The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida

I.J. van der Linden, M. den Heijer, L.A. Afman, H. Gellekink, S.H. Vermeulen, L.A.J. Kluijtmans, H.J. Blom

Research output: Contribution to journalArticleAcademicpeer-review

60 Citations (Scopus)


The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in homocysteine remethylation. In some studies, the 66A>G polymorphism in the MTRR gene was associated with increased neural tube defect (NTD) risk. Using a case-control design, we studied the association between the MTRR 66A>G polymorphism and spina bifida risk in 121 mothers, 109 spina bifida patients, 292 control women, and 234 pediatric controls. Possible interactions between the MTRR 66A>G variant and the MTR 2756A>G polymorphism, the MTHFR 677C>T variant, plasma vitamin B12, and plasma methylmalonic acid (MMA) levels were examined in the 121 mothers and 292 control women. Meta-analyses were conducted to set the results of the case-control study in the context of eligible literature on the relation between the MTRR 66A>G variant and NTD risk. Finally, a transmission disequilibrium test was performed for 82 complete mother–father–child triads to test for preferential transmission of the MTRR risk allele. In our case-control study, the MTRR 66A>G polymorphism had no influence on spina bifida risk in children [odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4–1.1]. The MTRR 66GG genotype increased maternal spina bifida risk by 2.1-fold (OR 2.1, 95% CI 1.3–3.3). This risk became more pronounced in combination with the MTHFR 677TT genotype (OR 4.0, 95% CI 1.3–12.5). Moreover, we demonstrate a possible interaction between the MTRR 66GG genotype and high plasma MMA levels (OR 5.5, 95% CI 2.2–13.5). The meta-analyses demonstrated that the maternal MTRR 66GG genotype was associated with an overall 55% (95% CI 1.04–2.30) increase in NTD risk and that the MTRR 66GG genotype did not increase NTD risk in children (OR 0.96, 95% CI 0.46–2.01). These data show that the MTRR 66GG genotype is a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low.
Original languageEnglish
Pages (from-to)1047-1054
JournalJournal of Molecular Medicine
Issue number12
Publication statusPublished - 2006


  • periconceptional vitamin supplementation
  • neural-tube defects
  • plasma homocysteine
  • methylmalonic acid
  • flavoprotein
  • prevention
  • cobalamin

Fingerprint Dive into the research topics of 'The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida'. Together they form a unique fingerprint.

  • Cite this

    van der Linden, I. J., den Heijer, M., Afman, L. A., Gellekink, H., Vermeulen, S. H., Kluijtmans, L. A. J., & Blom, H. J. (2006). The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. Journal of Molecular Medicine, 84(12), 1047-1054.