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

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Abstract

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.

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Acknowledgements

We gratefully thank J. P. van Doren and A. J. van Rooij for measuring plasma MMA levels. This study was supported by grant no. MAR04-0121 from the Prinses Beatrix Fonds, The Netherlands; grant nos. 1999T023 and 2002B68 from The Netherlands Heart Foundation; and by The Netherlands Organization for Scientific Research (VENI grant NWO).

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Authors and Affiliations

  1. Laboratory of Pediatrics and Neurology (830), Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Ivon J. M. van der Linden, Lydia A. Afman, Henkjan Gellekink, Leo A. J. Kluijtmans & Henk J. Blom

  2. Department of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Martin den Heijer, Henkjan Gellekink & Sita H. H. M. Vermeulen

  3. Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Martin den Heijer

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  1. Ivon J. M. van der Linden
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Correspondence to Henk J. Blom.

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van der Linden, I.J.M., den Heijer, M., Afman, L.A. et al. The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. J Mol Med 84, 1047–1054 (2006). https://doi.org/10.1007/s00109-006-0093-x

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