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:1.5.1.20 (methylenetetrahydrofolate reductase)
2,134 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it has been proposed that abnormalities in coagulation and fibrinolysis contribute to the development of preeclampsia by increasing the thrombotic tendency. This hypothesis was tested in women who have had preeclampsia (cases) compared with matched controls. Polymorphisms in the thrombophilia genes [plasminogen activator inhibitor type 1 [PAI-1 -675(4G/5G)], thrombin activatable fibrinolysis inhibitor (TAFI -438G/A and 1040C/T), methylenetetrahydrofolate reductase (MTHFR 677C/T), factor V (FV Leiden R/Q506), prothrombin (FII 20210G/A) and factor XIIIA (FXIIIA V/L34)] were determined in 157 women with preeclampsia and 157 women with uncomplicated pregnancy. The associated risk of preeclampsia was analyzed using logistic regression methods. The frequency distributions of the genotypes of these six polymorphisms in thrombophilia genes were similar in the case and control groups. We found no differences in the prevalence of genetic risk factors of thrombosis in women with preeclampsia compared with controls, which makes it unlikely that these polymorphisms are risk factors for preeclampsia.
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PMID:Preeclampsia and its interaction with common variants in thrombophilia genes. 1533 35

Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account known factors influencing plasma homocysteine levels. Ninety-five patients with past sCAD were compared with 95 age- and sex-matched healthy individuals. Homocysteine, vitamin B6, B12, folate, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), cystathionine beta-synthase (CBS 844ins68bp) and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 G1958A) were assessed and any associations were analysed using multivariate statistics. The occurrence of sCAD was associated with elevated homocysteine levels with an odds ratio of 1.327 per 20 % percentile. Homocysteine levels were influenced by gender, smoking status, occurrence of hypertension, vitamin B12 and folate levels, and by the MTHFR TT genotype. MTHFR, CBS 844ins68bp, and MTHFD1 G1958A genotype were not independently associated with the occurrence of sCAD. These data suggest that elevated homocysteine is associated with the occurrence of sCAD. The MTHFR C677T polymorphism is associated with the homocysteine level.
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PMID:Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections. 1550 5

The role of nutrient-related genetic susceptibility factors for pre-cancerous lesions is gaining attention. We conducted a study to examine associations between polymorphisms in folate pathway coenzymes (methylenetetrahydrofolate reductase [MTHFR] and methionine synthase [MS]) and cervical intraepithelial neoplasia (CIN) 2 or 3 in a population exposed to folic acid by the food fortification program in the United States. Status of MTHFR and MS and circulating concentrations of folate, vitamins B12, A, E, C and total carotene were ascertained in 170 Caucasian and 266 African-American women positive for high-risk human papilloma virus (HR-HPV). Polymorphism status was determined using polymerase chain reaction assays. Micronutrient concentrations were measured using radiobinding assays, high performance liquid chromatography or spectrophotometry. Presence/absence of CIN 2 or 3 was determined on the basis of histology results and the association with risk factors was examined using multivariable analyses. Eighty women had CIN 2 or 3 lesions and they were compared to 356 women who had CIN 1, ASCUS or normal cytology. We found that women polymorphic for MTHFR were less likely to have CIN 2 or 3 (odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.23-0.79). No associations were seen with MS polymorphism alone (OR = 0.72, 95% CI = 0.43-1.21); however, women polymorphic for both MTHFR and MS were less likely to have CIN 2 or 3 (OR = 0.21, 95% CI = 0.08-0.62). We conclude that these polymorphisms in the folate metabolic pathway were associated with a lower likelihood of CIN 2 or 3 in a population exposed to adequate amounts of folate from exposure to food fortification with folic acid.
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PMID:Women with polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are less likely to have cervical intraepithelial neoplasia (CIN) 2 or 3. 1551 69

Folate and methionine are important nutrients in the "one-carbon" metabolism that is closely associated with DNA synthesis and DNA methylation. Genetic variation in these pathways may change susceptibility to cancer development. We have previously reported associations between lymphoma risk and germline polymorphisms in genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase (MTR A2756G), finding the genotype other than the MTHFR 677CC/1298AA to confer a half-risk compared to the MTHFR 677CC/1298AA and a 3-fold higher risk with the MTR GG genotype than the AA/AG genotypes. To confirm the association and explore the histological difference, we extended the previous case series. A case-control study was conducted in Japan with a total of 372 lymphoma cases and 500 noncancer controls examined for genotypes. The relative risks were estimated by unconditional logistic regression analysis. In overall analyses, the age-sex adjusted odds ratio (OR) for the subjects harboring MTHFR 677T or 1298C alleles relative to 677CC/1298AA genotype was 0.58 (95% confidence interval: 0.41-0.83, P = 0.002). The MTR GG genotype showed an OR of 1.75 (0.87-3.52, P = 0.114). These findings were validated in separate analyses of the 273 new incident cases. Subgroup analyses according to histological subtype [diffuse large B-cell lymphoma (DLB), follicular lymphoma (FL), low-grade lymphoma of mucosa associated lymphoid tissue (MALT), and others] illustrated similar associations with certain exceptions for FL and MALT. Our data showed an association between the MTHFR polymorphisms and malignant lymphoma risk for all histological subtypes, although the extent of contribution of these polymorphisms may differ somewhat with histological subtype. Lack of association with MTR polymorphism was also confirmed.
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PMID:Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. 1555 Dec 85

Risk factors for cardiovascular diseases and venous thromboembolism involve both acquired and hereditary conditions. Among the latter, mutations in genes coding for coagulation factors (factor V Leiden [Arg506Gly], G20210A in the 3'-untranslated region of factor II ) and variant C677T of the methylenetetrahydrofolate reductase (MTHFR ) are often involved and co-inherited. These three factors were genotyped simultaneously in the same 96-well plate, using a real-time polymerase chain reaction (PCR) Taqman assay and minor groove binding DNA oligonucleotides (MGB probes). While primers and MGB probes matched their corresponding single nucleotide polymorphism (SNP), the real-time MGB program was identical for each target gene. Homozygous wild-type (WT; -/-), heterozygous (+/-) or homozygous (+/+) variants (n = 362) were selected for factor V (n = 115, with -/-, 40; +/-, 40; +/+, 35), factor II (n = 122, with -/-, 60; +/-, 60; +/+, 2), and MTHFR (n = 120, with -/-, 40; +/-, 40; +/+, 40), according to the results of conventional PCR-restriction fragment length polymorphism (PCR-RFLP), but the allelic discrimination was performed blind. Results of the real-time MGB and PCR-RFLP assays were identical. This new assay was easy and fast with high throughput, without risk of molecular carryover, and cost-effective for laboratories utilizing the Taqman or related fluorescence reading methods. These advantages make it particularly suitable for large-scale combined genotyping of several polymorphisms in the routine setting.
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PMID:Rapid combined genotyping of factor V, prothrombin and methylenetetrahydrofolate reductase single nucleotide polymorphisms using minor groove binding DNA oligonucleotides (MGB probes) and real-time polymerase chain reaction. 1557 97

The 5,10-methylenetetrahydrofolate reductase ( MTHFR ) gene 677C --> T polymorphism causes an A222V amino acid change which affects MTHFR enzyme activity and can increase homocysteine, a vascular disease risk factor. This polymorphism was examined for association with stroke. In a case-control study of 241 ischemic stroke patients and 304 controls in Hong Kong, the V allele increased in stroke [28% vs. 20%, odds ratio (OR) 1.5, p=0.003]. A lack of significance for the increase in the VV genotype (7.5% vs. 4.6%, OR 1.7, p = 0.16) may be due to its rarity in this region. V -allele carriers had more severe strokes (according to the NIH stroke scale). The association of the V allele with stroke occurred mostly in women or older subjects and was due to decreasing V allele frequency with age, as seen in other studies. This V frequency decline with age might be due to a loss of V -carrying controls from a higher risk of cancer, vascular disease, bone fracture, and kidney failure when folate is sparse. Examination of previous studies revealed that the association of VV genotype with stroke appeared stronger in Japan than elsewhere, possibly due to dietary differences. Perhaps folate supplementation for stroke prevention would particularly benefit VV individuals in such high-risk regions.
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PMID:Methylenetetrahydrofolate reductase gene A222V polymorphism and risk of ischemic stroke. 1557 98

The relationship between MTHFR (C677T) genotypes of the methylenetetrahydrofolate reductase, bone mineral density (BMD), and vertebral fracture was studied in 657 Chinese men and women. No association between MTHFR (C677T) and BMD was found in postmenopausal women (aged 55-59 years, n=178), elderly women (aged 70-79 years, n=247), or elderly men (aged 70-79 years, n=232) at the hip, spine, or total body (P >0.05 by ANCOVA). In all study groups, there was no effect of an interaction between MTHFR (C677T) and daily dietary calcium intake on BMD (P >0.05 for the interaction effects by two-way ANCOVA). No statistically significant association was observed between MTHFR (C677T) genotypes and vertebral fracture. The MTHFR (C677T) genotypes for CC, CT, and TT among elderly women with or without vertebral fracture were 5%, 33%, 62%; 6%, 37%, and 57%, respectively, and those for elderly men with and without vertebral fracture were 9%, 31%, 60%; 5%, 35%, and 60%, respectively. The prevalence of TT in our study group was 5% compared to 8% in the Danish or 18.6% in the Japanese. We found no association between MTHFR (C677T) and BMD of Chinese men or women. It would be interesting to study the interactions with folate, B12, and homocysteine.
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PMID:Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and bone mineral density in Chinese men and women. 1558 18

Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. We recently reported that a promoter polymorphism in TS modified the risk of colorectal cancer as well as the survival rate after the disease. To explore whether TS may play an important role in colorectal carcinogenesis early in the multistaged pathogenic pathway, we investigated the relation between the TS promoter polymorphism and risk of colorectal adenoma in a nested case-control study within the prospective Health Professionals Follow-up Study. We ascertained the TS genotype from 373 incident colorectal adenoma cases and 720 control subjects. Although there was no overall association between the TS promoter polymorphism and adenoma risk, we observed a significant TS-alcohol interaction (P for interaction = 0.009); relative to low alcohol consumers with the 2R/2R genotype, those with high alcohol consumption (>30 g/d) were not at elevated risk if they had the 2R/2R genotype [relative risk (RR), 0.80; 95% confidence interval (95% CI), 0.34-1.90], but were at higher risk if they had the 2R/3R genotype (RR, 1.70; 95% CI, 0.87-3.31), and at the highest risk (RR, 3.16; 95% CI, 1.50-6.63) if they had the 3R/3R genotype. In addition, a significant interaction was observed between the TS promoter polymorphism and the 677C > T polymorphism of methylenetetrahydrofolate reductase (MTHFR; P for interaction = 0.007). These findings lend additional support that one-carbon metabolism is an important process in pathogenesis of colorectal cancer.
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PMID:Polymorphism in the thymidylate synthase promoter enhancer region and risk of colorectal adenomas. 1559 87

Women who are using oral contraceptives can acquire APC resistance, measured by the effect of APC on the endogenous thrombin potential (ETP). The objective of our study was to examine whether persistentAPC resistance determined with an ETP-based normalized APC sensitivity ratio (nAPCsr) is a risk marker for venous thromboembolism in women with pregnancy-associated thromboembolism. We determined the activities of antithrombin, protein C, protein S, and performed a genetic analysis of factor V Leiden G1691A, prothrombin mutation G20210A, and methylenetetrahydrofolate reductase mutation (MTHFR C677T) in 65 women with venous thromboembolism during pregnancy or the puerperium and in 114 normal women. A significantly (p<0.05) higher nAPCsr was present in normal women using hormones, in younger women (<or=45 yrs), and in women with carrier status of factorV Leiden. In normal women without factor V Leiden a significant (p<0.05) negative correlation of nAPCsr with age (r=-0.39), antithrombin activity (r=-0.38), protein S activity (r=-0.26), and a significant positive correlation with hormone intake (r=0.36) was present. nAPCsr is influenced by several coagulation parameters, which are modified by the use of oral contraceptives. Consequently, a multivariate analysis of our data did not show a significant association of nAPCsr to venous thromboembolism, neither as a continuous variable (odds ratio 0.8, 95% CI 0.6-1.1, p=0.10) nor using a cutoff value (nAPCsr cut-off 3.1: odds ratio 1.2, 95% CI 0.3-5.3, p=0.77). Our study demonstrates that nAPCsr is not a risk marker for pregnancy-associated venous thromboembolism.
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PMID:Venous thromboembolism during pregnancy is not associated with persistent elevated activated protein C (APC) sensitivity ratio based on the endogenous thrombin potential. 1571 47

The authors report the case of a 39-year-old male patient who had an ischemic stroke (complete infarction of right anterior cerebral circulation) and an acute myocardial infarction during the same year. Molecular study revealed he was homozygous for the 677C-->T mutation in the gene coding for methylenetetrahydrofolate reductase, a key enzyme of folate metabolism; deficiency of this enzyme is associated with increased cardiovascular risk and neurological lesions. Some considerations are put forward about hyperhomocysteinemia and the MTHFR 677C-->T mutation as cardiovascular risk factors.
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PMID:The methylenetetrahydrofolate reductase (MTHFR) 677C-->T mutation and cardiovascular risk--A case of ischemic stroke and acute myocardial infarction. 1577 69


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