Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida

Put, N.M.J. van der; Trijbels, Frans J.M.; Heuvel, Lambertus P. van den; Blom, Henk J.; Steegers‐Theunissen, R.P.M.; Eskes, T.K.A.B.; Mariman, E.C.M.; Heyer, Michelle; Frosst, P.; Rozen, Rima

doi:10.1016/s0140-6736(95)91743-8

Cited by 779 publications

(487 citation statements)

References 8 publications

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“…Given the established protective effects however, of folic acid supplementation on the occurrence and reoccurrence of NTD, polymorphisms in genes encoding the proteins that are directly involved in folate metabolism, uptake and transport have been investigated. The reduced activity of the MTHFR enzyme in individuals with the MTHFR 677TT genotype, decreases the availability of 5-methyltetrahydrofolate which plays a key role in methylation (10) and decreases global DNA methylation (63,64) ; therefore, it is no surprise that this specific mutant gene has been extensively investigated as a genetic risk factor for NTD (65,66) . Over the past two decades, several reports have shown a 2 to 4-fold increased risk of NTD if the infant or the mother has the MTHFR 677TT genotype (65,(67)(68)(69)(70) .…”

Section: The Role Of the Mthfr 677c T Polymorphism In Neural Tube Defmentioning

confidence: 99%

“…The reduced activity of the MTHFR enzyme in individuals with the MTHFR 677TT genotype, decreases the availability of 5-methyltetrahydrofolate which plays a key role in methylation (10) and decreases global DNA methylation (63,64) ; therefore, it is no surprise that this specific mutant gene has been extensively investigated as a genetic risk factor for NTD (65,66) . Over the past two decades, several reports have shown a 2 to 4-fold increased risk of NTD if the infant or the mother has the MTHFR 677TT genotype (65,(67)(68)(69)(70) . van der Put et al (71) reported an even higher risk of an NTD pregnancy if both the mother and the fetus were homozygous for the MTHFR 677C T polymorphism.…”

Section: The Role Of the Mthfr 677c T Polymorphism In Neural Tube Defmentioning

confidence: 99%

“…Over the past two decades, several reports have shown a 2 to 4-fold increased risk of NTD if the infant or the mother has the MTHFR 677TT genotype (65,(67)(68)(69)(70) . van der Put et al (71) reported an even higher risk of an NTD pregnancy if both the mother and the fetus were homozygous for the MTHFR 677C T polymorphism. The large meta-analysis conducted by Botto and Yang (9) considered the frequency of the MTHFR 677C T polymorphism and the risk of NTD across a number of different countries and ethnic groups.…”

Section: The Role Of the Mthfr 677c T Polymorphism In Neural Tube Defmentioning

confidence: 99%

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MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

et al. 2013

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Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme which requires riboflavin as its co-factor. A common polymorphism (677C→T) in the MTHFR gene results in reduced MTHFR activity in vivo which in turn leads to impaired folate metabolism and elevated homocysteine concentrations. Homozygosity for this polymorphism (TT genotype) is associated with an increased risk of a number of conditions including heart disease and stroke, but there is considerable variability in the extent of excess risk in various reports. The present review will explore the evidence which supports a role for this polymorphism as a risk factor for a number of adverse health outcomes, and the potential modulating roles for B-vitamins in alleviating disease risk. The evidence is convincing in the case which links this polymorphism with hypertension and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, elevated blood pressure was found to be highly responsive to riboflavin intervention specifically in individuals with the MTHFR 677TT genotype. Future intervention studies targeted at these genetically predisposed individuals are required to further investigate this novel gene–nutrient interaction. This polymorphism has also been associated with an increased risk of neural tube defects (NTD) and other adverse pregnancy outcomes; however, the evidence in this area has been inconsistent. Preliminary evidence has suggested that there may be a much greater need for women with the MTHFR 677TT genotype to adhere to the specific recommendation of commencing folic acid prior to conception for the prevention of NTD, but this requires further investigation.

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Section: The Role Of the Mthfr 677c T Polymorphism In Neural Tube Defmentioning

confidence: 99%

Section: The Role Of the Mthfr 677c T Polymorphism In Neural Tube Defmentioning

confidence: 99%

Section: The Role Of the Mthfr 677c T Polymorphism In Neural Tube Defmentioning

confidence: 99%

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MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

et al. 2013

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“…4,5 Reduced enzymatic activity has been observed in TT677 or CC1298 homozygotes, and to a lesser extent in heterozygous individuals. 4,6,7 The role of MTHFR variants in a number of disorders, involving disturbances in folate metabolism, such as neural tube defects (NTDs), 8 vascular disease 9,10 and cancer susceptibility, is well documented. 11,12 Recently, the potential role of these polymorphisms in response to MTX treatment has been addressed in several studies.…”

Section: Introductionmentioning

confidence: 99%

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Krajinović

Lemieux-Blanchard²,

Chiasson³

et al. 2003

Pharmacogenomics J

153

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The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis (hazard ratio (HR) ¼ 2.2, 95% confidence interval (CI), 1.0-4.7 and 2.8, 95% CI, 1.1-7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant (HR ¼ 2.2, 95% CI, 0.9-5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR ¼ 9.0, 95% CI, 1.9-42.8 and 8.9, 95% CI, 1.8-44.6, respectively). These results reveal the role of gene-gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.

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“…This mutation can be regarded as a genetic risk factor for spina bifida and supports the hypothesis of defective folate metabolism in at least a subset of mothers with neural tube defects. 24 Cystathionine synthesase abnormalities can also raise homocysteine and this has also been reported in a minority of patients with neural tube defects. 25 Overcoming an abnormality in homocysteine metabo lism, particularly an abnormality of methionine synthase by folic acid supplementation, is presently the favoured postulated mechanism of action of folic acid.…”

Section: Mechanism Of Action Of Folic Acidmentioning

confidence: 96%

Folic acid and neural tube defects

Minns

1996

Spinal Cord

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Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida

Abstract: The following full text is a publisher's version. For additional information about this publication click this link.

Cited by 779 publications

References 8 publications

MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Folic acid and neural tube defects

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