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)

We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI(50, cont)) or short-term (3 hours; TSI(50, short)) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI(50, cont). In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL.
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PMID:Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. 1579 93

The aim of this study was to investigate the association of environmental factors (dietary folate, methionine and drinking status) and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene, as well as the combination of these factors, with the risk of colon cancer and rectal cancer. A case-control study of 53 colon cancer patients, 73 rectal cancer patients and 343 healthy controls was conducted. Genotypes of C677T and A1298C polymorphisms were analyzed by PCR-RFLP. The dietary folate and methionine intakes were assessed using food-frequency questionnaires and food consumption tables. Unconditional logistic regression was applied to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs). The frequency of MTHFR 677T and 1298C alleles in healthy population were 39.4 and 17.2%, respectively. After adjustment for specific variants, the MTHFR 677TT genotype showed a significantly reduced risk of colon cancer compared with the wild type (OR=0.22, 95% CI: 0.50-0.98), and 1298C allele-carrier showed an inverse association with the risk of rectal cancer compared to the wild type (OR=0.52, 95% CI: 0.28-0.98). Adequate intake of folate was a protective factor from colon cancer (OR=0.32, 95% CI: 0.12-0.88) and MTHFR C677T polymorphism showed a statistically significant effect (OR=0.25, 95% CI: 0.06-0.93), reducing the risk of colon cancer in groups that have an intake of folate exceeding 115.64ng per 1000kcal per day. This study suggests that MTHFR C677T and A1298C polymorphisms are associated with the reduced risk of colon and rectal cancers, respectively. Adequate folate intake shows an inverse association with the risk of colon cancer. There is a significant interaction between MTHFR C677T polymorphism and folate intake in reducing the risk of colon cancer.
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PMID:Diets, polymorphisms of methylenetetrahydrofolate reductase, and the susceptibility of colon cancer and rectal cancer. 1582 74

There is growing evidence that folate metabolism is involved in migraine pathophysiology, mainly in migraine with aura. Even though folate metabolism is regulated by a number of enzymes, only two functional polymorphisms have been tested in association studies with migraine. Here, we have explored the possible role in migraine of other folate-metabolizing enzymes which are in close interdependency with 5',10'-methylenetetrahydrofolate reductase analyzing functional polymorphisms of these enzymes in a case-control study. Individually, thymidylate synthase (TS), methenyltetrahydrofolate cyclohydrolase formyltetrahydrofolate synthase (MTHFD1), or methionine synthase (MS) polymorphisms did not modify the general risk for suffering migraine. Nevertheless, we observed a strong interaction between TS and MTHFR mutated genotypes, which increased over 8-fold the risk for experiencing aura among migraineurs; MTHFD1 and MTHFR mutated genotypes also increased together the risk for migraine in general (OR = 3.08; 95% CI = 1.3-7.4). We conclude that the pathogenetic role of the MTHFR T677 allele in migraine is modulated by functional polymorphisms of TS and MTHFD1.
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PMID:Thymidylate synthase promoter tandem repeat and MTHFD1 R653Q polymorphisms modulate the risk for migraine conferred by the MTHFR T677 allele. 1595 55

A simple bacterial model for studying effects of human mutations in vivo, when homologous genes exist in bacterial and human cells, is presented. We have constructed Escherichia coli strains bearing different alleles of the metF gene, an ortologue of human MTHFR gene, coding for 5,10-methylenetetrahydrofolate reductase. These strains bear a null mutation in the chromosomal metF gene and different metF alleles on plasmid(s), and thus there are merozygotes mimicking wild-type homozygotes, heterozygotes and recessive mutant homozygotes. The A177V mutantion in metF corresponds to one of the most common MTHFR polymorphism, A222V, which has been shown to be associated with increased levels of homocysteine in plasma that, in turn, causes many serious medical problems. Results of relatively simple and quick experiments with these strains are compatible with previously published reports on effects of the A222V substitution in the product of MTHFR gene. In addition, these results suggest either impairment of formation of heterodimers and/or heterotetramers by wild-type and A177V metF variants or dominance of the wild-type polypepides in such structures. Moreover, positive effects of folic acid and vitamins B2 and B12 on physiology of the mutant cells, suggested on the basis of clinical studies, is confirmed. Therefore, we conclude that the bacterial model described in this report may be a useful tool in studies on human mutations.
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PMID:A bacterial model for studying effects of human mutations in vivo: Escherichia coli strains mimicking a common polymorphism in the human MTHFR gene. 1596 Nov 24

One of the known risk factors for developing Alzheimer disease (AD) is hyperhomocysteinemia. The latter may result from mutations of the genes coding for three key enzymes involved in homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MS], and cystathionine beta-synthase [CBS]). Although MTHFR and MS polymorphisms have been shown to be positively associated with AD in some populations, the relationship of the CBS gene with AD remains undefined. In order to evaluate whether AD is associated with CBS gene changes leading to decreased CBS activity and homocysteine accumulation, we genotyped the CBS 844ins68 mutation and VNTR polymorphisms of the CBS gene in 206 AD patients and 186 age-matched controls. A slight increase in both 844ins68 mutation and VNTR allele 19 frequencies was detected in the whole AD patient group, compared with controls. The division of AD patients and controls into three age-at-onset/age dependent subgroups (<65 years, 65-74 years, > 75 years) revealed that the 844ins68 mutation and VNTR allele 19 are independent risk factors for AD development in subjects aged 75 years or more.
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PMID:Cystathionine beta synthase as a risk factor for Alzheimer disease. 1597 77

One-carbon metabolism, in which folate plays an essential role, is involved in DNA methylation and synthesis, and is suspected of impacting on colorectal carcinogenesis. Alcohol is well recognized as a risk factor for colorectal cancer (CRC) and interactions with one-carbon metabolism have also been suggested. Therefore, functional polymorphisms in genes encoding members of this pathway, MTHFR C677T and A1298C (genes for methylenetetrahydrofolate reductase), MTR A2756G (gene for methionine synthase) and TS (gene for thymidylate synthase) tandem repeats polymorphisms, have attracted attention. We conducted a matched case-control study with 257 incident CRC cases and 771 non-cancer controls at the Aichi Cancer Center to clarify associations among folate intake and four polymorphisms with reference to CRC risk. Gene-environment interaction between polymorphisms, drinking and folate consumption was also evaluated. None of the polymorphisms showed any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption the MTHFR 677CC type showed a significantly reduced risk (odds ratio (OR) = 0.45, 95% confidence interval (CI): 0.23-0.86) (P = 0.01). MTR GG showed increased risk only among drinkers (OR = 3.35, 1.40-8.05) (P = 0.047). TS polymorphism did not show statistical significance by genotype alone, while interaction with drinking was significant (P = 0.028). The association was not changed even after stratification by daily folate consumption and drinking habit. In conclusion, we found consistently significant interactions between one-carbon metabolism-related polymorphisms and alcohol drinking.
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PMID:One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. 1605 37

To determine whether the C677T polymorphism of the methylenetetrahydrofolate reductase ( MTHFR) gene and the Leiden mutation of coagulation factor V (FV) are associated with recurrent spontaneous abortion (RSA) of unexplained etiology in Japanese participants, the genotypes of the two polymorphisms were determined and compared between cases of unexplained RSA and normal pregnant controls. Eighty-three Japanese participants, consisting of 45 women with explained RSA and 38 women with unexplained RSA, and 174 controls were recruited in the study. The frequencies of the T677 allele/TT genotype were not significantly different among women with explained RSA (35.6%/13.3%), women with unexplained RSA (34.2%/7.9%), primigravid controls (35.1%/11.7%), and multigravid controls (39.7%/16.5%). In the cases of unexplained RSA, the frequencies of the T677 allele and TT genotype tended to increase according to the number of previous spontaneous abortions, but the increase was without statistical significance: the frequencies of the T677 allele and TT genotype in women with two abortions were 18.2% and 0%, whereas in women with three abortions the frequencies were 38.0% and 9.5%, and in women with four or more abortions the frequencies were 50.0% and 16.7%, respectively. In addition, no Leiden mutation of FV was detected in the women with RSA or the controls. Neither T677 of the MTHFR nor the Leiden mutation of FV was associated with unexplained RSA in the Japanese population.
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PMID:MTHFR C677T Polymorphism and factor V Leiden mutation are not associated with recurrent spontaneous abortion of unexplained etiology in Japanese women. 1605 95

This study investigated whether methylenetetrahydrofolate reductase MTHFR 677C>T polymorphism modified gastric cancer (GC) risk independently as well as in combination with folate intake and alcohol consumption. A hospital-based case-control study of 201 cases and 427 controls was conducted in three geographical areas of Mexico, between 1994 and 1996. The MTHFR 677T allele frequency was 51.0% in cases compared with 45.3% in controls. After controlling for dietary sources of folate, alcohol intake and other selected variables, a significant increase in GC risk was found among carriers of the 677TT genotype compared with those with the 677CC genotype (odds ratio (OR) 1.62, 95% confidence interval (CI) 1.00-2.59), with a significant trend (P = 0.048). There were no significant interactions between the MTHFR polymorphism and consumption of folate and alcohol. Our results suggest that the high prevalence of MTHFR 677T allele may be a contributor to the high rate of morbidity and mortality in GC in Mexico.
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PMID:Methylenetetrahydrofolate reductase 677C>T polymorphism and gastric cancer susceptibility in Mexico. 1635 59

We present a case of a patient who received nitrous oxide on two occasions within a period of 8 weeks and who subsequently developed a diffuse myelopathy, characterized by upper extremity paresis, lower extremity paraplegia and neurogenic bladder. Laboratory testing revealed hyperhomocysteinaemia and low levels of vitamin B(12). Because of this uncommon clinical presentation, we analysed the patient's DNA, and found a polymorphism in the MTHFR gene that is associated with the thermolabile isoform of the 5,10-methylenetetrahydrofolate reductase enzyme, which explained the myelopathy experienced by the patient after being exposed to nitrous oxide. Soon after initiating supplementary therapy with folic acid and vitamin B(12), the neurological symptoms subsided.
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PMID:Reversible nitrous oxide myelopathy and a polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase. 1636 Dec 98

The objectives of this study were: to determine plasma total homocysteine tHcy levels and the prevalence of hyperhomocysteinemia in children with type 1 diabetes, to determine correlates of plasma tHcy levels with nutritional factor such as serum folic acid and vitamin B12 levels, genetic factors as methylenetetrahydrofolate reductase MTHFR gene polymorphism (C677T and A1298C), to attempt to identify possible dependencies between tHcy and the degree of metabolic control, the duration of the disease and presence of complications, and also to determine the relationship between other coronary risk factors. Plasma tHcy levels and other related parameters performed in 32 children with type 1 diabetes and 23 age-sex matched healthy children. Median tHcy level was higher in the patient group (11.38, 3.28 to 66.01 micromol/l) than the control group (8.78, 1.06 to 13.66 mol/l) (p < 0.05). A 28.1 per cent (n = 9) of the diabetic patients had hyperhomocysteinemia, four case with mild and five case with moderate. Plasma tHcy levels were positively correlated with disease duration and C-reactive protein CRP levels and negatively correlated with disease onset age. The hyperhomocysteinemic group had higher CRP levels, longer disease duration and early onset of disease than non-hyperhomocysteinemic group (p < 0.05 in both), respectively. The hyperhomocysteinemic group had significantly higher CRP, total cholesterol, triglyceride, apolipoprotein B, systolic blood pressure, blood urea nitrogen and creatinine levels and lower folate, apolipoprotein A1 levels and glomerular filtration rate values than the control group. Plasma tHcy levels were higher in diabetic children with poor metabolic control. Because of hyperhomocysteinemia is common in diabetic children and plasma tHcy levels correlated with early onset of the disease and disease duration, we recommend the usage of plasma tHcy levels as a risk indicator parameter with other coronary risk factor for detecting and preventing cardiovascular disease in diabetic children.
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PMID:Plasma total homocysteine levels in children with type 1 diabetes: relationship with vitamin status, methylene tetrahydrofolate reductase genotype, disease parameters and coronary risk factors. 1640 15


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