© 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
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Abstract |
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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
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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Introduction |
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Determination 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 ß-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. Demyelination of the brain in patients with severe MTHFR deficiency appears to be associated with hypomethioninemia and reduced S-adenosylmethionine accumulation or depletion of other metabolites in addition to hyperhomocyst(e)inemia.10 However, except for hyperhomocyst(e)inemia, determination of other biochemical abnormalities in mild MTHFR deficiency seems beyond the range of detection. Nonetheless, there is evidence to support the unique aspect of thermolabile MTHFR and the TT genotype in nonvascular diseases. It has been reported that mild MTHFR deficiency is positively associated with various nonvascular diseases, such as nonvascular cardiac disease, neural tube defects, colorectal cancer, and schizophrenia/depression.11 12 13 14 15 16
We postulate that the pathogenicity of mild MTHFR deficiency is not only confined to hyperhomocyst(e)inemia but is also related to the accumulation or depletion of another metabolite(s). To elucidate the new feature of mild MTHFR deficiency in the development of cerebrovascular disease, we chose to compare the role of the TT genotype of MTHFR with and without hyperhomocyst(e)inemia in the occurrence of 2 different types of cerebrovascular disease, cerebral infarction and vascular dementia.
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Methods |
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Study subjects were all unrelated Korean patients aged 65 to 90 years who were admitted to Inchon Neuropsychiatric Hospital, where patients with dementia had been referred from other hospitals for chronic care. Patients were consecutively recruited from January through October 1998 if they met the following criteria: vascular dementia on the basis of National Institute of Neurological Disorders and Stroke (NINDS)–Association Internationale pour la Recherche et l’Enseignement en Neurologie (AIREN) criteria17 and a Hachinski Ischemic Score of
7.18 Brain CT or MRI
was performed in all patients undergoing the study and assessed by 2
neuroradiologists. ECG, serum multiphasic analysis, and thyroid
function tests were examined. Fourteen demented patients with
intracranial hemorrhage, cancer, renal dysfunction (serum
creatinine 132.6 µmol/L), hypothyroidism,
alcoholism, folate or vitamin B12 deficiency, or
use of multivitamins or estrogen were excluded from the study. One
hundred forty-three patients were selected for the dementia
group.
During the study period, 196 patients who had undergone brain MRI or CT
and were assessed as cerebral infarction subjects were then enrolled
for the study. Healthy individuals were eligible for inclusion if they
did not have a past history of stroke. Three hundred eighty-two
subjects consented to participate in the study. Laboratory data of the
cases were examined. Social and medical histories were obtained through
interviews by investigators. Subjects with Mini-Mental State
Examination scores of 
24 were excluded.19 Other
exclusion criteria were identical to those of cases, according to which
74 patients with cerebral infarction and 76 healthy subjects were
excluded. Of 306 healthy subjects, 89 had evidence of
symptomatic coronary artery disease. Matched for
sex and age within 4 years, a total of 122 patients with cerebral
infarction and 217 healthy subjects free of coronary artery
disease and stroke were selected for control group. The study was
approved by the local ethics committee. Informed consent was obtained
from family members or participants.
As previously described,20 plasma homocyst(e)ine, folate, and vitamin B12 were determined by use of high-performance liquid chromatography, fluorescence detection, and radioimmunoassay. DNA was amplified by polymerase chain reaction. Polymerase chain reaction primers for amplification of the MTHFR mutation have been described elsewhere.21 Amplified 198-bp fragments were incubated with HinfI (Takara) for digestion, because the nucleotide 677 mutation creates a restriction site for HinfI. Genotypes were determined through gel electrophoresis and ethidium bromide staining. The mutant allele was designated as T; the wild-type, as C.
A 
2 test for categorical variables and a
t test for continuous variables were applied for
comparison between groups. Because plasma homocyst(e)ine and serum
triglyceride levels were not normally distributed, natural
logarithmic transformation was used. Plasma homocyst(e)ine and other
values among MTHFR genotypes were compared by ANOVA, followed
by the Duncan test for multiple comparisons. Multiple logistic
regression analysis was used to estimate the adjusted odds
ratio (OR) for vascular dementia. SAS statistical software (version
6.12, SAS Institute) was used.
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Results |
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Demographic data, serum lipid profiles, and prevalence of major risk factors in 143 patients with vascular dementia, 122 patients with cerebral infarction, and 217 clinically healthy subjects are shown in Table 1
. Average onset of vascular
disease was 73.5 years. Mean plasma homocyst(e)ine concentration was
higher in the 2 patient groups than in the normal control group. The
proportion of moderate hyperhomocyst(e)inemia was higher in patients
with vascular dementia than in stroke patients or in control subjects
(42.6%, 20%, and 10.1%, respectively; P=0.001). No
significant differences of any risk factors were seen in patients with
vascular dementia compared with patients with cerebral infarction.
Among other risk factors, a statistically significant difference
between the 2 groups with cerebrovascular disease and the healthy group
was found for the frequency of diabetes mellitus and smoking but not
for hypertension, atrial fibrillation, and lipid values.
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We found a higher frequency of the TT genotype of MTHFR in
patients with vascular dementia than in stroke patients or in control
subjects (25.2%, 9.8%, and 12.0%, respectively; P=0.001);
data are reported in Table 2. The OR
adjusted for hypertension, smoking, diabetes mellitus, atrial
fibrillation, age, and sex was 2.56 (95% CI 1.92 to 3.42,
P=0.001). Demented patients with multiple infarcts had a
3.1-fold higher frequency of TT genotype (95% CI 2.23 to 4.39,
P=0.0007). When patients were subdivided by the severity of
stroke lesions, the TT genotype was positively associated with
the group with multiple infarcts (OR 3.13, 95% CI 2.23 to 4.39;
P=0.0007) but not with the group with single infarcts in
patients with vascular dementia. In contrast, neither infarct group
showed any significant association with the TT genotype in
patients with cerebral infarction (Table 3).
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We stratified study subjects into normal (<15 µmol/L) and
hyperhomocyst(e)inemic (15 µmol/L) groups to investigate a
possible independent relationship of the MTHFR TT genotype in
the development of cerebral infarction with or without dementia.
Distribution of the combination of hyperhomocyst(e)inemia and the TT
genotype of MTHFR in the 2 groups of patients (those with
vascular dementia and those with strokes) and in normal control
subjects is shown in Table 4. In
the groups with hyperhomocyst(e)inemia, the combination of
hyperhomocyst(e)inemia and the TT genotype of MTHFR was
significantly associated with the risk of vascular dementia (OR 4.13,
95% CI 2.18 to 7.85; P=0.03) compared with
hyperhomocyst(e)inemia combined with the CT/CC genotype. A
similar association was not found in patients with cerebral infarction.
On the other hand, in the groups with normohomocyst(e)inemia, there was
no significant association of the TT genotype with vascular
dementia (OR 1.06, 95% CI 0.71 to 1.58; P=0.88). In a
multiple logistic regression analysis to assess the effect of
hyperhomocyst(e)inemia and the MTHFR TT genotype on vascular
dementia, the MTHFR TT genotype remained significantly related
to vascular dementia (regression coefficient ß=0.69, standard error
0.32; P=0.03) after controlling for age, sex, hypertension,
diabetes mellitus, and hyperhomocyst(e)inemia.
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Discussion |
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Our previous study demonstrated a positive association of cerebral infarction with hyperhomocyst(e)inemia but not with the TT genotype of MTHFR.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. On the other hand, mild MTHFR deficiency due to the TT genotype may cause another defect(s) in folic acid and methionine metabolism. Thus, it is important to evaluate the role of the combination of hyperhomocyst(e)inemia and the TT genotype of MTHFR. Severe hyperhomocyst(e)inemia (homocystinuria) due to MTHFR deficiency manifests itself in more pronounced clinical features, particularly neurological abnormalities, compared with hyperhomocyst(e)inemia due to cystathionine ß-synthase deficiency.8 9 To examine whether a pattern similar to that found in severe MTHFR deficiency occurs in moderate MTHFR deficiency, it seems appropriate to compare the role of the TT genotype with hyperhomocyst(e)inemia in patients with cerebrovascular disease with and without cognitive impairment.
The association between the C677T mutation of MTHFR and vascular dementia has been previously evaluated by a number of investigators. Nilsson et al22 reported a high prevalence of hyperhomocyst(e)inemia in psychogeriatric patients and suggested a possible genetic defect in demented patients with hyperhomocyst(e)inemia irrespective of folic acid depletion. Chapman et al23 observed the lack of a significant association between the MTHFR genotype and vascular dementia, which was probably due to the insufficient number of the sample. In the present study, we have demonstrated a positive association of hyperhomocyst(e)inemia in cerebrovascular patients with and without vascular dementia. In contrast, we have found a positive association of the TT genotype only with cerebrovascular disease in patients with vascular dementia. However, it is noteworthy that a significant association is confined to hyperhomocyst(e)inemic patients but not to normohomocyst(e)inemic patients with vascular dementia. In addition, the severity of infarction is related to the presence of the MTHFR deficiency with hyperhomocyst(e)inemia. When patients were subdivided into 2 groups with single and multiple infarcts, a positive association was found in the group with multiple infarcts but not in the group with single infarcts. The results demonstrated not only the importance of hyperhomocyst(e)inemia but also another feature of MTHFR deficiency in the development of vascular dementia.
In an earlier study, we demonstrated a positive correlation between thermolabile MTHFR and nonvascular heart disease.11 The TT mutation of C677T is found in the majority (92.6%) of patients with thermolabile MTHFR (S.-S. Kang, M.H. Kim, unpublished data, 1996). A similar positive correlation was also observed in other nonvascular diseases, such as neural tube defects, colon cancer, and schizophrenia/depression.12 13 14 15 16 This suggests that pathogenicity of the TT genotype involves more than hyperhomocyst(e)inemia. Higher homocyst(e)ine and lower folate levels were found in patients with Alzheimer’s disease than in control subjects, indicating the importance of hyperhomocyst(e)inemia.24 Because hyperhomocyst(e)inemia is caused by various genetic and nongenetic conditions, it is important to evaluate an associated pathogenicity due to the primary defect. The present study indicated a significant association of these diseases with the mutation of MTHFR when hyperhomocyst(e)inemia was also present. The deficiency of MTHFR causes an accumulation of 5,10-methylenetetrahydrofolate as well as the inhibition of 5-methyltetrahydrofolate synthesis. Reduced synthesis of 5-methyltetrahydrofolate will cause decreased homocysteine remethylation. Hypomethioninemia and reduced S-adenosylmethionine occur frequently in severe MTHFR deficiency. Depletion of cerebrospinal fluid S-adenosylmethionine rather than hyperhomocyst(e)inemia appears to be closely associated with demyelination of the brain.10 25 Alternatively, accumulation of 5,10-methylenetetrahydrofolate due to MTHFR deficiency may be involved in the development of cognitive abnormalities. This may inhibit serine hydroxymethyltransferase-directed reaction or enhance trifunctional peptide-directed metabolism of 5,10-methenyl- and 10-formyl-tetrahydrofolate synthesis. A change in these reactions may cause a different pathogenic effect of MTHFR deficiency unrelated to hyperhomocyst(e)inemia.
In summary, we investigated the nature of the MTHFR TT genotype in the development of cerebrovascular disease. The risk for the TT genotype with and without hyperhomocyst(e)inemia was compared in cerebrovascular patients with and without vascular dementia. The magnitude of cerebral infarction was also included in the evaluation. The present study confirmed a significant correlation between hyperhomocyst(e)inemia and cerebrovascular disease with or without vascular dementia. In contrast, only hyperhomocyst(e)inemic patients who had multiple cerebral infarctions and dementia had a positive association with the TT genotype. Such a unique feature of mild MTHFR deficiency is analogous to that of homocystinuria due to severe MTHFR deficiency, which is different from severe cystathionine ß-synthase deficiency. We conclude that the pathogenicity of MTHFR TT genotype involves more than hyperhomocyst(e)inemia. Hence, the presence or absence of the TT genotype appears to be an important condition for understanding the role of hyperhomocyst(e)inemia in patients with cerebrovascular disease.
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Acknowledgments |
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This study was supported in part by funds from the Samsung Biomedical Research Institute (C-99-082-1) and the Samsung Medical Center.
Received March 27, 2000; accepted April 5, 2000.
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