism could be used as a predictor of MTX toxicity in RA patients. However, large randomized prospective studies will be required to effectively replicate and validate these findings.

Keywords: MTHFR; meta-analysis; rheumatoid arthritis; single nucleotide polymorphisms.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antirheumatic Agents
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / genetics*
  • Asian People / genetics
  • Female
  • Folic Acid
  • Genotype
  • Humans
  • Male
  • Methotrexate / therapeutic use
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Treatment Outcome
  • White People / genetics


  • Antirheumatic Agents
  • Folic Acid
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Methotrexate