Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of homozygosity for the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene as an independent risk factor for primary and recurrent stroke has been questioned, although recent data appear to be supportive. However, the association of homozygous C677T MTHFR mutation with silent brain infarctions in infancy has not been reported. The authors describe an 11-month-old male who had suffered a silent brain infarction followed by a symptomatic arterial stroke. The evaluation revealed mildly elevated homocysteine levels secondary to homozygous C677T alleles for MTHFR and iron deficiency anemia. An extensive evaluation for other causes of infarction was negative. We suggest that the mother's homozygous MTHFR status played a role in the early onset of stroke and that iron deficiency anemia may have contributed to the recurrence. The patient was treated with anticoagulation therapy, folic acid, and iron supplementation and has not had a recurrent event during 3 years of follow-up. This case provides further evidence that homozygous MTHFR mutation is a predisposing factor for early and recurrent pediatric stroke, including silent infarcts, especially in the presence of other risk factors.
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PMID:Homozygous MTHFR C677T gene mutation and recurrent stroke in an infant. 1681 86

Sickle cell disease (SCD) is one of the most common inherited diseases in the world and the patients present notorious clinical heterogeneity. It is known that patients with SCD present activation of the blood coagulation and fibrinolytic systems, especially during vaso-occlusive crises, but also during the steady state of the disease. We determined if the presence of the factor V gene G1691A mutation (factor V Leiden), the prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may be risk factors for vascular complications in individuals with SCD. We studied 53 patients with SCD (60% being women), 29 with SS (sickle cell anemia; 28 years, range: 13-52 years) and 24 with SC (sickle-hemoglobin C disease; 38.5 years, range: 17-72 years) hemoglobinopathy. Factor V Leiden, MTHFR C677T polymorphism, and prothrombin G20210A variant were identified by PCR followed by further digestion of the PCR product with specific endonucleases. The following vascular complications were recorded: stroke, retinopathy, acute thoracic syndrome, and X-ray-documented avascular necrosis. Only one patient was heterozygous for factor V Leiden (1.8%) and there was no prothrombin G20210A variant. MTHFR 677TT polymorphism was detected in 1 patient (1.8%) and the heterozygous form 677TC was observed in 18 patients (34%, 9 with SS and 9 with SC disease), a prevalence similar to that reported by others. No association was detected between the presence of the MTHFR 677T allele and other genetic modulation factors, such as alpha-thalassemia, beta-globin gene haplotype and fetal hemoglobin. The presence of the MTHFR 677T allele was associated with the occurrence of vascular complications in SCD, although this association was not significant when each complication was considered separately. In conclusion, MTHFR C677T polymorphism might be a risk factor for vascular complications in SCD.
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PMID:The clinical impact of MTHFR polymorphism on the vascular complications of sickle cell disease. 1690 20

Growing evidence indicates that elevated total homocysteine (tHcy) levels can elicit autoimmune response in vivo. Antibodies against Nepsilon-Hcy-proteins have been shown to be associated with stroke and premature myocardial infarction. The aim of the current study was to investigate the effect of treatment with folic acid on anti-Nepsilon-Hcy-albumin and -hemoglobin antibodies. We recruited 20 apparently healthy men and 12 male patients with documented coronary artery disease (CAD). All participants had plasma fasting tHcy levels >15 microM. At baseline, and after three and six months of treatment with folic acid 1 mg daily, we determined tHcy, serum folate and vitamin B12 levels, along with serum anti-Nepsilon-Hcy-albumin and -hemoglobin IgG antibodies using the home-made immunoenzymatic assays. Both groups did not differ with regard to age, tHcy, folate, lipid profile, and CRP. The only significant difference between healthy subjects and CAD patients was levels of antibodies against Nepsilon-Hcy-albumin. As expected, folic acid administration led to significant decreases in tHcy and increases in folate levels in both groups. Levels of both anti-Nepsilon-Hcy-albumin and -hemoglobin antibodies fell markedly following a three-month folic acid administration in healthy subjects, but not in CAD patients, without any changes at six months in either group. Folic acid administration resulted in a loss of significant correlations between tHcy and antibodies both following three and six months of the therapy in healthy subjects, in contrast to CAD patients. Carriers of the methylenetetrahydrofolate reductase (MTHFR) 677T allele with CAD had significantly higher levels of anti-Nepsilon-Hcy-albumin before and during folic acid administration as compared to healthy subjects. In conclusion, our findings suggest that Hcy-related autoimmune response is resistant to folic acid administration in CAD patients, while in healthy subjects reduced tHcy levels are associated with suppressed production of antibodies against Nepsilon-Hcyproteins. These observations might explain at least in part the failure of vitamin therapy to reduce the risk of cardiovascular events as recently reported.
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PMID:Folic acid administration and antibodies against homocysteinylated proteins in subjects with hyperhomocysteinemia. 1695 77

We describe the anesthetic management of a patient with placenta previa presenting for a cesarean section, who had methylenetetrahydrofolate reductase (MTHFR) deficiency. Methylenetetrahydrofolate reductase deficiency increases homocysteine levels in the body and, therefore, predisposes to thrombosis. After a cerebrovascular accident at 8 weeks of gestational age, the patient received anticoagulants throughout the course of her pregnancy. Bleeding from the placenta previa occurred at 30 weeks of gestational age. Although general anesthesia was indicated for this patient because of her hemodynamic instability and an anticoagulated state, nitrous oxide is contraindicated in such patients. Thus, we chose a subarachnoid block because the patient remained hemodynamically stable, and anticoagulation had been stopped 8 hours before surgery. To our knowledge, there is no reported case of a parturient with MTHFR deficiency complicated with a cerebrovascular accident and associated with placenta previa presenting for a cesarean section. Anesthetic considerations are discussed in patients presenting with placenta previa associated with MTHFR deficiency.
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PMID:Anesthesia for cesarean section in a patient with placenta previa and methylenetetrahydrofolate reductase deficiency. 1698 Jan 65

Hyperhomocysteinemia is an independent risk factor for ischemic stroke. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a critical role in modulating the levels of plasma homocysteine. Two polymorphisms in the MTHFR gene, C677T, A1298C result in reduced enzyme activity. The mechanisms of ischemic and hemorrhagic stroke are not well understood. Although controversial, previous studies have shown evidence of causality of both stroke subtypes in patients with methylenetetrahydrofolate reductase gene polymorphisms. Therefore, we examined whether the C677T and A1298C polymorphisms of MTHFR gene are genetic risk factors for both ischemic and hemorrhagic stroke in a Turkish Caucasian population. In a case-control study, 120 total unrelated stroke patients (92 ischemic stroke, 28 hemorrhagic stroke), and 259 healthy controls were genotyped for C677T and A1298C polymorphisms of the MTHFR gene using a PCR-RFLP based-method. The MTHFR 1298C allele (chi(2)=8.589; P=0.014), C1298C genotype (OR=2.544; P=0.004), and C677C/C1298C compound genotype (OR=3.020; P=0.001) were associated with overall stroke. The MTHFR 1298C allele (chi(2)=11.166; P=0.004), C1298C genotype (OR=2.950; P=0.001), and C677C/C1298C compound genotype (OR=3.463, P=0.0001) were strongly associated with ischemic stroke. Interestingly however, the MTHFR 677T allele (chi(2)=6.033; P=0.049), T677T genotype (OR=3.120; P=0.014), and T677T/A1298A compound genotype (OR=4.211; P=0.002) were associated with hemorrhagic stroke. In conclusion, the C677T and A1298C polymorphisms of the MTHFR gene are genetic risk factors for hamorrhagic and ischemic stroke respectively, independent of other atherothrombotic risk factors.
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PMID:Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C. 1711 27

Hyperhomocysteinemia has been identified as a risk factor for venous and arterial thrombosis especially in adult populations. Twenty-eight patients with an initial diagnosis of ischemic stroke and 100 controls, aged <or=18 years, were enrolled in this study. The mean plasma total homocysteine (tHcy) levels in patients and controls were significantly different with values of 8.7+/-3.6 and 7.5+/-2.4 micromol/L, respectively (P=0.01). The plasma tHcy at the 95th percentile was 11.5 micromol/L and patients whose plasma tHcy was above the 95th percentile had an odds ratio of 8.2 (95% confidence interval 1.4-47.2, P=0.02) for developing ischemic stroke. The genetic and acquired factors that could have affected plasma tHcy levels were studied and no differences were found between patients and controls. Factors that were investigated were vitamin B12, red blood cell folate, and serum folate levels as well as methylenetetrahydrofolate reductase C677T polymorphism. It is of note, however, that subjects whose plasma tHcy was above the 95th percentile had significantly lower serum folate levels (P=0.02).
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PMID:Homocysteine, MTHFR C677 T, vitamin B12, and folate levels in Thai children with ischemic stroke: a case-control study. 1716 49

Stroke is a heterogeneous multifactorial disease and is thought to have a polygenic basis. Case-control studies on gene sequence variations have identified a number of potential genetic predisposition factors, but due to the conflicting results, uncertainty remains on the effect of these polymorphisms on risk for the development of stroke. To qualitatively and quantitatively assess the risk associated with different gene polymorphisms for stroke in Asian populations, we comprehensively searched and identified all the studies of association. Clinically overt case-control studies were selected only if neuroimaging had been used as the confirmatory measure for diagnosis of stroke. We performed a meta-analysis of the three most investigated genes, viz., methylenetetrahydrofolate reductase (MTHFR), apolipoprotein E (ApoE) and angiotensin-converting enzyme (ACE). Statistically significant association with stroke were identified for C677T polymorphism of MTHFR [random effects odds ratio (OR) = 1.47, 95% confidence interval (95% CI) 1.19, 1.82; P = 0.0004] and marginally significant association was detected with allele epsilon 4 of ApoE (random effects OR = 1.47, 95% CI 1.00, 2.15; P = 0.049). The sensitivity analysis (exclusion of studies with controls not in Hardy-Weinberg equilibrium) revealed a significant association of stroke with the MTHFR C677T and ApoE epsilon 4 alleles but showed no association with ACE gene insertion/deletion polymorphism.
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PMID:Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis. 1717 Dec 28

Homocysteine is a thiol aminoacid synthesized during the metabolism of methionine. Increased plasma levels of homocysteine can be the result of mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine-beta synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR). Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or vitamin B12 (methylcobalamin), can induce hyperhomocysteinemia. Over the last decade, following in vitro and in vivo observations of a homocysteine-associated vascular pathology, convincing epidemiological evidence has been gathered on the relation between moderate elevation of plasma homocysteine and vascular disease, including cerebral ischemia. However, causality has yet to be established. The association between homocysteine and ischemic stroke might be a spurious epidemiological finding because of confounding or it might reflect reverse causality. If this is the case, elevated levels of plasma homocysteine should be interpreted as an epiphenomenon secondary to the vascular disease itself. Thus, whether lowering homocysteine concentration prevents cerebral ischemia remains to be determined. The only method to answer the question of the causal relation between homocysteine and ischemic stroke is by intervention trials in which patients at high vascular risk, such as those who have had a recent cerebral ischemic event are randomly allocated to placebo or homocysteine-lowering multivitamin therapy, and followed prospectively. Some of these randomized controlled trials are currently ongoing. Their results should hopefully resolve the issue in the next future.
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PMID:Homocysteine and cerebral ischemia: pathogenic and therapeutical implications. 1730 30

There is evidence to suggest that increased levels of homocysteine play a significant role in vascular disease. It has been suggested that lowering homocysteine levels by dietary folate supplementation may reduce the risk of stroke and coronary heart disease. It is plausible that homocysteine may also play a role in the pathogenesis of abdominal aortic aneurysms (AAA) and that patients with this disease may benefit from folate supplementation. Our objective was to review the published work with regard to the role of homocysteine in the pathogenesis of AAA. Searches were carried out in published work in English with the keywords 'abdominal aortic aneurysm' and 'homocysteine'. There is evidence from in vitro and animal model studies that activation of metalloproteinases by homocysteine can influence aortic wall structure. Several case-control studies report an association between increased levels of homocysteine and the presence of an AAA. There are conflicting genotypic data concerning the association between methylenetetrahydrofolate reductase gene variants and AAA. Although there is evidence for an association between homocysteine and AAA, it is not strong enough to conclude that it plays a causal role in the pathogenesis of AAA. Further research is needed, given the potential benefit that simple vitamin supplementation may have for patients with AAA.
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PMID:Homocysteine and abdominal aortic aneurysms. 1749 68

Stroke is a polygenic or multifactorial disease, and each single susceptibility gene has modest effects. We hypothesize that combined effects of multiple genes might confer a higher stroke risk than a single susceptibility gene. To test our hypothesis we initially recruited 2000 stroke patients (44.3% thrombosis, 28.3% lacunar infarction and 27.4% intracerebral hemorrhage) and 2000 controls, and examined 6 polymorphisms in 5 candidate genes for stroke. Plasma lipoprotein(a) [Lp(a)] level was defined as a categorical variable and also included. Interactions between genetic risk factors were detected by the multifactor dimensionality reduction (MDR) method and further evaluated by multivariate logistic regression analyses. A significant combined effect on stroke due to the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR), the T2354A polymorphism of 5-lipoxygenase activating protein (ALOX5AP), and Lp(a) level, was detected using the MDR method. Furthermore, the combination of MTHFR 677TT, ALOX5AP 2354AA and Lp(a) elevation (Lp(a) concentration > or = 30 mg/dL) was found to be strongly associated with thrombotic stroke in males (OR, 10.419; 95%CI, 2.602 to 41.749; P= 0.001) using the multivariate logistic regression model. In conclusion, our results show that a combination of genetic risk factors can confer a higher risk for stroke than a single risk factor, indicating that people with multiple genetic risk factors have a higher risk of stroke and should be targets for prevention of this disease.
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PMID:Interaction of genetic risk factors confers higher risk for thrombotic stroke in male Chinese: a multicenter case-control study. 1752 9


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