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MTHFR 677C→T Polymorphism and Risk of Coronary Heart Disease
Abstract and Figures
Context
In observational studies, individuals with elevated levels of plasma
homocysteine tend to have moderately increased risk of coronary heart disease
(CHD). The MTHFR 677C→T polymorphism is a genetic
alteration in an enzyme involved in folate metabolism that causes elevated
homocysteine concentrations, but its relevance to risk of CHD is uncertain.Objective
To assess the relation of MTHFR 677C→T
polymorphism and risk of CHD by conducting a meta-analysis of individual participant
data from all case-control observational studies with data on this polymorphism
and risk of CHD.Data Sources
Studies were identified by searches of the electronic literature (MEDLINE
and Current Contents) for relevant reports published before June 2001 (using
the search terms MTHFR and coronary
heart disease), hand searches of reference lists of original studies
and review articles (including meta-analyses) on this topic, and contact with
investigators in the field.Study Selection
Studies were included if they had data on the MTHFR 677C→T genotype and a case-control design (retrospective or nested
case-control) and involved CHD as an end point. Data were obtained from 40
(34 published and 6 unpublished) observational studies involving a total of
11 162 cases and 12 758 controls.Data Extraction
Data were collected on MTHFR 677C→T genotype,
case-control status, and plasma levels of homocysteine, folate, and other
cardiovascular risk factors. Data were checked for consistency with the published
article or with information provided by the investigators and converted into
a standard format for incorporation into a central database. Combined odds
ratios (ORs) for the association between the MTHFR 677C→T
polymorphism and CHD were assessed by logistic regression.Data Synthesis
Individuals with the MTHFR 677 TT genotype
had a 16% (OR, 1.16; 95% confidence interval [CI], 1.05-1.28) higher odds
of CHD compared with individuals with the CC genotype. There was significant
heterogeneity between the results obtained in European populations (OR, 1.14;
95% CI, 1.01-1.28) compared with North American populations (OR, 0.87; 95%
CI, 0.73-1.05), which might largely be explained by interaction between the MTHFR 677C→T polymorphism and folate status.Conclusions
Individuals with the MTHFR 677 TT genotype
had a significantly higher risk of CHD, particularly in the setting of low
folate status. These results support the hypothesis that impaired folate metabolism,
resulting in high homocysteine levels, is causally related to increased risk
of CHD.
Figures in this Article
Homocysteine is a sulfur-containing amino acid that plays a pivotal
role in methionine metabolism. Genetic defects of the enzymes or dietary deficiency
of B-vitamin cofactors involved in this metabolism result in elevated homocysteine
levels. Elevated homocysteine levels have been associated with increased risk
of coronary heart disease (CHD),1 but whether
this association is causal is uncertain.2 Observational
studies have shown that individuals with low folate levels or intake have
a higher risk of CHD,3- 6 and
it is possible that these associations may be independent of homocysteine.7
A common polymorphism exists for the gene that encodes the methylene
tetrahydrofolate reductase (MTHFR) enzyme, which
converts 5,10-methylene tetrahydrofolate to 5-methyltetrahydrofolate, required
for the conversion of homocysteine to methionine. Individuals who have a C-to-T
substitution at base 677 of the gene (amino acid change A222V) have reduced
enzyme activity and higher homocysteine8 and
lower folate levels than those without this substitution.9- 13 Elucidation
of an association, if any, between this polymorphism and CHD risk might be
informative regarding the hypothesis that impaired folate metabolism, resulting
in high homocysteine concentrations, plays a causal role in the occurrence
of CHD.
Individual studies and previous meta-analyses of such studies8,14 included too few subjects to provide
conclusive evidence for or against an association of this polymorphism and
CHD risk.15 The aim of this study was to assess
the relation of the MTHFR 677C→T polymorphism
with risk of CHD by conducting a meta-analysis of individual participant data
from all case-control observational studies that had data on this polymorphism
and risk of CHD.
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... Several studies have investigated the mechanism behind lowering the concentration of tHcy by giving folic acid in cases of the MTHFR 677C→T genotype. One meta-analysis showed that cases with the polymorphisms in MTHFR 677TT had a 16% (OR: 1.16; 95%CI: 1.05, 1.28) higher risk of chronic heart disease compared with individuals with the CC genotype [43]. However, after dividing the genotype groups into high or low folic acid status, the genotype effects were noticed to be invalid in the high folic acid status group [43]. ...
... One meta-analysis showed that cases with the polymorphisms in MTHFR 677TT had a 16% (OR: 1.16; 95%CI: 1.05, 1.28) higher risk of chronic heart disease compared with individuals with the CC genotype [43]. However, after dividing the genotype groups into high or low folic acid status, the genotype effects were noticed to be invalid in the high folic acid status group [43]. There was a similar risk for CHD in the MTHFR 677TT genotype adults seen in patients with the CC genotype (OR: 0.99; 95%CI: 0.77, 1.29). ...
... There was a similar risk for CHD in the MTHFR 677TT genotype adults seen in patients with the CC genotype (OR: 0.99; 95%CI: 0.77, 1.29). Cases with the MTHFR 677TT genotype who had low folic acid concentrations were at higher risk for CHD (OR: 1.44; 95%CI: 1.12, 1.83) compared to those with high folic acid status and the CC genotype [43]. Although all the included studies were for folic acid supplementation, the phenomena of impacts of the higher risk genotype are overcome by adequate serum folic acid concentrations which can be reached by folic acid fortification [43]. ...
Inadequate folate intake during pregnancy is the leading cause of the development of neural tube defects (NTDs) in newborns. For this reason, mandatory fortification of folic acid, a synthetic, easily bioavailable form, in processed cereals and cereal products has been implemented in the US since 1 January 1998 to reduce the risk of NTD in newborn children. This report aimed to review the literature related to the impact of mandated folic acid fortification on the intended and unintended benefits to health. Potential adverse effects were also discussed. We searched Pubmed, Google Scholar, Embase, SCOPUS, and Cochrane databases for reports. About 60 reports published between January 1998 and December 2022 were reviewed, summarized, and served as background for this review. The intended benefit was decreased prevalence of NTDs, while unintended benefits were reduction in anemia, blood serum homocysteine, and the risk of developing cardiovascular diseases. Potential issues with folic acid fortification are the presence of unmetabolized folic acid in circulation, increased risk of cancer, and the masking of vitamin B-12 deficiency. From a health perspective, it is important to monitor the impact of folic acid fortification periodically.
... A C to T substitution at nucleotide 677 results in the substitution of a valine codon for alanine, causing an enzyme activity deficiency [5], thus inhibiting the remethylation of homocysteine (Hcy) to methionine, and affecting folate distribution. Many epidemiological studies have demonstrated that this variant results in increased circulating Hcy levels under the condition of impaired folate status [5,8,9], as well as clinical implications of cardiovascular disorders [10]. Of note, the prevalence of the MTHFR C677T mutation varies in different ethnicities [11], and it has been reported that Chinese populations have a higher rate of the homozygous variant MTHFR 677TT (~ 25%) [12]. ...
Background and purpose
The enzyme methylenetetrahydrofolate reductase ( MTHFR ) plays a crucial role in directing folate species towards nucleotide synthesis or DNA methylation. The MTHFR polymorphisms C677T and A1298C have been linked to cancer susceptibility, but the evidence supporting this association has been equivocal. To investigate the individual and joint associations between MTHFR C677T, A1298C, and digestive system cancer in a Chinese hypertensive population, we conducted a population-based case–control study involving 751 digestive system cancer cases and one-to-one matched controls from the China H-type Hypertension Registry Study (CHHRS).
Methods
We utilized the conditional logistic regression model to evaluate multivariate odds ratios (ORs) and 95% confidence intervals (CIs) of digestive system cancer.
Results
The analysis revealed a significantly lower risk of digestive system cancer in individuals with the CT genotype (adjusted OR: 0.71; 95% CI 0.52, 0.97; P = 0.034) and TT genotype (adjusted OR: 0.57; 95% CI 0.40, 0.82; P = 0.003; P for trend = 0.003) compared to those with the 677CC genotype. Although A1298C did not show a measurable association with digestive system cancer risk, further stratification of 677CT genotype carriers by A1298C homozygotes (AA) and heterozygotes (AC) revealed a distinct trend within these subgroups.
Conclusion
These findings indicate a potential protective effect against digestive system cancer associated with the T allele of MTHFR C677T. Moreover, we observed that the presence of different combinations of MTHFR polymorphisms may contribute to varying susceptibilities to digestive system cancer.
... The difference between the European and American populations can be attributed to the enrichment of foods with folic acid in North America. Therefore, folic acid deficiency was not observed in North America, so the effect of the C677T MTHFR polymorphism did not influence the risk of developing CHD [93]. ...
Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in the one-carbon cycle. This enzyme is essential for the metabolism of methionine, folate, and RNA, as well as for the production of proteins, DNA, and RNA. MTHFR catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to its active form, 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Numerous variants of the MTHFR gene have been recognised, among which the C677T variant is the most extensively studied. The C677T polymorphism, which results in the conversion of valine to alanine at codon 222, is associated with reduced activity and an increased thermolability of the enzyme. Impaired MTHFR efficiency is associated with increased levels of homocysteine, which can contribute to increased production of reactive oxygen species and the development of oxidative stress. Homocysteine is acknowledged as an independent risk factor for cardiovascular disease, while chronic inflammation serves as the common underlying factor among these issues. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and an increased risk of cardiovascular disease, hypertension, diabetes, and overweight/obesity. There is substantial evidence supporting this association, although several studies have concluded that the polymorphism cannot be reliably used for prediction. This review examines the latest research on MTHFR polymorphisms and their correlation with cardiovascular disease, obesity, and epigenetic regulation.
... The latest study by our research team revealed that patients with rs9651118 polymorphisms had a significantly better Matsushima grade after EDAS than that in wild-type (TT) patients, regardless of whether the mutation was homozygous (CC) or heterozygous (TC). At the same time, some studies have shown that serum Hcy levels of TT rs9651118 were significantly higher than those of mutant CC and TC, and that this difference was associated with intron variation [31][32][33][34][35]. This illustrates that the MTHFR gene rs9651118 polymorphism is positively correlated with collateral circulation formation. ...
Indirect revascularization is one of the main techniques for the treatment of Moyamoya disease. The formation of good collateral circulation is a key measure to improve cerebral blood perfusion and reduce the risk of secondary stroke, and is the main method for evaluating the effect of indirect revascularization. Therefore, how to predict and promote the formation of collateral circulation before and after surgery is important for improving the success rate of indirect revascularization in Moyamoya disease. Previous studies have shown that vascular endothelial growth factor, endothelial progenitor cells, Caveolin-1, and other factors observed in patients with Moyamoya disease may play a key role in the generation of collateral vessels after indirect revascularization through endothelial hyperplasia and smooth muscle migration. In addition, mutations in the genetic factor RNF213 have also been associated with this process. This study summarizes the factors and mechanisms influencing collateral circulation formation after indirect revascularization in Moyamoya disease.
... A deficiency of vitamins B12 and B9 may result in elevated total homocysteine (tHcy) in the blood, which is associated with the progression of CVD [147][148][149][150]. Folic acid and vitamin B12 supplementation reduced blood homocysteine levels by 25 percent and 7 percent, respectively, in a meta-analysis of 12 randomized controlled trials [151]. ...
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, far ahead of cancer. Epidemiological data emphasize the participation of many risk factors that increase the incidence of CVDs, including genetic factors, age, and sex, but also lifestyle, mainly nutritional irregularities and, connected with them, overweight and obesity, as well as metabolic diseases. Despite the importance of cardiovascular problems in the whole society, the principles of prevention of CVDs are not widely disseminated, especially among the youngest. As a result, nutritional neglect, growing from childhood and adolescence, translates into the occurrence of numerous disease entities, including CVDs, in adult life. This review aimed to draw attention to the role of selected minerals and vitamins in health and the development and progression of CVDs in adults and children. Particular attention was paid to the effects of deficiency and toxicity of the analyzed compounds in the context of the cardiovascular system and to the role of intestinal microorganisms, which by interacting with nutrients, may contribute to the development of cardiovascular disorders. We hope this article will draw the attention of society and the medical community to emphasize promoting healthy eating and proper eating habits in children and adults, translating into increased awareness and a reduced risk of CVD.
Introduction
Homocysteine (Hcy) is a cellular poison, side product of the hydrolysis of S-Adenosyl Homocysteine, produced after the universal methylation effector S -Adenosylmethionine liberates a methyl group to recipient targets. It inhibits the methylation processes and its rising is associated with multiple disease states and ultimately is both a cause and a consequence of oxidative stress, affecting male gametogenesis. We have determined hyper homocysteinhemia (HHcy) levels can be reliably reduced in hypofertile patients in order to decrease/avoid associated epigenetic problems and protect the health of future children, in consideration of the fact that treatment with high doses of folic acid is inappropriate.
Methods
Homocysteine levels were screened in male patients consulting for long-standing infertility associated with at least three failed Assisted Reproductive Technology (ART) attempts and/or repeat miscarriages. Seventy-seven patients with Hcy levels > 15 µM were treated for three months with a combination of micronutrients including 5- MethylTetraHydroFolate (5-MTHF), the compound downstream to the MTHFR enzyme, to support the one carbon cycle; re-testing was performed at the end of a 3 months treatment period. Genetic status for Methylenetetrahydrofolate Reductase (MTHFR) Single nucleotide polymorphisms (SNPs) 677CT (c.6777C > T) and 1298AC (c.1298A > C) was determined.
Results
Micronutrients/5-MTHF were highly efficient in decreasing circulating Hcy, from averages 27.4 to 10.7 µM, with a mean observed decrease of 16.7 µM. The MTHFR SNP 677TT (homozygous form) and combined heterozygous 677CT/1298AC status represent 77.9% of the patients with elevated Hcy.
Discussion
Estimation HHcy should not be overlooked in men suffering infertility of long duration. MTHFR SNPs, especially 677TT, are a major cause of high homocysteinhemia (HHcy). In these hypofertile patients, treatment with micronutrients including 5-MTHF reduces Hcy and even allows spontaneous pregnancies post treatment. This type of therapy should be considered in order to ensure these patients' quality of life and avoid future epigenetic problems in their descendants.
Introduction
This study investigated the effect of indirect revascularization surgery in adult patients with moyamoya disease (MMD) complicated with hyperhomocysteinemia (HHcy), and the effect of HHcy on the progression of adult MMD.
Methods
A retrospective case‐control study was conducted in patients with MMD, with or without HHcy (n = 123). Postoperative collateral angiogenesis was evaluated using the Matsushima grading system and disease progression using the Suzuki staging system. Cerebral blood flow was evaluated before and after surgery using dynamic susceptibility contrast magnetic resonance imaging (DSC‐MRI) and neurological function prognosis using the improved Rankin score (mRS). Univariate and multivariate logistic regression analyses were performed to determine risk factors for the clinical outcomes.
Results
There was no significant difference in the Suzuki stage composition ratios between the HHcy group and the non‐HHcy group before and after surgery. Non‐HHcy patients were more likely to grow new collateral circulating vessels after encephaloduroarteriosynangiosis (EDAS). Moreover, postoperative DSC‐MRI indicated that the time to peak significantly improved.
Conclusions
HHcy level may be a specific predictor of adverse clinical outcomes after EDAS in patients with MMD and a risk factor for poor collateral circulation and poor prognosis. Patients with MMD complicated with HHcy need to strictly control homocysteine levels before EDAS surgery.
Background and objectives:
High homocysteine levels are associated with increased risk of hypertension and stroke. Homocysteine is metabolized by the methylenetetrahydrofolate reductase (MTHFR). We aimed to investigate the levels of homocysteine and their association with hypertension, stroke, and antihypertensive medication usage in patients with different MTHFR C677T genotypes.
Methods and results:
Genotype frequency of MTHFR polymorphism was performed, and plasma homocysteine levels were measured in 2,640 adult Lebanese patients. Hypertension, history of stroke, and list of medications were documented, among other clinical and demographic parameters. The TT mutant genotype and the T mutant allele of MTHFR were more prevalent in hyperhomocysteinemia (HHcy) and H-hypertensive (H-HTN, defined as hypertension with hyperhomocysteinemia) patients when compared to non-HHcy subjects and non H-HTN patients respectively. Homocysteine levels were significantly higher in hypertensive patients specifically among those on diuretics. A higher level of homocysteine was found in hypertensive patients with the MTHFR T allele compared to patients carrying the C allele. Among the T allele carriers, the average plasma homocysteine level was 13.3 ± 0.193 μmol/L for hypertensive subjects compared to 11.9 ± 0.173 μmol/L (non-hypertensives). Furthermore, homocysteine levels significantly correlated with stroke risk in patients with the T alleles.
Conclusions:
We found an association of homocysteine with hypertension, hypertensive medication, and stroke risk among patients with the MTHFR T allele and the TT genotype. The association of diuretics therapy with higher homocysteine levels calls for routine measurements and therapeutic control of homocysteine in patients on diuretic, to improve health-related outcomes.
Background:
Some critics argue that bias from population stratification (the mixture of individuals from heterogeneous genetic backgrounds) undermines the credibility of epidemiologic studies designed to estimate the association between a genotype and the risk of disease. We investigated the degree of bias likely from population stratification in U.S. studies of cancer among non-Hispanic Caucasians of European origin.
Methods:
An expression of the confounding risk ratio-the ratio of the effect of the genetic factor on risk of disease with and without adjustment for ethnicity-is used to measure the potential relative bias from population stratification. We first use empirical data on the frequency of the N-acetyltransferase (NAT2) slow acetylation genotype and incidence rates of male bladder cancer and female breast cancer in non-Hispanic U.S. Caucasians with ancestries from eight European countries to assess the bias in a hypothetical population-based U.S. study that does not take ethnicity into consideration. Then, we provide theoretical calculations of the bias over a large range of allele frequencies and disease rates.
Results:
Ignoring ethnicity leads to a bias of 1% or less in our empirical studies of NAT2. Furthermore, evaluation of a wide range of allele frequencies and representative ranges of cancer rates that exist across European populations shows that the risk ratio is biased by less than 10% in U.S. studies except under extreme conditions. We note that the bias decreases as the number of ethnic strata increases.
Conclusions:
There will be only a small bias from population stratification in a well-designed case-control study of genetic factors that ignores ethnicity among non-Hispanic U.S. Caucasians of European origin. Further work is needed to estimate the effect of population stratification within other populations.
The aim of this work was to evaluate the role of homocysteine, and the MTHFR 677C-->T allele as risk factors for premature coronary artery disease and to analyse the inheritance of this metabolic disorder.
Case-control and family studies were performed in a sample of 76 male patients (age < 55), 95 age-matched controls and 89 patients' offspring. Plasma total homocysteine concentrations, its nutritional determinants and the frequency of the MTHFR 677C-->T allele were measured, in addition to conventional risk factors.
Mild hyperhomocysteinemia (above the 90th percentile of the control group) was seen in 22.4% of patients (P = 0.02) and was an independent predictor of premature coronary artery disease (odds ratio of 3.2). The frequencies of the 677T allele in patients and controls were 0.37 and 0.36 and those of the TT genotype were 0.15 and 0.14, respectively. Homozygosity for the 677T allele was associated with significantly higher homocysteine values (P < 0.00001). Among TT patients, 64% had mild hyperhomocysteinemia, as compared to 23% of TT controls. Mild hyperhomocysteinemia showed a strong hereditary component, as 36% of patients' offspring had homocysteine levels above the age-adjusted 90th percentile compared to only 13% of patients' spouses. Among children with the TT genotype, the proportion raised to 83% (P < 0.001).
In this Spanish population, mild hyperhomocysteinemia is associated with the risk of premature coronary artery disease and is highly prevalent in offspring of patients with this condition. The MTHFR TT genotype is associated with hyperhomocysteinemia, but not with coronary artery disease.
Context.—
Hyperhomocysteinemia is caused by genetic and lifestyle influences,
including low intakes of folate and vitamin B6. However, prospective
data relating intake of these vitamins to risk of coronary heart disease (CHD)
are not available.Objective.—
To examine intakes of folate and vitamin B6 in relation to
the incidence of nonfatal myocardial infarction (MI) and fatal CHD.Design.—
Prospective cohort study.Setting and Patients.—
In 1980, a total of 80082 women from the Nurses' Health Study with no
previous history of cardiovascular disease, cancer, hypercholesterolemia,
or diabetes completed a detailed food frequency questionnaire from which we
derived usual intake of folate and vitamin B6.Main Outcome Measure.—
Nonfatal MI and fatal CHD confirmed by World Health Organization criteria.Results.—
During 14 years of follow-up, we documented 658 incident cases of nonfatal
MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors,
including smoking and hypertension and intake of alcohol, fiber, vitamin E,
and saturated, polyunsaturated, and trans fat, the
relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence
interval [CI], 0.55-0.87) for folate (median intake, 696 µg/d vs 158
µg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median
intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR
was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate
and vitamin B6 intake compared with the opposite extreme. Risk
of CHD was reduced among women who regularly used multiple vitamins (RR=0.76;
95% CI, 0.65-0.90), the major source of folate and vitamin B6,
and after excluding multiple vitamin users, among those with higher dietary
intakes of folate and vitamin B6. In a subgroup analysis, compared
with nondrinkers, the inverse association between a high-folate diet and CHD
was strongest among women who consumed up to 1 alcoholic beverage per day
(RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI,
0.13-0.58).Conclusion.—
These results suggest that intake of folate and vitamin B6
above the current recommended dietary allowance may be important in the primary
prevention of CHD among women.
Figures in this Article
THREE DECADES AGO, premature vascular occlusive disease was identified
in patients with inborn metabolic disorders associated with homocysteinuria,
leading to the hypothesis that elevated blood homocysteine levels may cause
coronary disease.1- 2 More recently,
evidence linking moderately elevated blood homocysteine levels to increased
risk3 has focused attention on genetic and
lifestyle determinants of homocysteine levels. Folate and vitamin B6 are important cofactors for metabolism. Supplementation of the diet
above the recommended dietary allowance (RDA) with folate alone,4- 5
or in combination with vitamin B6 and vitamin B12, reduces
homocysteine levels.3,6- 9
The current RDA for folic acid for nonpregnant women is 180 µg/d,10 and the average dietary intake in this country among
adult women is approximately 225 µg/d.11
Because of evidence that this level of intake may be insufficient to minimize
risk of neural tube defects, and possibly coronary heart disease (CHD), some
have urged that the RDA be reset to the earlier level of 400 µg/d.12
Although homocysteine may be atherogenic, it also may be only a marker
of folate and vitamin B6 status. Recent epidemiologic evidence
suggests that populations with higher plasma levels of folate and pyridoxal
5‘-phosphate (PLP, the active form of vitamin B6) have lower
risk of carotid artery stenosis13 and CHD.14- 16 In 1 retrospective
study15 of 130 myocardial infarction (MI) cases
and 118 controls, folate intake was inversely associated with CHD risk. To
our knowledge, this relation has not been prospectively studied. Furthermore,
previous studies have not examined the independent effects of folate and vitamin
B6 from food or from supplements on risk of CHD, nor have previous
studies collected sufficient detail to examine subpopulations of individuals
at higher risk of CHD due to factors that may directly or indirectly affect
circulating levels of folate (eg, smoking, parental history of MI, and alcohol).
Therefore, we examined the relation of intakes of folate and vitamin B6 to risk of CHD among 80082 women enrolled in the Nurses' Health Study
and followed prospectively for 14 years (1980-1994).
Background: Hyperhomocysteinemia, an independent and graded risk factor for coronary artery disease, can result from both environmental and hereditary factors. C677T mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene [alanine/valine (A/V) polymorphism], one of the key enzymes involved in catalyzing the remethylation of homocysteine, has recently been reported.
Objective: To evaluate the incidence of the MTHFR genotypes and their significance in determining the risk for myocardial infarction of Japanese men.
Method: The subjects consisted of 199 healthy men (mean age, 60 years) and 230 male patients with myocardial infarction (mean age, 59 years). The coronary-artery lesions were evaluated by coronary angiography. The MTHFR genotype was analyzed by polymerase chain reaction and then by digestion with HinfI. Total plasma levels of homocysteine for each MTHFR genotype were compared with those in healthy controls.
Results: The prevalences of the A and V alleles among the healthy male subjects were 0.652 and 0.348 in the Hardy-Weinberg equilibrium. The total levels of homocysteine in the plasma of the healthy male subjects were 8.6±3.3, 8.9±4.1, and 11.6±5.6 mmol/l, for AA, AV, and VV genotypes, respectively. Individuals with the VV homozygous mutant genotype thus had the highest plasma levels of homocysteine. Logistic analysis revealed that the levels of high-density lipoprotein cholesterol, hypertension, diabetes mellitus, MTHFR VV genotype, and triglycerides were all independent risk factors for myocardial infarction. The VV genotype was more prevalent among patients with myocardial infarction (mean age, 59 years) than it was among the control subjects (17.0 versus 10.6%, P <0.05). However, there were no differences in the numbers of stenotic coronary arteries among the MTHFR genotypes.
Conclusion: The VV genotype of MTHFR increases plasma levels of homocysteine in healthy controls, and this mutation indicates a genetic predisposition toward a greater than normal risk of myocardial infarction for Japanese men.
Moderate hyperhomocysteinaemia (MHH) is associated with arterial and venous thrombosis. A main genetic defect related to MHH is a C to T substitution at nucleotide 677 of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. A prothrombin 20210A mutation was recently identified as a risk factor for arterial and venous thrombosis. However, studies on the prevalence of mutant MTHFR C677T and prothrombin G20210A and their association with thrombosis were controversial and seldom reported in the Chinese population. We investigated the prevalence of MTHFR C677T and prothrombin G20210A genotypes by polymerase chain reaction (PCR) followed by restriction enzyme digestion in 420 Chinese subjects: 53 with deep venous thrombosis (DVT); 145 with cerebrovascular disease [115 cerebral infarction, 30 cerebral haemorrhage (CH)]; 100 with coronary artery disease (CAD); and 122 control subjects. The prevalence of the mutated MTHFR 677TT genotype and the 677T allele in normal controls was 12·3% and 30·7% respectively, similar to that in Caucasians and Japanese. The mutant 677T homozygotes and alleles were more frequent in patients with DVT than in controls (18·9% vs. 12·3%, 0·01 < P < 0·025; 48·1% vs. 30·7%, P < 0·005). The relative risk of DVT among the carriers of 677TT and 677T were significantly increased [odds ratios: 3·4, 95% confidence interval (CI) 1·3–9·5, and 3·6, 95% CI 1·7–7·7, respectively). The mutant MTHFR heterozygous 677C/T carriers were increased in patients with cerebral infarction compared with controls (53·9% vs. 36·9%, 0·01 < P < 0·025). Relative risk of cerebral infarction was 0·96 (95% CI 0·4–2·3) for 677TT homozygotes and 1·99 (95% CI 1·2–3·4) for 677C/T heterozygotes. However, the distribution of the MTHFR TT genotype was less frequent in patients with CAD with coronary artery stenosis of > 50% than in controls (2·8% vs. 12·3%, 0·025 < P < 0·05). Relative risk of CAD was not increased among the carriers of 677TT and 677T (odds ratios: 0·2, 95% CI 0–1·1, and 0·97, 95% CI 0·5–1·8, respectively). There were no differences in the distribution of the MTHFR genotypes among CH, CAD with coronary artery stenosis of < 50% and controls. The prothrombin 20210A mutation was not found in any patients or controls. These results demonstrated that MTHFR 677T was associated with DVT and cerebral infarction but was less associated with CAD in the Chinese population.
Low folate intake is an important determinant of elevated blood levels of homocysteine. Because elevated homocysteine has been shown to be a possible graded risk factor for CHD, sufficient folate intake may be important in the prevention of CHD. The magnitude of the association between folate and CHD is consistent with its effects on homocysteine.