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A common gene variant in methionine synthase reductase is not associated with peak homocysteine concentrations after nitrous oxide anesthesia

Nagele, Petera b; Zeugswetter, Barbarab; Eberle, Corinnac; Hüpfl, Michaelb; Mittlböck, Martinad; Födinger, Manuelac

Pharmacogenetics and Genomics: May 2009 - Volume 19 - Issue 5 - p 325-329
doi: 10.1097/FPC.0b013e328328d54c
Original Articles

Objectives Oxidation of vitamin B12 by nitrous oxide leads to the inactivation of methionine synthase resulting in elevated plasma total homocysteine concentrations. Methionine synthase reductase is the only human enzyme that is able to reverse the oxidation of vitamin B12, which also occurs naturally by reactive oxygen species. A common polymorphism in methionine synthase reductase, MTRR 66A>G, is associated with reduced enzyme activity. Thus, we hypothesized that patients with this gene variant develop higher plasma total homocysteine concentrations after nitrous oxide anesthesia than wild-type patients.

Methods In this follow-up investigation of a previous gene association study, we prospectively included 140 healthy individuals undergoing elective surgery under general anesthesia that included 66% nitrous oxide. Peak postoperative plasma total homocysteine was the main outcome variable and was measured within 2 h after the end of anesthesia. The MTRR 66A>G genotype was determined after completion of the study. The association between genotype and peak postoperative total homocysteine was modeled with a general linear model.

Results No association between MTRR 66A>G and immediate postoperative plasma total homocysteine after nitrous oxide anesthesia was detected. All three groups, stratified by genotype (MTRR 66AA, AG, GG), shared similar baseline characteristics and increases in plasma total homocysteine. The average increase in plasma homocysteine was 2.4 μmol/l (+28%) in all three groups indicating the expected inactivation of methionine synthase by nitrous oxide through oxidation of vitamin B12, but no genetic effect.

Conclusion In conclusion, this study showed that the MTRR 66A>G gene variant is not associated with peak elevated postoperative plasma total homocysteine after nitrous oxide anesthesia. Whether the gene influences the rate of recovery of methionine synthase remains to be determined.

aDepartment of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA

bDepartment of Anesthesiology, Critical Care Medicine and Pain Therapy

cClinical Institute of Medical and Chemical Laboratory Diagnostics

dCore Unit for Medical Statistics and Informatics, Section of Clinical Biometrics, Medical University of Vienna, Vienna, Austria

Correspondence to Dr Peter Nagele, MD, Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, PO Box 8054, St Louis, MO 63110, USA

Tel: +1 314 362 5129; fax: +1 314 362 1185; e-mail:

Received 20 November 2008 Accepted 5 January 2009

© 2009 Lippincott Williams & Wilkins, Inc.