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

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

A common genetic polymorphism results from a C-->T substitution in the gene encoding methylenetetrahydrofolate reductase (MTHFR), the enzyme that produces 5-methyltetrahydrofolate (5-methyl-THF) required for the conversion of homocysteine to methionine. In individuals with the T/T genotype (T/T), functional metabolic effects include changes in one-carbon folate derivatives, elevations in plasma homocysteine and differences in response to folic acid supplementation compared with normal (C/C) or heterozygous (C/T) genotypes. The metabolic changes associated with the T/T genotype are postulated to modify risk for chronic disease (e.g., vascular disease and cancer) and neural tube defects (NTD) when accompanied by folate deficiency. The modulation of these metabolic abnormalities by increasing folate intake suggests that folate requirements may be different in affected individuals (T/T) relative to normal (C/C) or heterozygous (C/T) individuals. The complex interaction between this common genetic polymorphism of MTHFR and folate intake is the focus of intense investigation.
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PMID:Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. 1022 79

Elevated plasma total homocysteine (tHcy) levels, either measured in the fasting state or after oral methionine loading, are associated with an increased risk of atherothrombotic disease. Fasting and post-methionine hyperhomocysteinemia (HHC) overlap to a limited extent; both can occur as familial traits. We investigated determinants of fasting, postmethionine and delta (ie, post-methionine minus fasting levels) tHcy levels in 510 subjects of 192 HHC-prone families including 161 patients with clinical vascular disease and 349 without vascular disease. We focused on tHcy levels in relation to levels of vitamin B12, B6 and folate and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Multivariate linear analyses adjusted for the presence of vascular disease showed that fasting tHcy was significantly related to folate and vitamin B12, and the presence of the MTHFR TT genotype and the T allele, and to age, smoking habits, and serum levels of creatinine. Both post-methionine and delta tHcy levels were related to serum folate levels, and the presence of the MTHFR TT genotype and the T allele, and to postmenopausal status, and body mass index. An interaction was found between MTHFR TT genotype and serum folate levels for both fasting and post-methionine tHcy, ie, for a given decrease in serum folate, homocysteine levels increased more in subjects with the TT genotype than in those with the CC genotype. Fasting, post-methionine and delta tHcy were higher in patients with vascular disease than in their healthy siblings, but these levels were less dependent on serum folate levels (P<0.05), whereas the effect of MTHFR genotype was stronger (P=0.01). This study found evidence that post-methionine and delta tHcy levels are not only influenced by factors affecting homocysteine transsulfuration but also by factors that affect remethylation. The explained variances of fasting, post-methionine and delta tHcy were 49%, 62%, and 78%, respectively. We also found evidence, in patients with premature vascular disease but not in their healthy siblings, for a factor that increases tHcy levels but weakens the normal inverse relation between folate and tHcy and amplifies the effect of the MTHFR genotype.
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PMID:Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease. 1032 85

Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12.
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PMID:Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. 1038 41

Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) is a common genetic cause of increased homocysteine (HCY) levels. Post-methionine-load HCY concentrations allow identification of certain cases of hyperhomocysteinaemia not demonstrated by fasting levels. This study investigated the relationship between MTHFR polymorphism and (1) fasting HCY levels (77 patients); (2) post-methionine HCY levels (54 patients); and (3) postprandial HCY concentrations (36 patients) in cardiovascular disease. As expected, mean fasting HCY value was higher in the +/+ patients. Moreover, patients who were homozygous for the mutation exhibited significantly increased mean post-methionine-load HCY; in contrast, literature results are conflicting. Mean postprandial HCY, which is not known to be increased in controls, was also increased in the (+/+) patients, although the difference did not reach statistical significance, probably owing to the small size of the sample. MTFHR polymorphism is known to be aggravated by a drop in circulating folate. Additional risk factors may be more prevalent in patients with cardiovascular disease.
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PMID:Fasting, postprandial, and post-methionine-load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease. 1039 90

The two key enzymes, methylenetetrahydrofolate reductase and methionine synthase involved in methionine synthesis from homocysteine were studied in atherogenic diet fed mice. Methylenetetrahydrofolate reductase activity was elevated while methionine synthase was impaired in atherogenic diet fed group. Impaired methionine synthase activity would adversely affect the methionine synthesis from homocysteine, resulting in a rise in the homocysteine levels, which are atherogenic. This is reflected by the increased levels of very low density and low density lipoprotein cholesterol values and a higher ratio for total cholesterol to high density lipoprotein cholesterol.
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PMID:Atherogenic diet alters folate enzymes in mice: implications of folate deficient homocysteinemia. 1041 Apr 64

The cases of three infants, two Saudi and one Bahraini, with methylenetetrahydrofolate reductase (MTHFR) deficiency are reported. They presented in the neonatal period with lethargy, poor feeding, hypotonia, and frequent apneas. Tandem mass spectrometry (MS/MS) of a blood spot indicated very low methionine level and of urine revealed high homocysteine. The diagnosis was confirmed by demonstrating severe deficiency of MTHFR in the cultured skin fibroblast. All patients were treated with folinic acid, vitamin B12, betaine, and methionine, with good initial response to the therapy. In two patients, the diagnosis was late and their disease was severe, resulting in neurological crippling. However, in the third patient, who was diagnosed and treated early, the current neurological status is normal. In her case, at 1 month of age, the brain FDG PET scan documented very faint cerebral and cerebellar cortical activities. After 5 months of intensive therapy, that included 200-600 mg/kg per day methionine, she had a dramatic clinical and biochemical recovery as well as a parallel improvement in FDG PET. Brain MR spectroscopy indicated normal neuronal glial and myelin markers for her age. We conclude that the functional changes confirmed by the FDG PET study were better correlated with the clinical course of the patient and adequately monitored the response to therapy. This disease warrants early detection through neonatal screening program, since the beneficial effect of early administration of adequate therapy with combined use of betaine and a high dose of methionine is rewarding and may be the treatment of choice for MTHFR deficiency.
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PMID:Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency. 1041 24

To assess the variability of plasma homocysteine levels, fasting and post-methionine homocysteine levels were measured twice, at baseline and after follow-up of 1-4 months, in 16 individuals with normal and 26 with elevated homocysteine levels after methionine loading. The intra-individual coefficients of variation varied from 15 to 23% for fasting and post-methionine homocysteine levels, whether these levels were within the normal range or not. As a result, test-retest agreement was poor when subjects were dichotomized as having 'normal' or 'abnormal' homocysteine levels (itself a questionable concept). There was a relation between the average post-methionine homocysteine levels (at the first and second measurement) and the difference between both measurements (r = 0.37, P = 0.016). In normohomocysteinaemic individuals, delta (i.e., the difference between baseline and follow-up) fasting homocysteine and delta post-methionine homocysteine were correlated negatively with delta folate serum levels: r = -0.64, P = 0.007 and r = -0.50, P = 0.05, respectively. Individuals homozygous for the 677 C-->T mutation in the 5,10-methylenetetrahydrofolate reductase gene showed a greater variation of fasting homocysteine levels than those homozygous for the wild type (P = 0.017). In summary, we suggest that there is a substantial intra-individual variability in plasma homocysteine levels over time and that this variability is significantly related to the variability in serum folate levels, especially in normohomocysteinaemic individuals.
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PMID:Variability of fasting and post-methionine plasma homocysteine levels in normo- and hyperhomocysteinaemic individuals. 1043 53

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.
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PMID:Homocysteine metabolism. 1044 23

Placental infarction or abruption, recurrent pregnancy loss and pre-eclampsia are thought to arise due to defects within the placental vascular bed. Deficiencies of vitamin B12 and folate, or other abnormalities within the methionine-homocyst(e)ine pathway have been implicated in the development of such placental diseases. We conducted a systematic literature review to quantify the risk of placental disease in the presence of these metabolic defects. Studies were identified through OVID Medline between 1966 and February 1999. Terms relating to the measurement of vitamin B12, folic acid, methylenetetrahydrofolate reductase or homocyst(e)ine were combined with those of pre-eclampsia, placental abruption/infarction or spontaneous and habitual abortion. Human studies comprising both cases and controls and published in the English language were accepted. Their references were explored for other publications. Data were abstracted on the matching of cases with controls, the mean levels of folate, B12 or homocyst(e)ine in each group or the frequency of the homozygous state for the thermolabile variant of methylenetetrahydrofolate reductase. The definition of 'abnormal' for each exposure was noted and the presence or absence of the exposure of interest for each outcome was calculated as an absolute rate with a 95 per cent confidence interval. The crude odds ratios were calculated for each study and then pooled using a random effects model. Eighteen studies were finally included. Eight studies examined the risk of placental abruption/infarction in the presence of vitamin B12 or folate deficiency, or hyperhomocyst(e)inaemia. Folate deficiency was a prominent risk factor for placental abruption/infarction among four studies, though not statistically significant (pooled odds ratio 25.9, 95 per cent CI 0.9-736.3). Hyperhomocyst(e)inaemia was also associated with placental abruption/infarction both without (pooled odds ratio 5.3, 95 per cent CI 1.8-15.9) and with methionine loading (pooled odds ratio 4.2, 95 per cent CI 1.2-15.0), as was the homozygous state for methylenetetrahydrofolate reductase (pooled odds ratio 2.3, 95 per cent CI 1.1-4.9). Vitamin B12 deficiency was not a demonstrable risk factor. Eight studies examined blood levels among women with spontaneous abortion or recurrent pregnancy loss. The pooled odds ratios were 3.4 (95 per cent CI 1.2-9.9) for folate deficiency, 3.7 (95 per cent CI 0.96-16.5) for hyperhomocyst(e)inaemia following methionine challenge, and 3.3 (95 per cent CI 1.2-9.2) for the methylenetetrahydrofolate reductase mutation. Five case-control studies examined the relationship between pre-eclampsia and abnormal levels of vitamin B12, folate, homocyst(e)ine or methylenetetrahydrofolate reductase. Folate deficiency was not an associated risk factor (odds ratio 1.2, 95 per cent CI 0.5-2.7), but hyper-homocyst(e)inaemia was (pooled odds ratio 20.9, 95 per cent CI 3.6-121.6). Similarly, homozygosity for the methylenetetrahydrofolate reductase thermolabile variant was associated with a moderate risk of preeclampsia (odds ratio 2.6, 95 per cent CI 1.4-5.1). Some pooled data were associated with significant statistical heterogeneity, however. There is a general agreement among several observational studies that folate deficiency, hyperhomocyst(e)inaemia and homozygosity for the methylenetetrahydrofolate reductase thermolabile variant are probable risk factors for placenta-mediated diseases, such as pre-eclampsia, spontaneous abortion and placental abruption. Vitamin B12 deficiency is less well defined as an important risk factor. Due to the limited quality of these data, including insufficient matching of cases with controls, and possible laboratory measurement bias relating to pregnancy, prospective studies are needed to confirm these findings and guide future preventative and therapeutic research.
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PMID:Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: A systematic review. 1045 5

We previously reported (J. Chen et al., Cancer Res., 56: 4862-4864, 1996; J. Ma et al., Cancer Res., 57: 1098-1102, 1997) that a 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism (677C-->T, ala-->val) was associated with lower risk of colorectal cancer. In this study, we examined the relationship of a polymorphism (2756A-->G, asp-->gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls. The frequency of the homozygous variant genotype (gly/gly) was slightly lower among cases (3%) than controls (5%). The odds ratio for the gly/gly genotype was 0.59 [95% confidence interval (CI), 0.27-1.27] compared with those with the homozygous wild type (asp/asp). There were no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR polymorphism. However, similar to the interaction observed for the MTHFR polymorphism among men who consumed less than 1 alcoholic drink/day, those with the gly/gly genotype had a lower risk of colorectal cancer with an odds ratio of 0.27 (95% CI, 0.09-0.81) compared with those with the asp/asp genotype. The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our study had limited statistical power because of the low frequency of the MTR variant genotype, which is reflected in the wide CIs. Hence, these findings need to be confirmed in larger populations.
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PMID:A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. 1049 2


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