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.

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

“…In earlier work, we identified a very common polymorphism in the methionine synthase reductase (MTRR) gene, c.66A→G (p.I22M), which is present in the homozygous state in approximately 25% of North Americans and Europeans [9]. This mutation, which affects the interaction between methionine synthase and methionine synthase reductase [10], has been examined in several clinical reports as a risk factor for NTD, with positive associations in some but not all studies [9,11,12]. However, few clinical studies have investigated the association between MTR/MTRR/ vitamin B 12 and risk for CHD.…”

“…This mutation, which affects the interaction between methionine synthase and methionine synthase reductase [10], has been examined in several clinical reports as a risk factor for NTD, with positive associations in some but not all studies [9,11,12]. However, few clinical studies have investigated the association between MTR/MTRR/ vitamin B 12 and risk for CHD. The only study to examine the effect of MTRR polymorphisms concluded that neither maternal nor case genotype significantly affected risk [13].…”

“…The only study to examine the effect of MTRR polymorphisms concluded that neither maternal nor case genotype significantly affected risk [13]. However, a study found that inadequate maternal intake of vitamin B 12 , which leads to methionine synthase deficiency, was associated with increased risk for a CHD-affected child [14].…”

Genetic defects in folate and cobalamin pathways affecting the brain

“…Few studies reported gene-gene interactions with the MTHFR C677T genotype [ 92 , 103 ], other studies found a protective effect for the MTHFR 1298 C allele [ 104 , 105 ]. In addition, the MTRR 66GG genotype in the mothers was associated with a 2.1-fold (OR 2.1, 95% CI 1.3 -3.3) higher risk for having a child with NTD [ 106 ]. The MTR A2756G, the MTRR A66G [ 107 ], and the MTHFD1 1958AA polymorphisms [ 108 ] were also reported to enhance the maternal risk of having a child with spina bifida [ 28 , 107 ].…”

Genetic Bases for Predisposition to Common Multifactorial Disease in Man. Part I.

“…MTR 2756GG genotype is an inherited vascular risk factor in the pathogenesis of sudden sensorineural hearing loss (26). Maternal polymorphisms in the MTR gene may put the fetus at increased risk for birth defects, such as spina bifi da; heart defects and preterm delivery (18,87,88).…”