Thermolabile variant of 5, 10-methylenetetrahydrofolate reductaseassociated with low red-cell folates: implications for folate intake recommendations

Molloy, Anne M.; Daly, Seán; Mills, James L.; Kirke, Peadar N.; Whitehead, Alexander S.; Ramsbottom, Dorothy; Conley, Mary; Weir, Donald G.; Scott, John M.

doi:10.1016/s0140-6736(96)12049-3

Cited by 309 publications

(191 citation statements)

References 13 publications

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“…Epidemiological studies investigating the relationship between the MTHFR 677C T polymorphism and bone health add further evidence to support the view that impaired folate metabolism (and the related phenotypes of elevated homocysteine and lower folate concentrations (19,20) ) may be implicated in adverse outcomes (Table 3) (39,(47)(48)(49)(50)(51)(52)(53) . Convincingly evidence from a recent meta-analysis of twenty studies (3525 cases and 17 909 controls) found that the 677C T polymorphism was associated with BMD at all measured sites, and with a 23 % increased risk for all fractures in individuals with the MTHFR 677TT genotype compared with those with the CT or CC genotypes (13) .…”

Section: Genetic Evidencementioning

confidence: 91%

B-vitamins and bone in health and disease: the current evidence

et al. 2014

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Osteoporosis, a metabolic skeletal disease characterised by decreased bone mass and increased fracture risk, is a growing public health problem. Among the various risk factors for osteoporosis, calcium and vitamin D have well-established protective roles, but it is likely that other nutritional factors are also implicated. This review will explore the emerging evidence supporting a role for certain B-vitamins, homocysteine and the 677C→T polymorphism in the gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase, in bone health and disease. The evidence, however, is not entirely consistent and as yet no clear mechanism has been defined to explain the potential link between B-vitamins and bone health. Coeliac disease, a common condition of malabsorption, induced by gluten ingestion in genetically susceptible individuals, is associated with an increased risk both of osteoporosis and inadequate B-vitamin status. Given the growing body of evidence linking low bone mineral density and/or increased fracture risk with low B-vitamin status and elevated homocysteine, optimal B-vitamin status may play an important protective role against osteoporosis in coeliac disease; to date, no trial has addressed this possible link.

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Section: Genetic Evidencementioning

confidence: 91%

B-vitamins and bone in health and disease: the current evidence

et al. 2014

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“…Because no elevation of blood homocysteine has been observed when plasma folate concentrations are greater than 15.4 nmol/L (Jacques et al, 1996), folate deficiency could be partially responsible for the expression of the MTHFR thermolabile genotype. However, as discussed below (see "Genetic and/or Nutritional Factor-Mediated Hyperhomocysteinemia and Incidence of Cardiovascular Disease"), the hyperhomocysteinemia observed in homozygous patients for this mutation of the MTHFR gene might merely result from a greater folate need (Jacques et al, 1996;Molloy et al, 1997).…”

Section: Genetic Factorsmentioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

228

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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“…It is apparent that mothers with the Mthfr polymorphism are more vulnerable to homocysteine accumulation and face an increased risk to defects in development and growth. In fact, one study assessed the relationship between MTHFR genotype and folate levels in both RBC's and plasma of both pregnant and non-pregnant females (18). The authors found that circulating folate levels were decreased in both pregnant and non-pregnant women with the MTHFRTT genotype.…”

Section: Folate Status Associations With Methylenetetrahydrofolate Rementioning

confidence: 99%

Impact of Maternal Folate Deficiencies on Early Neurological Development: A Narrative Review

Emmerson¹,

Jadavji²

2016

J Pediatr Rev

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Context: Folates are B-vitamins that cannot be generated de novo and are therefore obtained from the diet. In the brain, these vitamins are involved in nucleotide synthesis, DNA repair, lipid metabolism, methylation and neurotransmitter synthesis. It is well established that adequate levels of maternal folates are required for closure of the neural tube within the first month of pregnancy, however, it is not clear whether maternal folates are needed throughout pregnancy for brain development and whether they influence offspring neurological function after birth. The aim of this review is to outline current literature from epidemiological and animal model studies that shows maternal supplementation of folates throughout pregnancy does indeed affect offspring neurological function after birth. Evidence Acquisition: A Medline search was performed using the following mesh terms, maternal-fetal exchange, folic acid, offspring neurologic manifestations, methylenetetrahydrofolate reductase (MTHFR), embryology, and behavior. Results: The studies described in the present review have reported that maternal deficiencies in folates during pregnancy result in changes in behavior as well as in blood and brain tissue in offspring, including altered methylation, including reduced levels of the global methyl donor S-adenosylmethionine (SAM), and increased levels of oxidative stress. Conclusions:The data summarized here outlines the importance of adequate levels of folates throughout pregnancy to facilitate appropriate neurological development of offspring after birth.

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Thermolabile variant of 5, 10-methylenetetrahydrofolate reductaseassociated with low red-cell folates: implications for folate intake recommendations

Cited by 309 publications

References 13 publications

B-vitamins and bone in health and disease: the current evidence

B-vitamins and bone in health and disease: the current evidence

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Impact of Maternal Folate Deficiencies on Early Neurological Development: A Narrative Review

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