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

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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.
LanguageEnglish
Pages1047-1054
JournalJournal of Molecular Medicine
Volume84
Issue number12
DOIs
Publication statusPublished - 2006

Fingerprint

Spinal Dysraphism
Mothers
Neural Tube Defects
Genotype
Confidence Intervals
Odds Ratio
Methylmalonic Acid
Vitamin B 12
Meta-Analysis
Case-Control Studies
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
methionine synthase reductase
Homocysteine
Enzymes
Fathers
Alleles
Pediatrics

Keywords

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

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. https://doi.org/10.1007/s00109-006-0093-x
van der Linden, I.J. ; den Heijer, M. ; Afman, L.A. ; Gellekink, H. ; Vermeulen, S.H. ; Kluijtmans, L.A.J. ; Blom, H.J. / The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. In: Journal of Molecular Medicine. 2006 ; Vol. 84, No. 12. pp. 1047-1054.
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title = "The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida",
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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van der Linden, IJ, den Heijer, M, Afman, LA, Gellekink, H, Vermeulen, SH, Kluijtmans, LAJ & Blom, HJ 2006, 'The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida', Journal of Molecular Medicine, vol. 84, no. 12, pp. 1047-1054. https://doi.org/10.1007/s00109-006-0093-x

The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. / van der Linden, I.J.; den Heijer, M.; Afman, L.A.; Gellekink, H.; Vermeulen, S.H.; Kluijtmans, L.A.J.; Blom, H.J.

In: Journal of Molecular Medicine, Vol. 84, No. 12, 2006, p. 1047-1054.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida

AU - van der Linden, I.J.

AU - den Heijer, M.

AU - Afman, L.A.

AU - Gellekink, H.

AU - Vermeulen, S.H.

AU - Kluijtmans, L.A.J.

AU - Blom, H.J.

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

KW - periconceptional vitamin supplementation

KW - neural-tube defects

KW - plasma homocysteine

KW - methylmalonic acid

KW - flavoprotein

KW - prevention

KW - cobalamin

U2 - 10.1007/s00109-006-0093-x

DO - 10.1007/s00109-006-0093-x

M3 - Article

VL - 84

SP - 1047

EP - 1054

JO - Journal of Molecular Medicine

T2 - Journal of Molecular Medicine

JF - Journal of Molecular Medicine

SN - 0946-2716

IS - 12

ER -