© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia
From the Department of Family Medicine (J.-H.Y.), Samsung Medical Center, Center for Clinical Research, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea; the Department of Geriatric Medicine (G.-D.C.), Inchon Eun-Hye Hospital, Neuropsychiatric Hospital, Inchon, South Korea; and the Section of Genetics (S.-S.K.), Department of Pediatrics, Rush Medical College and Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Ill.
Correspondence to Jun-Hyun Yoo, MD, PhD, Department of Family Medicine, Samsung Medical Center, Center for Clinical Research, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, South Korea. E-mail drjhyoo{at}samsung.co.kr
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 
15 µmol/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
ß-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.
Key Words: methylenetetrahydrofolate reductase • genes • cerebral infarction • hyperhomocyst(e)inemia • vascular dementia
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