Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modest elevations of circulating homocyst(e)ine are common in patients with vascular disease. We explored in normal and coronary artery disease (CAD) populations the distribution of a mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene that results in enzyme thermolability and reduced activity and in homocyst(e)ine elevation to assess its relevance to risk. We identified the C to T substitution at the MTHFR locus and compared the distributions of genotypes in 565 patients aged < or = 65 years without and with angiographically documented CAD and in 225 healthy subjects. In the patients, we also assessed interrelations between genotypes and CAD occurrence and severity, as well as standard risk factors. The frequency of homozygotes for the mutation was the same in patients with and without CAD and in healthy subjects (11.6%, 11.0%, and 10.7%, respectively: P > .5 for each). There was also no excess among the 419 patients with severe disease (ie, one or more vessels with > 50% luminal obstruction) compared with those with no or mild CAD (odds ratio: 1.004; 95% confidence interval: 0.59 to 1.70). Homozygosity for the mutation was also not associated with a history of myocardial infarction or the presence or severity of angina. However, body mass index increased linearly with the presence of the mutant allele (P = .005), and the mutation and hypertension were weakly associated (P = .036). We conclude that the MTHFR genotype is not a risk factor for coronary disease in this Australian population but that the strong association found with body mass index should be explored further.
...
PMID:Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. 867 63

In a review of research by the author and her colleagues, the genetic basis of hyperhomocysteinemia and the relation between this condition and plasma folate levels are elucidated. There has recently been renewed interest in homocysteine metabolism because hyperhomocysteinemia has been associated with occlusive arterial disease and neural tube defects. The article focuses on a critical enzyme of folate metabolism, 5,10-methylenetetrahydrofolate reductase. A deficiency of this enzyme results in hyperhomocysteinemia and a wide variety of neurologic and vascular symptoms. Molecular genetic analysis of the enzyme has led to the identification of nine rare mutations associated with a severe-deficiency phenotype as well as one common mutation (found in 35% to 40% of alleles in the general population) that is proposed as a risk factor in some forms of cardiovascular disease and in neural tube defects.
...
PMID:Molecular genetic aspects of hyperhomocysteinemia and its relation to folic acid. 872 20

A girl aged 7.5 years with deficiency of 5,10-methylenetetrahydrofolate reductase was treated from early infancy with betaine, 3-6 g daily. She has slight microcephaly, moderate developmental delay, and impaired vision but there have been no obvious signs of folate deficiency. From 4 years of age, she developed an unexplained extreme increase in appetite and weight. Recent magnetic resonance imaging of her brain was normal. The plasma methionine levels have been normal but in the lower range, and the total plasma homocysteine concentrations have been moderately increased (54 to 85 mumol/l) without obvious correlation with the different betaine doses given. Folic acid has sometimes been added.
...
PMID:Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency. 878 31

Folate derivatives are important in experimental colorectal carcinogenesis; low folate intake, particularly with substantial alcohol intake, is associated with increased risk. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate, required for purine and thymidine syntheses, to 5-methyltetrahydrofolate, the primary circulatory form of folate necessary for methionine synthesis. A common mutation (677C-->T) in MTHFR reduces enzyme activity, leading to lower levels of 5-methyltetrahydrofolate. To evaluate the role of folate metabolism in human carcinogenesis, we examined the associations of MTHFR mutation, plasma folate levels, and their interaction with risk of colon cancer. We also examined the interaction between genotype and alcohol intake. We used a nested case-control design within the Physicians' Health Study. Participants were ages 40-84 at baseline when alcohol intake was ascertained and blood samples were drawn. During 12 years of follow-up, we identified 202 colorectal cancer cases and matched them to 326 cancer-free controls by age and smoking status. We genotyped for the MTHFR polymorphism and measured plasma folate levels. Men with the homozygous mutation (15% in controls) had half the risk of colorectal cancer [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27-0.87] compared with the homozygous normal or heterozygous genotypes. Overall, we observed a marginal significant increased risk of colorectal cancer (OR, 1.78; 95% CI, 0.93-3.42) among those whose plasma folate levels indicated deficiency (<3 ng/ml) compared with men with adequate folate levels. Among men with adequate folate levels, we observed a 3-fold decrease in risk (OR, 0.32; 95% CI, 0.15-0.68) among men with the homozygous mutation compared with those with the homozygous normal or heterozygous genotypes. However, the protection due to the mutation was absent in men with folate deficiency. In men with the homozygous normal genotype who drank little or no alcohol as reference, those with the homozygous mutation who drank little or no alcohol had an 8-fold decrease in risk (OR, 0.12; 95% CI, 0.03-0.57), and for moderate drinkers, a 2-fold decrease in risk (OR, 0.42; 95% CI, 0.15-1.20); no decrease in risk was seen in those drinking 1 or more drinks/day. Our findings provide support for an important role of folate metabolism in colon carcinogenesis. In particular, these results suggest that the 677C-->IT mutation in MTHFR reduces colon cancer risk, perhaps by increasing 5,10-methylenetetrahydrofolate levels for DNA synthesis, but that low folate intake or high alcohol consumption may negate some of the protective effect.
...
PMID:Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. 906 78

The common 677C-->T mutation (+) in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme, has been associated with spina bifida neural tube defects (NTD). We combined all known Dutch control groups, a total of 1273 individuals, and found a prevalence of the 677C-->T mutation of 8.4%. When compared with the frequencies in 55 SB patients and to mothers with a child with SB their parents, this gave an OR of 1.9 [95% CI 1.1-3.3] for mothers and an OR of 1.5 [95% CI 0.74-3.1] for patients. The frequency of this mutation and its associated risk for NTD may be population-dependent. However, the frequencies of the 677C-->T mutation in different national and international control groups are almost all in the same range. We therefore combined the observed frequencies of the 677C-->T mutation in all reported studies. The mutation was present in 9.2% of controls, resulting in ORs for all reported NTD patients and their parents of: 1.7 [95% CI: 1.1-2.6]; 1.8 [95% CI: 1.1-3.1] and 1.9 [95% CI: 1.3-2.8] for mothers (combined prevalence 14.5%), fathers (combined prevalence 15.5%) and NTD patients (combined prevalence 16.4%), respectively, vs. all international controls. This meta-analysis confirms that the 677C-->T mutation is a genetic risk factor for NTD.
...
PMID:Is the common 677C-->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. 906 1

The molecular basis for the well-established hierarchy of susceptibility to valproic acid-induced neural tube defects in inbred mouse strains was examined using in situ transcription and anti-sense RNA amplification methodologies with both univariate and multivariate analyses of the resulting gene expression data. The highly sensitive SWV strain demonstrated a significant reduction in the expression of the folate binding protein (FBP-1) following the teratogenic insult at gestational day 8:18, while the more resistant LM/Bc embryos were up-regulating this gene in response to valproic acid treatment. More importantly, at all 3 gestational timepoints spanning the period of murine neural tube closure examined in this study, the LM/Bc embryos had significantly higher MTHFR (5,10-methylenetetrahydrofolate reductase) gene expression levels compared to the SWV embryos. As this folate pathway enzyme is important in homocysteine and methionine metabolism, it suggests that the SWV embryos may be hypomethylated, and essential gene expression during critical periods of neural tube closure is compromised by the teratogenic exposure to valproic acid. This study represents the first evidence of a strain difference in transcriptional activity in response to a teratogenic exposure that might be causally related to the development of the teratogen-induced congenital malformations.
...
PMID:Strain-dependent alterations in the expression of folate pathway genes following teratogenic exposure to valproic acid in a mouse model. 918 71

Homozygosity for a 677C-->T mutation at the locus that codes for 5,10-methylenetetrahydrofolate reductase (MTHFR), a folate-dependent crucial enzyme in homocysteine metabolism, may render the enzyme thermolabile and less active and has been associated with increased levels of plasma total homocysteine (tHcy). We assessed whether this mutation was associated with increased risk of coronary atherosclerosis and plasma levels of tHcy and furthermore studied whether folate status would modify the associations. Data were collected from subjects with substantial coronary atherosclerosis (> or = 90% occlusion in one and > or = 40% occlusion in a second coronary artery, referred to as cases, n = 131) or virtually no coronary narrowing (referred to as coronary controls, n = 87) and from a population-based control group (n = 100), all residing in the Rotterdam area, The Netherlands. Both males and females, aged 25-65 years were studied. The frequency of homozygosity for the mutation (+/+) in cases (10.0%) did not significantly differ statistically from that observed in coronary controls (11.5%, P = 0.71), population-based controls (7.0%, P = 0.43), or combined control groups (9.1%, P = 0.80). In the overall group (as well as in the three subgroups), plasma tHcy levels, fasting and to a lesser extent after a methionine-loading test, were higher in +/+ subjects than in homozygous normal subjects (-/-), whereas heterozygous subjects (+/-) had intermediate levels (Ptrend = 0.001). The +/+ subjects with erythrocyte folate levels < 790 nmol/l (population median) had a 77%, (95% CI, 27-144%) higher geometric mean fasting tHcy (21.4, micromol/l) than those with higher erythrocyte folate (12.1 micromol/l). The odds ratio (OR) of coronary atherosclerosis for +/+ subjects, with +/- and -/- subjects as the reference group, in analyses with combined control groups, was 1.1 (95% CI, 0.5-2.4). The ORs were 2.2 (95% CI, 0.7-6.8) and 0.6 (95% CI, 0.2-1.7) among subjects with low and high folate levels, respectively. Our study indicates that homozygosity for the 677C-->T MTHFR mutation, especially in combination with low folate status, predisposes to high plasma levels of fasting tHcy. However, homozygosity for this mutation, whether or not in combination with low folate status, was not associated with increased risk of coronary artery disease.
...
PMID:The 677C-->T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. 924 65

Elevated plasma homocysteine concentration is an independent risk factor for vascular disease in humans. In addition to nutritional and genetic factors, an interruption of the coordinate regulatory function of S-adenosylmethionine has been proposed to be involved in the occurrence of hyperhomocysteinemia. The effect of oral S-adenosylmethionine on homocysteine metabolism in humans is unknown. We investigated the effect of oral S-adenosylmethionine (400 mg) on plasma levels of 5-methyltetrahydrofolate, which is the active form of folate in the remethylation of homocysteine to methionine, S-adenosylhomocysteine, the demethylated product of S-adenosylmethionine, homocysteine and methionine over 24 hr in 14 healthy subjects. After oral administration, S-adenosylmethionine increased from 38.0 +/- 13.4 to 361.8 +/- 66.4 nmol/liter (mean +/- S.E., P < .001) and returned to base-line values with a half-life of 1.7 +/- 0.3 hr. Both S-adenosylhomocysteine and 5-methyltetrahydrofolate showed a significant transient increase (from 29.9 +/- 3.7 to 51.7 +/- 7.1 nmol/liter, and from 25.1 +/- 2.5 to 36.2 +/- 3.5 nmol/liter, respectively, P < .001), although homocysteine and methionine did not change over the time of measurement. These changes were not found in subjects without previous S-adenosylmethionine administration. The observed metabolic changes suggest that S-adenosylmethionine, at least in concentrations obtained in this study, does not inhibit 5,10-methylenetetrahydrofolate reductase, the 5-methyltetrahydrofolate forming enzyme. Rather they indicate a positive effect on 5-methyltetrahydrofolate, a key cofactor in homocysteine metabolism, which should be considered in homocysteine lowering strategies for the prevention of vascular disease.
...
PMID:Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. 926 50

Hyperhomocysteinemia is an independent risk factor for atherosclerosis and cardiovascular disease. The cause of hyperhomocysteinemia is either an inborn metabolic defect or acquired. Main causes are either a defective homocysteine remethylation (thermolability of the enzyme 5,10-methylenetetrahydrofolate reductase) or nutritional deficiencies of B vitamins especially folic acid. The relative risk for myocardial infarction has been found of 3,1 in case of hyperhomocysteinemia. It is considered that a 5 microM/l homocysteine increment elevates vascular risk by as much as cholesterol increases of 20 mg/dl. B vitamins supplements are potentially useful.
...
PMID:[Hyperhomocysteinemia: risk factor for premature atheromatosis]. 927 96

Folic acid intake reduces the risk of neural tube defects (NTDs). Although the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for NTDs, it only partly explains the elevated homocysteine levels in mothers of children with NTDs. We measured vitamin B12, folate and homocysteine in patients with spina bifida (SB), their parents, and in controls, to investigate which other enzymes of homocysteine metabolism might be defective. Because homozygosity for the 677C-->T mutation causes decreased plasma folate and increased red-cell folate (RCF) and plasma homocysteine levels, we excluded individuals homozygous for that mutation. The remaining SB patients and their parents still had lowered plasma folate and elevated total homocysteine levels, and a small subset had decreased vitamin B12 levels. Red-cell folate was the same in all groups, suggesting that dietary folate intake and its uptake was normal. Risk of SB was increased at the 25th percentile of plasma folate and at the 75th percentile of homocysteine values in SB patients and their parents, and at the 5th and 25th percentiles of vitamin B12 in mothers with SB-affected offspring. This underlines the functional importance of homocysteine remethylation to methionine. There was no correlation between vitamin B12 and homocysteine or RCF. In combination with the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our data do not support a major involvement of methionine synthase in the aetiology of SB. Our data rather favour the involvement of genetic variation at loci coding for the formation of 5-methyltetrahydrofolate, such as MTHFR, methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.
...
PMID:Altered folate and vitamin B12 metabolism in families with spina bifida offspring. 932 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---