Chapter category: Nucleus
Neural Tube Defects, Other Congenital Malformations and Single Nucleotide Polymorphisms in the 5,10 Methylenetetrahydrofolate Reductase (MTHFR) Gene
MTHFR Polymorphisms and Disease
Edited by: Per Magne UelandISBN: 1-58706-217-8
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Chapter authors:
Stein Emil Vollset and Lorenzo D. Botto
We reviewed, and provide a meta-analysis of, more than 40 published case-control studies on associations between single nucleotide polymorphisms (SNPs) of the 5,10-methylenetetrahydrofolatereductase (MTHFR) gene and congenital malformations. Most studies focused on neural tube defects (NTDs) and the 677C->T polymorphism. Based on 21 reports with data from 1,657 cases of NTDs, we found that compared with the CC genotype (no T allele), the TT genotype (that is, homozygosity for MTHFR 677C->T SNP) was associated with an odds ratio of 1.76 (95% confidence interval [CI] 1.45-2.14) for NTDs, whereas for the CT genotype (heterozygosity for the 677C->T SNP) the corresponding odds ratio was 1.26 (95% CI: 1.09-1.45). Similar or slightly higher risk estimates were associated with maternal genotype, whereas only a weak relationship was demonstrated with paternal genotype. Studies of the 677C->T SNP in relation to risk for Down syndrome (5 studies), and orofacial clefts (4 studies) provide conflicting evidence, and their summary odds ratios are close to one, consistent with a minor role (if any) for the 677C->T SNP in these conditions. Two studies report an increased risk for cardiac malformations associated with TT genotype of the fetus or child, though small sample sizes and methodologic issues limit the interpretation of these findings. Thus far, no reports have been published on the other malformations, such as urinary tract and limb reduction defects, which have been found in some studies to be inversely associated with preconceptional use of folic acid or multivitamins. Five case-control studies of the second functional SNP of the MTHFR gene, the 1298A->C SNP, suggest a 29% and 20% risk increase for NTD associated with the AC and CC genotypes, respectively. This slight positive association, however, is driven by one study whose results do not agree with the others. Combining the only two studies that report complete data for the two SNPs (677C->T and 1298A->C), the highest risk for NTDs is observed for individuals with combined heterozygosity of 677C->T and 1298A->C SNPs.
Additional chapters from this book:
Methylenetetrahydrofolate Reductase and Venous Thrombosis
Miranda B.A.J. Keijzer and Martin den Heijer
Venous thrombosis is a common disease which is associated with significant morbidity and potentially lethal complications.1,2 Elevated homocysteine concentration (hyperhomocysteinemia) is an indepen...
Methylenetetrahydrofolate Reductase Polymorphisms: Pharmacogenetic Effects
Bernd Christian Schwahn and Rima Rozen
The MTHFR enzyme is not a primary target of drug therapy. However, the investigation of possible pharmacogenetic effects of MTHFR polymorphisms is an emerging field that is being explored for an inc...
Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms
Daniel Leclerc, Sahar Sibani and Rima Rozen
Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate and homocysteine metabolism. Research performed during the past decade has clarified our understanding of MTHFR defic...
Methylenetetrahydrofolate Reductase Polymorphisms and Renal Failure
Manuela Fodinger and Gere Sunder-Plassmann
Hyperhomocysteinemia is present in more than 90 % of dialysis patients and in approximately 60 % to 80 % of kidney transplant patients. It is well established that the MTHFR 677TT genotype aggravate...
Neuropsychiatric Disease and Methylenetetrahydrofolate Reductase
Bjorn Regland
Disturbances in single-carbon metabolism appear to be related to all sorts of neuropsychiatric disorders, which reflect the central importance of single-carbon units in brain cellular metabolism. Su...
Neural Tube Defects, Other Congenital Malformations and Single Nucleotide Polymorphisms in the 5,10 Methylenetetrahydrofolate Reductase (MTHFR) Gene
Stein Emil Vollset and Lorenzo D. Botto
We reviewed, and provide a meta-analysis of, more than 40 published case-control studies on associations between single nucleotide polymorphisms (SNPs) of the 5,10-methylenetetrahydrofolatereductase...
Methylenetetrahydrofolate Reductase 677C->T Polymorphism and Risk of Arterial Occlusive Disease
Mariska Klerk and Petra Verhoef
Moderately elevated plasma levels of homocysteine are associated with increased risk of arterial occlusive disease (AOD), but whether this association is causal is uncertain. Retrospective studies o...
Mild MTHFR Deficiency and Folate Status
Paul F. Jacques and Silvina Furlong Choumenkovitch
Mild methylenetetrahydrofolate reductase (MTHFR) deficiency can result from a missense mutation, a cytosine-to-thymidine transition at base pair 677 of the MTHFR gene (677C-T). This mutation results...
Severe Methylenetetrahydrofolate Reductase Deficiency
Mary Ann Thomas and David S. Rosenblatt
Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of folate metabolism that is associated with elevated levels of homocysteine and decreased levels of methionine and S...
Assays for Methylenetetrahydrofolate Reductase Polymorphisms
Arve Ulvik and Per M. Ueland
To date, two functional polymorphisms, 677C T in exon 41 and 1298A?C in exon in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR) have been found and characterized. Both lead ...
Biochemical Characterization of Human Methylenetetrahydrofolate Reductase and Its Common Variants
Kazuhiro Yamada and Rowena G Matthews
Methylenetetrahydrofolate reductase (MTHFR) catalyzes the NADPH-linked reduction of methylenetetrahydrofolate to methyltetrahydrofolate. The human enzyme is an ~70 kDa polypeptide with two regions, ...
The Molecular Dynamics of Abnormal Folate Metabolism and DNA Methylation Implications for Disease Susceptibility and Progression
S. Jill James
Normal folate-dependent one-carbon metabolism is essential for a) the synthesis and balance of deoxynucleotide triphosphate (dNTP) DNA precursor pools required for error-free DNA synthesis and repai...
Pregnancy Complications
Willianne L.D.M. Nelen and Henk J. Blom
Elevated homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C->T polymorphism have been identified as risk factors for arterial and venous thrombosis. More recently, ...
Riboflavin and Methylenetetrahydrofolate Reductase
Steinar Hustad, Jorn Schneede and Per Magne Ueland
The flavoenzyme methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5, 10–methylenetetrahydrofolate to 5-methyltetrahydrofolate, which serves as a methyl group donor in the conve...
MTHFR Polymorphisms and Colorectal Neoplasia
Jimmy W. Crott and Joel B. Mason
Folate is essential for the synthesis, repair and methylation of DNA, processes that are central to maintaining the integrity of the genome. It is therefore not surprising that aberrations in fo...
