Influence of methylenetetrahydrofolate reductase gene polymorphisms on homocysteine concentrations after nitrous oxide anesthesia

Anesthesiology. 2008 Jul;109(1):36-43. doi: 10.1097/ALN.0b013e318178820b.


Background: Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (677C>T, 1298A>C) cause elevated plasma homocysteine concentrations and have been linked to fatal outcomes after nitrous oxide anesthesia. This study tested the hypothesis that patients with common MTHFR 677C>T or 1298A>C mutations develop higher plasma homocysteine concentrations after nitrous oxide anesthesia than wild-type patients.

Methods: In this prospective, observational cohort study with blinded, mendelian randomization, the authors included 140 healthy patients undergoing elective surgery. All patients received 66% nitrous oxide for at least 2 h. The main outcome variable, plasma total homocysteine, and folate, vitamin B12, and holotranscobalamin II were measured before, during, and after surgery. After completion of the study, all patients were tested for their MTHFR 677C>T or 1298A>C genotype.

Results: Patients with a homozygous MTHFR 677C>T or 1298A>C mutation (n = 25) developed higher plasma homocysteine concentrations (median [interquartile range], 14.9 [10.0-26.4] microm) than wild-type or heterozygous patients (9.3 [7.5-15.5] microm; n = 115). The change in homocysteine after nitrous oxide anesthesia was tripled in homozygous patients compared with wild-type (5.6 microm [+60%] vs. 1.8 microm [+22%]). Only homozygous patients reached average homocysteine levels considered abnormal (> 15 microm). Plasma 5-methyl-tetrahydrofolate concentrations increased uniformly by 20% after nitrous oxide anesthesia, indicating the inactivation of methionine synthase and subsequent folate trapping. Holotranscobalamin II concentrations remained unchanged, indicating no effect of nitrous oxide on vitamin B12 plasma concentrations.

Conclusions: This study shows that patients with a homozygous MTHFR 677C>T or 1298A>C mutation are at a higher risk of developing abnormal plasma homocysteine concentrations after nitrous oxide anesthesia.

Trial registration: NCT00482456.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anesthesia, Inhalation / adverse effects*
  • Cohort Studies
  • Female
  • Genotype
  • Homocysteine / blood*
  • Humans
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Middle Aged
  • Nitrous Oxide / adverse effects*
  • Polymorphism, Genetic / drug effects
  • Polymorphism, Genetic / genetics*
  • Prospective Studies
  • Single-Blind Method


  • Homocysteine
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Nitrous Oxide

Associated data