Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia

Abstract

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...

Dose-Related Association of MTHFR 677T Allele With Risk of Ischemic Stroke

“…26 -56 Only 2 studies reported crude ORs for ischemic stroke associated with TT and CT genotypes. 40,42 Crude ORs were recalculated in the remaining studies because (a) no OR provided in original publication (14 studies) † (b) adjusted but not crude OR provided (5 studies) 41,45,47,53,54 (c) risk was calculated only for TT genotype compared with a combined CTϩCC group (6 studies) 26,30,31,33,43,46 (d) subgroups with imaging-proven intracerebral hemorrhage included so ORs specific for IS calculated (4 studies). 37,48,52,56 One study 36 reported OR separately for white and black ethnicities-these were included separately, making a total of 32 study samples in the overall analysis (Table).…”

Investigation of the association between 677C>T and 1298A>C 5,10-methylenetetra- hydrofolate reductase gene polymorphisms and normal-tension glaucoma

“…The frequency of TT genotype in younger NTG patients in our study (38.9%) is much higher when it is compared with the results reported in different ethnic populations (2-17.9%). 10,13,14,16,[22][23][24][25][26][27][28][29] Genetic traits of a disease should be more important in younger patients than in older ones. If one has a genetic predisposition to a disease, it is likely that the disease should develop earlier.…”

“…TT genotype has been proven to be associated with vascular diseases such as cardiovascular and cerebrovascular diseases. 10,[13][14][15][16] Another MTHFR gene polymorphism of 1298A4C was reported to be associated with lower blood folate levels and higher blood homocysteine levels in some studies. 17 MTHFR gene polymorphism and resultant hyperhomocysteinaemia as a risk factor of vascular diseases prompted us to investigate the association between MTHFR gene polymorphism and NTG.…”

MTHFR Gene Polymorphism as a Risk Factor for Silent Brain Infarcts and White Matter Lesions in the Japanese General Population

“…17,25 Although we did not analyze cognitive function in the present study, an association between impaired cognitive function and SBI and white matter lesions has also been reported. 14,22 In several studies, the MTHFR TT genotype has also been demonstrated to be a risk factor for dementia, 26,27 although conflicting results have also been reported. 28,29 These findings suggest a possible association between the MTHFR TT genotype and cognitive impairment in the general population.…”