Spina bifida, folate metabolism, and dietary folate intake in a Northern Canadian aboriginal population

Arbour, Laura; Christensen, Benedicte; Delormier, Treena; Platt, Robert W.; Gilfix, Brian M.; Forbes, Patricia A.; Kovitch, Ingrid; Morel, J; Rozen, Rima

doi:10.3402/ijch.v61i4.17492

Cited by 15 publications

(16 citation statements)

References 29 publications

(21 reference statements)

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“…We included 25 eligible studies [17]–[41] in our meta-analysis. The studies contained data on 5999 mothers (2429 case mothers and 3570 control mothers) who had an MTHFR C677T polymorphism in the case-control design.…”

Section: Resultsmentioning

confidence: 99%

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

et al. 2012

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BackgroundMethylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs.MethodsAn electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis.ResultsA significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR = 2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR = 1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR = 1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR = 1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls.ConclusionThe results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted.

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Section: Resultsmentioning

confidence: 99%

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

et al. 2012

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“…At least one study has observed a high incidence of neural tube defects in an indigenous population with constitutional low folate intake and significantly decreased plasma folate, yet homocysteine concentrations were low, suggesting disturbed folate metabolism without hyperhomocysteinemia. [185] Clinical association studies have suggested a role for MTHFR and homocysteine in a wide variety of disorders, although not all studies have reached the same conclusion. Many of the caveats in the interpretation of the epidemiologic data have already been discussed.…”

Section: Discussionmentioning

confidence: 97%

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene

Schwahn

Rozen

2001

American Journal of PharmacoGenomics

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186

151

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5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism by channeling one-carbon units between nucleotide synthesis and methylation reactions. Severe enzyme deficiency leads to hyperhomocysteinemia and homocystinuria, with altered folate distribution and a phenotype that is characterized by damage to the nervous and vascular systems. Two frequent polymorphisms in the human MTHFR gene confer moderate functional impairment of MTHFR activity for homozygous mutant individuals. The C to T change at nucleotide position 677, whose functional consequences are dependent on folate status, has been extensively studied for its clinical consequences. A second polymorphism, an A to C change at nucleotide position 1298, is not as well characterized. Still equivocal are associations between MTHFR polymorphisms and vascular arteriosclerotic or thrombotic disease. Neural tube defects and pregnancy complications appear to be linked to impaired MTHFR function. Colonic cancer and acute leukemia, however, appear to be less frequent in individuals homozygous for the 677T polymorphism.MTHFR polymorphisms influence the homocysteine-lowering effect of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. However, only preliminary evidence exists for gene-drug interactions. This review summarizes the biochemical basis and clinical evidence for interactions between MTHFR polymorphisms and several disease entities, as well as potential interactions with drug therapies. Future investigations of MTHFR in disease should consider the influence of other variants of functionally-related genes as well as the medication regimen of the patients. Animal models for genetic deficiencies in folate metabolism will likely play a greater role in our understanding of folate-dependent disorders.

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“…However, a community intervention program in China showed that high-compliance use of 400 mg of folic acid/d did result in neural tube defect birth prevalence in a population with a high TT genotype prevalence that was similar to a population with low TT genotype prevalence (57,60). There is limited evidence to conclude whether a mandatory folic acid fortification program could mitigate the risk conferred by the polymorphism (61)(62)(63). More research is needed to understand how to bridge gaps in blood folate concentrations because of the MTHFR 677C.T polymorphism.…”

Section: Implications For Neural Tube Defect Preventionmentioning

confidence: 95%

Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies

Tsang

Devine

Cordero

et al. 2015

The American Journal of Clinical Nutrition

113

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Spina bifida, folate metabolism, and dietary folate intake in a Northern Canadian aboriginal population

Cited by 15 publications

References 29 publications

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene

Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies

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