A Common Polymorphism in the Methylenetetrahydrofolate Reductase Gene, Homocysteine, and Ischemic Cerebrovascular Disease

Markus, Hugh S.; Ali, Nadira; Swaminathan, R.; Sankaralingam, A.; Molloy, Jane; Powell, John

doi:10.1161/01.str.28.9.1739

Cited by 158 publications

(92 citation statements)

References 13 publications

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“…20 In 3 earlier studies, 2 found a significant association between the C677T genotype of MTHFR and cerebral infarction. [5][6][7] If indeed the pathogenic effect of the TT genotype is based only on hyperhomocyst(e)inemia, the MTHFR TT genotype and hyperhomocyst(e)inemia should manifest a more or less similar pattern of association with cerebrovascular disease. In fact, the TT genotype of MTHFR does not always produce hyperhomocyst(e)inemia.…”

Section: Discussionmentioning

confidence: 99%

“…2 This might explain the inconsistent results found when the association between the TT mutation of MTHFR and cerebrovascular disease was evaluated. [5][6][7] In severe hyperhomocyst(e)inemia, neurological and vascular manifestations are more pronounced despite less severe hyperhomocyst(e)inemia in patients with severe MTHFR deficiency compared with patients with severe cystathionine ␤-synthase deficiency. 8,9 This suggests that the pathogenic feature of hyperhomocyst(e)inemia with MTHFR deficiency may be different from that of hyperhomocyst(e)inemia alone.…”

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confidence: 99%

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Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia

Yoo

Choi

Kang

2000

ATVB

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Abstract-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 Ն15 mol/L] was higher in cerebrovascular patients with or without dementia than in normal control subjects (42.6%, 20.5%, and 10.1%, respectively; Pϭ0.001). 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; Pϭ0.01). 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. Key Words: methylenetetrahydrofolate reductase Ⅲ genes Ⅲ cerebral infarction Ⅲ hyperhomocyst(e)inemia Ⅲ vascular dementia D etermination of plasma homocyst(e)ine (the total of free and protein-bound forms of homocysteine and its derivatives) became an important method in evaluating the risk of cardiovascular and cerebrovascular diseases. It is understood that the severity and duration of hyperhomocyst(e)inemia is closely related to the extent and progress of occlusive vascular disease. Although severe hyperhomocyst(e)inemia (known as homocystinuria) causes thromboembolism and vascular damage in children and young adults, moderate and intermediate hyperhomocyst(e)inemia is believed to be associated with occlusive vascular disease in adults. 1,2 Moderate hyperhomocyst(e)inemia is caused by genetic or environmental factors or a combination of both factors. 1,2 The most common genetic defect is thermolabile methylenetetrahydrofolate reductase (MTHFR), such as the homozygous C677T mutation. 3,4 This mutation causes an increased susceptibility to produce hyperhomocyst(e)inemia. However, the TT genotype of MTHFR requires an additional genetic or environmental factor for persistent hyperhomocyst(e)inemia. 2 This might explain the inconsistent results found when the association between the TT mutation of MTHFR and cerebrovascular disease was evaluated. [5][6][7] In severe hyperhomocyst(e)inemia, neurological and vascular manifestations are more pronounced despite less severe hyperhomocyst(e)inemia in patients with severe MTHFR deficiency compared with patients with severe cystathionine ␤-synthase deficiency. 8,9 This suggests that the pathogenic feature of hyperh...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia

Yoo

Choi

Kang

2000

ATVB

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“…Conflicting results regarding candidate gene studies for stroke emphasize the complexity of this multifactorial, complex disorder. Genes encoding for endothelial nitric oxide (eNOS), Apolipoprotein E, as well as candidate genes in the area of homeostasis and thrombosis have been proposed (Carter et al, 1998;Kessler et al, 1997;Markus et al, 1997).…”

Section: Genetic Aspects Of Stroke and Head Traumamentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

568

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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“…14,15 The findings from the small number of prospective studies that have addressed associations between tHcy concentrations and incident coronary heart diseases (CHD) or stroke are inconsistent [16][17][18][19][20][21][22] Homozygosity for a defective thermolabile variant of MTHFR, a common genetic polymorphism which results in hyperhomocysteinemia, has not been consistently linked with cardiovascular disease endpoints. 23,24 Although the importance of gene markers will vary depending on relevant environmental exposures, diet in this instance, the findings from gene association studies conducted to-date are distinctly unimpressive. The biological plausibility of the tHcy-vascular disease hypothesis rests partially on studies that have used unphysiologically high doses of homocysteine.…”

Section: Thcy and Cardiovascular Diseasementioning

confidence: 99%

Homocysteine, hypertension and stroke

Perry

1999

J Hum Hypertens

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The balance of evidence from observational studies suggests that elevated homocysteine levels are associated with increased risk of carotid artery disease and stroke. There is however a paucity of prospective studies. There are also concerns regarding confounding due to factors associated with hyperhomocysteinemia, including renal impairment, an atherogenic diet and cigarette smoking. Homozygosity for a defective thermolabile variant of MTHFR, a common genetic polymorphism which results in hyperhomocysteinemia, has not been consistently linked with stroke or other vascular disease. There is a need for additional prospective studies with data on relevant confounders, sufficient power to characterise the form of the association between homocysteine concentrations and stroke risk, whether linear or threshold, and power to study interactions between homocysteine, other dietary markers and established stroke risk factors such as smoking and

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A Common Polymorphism in the Methylenetetrahydrofolate Reductase Gene, Homocysteine, and Ischemic Cerebrovascular Disease

Cited by 158 publications

References 13 publications

Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia

Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Homocysteine, hypertension and stroke

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