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)

Hyperhomocysteinemia is reported to be associated with an increase in the incidence of ischemic heart disease and cerebrovascular disease. Genetic aberrations in methylenetetrahydrofolate reductase (MTHFR) may account for reduced enzyme activity and elevated plasma homocysteine level. A recent report revealed that a common mutation (677C to T; Ala to Val) in the MTHFR gene is associated with decreased specific MTHFR activity and with increased risk for coronary artery disease in the homozygous state (Val/Val). In the present study, we investigated whether the MTHFR gene is a genetic risk factor for cerebrovascular disease (CVD). To undertake a case-control study, we selected the patients with cerebral infarction (n = 48) or cerebral hemorrhage (n = 35) and examined the association between MTHFR gene polymorphism and CVD. The genotype distribution of the MTHFR gene was not significantly different between cases and controls. Because the possibility of matching the morbidity of the effects of hypertension, the lack of association could not be excluded in the first study; however, we also examined whether the MTHFR mutation was associated with any clinical risk factor for CVD or with hypertension. It turned out that the subjects with the Val allele of the MTHFR gene had significantly lower blood pressure than the subjects with other genotypes in the general population (P = .02), and that the frequency of the Val/Val genotype in hypertensive subjects (n = 173) was significantly lower than in control subjects (n = 184) (P = .03). From these results, we conclude that the Val/Val homozygous state of the MTHFR gene increased the risk of thrombosis, but reduced the blood pressure, which resulted in the lack of increased risk for CVD.
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PMID:Methylenetetrahydrofolate reductase gene polymorphism: relation to blood pressure and cerebrovascular disease. 971 96

Hyperhomocyst(e)inemia has been identified as an independent risk factor for atherosclerotic and thromboembolic diseases such as coronary artery disease, cerebral artery disease, and venous thrombosis. Recently, the alanine/valine (A/V) gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes that catalyzes the remethylation of homocysteine, was reported. The VV genotype is correlated with increased plasma homocyst(e)ine levels as a result of the reduced activity and increased thermolability of this enzyme. In this study, we examined the association between the V allele of the MTHFR gene and ischemic stroke in an elderly Japanese population. The diagnosis of cerebral infarction of all study patients was confirmed by CT of the brain. The MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. In 256 stroke patients and 325 control subjects, the frequencies of the V allele were 0.45 and 0.32, respectively. The odds ratios and 95% confidence intervals adjusted for the other risk factors were, respectively, 1.51 (1.02 to 2.23) for the AV genotype and 3.35 (1.94 to 5.77) for the VV genotype compared with the AA genotype. Both of these effects were statistically significant (P=0.041 and P<0.001, respectively). In patients with multiple infarcts in particular, the allele frequency of the V mutation was 0.56, and the association between the V allele and stroke was highly significant. Plasma homocyst(e)ine levels were significantly higher in patients with the VV genotype than in patients with the AA or AV genotype, especially those with low plasma folate levels. The V allele of the MTHFR gene was significantly associated with cerebral infarction in an elderly Japanese population in a codominant manner. The VV genotype may contribute to risk for ischemic stroke through a predisposition to increased plasma homocyst(e)ine levels, and dietary folate supplementation may be of benefit, particularly to patients with this genotype.
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PMID:Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese. 974 36

Inherited gene defects related to the coagulation system have been reported as risk factors for ischemic stroke. These gene defects include a G-A transition at nucleotide 1691 in exon 10 of the Factor V gene causing activated protein C resistance; a G-A transition in the 3' untranslated region of the prothrombin gene at nucleotide position 20210 (G-A), which is associated with increased levels of prothrombin activity; and a C-T polymorphism at nucleotide 677 in the methylenetetrahydrofolate reductase gene responsible for an alanine to valine substitution, resulting in the synthesis of a thermolabile form of methylenetetrahydrofolate reductase that causes increased levels of homocysteine. The case-control study included 28 patients with cerebral infarction; all were 18 years of age or younger (range, 10 months to 18 years). Seven (25%) of the 28 patients were heterozygous for the FV1691 mutation. Five (17.8%) of the patients carried the PT20210A mutation. Two (7.1%) of the patients carried both mutations. When compared to controls, the difference was significant for both mutations (P = .007; .04). The frequency of allele T of methylenetetrahydrofolate reductase 677 was 0.3214, which was not significant when compared to controls (0.231; P = .3). A total of 12 (42.8%) patients carried one or both of the mutations FV1691 G-A and PT20210 G-A. From our data, it appears that FV1691 G-A and PT20210 G-A are associated with cerebral infarct risk independently. Risk assessment of double prothrombotic gene alterations did not reveal synergy between these mutations. In conclusion, the presence of FV1691 A and PT20210 A mutations but not the methylenetetrahydrofolate reductase 677 TT mutation correlate with the occurrence of cerebral infarction in children.
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PMID:Factor V1691 G-A, prothrombin 20210 G-A, and methylenetetrahydrofolate reductase 677 C-T variants in Turkish children with cerebral infarct. 1059 55

Moderate hyperhomocysteinaemia (MHH) is associated with arterial and venous thrombosis. A main genetic defect related to MHH is a C to T substitution at nucleotide 677 of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. A prothrombin 20210A mutation was recently identified as a risk factor for arterial and venous thrombosis. However, studies on the prevalence of mutant MTHFR C677T and prothrombin G20210A and their association with thrombosis were controversial and seldom reported in the Chinese population. We investigated the prevalence of MTHFR C677T and prothrombin G20210A genotypes by polymerase chain reaction (PCR) followed by restriction enzyme digestion in 420 Chinese subjects: 53 with deep venous thrombosis (DVT); 145 with cerebrovascular disease [115 cerebral infarction, 30 cerebral haemorrhage (CH)]; 100 with coronary artery disease (CAD); and 122 control subjects. The prevalence of the mutated MTHFR 677TT genotype and the 677T allele in normal controls was 12.3% and 30.7% respectively, similar to that in Caucasians and Japanese. The mutant 677T homozygotes and alleles were more frequent in patients with DVT than in controls (18.9% vs. 12.3%, 0.01 < P < 0. 025; 48.1% vs. 30.7%, P < 0.005). The relative risk of DVT among the carriers of 677TT and 677T were significantly increased [odds ratios: 3.4, 95% confidence interval (CI) 1.3-9.5, and 3.6, 95% CI 1. 7-7.7, respectively). The mutant MTHFR heterozygous 677C/T carriers were increased in patients with cerebral infarction compared with controls (53.9% vs. 36.9%, 0.01 < P < 0.025). Relative risk of cerebral infarction was 0.96 (95% CI 0.4-2.3) for 677TT homozygotes and 1.99 (95% CI 1.2-3.4) for 677C/T heterozygotes. However, the distribution of the MTHFR TT genotype was less frequent in patients with CAD with coronary artery stenosis of > 50% than in controls (2. 8% vs. 12.3%, 0.025 < P < 0.05). Relative risk of CAD was not increased among the carriers of 677TT and 677T (odds ratios: 0.2, 95% CI 0-1.1, and 0.97, 95% CI 0.5-1.8, respectively). There were no differences in the distribution of the MTHFR genotypes among CH, CAD with coronary artery stenosis of < 50% and controls. The prothrombin 20210A mutation was not found in any patients or controls. These results demonstrated that MTHFR 677T was associated with DVT and cerebral infarction but was less associated with CAD in the Chinese population.
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PMID:Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. 1092 44

Although the major biochemical abnormality due to methylenetetrahydrofolate reductase (MTHFR) deficiency is hyperhomocyst(e)inemia, its pathogenicity appears to involve more than homocysteine toxicity. In patients with severe MTHFR deficiency, a metabolite(s) other than hyperhomocyst(e)inemia also appears to be associated with its clinical manifestation in cerebrovascular disease. To elucidate the specific role of the TT genotype of MTHFR in the development of cerebral infarction with and without cognitive impairment, we determined the prevalence of hyperhomocyst(e)inemia and the C677T genotypes of MTHFR in 143 patients with vascular dementia, 122 patients with cerebral infarction, and 217 healthy subjects matched for age and sex. Prevalence of hyperhomocyst(e)inemia [homocyst(e)ine >/=15 micromol/L] was higher in cerebrovascular patients with or without dementia than in normal control subjects (42.6%, 20.5%, and 10.1%, respectively; P=0.001). In contrast, a higher frequency of MTHFR TT genotype was found only in demented patients compared with nondemented patients and healthy controls (25.2%, 9.8%, and 12.0%, respectively; P=0.01). When the study subjects were divided into normohomocyst(e)inemic and hyperhomocyst(e)inemic groups, the TT genotype was significantly associated with the risk for vascular dementia in the hyperhomocyst(e)inemic group (odds ratio 4.13, 95% CI 2.18 to 7.85; P=0.03) but not in the normohomocyst(e)inemic group. Demented patients with multiple infarcts had a higher frequency of TT genotype (odds ratio 3.13, 95% CI 2.23 to 4.39; P=0.0007), whereas those with a single infarct did not (odds ratio 2.03, P=0.15). In contrast, there was no significant association of the TT genotype with multiple infarcts in hyperhomocyst(e)inemic stroke patients. Taken together, these findings indicate a possible role of MTHFR TT genotype combined with hyperhomocyst(e)inemia in the pathogenesis of vascular dementia. Similar to the relationship between homocystinuria due to severe MTHFR deficiency and severe cystathionine beta-synthase deficiency, the TT genotype of MTHFR in hyperhomocyst(e)inemic subjects is differentiated from the cases of the TT genotype without hyperhomocyst(e)inemia or hyperhomocyst(e)inemia without the TT genotype in the development of cerebrovascular disease.
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PMID:Pathogenicity of thermolabile methylenetetrahydrofolate reductase for vascular dementia. 1093 12

We investigated the effects of genetic factors on the prognosis of cerebral infarction in young adults in Taiwan. Because ischemic stroke with arterial occlusion or undetermined etiology is more likely to be related to a genetic prothrombotic state, 231 patients younger than 50 years (mean age 44.6 years, range 25 to 49 years) with acute ischemic stroke due to large artery atherosclerosis (n=90), small artery occlusion (n=114) or undetermined cause (n=27) were recruited and prospectively followed up for pre-determined outcome. On each patient, we screened the PlA1/PlA2 polymorphism of the platelet glycoprotein IIIa gene, 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene, G10976A polymorphism of the factor VII gene, C677T polymorphism of the methylenetetrahydrofolate reductase gene, and 27 base-pair repeat polymorphism of the endothelial nitric oxide synthase gene. End points were the composite outcome events of stroke, myocardial infarction, and death from all causes. During a mean duration follow-up of 29 months, composite outcome events occurred in 33 patients. There was a higher annual incidence rate of composite outcome events during the first year (9.1%, 95% CI 5.9-13.9%) than in the subsequent 2 years (2.6%, 95% CI 1.2-5.6%, p=0.038). None of the genetic polymorphism was associated with the composite outcome events. Past history of coronary artery disease or cerebrovascular disease was the only independent predictor of the composite outcome events (HR 3.71, 95% CI 1.69-8.14, p=0.001) at the Cox regression analysis. Our data indicate that the prothrombotic genetic polymorphisms do not have a significant influence on the prognosis in young ischemic stroke due to arterial occlusion or undetermined causes in Taiwan.
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PMID:Prognosis of young ischemic stroke in Taiwan: impact of prothrombotic genetic polymorphisms. 1535 55

The authors present a case of refractory multiple myeloma in an elderly patient with heterozygosity for the G20210A mutation of factor II and for the C677T mutation of methylenetetrahydrofolate reductase. This patient developed acute, multiple cerebral infarctions 5 months into the treatment with thalidomide. The patient improved on oral anticoagulation. The authors presume that thalidomide increased the risk of cerebral infarction in this predisposed patient. The presence of increased risk for thrombosis should alert clinicians to screen patients presenting with systemic thrombosis for inherited thrombophilia. This risk increases with the presence of diseases and therapies that predispose for a hypercoagulable state. They suggest that patients required to be on thalidomide should be screened for inherited thrombophilia and should be considered for prophylactic anticoagulation therapy.
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PMID:Should we screen patients for inherited thrombophilia before starting thalidomide? 1646 12

Plasma homocysteine (Hcy) concentration has been shown to be influenced by a mutation in the gene coding methylenetetrahydrofolate reductase (MTHFR). Although plasma Hcy has been shown to be related to atherosclerotic disorders, the association between MTHFR gene polymorphism and ischemic stroke remains controversial. In the present study we investigated the association between MTHFR gene polymorphism and risk factor-dependent augmentation for ischemic stroke in subjects with several risk factors for atherosclerosis, with special emphasis on the risk factor-gene interaction. The diagnosis of cerebral infarction in each patient was confirmed by computed tomography (CT) findings of the brain. MTHFR C677T polymorphism was genotyped with a conventional method. In 97 stroke patients (48 cases of atherothrombotic infarction, 38 cases of lacunar infarction, 9 cases of cardiac embolism, 2 others) and 241 age-and sex-matched healthy control subjects, the frequencies of the T allele were 0.44 and 0.39, respectively. In patients with CT-proven atherothrombotic infarction, the T allele frequency was 0.54 (P = .033 vs controls). The adjusted odds ratio in subjects with TT genotype for atherothrombotic infarction was 3.87 (95% confidence interval = 1.27-11.8). A general linear model analysis showed that an interaction between the HDL-C and MTHFR genotype was significantly associated with atherothrombotic infarction (F = 5.695; P = .018). These findings indicate that the T allele of the MTHFR gene is significantly associated with atherothrombotic infarction. Furthermore, the analysis of risk factor-gene interaction could be a useful tool for deriving specific predictive information about ischemic stroke in an elderly Japanese population.
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PMID:An association of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and ischemic stroke. 1790 3

Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members.
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PMID:MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family. 1906 58

Prothrombotic risk factors in children with ischemic stroke have been increasingly recognized with recent developments in technology. Extensive evaluation including a detailed family history is required to identify various inherited or acquired prothrombotic conditions. We report a 7-month-old male who presented with right hemiparesis. Acute cerebral infarction in the area supplied by the left lenticulostriate artery was confirmed through magnetic resonance imaging. De novo synthesis of antiphospholipid antibodies and homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism were identified as presumed prothrombotic risk factors. His twin sister and mother were also positive for antiphospholipid antibodies. Multiple risk factors for ischemic stroke should be considered, particularly in the perinatal and infancy period. This case also underlines the rare familial occurrence of antiphospholipid antibodies and its relationship to ischemic stroke in infancy.
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PMID:Ischemic stroke in a 7-month-old infant with antiphospholipid antibody and homozygous C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism. 2011 Feb 13


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