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)

Moderate hyperhomocysteinemia is a putative risk factor for cardiovascular disease. Molecular studies have demonstrated increased plasma homocysteine levels in the presence of DNA mutations in either the methylenetetrahydrofolate reductase (MTHFR) enzyme found in the remethylation pathway or the enzyme cystathione beta-synthase (CBS) of the transsulfuration pathway. To determine whether the mutation C-->T677 in the MTHFR gene or the T-->C833/844ins68 and G-->A919 mutations in the CBS gene are associated with myocardial infarction (MI) in African Americans, DNA was analyzed from samples obtained from a case-control study conducted at a large, inner-city hospital. One-hundred ten African American subjects with a diagnosis of MI and 185 race- and age-matched controls were recruited. Our results demonstrated that 15% of the MI cases were heterozygous for the C-->T677 (MTHFR) mutation, while 1.8% were homozygous. When compared to the controls in which 15% were heterozygous and 2.1% were homozygous, no significant association with MI was observed. In addition, 34% of the cases were heterozygous for the T-->C833 (CBS) mutation while 6% were homozygous. This is compared to 32% and 5% of the controls having the heterozygous and homozygous genotype, respectively. No significant association was observed for the T-->C833 (CBS) mutation among the cases and controls. Although this mutation has no significant association with MI, the prevalence of the heterozygous state was higher than what has been reported for whites (12%). No mutations for G-->A919 (CBS) were detected in the cases or controls. The racial differences of the CBS T-->C833 polymorphism suggest that further investigation into the other areas of the CBS gene is needed.
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PMID:Mutations in the genes regulating methylene tetrahydrofolate reductase (MTHFR C-->T677) and cystathione beta-synthase (CBS G-->A919, CBS T-->c833) are not associated with myocardial infarction in African Americans. 1145 68

Hyperhomocysteinemia is known to be associated with an increased risk of myocardial infarction, stroke, peripheral arterial disease, and venous thrombosis. Gene polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) may account for reduced enzyme activity and hyperhomocysteinemia. A recent study has documented evidence of polygenic regulation of plasma homocyteine. We report here on a case of occlusive stroke at young age and hyperhomocysteinemia with homozygous VN (677C to T) variant in the MTHFR gene as well as homozygous D/D (2756G to A) variant in the MS gene.
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PMID:Homozygous VN (677C to T) and d/D (2756G to A) variants in the methylenetetrahydrofolate and methionine synthase genes in a case of hyperhomocysteinemia with stroke at young age. 1146 Aug 81

Elevated plasma homocysteine is a new risk factor for atherosclerotic vascular disease resulting in progressive atherogenesis in the arteries of the limbs, the coronary arteries and the cerebrovascular system. Hyperhomocysteinemia may be induced by failure or decreased enzyme activity of the cystathionine-beta-synthase and methylenetetrahydrofolate reductase due to genetic mutation or deficiency of folic acid, vitamin B12 and vitamin B6. Oxidation of homocysteine to homocystine is accompanied with production of hydrogen peroxide inducing damage of endothelium through oxidative stress. The injury of the endothelium by homocysteine can be shown by measuring flow-induced vasodilation in men. The abnormalities of coagulation found in hyperhomocysteinemia is related to the impairment of the function of endothelial cells and inhibition of the thrombomodulin-protein C and glycosaminoglycan-antithrombin-III anticoagulant system. Homocysteine decreases the level of glutathione peroxidase in the endothelial cells, and inhibits its activation leading to the impairment of oxidative defensive mechanism, and to the free radical-induced NO-inactivation. In decreasing of plasma homocysteine level and preventing its influence on endothelium, moreover in improving of endothelial function the folic acid has cardinal importance, however the vitamin B12 and vitamin B6 also play role in the maintenance of normal homocysteine level of blood.
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PMID:[Homocysteine--a risk factor for atherosclerosis]. 1148 6

Preterm birth is the leading cause of infant mortality in industrialised societies. Its incidence is greatly increased among the socially disadvantaged, but the reasons for this excess are unclear and have been relatively unexplored. We hypothesise two distinct sets of causal pathways and mechanisms that may explain social disparities in preterm birth. The first set involves chronic and acute psychosocial stressors, psychological distress caused by those stressors, increased secretion of placental corticotropin releasing hormone (CRH), changes in sexual behaviours or enhanced susceptibility to bacterial vaginosis and chorioamnionitis, cigarette smoking or cocaine use, and decidual vasculopathy. The second hypothesised pathway is a gene-environment interaction based on a highly prevalent mutation in the gene for methylenetetrahydrofolate reductase (MTHFR), combined with low folate intake from the diet and from prenatal vitamin supplements, consequent hyperhomocysteinemia, and decidual vasculopathy. We propose to test these hypothesised pathways and mechanisms in a nested case-control study within a prospectively recruited and followed cohort of pregnant women with singleton pregnancies who deliver at one of four Montreal hospitals that serve an ethnically and socio-economically diverse population. Following recruitment during the late first or early second trimester, participating women are seen at 24-26 weeks, when a research nurse obtains a detailed medical and obstetric history; administers several scales to assess chronic and acute stressors and psychological function; obtains blood samples for CRH, red blood cell and plasma folate, homocysteine, and DNA for the MTHFR mutation; and performs a digital and speculum examination to measure cervical length and vaginal pH and to obtain swabs for bacterial vaginosis and fetal fibronectin. After delivery, each case (delivery at < 37 completed weeks following spontaneous onset of labour or prelabour rupture of membranes) and two controls are selected for placental pathological examination, hair analysis of cotinine, cocaine, and benzoylecgonine, and analysis of stored blood and vaginal specimens. Statistical analysis will be based on multiple logistic regression and structural equation modelling, with sequential construction of models of potential aetiological determinants and covariates to test the hypothesised causal pathways and mechanisms. The research we propose should improve understanding of the factors and processes that mediate social disparities in preterm birth. This improved understanding should help not only in developing strategies to reduce the disparities but also in suggesting preventive interventions applicable across the entire socio-economic spectrum.
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PMID:Socio-economic disparities in preterm birth: causal pathways and mechanisms. 1152 Apr 4

The relationship between hyperhomocysteinemia and coronary artery disease (CAD) was investigated and the influence of environmental factors (Folate, VitB12) and genetic factors [N5, N10-methylenetetrahydrofolate reductase gene (MTHFR) or MTHFR gene mutation] on plasma homocysteine (Hcy) levels and the risk of CAD observed. Fifty-one CAD patients and 30 CAD-free subjects were recruited in the study. The polymorphisms of MTHFR gene were analyzed by PCR-RFLP and plasma total Hcy levels were measured by high performance liquid chromatography with fluorescence detection. Plasma folate and vitamin B12 concentrations were measured by an automated chemiluminescence method. It was found that mean total plasma Hcy concentrations were significantly higher in CAD patients than in CAD-free subjects (P < 0.01). The differences were also apparent among the three genotypes of MTHFR gene in CAD group (P < 0.05). There was no significant difference in the genotype distributions and allele frequencies between the two groups. A strong inverse correlation was found between folate or vitamin B12 and plasma Hcy levels according to MTHFR genotype (P < 0.01). It was concluded that hyperhomocysteinemia is a new independent risk factor for CAD. However, MTHFR gene mutation alone does not relate significantly to the morbidity of CAD since hyperhomocysteinemia and its influence on the risk of CAD are decided by both environmental and genetic factors. Supplementary treatment with vitamins B can effectively lower the plasma levels of Hcy, thus maybe reducing the risk of CAD.
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PMID:The effect of polymorphisms of MTHER gene and vitamin B on hyperhomocysteinemia. 1152 37

The erythrocyte concentrations of the body's chief physiologic methyl donor S-adenosylmethionine (SAM) and of its metabolite and inhibitor S-adenosylhomocysteine (SAH), the plasma concentrations of total homocysteine (tHcy), and the activity of N(5,10) methylenetetrahydrofolate reductase (MTHFR) in lymphocytes were determined in healthy subjects and patients with diabetes mellitus without complications and at various stages of diabetic nephropathy, categorized according to the degree of progression of the disease. These groups were as follows: 1, control; 2, diabetics with no complications; 3, patients with albuminuria; 4, patients with an elevated plasma creatinine; and 5, patients on dialysis. No parameter studied exhibited significant differences between the type 1 and the type 2 diabetics. In control subjects, the blood concentrations of SAM were proportional to the activity of MTHFR; in diabetics, it was not. Consistent with previous observations, progression of nephropathy was accompanied by increased concentrations of tHcy. Increased erythrocyte concentrations of SAH, decreased erythrocyte concentrations of SAM, SAM/SAH ratios, and lymphocyte MTHFR activity also accompanied disease progression. The blood concentrations of SAH paralleled those of tHcy, while the concentrations of SAM showed a bimodal relationship with those of tHcy. These results provide further evidence that alterations in the blood concentrations of SAM and related compounds are abnormal in patients with diabetes, particularly in those with nephropathy. The deficiency of SAM may lead to methyl deficiencies, which may contribute to the high morbidity and mortality in patients with diabetic nephropathy. We have also demonstrated a decrease in lymphocyte MTHFR activity in patients with advanced nephropathy, suggesting that hyperhomocysteinemia in these patients may be due to a generalized metabolic abnormality. Further studies are needed to determine the pathogenesis of these abnormalities and whether they are present in renal failure due to causes other than diabetes or whether they are specific to diabetic nephropathy.
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PMID:Blood S-adenosylmethionine concentrations and lymphocyte methylenetetrahydrofolate reductase activity in diabetes mellitus and diabetic nephropathy. 1155 31

Few and contrasting data are available on the prevalence of hemostatic risk factors in patients with central retinal vein occlusion (CRVO). Aim of this study was to investigate the metabolic and inherited risk factors for venous thrombosis in 100 CRVO patients (age: 59 yrs; range 18-77) and in 100 controls (age: 56 yrs; range 18-84). In patients homocysteine (Hcy) levels were significantly higher than in controls and were affected by the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism (p < 0.001). The prevalences of activated protein C resistance (APCR), factor V Leiden positivity, elevated PAI-1 and Lp(a) levels were significantly higher in patients with respect to controls. At multivariate analysis, only hyperhomocysteinemia (OR 11, 95% CI 3.6-36.2; p < 0.0001) and elevated PAI-1 levels (OR 8.9, 95% CI 3.5-41.3; p < 0.01), in addition to hypertension (OR 40.5, 95% CI 8.6-188.8; p < 0.00001) and hypercholesterolemia (OR 3.1, 95% CI 1.6-20.5; p < 0.05), were independent risk factors for CRVO. These data demonstrate a potential role of hemostatic risk factors in the pathophysiology of CRVO.
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PMID:Thrombophilic risk factors in patients with central retinal vein occlusion. 1208 91

The genes for the enzymes methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS), methionine synthase reductase (MSR) and cytathionine-beta-synthase (CBS) play an important role in homocysteine metabolism. Rare mutations in these genes cause severe hyperhomocysteinemia and clinical symptoms. Growing interest has focused on common mutations with moderate effects on homocysteine levels. We studied 280 subjects of different age groups for the following mutations: MTHFR677C-->T and 1298A-->C, MS2756A-->G, MSR66A-->G and the 68 bp insertion in the CBS gene. The median value for homocysteine increased significantly with age (median homocysteine levels: 7.5, 12.4 and 16.5 micromol/l in the age groups 20-43, 65-75 and 85-96 years, respectively). The genotypes of the MTHFR677C-->T mutation were associated with differences in plasma homocysteine levels, but without reaching significance. Individuals homozygous for the MTHFR677C-->T mutation had a 2.3 micromol/l higher median homocysteine level compared to individuals with the wild-type allele. This effect was pronounced in combination with low folate levels and abolished with higher folate in plasma. For the other three mutations no association with homocysteine values could be determined. The analysis of homocysteine metabolite cystathionine by backward regression analysis revealed a significant correlation of the MS2756A-->G mutation with cystathionine level. This increase could indicate a disturbed remethylation. In summary, larger and homogeneous study populations are necessary to quantify the small effects of common mutations on homocysteine levels. This may also be the reason that no effects of genetic interactions between two genotypes were observed.
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PMID:Genetic defects as important factors for moderate hyperhomocysteinemia. 1159 36

Classical homocystinuria is associated with arterial vascular diseases and venous thrombosis. In the last decade, several studies have been published indicating that even mild hyperhomocysteinemia is a risk factor for venous thrombosis. The 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinemia, but this polymorphism does not seem to be a risk factor for venous thrombosis. Studies on the interaction between hyperhomocysteinemia and other thrombotic risk factors are conflicting. Little is known about the pathophysiology of venous thrombosis in hyperhomocysteinemia. Several mechanisms proposed for vascular disease may be applied to venous thrombosis as well. However, up to now there is no satisfying model which might explain a thrombophilic state at plasma homocysteine concentrations in the range of mild hyperhomocysteinemia. The results of a first clinical intervention study are expected in 2002. As the results are pending, clinicians could perform homocysteine measurements in patients with venous thrombosis if screening for thrombophilia is indicated. Vitamin supplementation could be prescribed if homocysteine levels are elevated. However, the patient should be informed about the uncertainty of the benefits of vitamin supplementation.
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PMID:Hyperhomocysteinemia as a risk factor for venous thrombosis. 1159 38

Glomerular filtration is one of the major determinants of plasma total homocysteine (tHcy). To evaluate the respective roles of residual glomerular filtration (by measuring a specific protein marker, cystatin C), genetic polymorphisms and nutritional status in tHcy blood levels in end-stage renal disease patients (ESRD) under hemodialysis and supplemented with folate, we measured tHcy, folate, vitamin B12 (B12), creatinine, cystatin C, albumin and C-reactive protein and determined the polymorphism of methylenetetrahydrofolate reductase (MTHFR) (C677T and A1289C) and of methionine synthase (MS) (A2756G) in 114 ESRD patients before hemodialysis and 76 control subjects. All patients received a folate supplementation of 700 microg/day. Hyperhomocysteinemia was observed in all patients and exceeded the upper normal limit by 2-fold in 52.4% of the patients. Serum folate was significantly increased and the B12 level was not different from controls. Folate, Cystatin C and creatinine were significantly correlated to tHcy, while no correlation was found between tHcy, albumin and C-reactive protein. No difference in genotype frequency between ESRD patients and controls was found for MTHFR A1289C and MS A2756G. The MTHFR 677TT genotype was less frequent and was associated with a significantly higher tHcy level in patients. Folate and residual glomerular filtration estimated by cystatin C and creatinine levels were two independent determinants of tHcy in ESRD patients. These data suggest that hyperhomocysteinemia is a consequence as well as a complicating factor of renal failure.
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PMID:Hyperhomocysteinemia is related to residual glomerular filtration and folate, but not to methylenetetrahydrofolate-reductase and methionine synthase polymorphisms, in supplemented end-stage renal disease patients undergoing hemodialysis. 1159 45


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