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.
authors.affiliation: Laboratory of Pediatrics and Neurology (830), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Ivon J M
authors.initials: IJ
authors.lastname: van der Linden
authors.forename: Martin
authors.initials: M
authors.lastname: den Heijer
authors.forename: Lydia A
authors.initials: LA
authors.lastname: Afman
authors.forename: Henkjan
authors.initials: H
authors.lastname: Gellekink
authors.forename: Sita H H M
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Leo A J
authors.initials: LA
authors.lastname: Kluijtmans
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016001:Confidence Intervals; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008764:Methylmalonic Acid / Q000097:blood; D008875:Middle Aged; D009035:Mothers; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D016135:Spinal Dysraphism / Q000235:genetics* / Q000378:metabolism
chemical_list: D008764:Methylmalonic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2)