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Review |

MTHFR 677C→T Polymorphism and Risk of Coronary Heart Disease:  A Meta-analysis FREE

Mariska Klerk, MSc; Petra Verhoef, PhD; Robert Clarke, MD; Henk J. Blom, PhD; Frans J. Kok, PhD; Evert G. Schouten, MD, PhD; and the MTHFR Studies Collaboration Group
[+] Author Affiliations

Author Affiliations: Division of Human Nutrition and Epidemiology, Wageningen University (Ms Klerk and Drs Verhoef, Kok, and Schouten), and Wageningen Centre for Food Sciences (Ms Klerk and Dr Verhoef), Wageningen, the Netherlands; Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, England (Dr Clarke); and the Laboratory of Pediatrics and Neurology, University Medical Center Nijmegen, Nijmegen, the Netherlands (Dr Blom).


JAMA. 2002;288(16):2023-2031. doi:10.1001/jama.288.16.2023.
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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 Data were obtained from 40 (34 published and 6 unpublished) observational studies involving a total of 11 162 cases and 12 758 controls.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,36 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.913 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.

Data Sources and Study Selection

Eligible studies were identified by searching the electronic literature (MEDLINE and Current Contents) for relevant reports published before June 2001 (using the search terms MTHFR and coronary heart disease), by hand searching reference lists of original studies and review articles (including meta-analyses) on this topic, and by personal contact with investigators in the field. 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.

Among a total of 53 published studies that examined the relation between the MTHFR 677C→T polymorphism and CHD risk, 6 studies were not included because they did not have a proper case-control design1620 or they studied cardiovascular mortality21 only. Data on 13 further studies were unavailable because the investigators were unable or unwilling to collaborate.2234 Data from 6 unpublished studies that fulfilled the eligibility criteria were included after personal contact with the investigators. Among the 6 unpublished studies, 4 had previously reported on the relationship between homocysteine and CHD,3538 whereas no data had been previously reported in 2 studies. Hence, data were available for these analyses from 40 studies (34 published4,11,12,14,3967 and 6 unpublished3538) involving 11 162 cases and 12 758 controls (Table 1).

Table Graphic Jump LocationTable 1. Characteristics of Included Studies*
Data Extraction

Data were collected on MTHFR 677C→T genotype, case-control status, and plasma levels of homocysteine, folate, and other cardiovascular risk factors, if available. 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. In the majority of the studies that included cases with myocardial infarction, diagnosis was defined using World Health Organization criteria.68 In most studies that included cases with coronary artery disease, diagnosis was based on angiographic confirmation of significant stenosis (≥50%) in at least 1 of the 3 major coronary arteries. However, 1 study also included cases with silent myocardial infarction and coronary revascularization.4 If studies included both population-based controls and hospital-based controls, only data on population-based controls were included. All studies used a standardized method to determine MTHFR 677C→T genotype,69 with 2 exceptions in which the method had been validated elsewhere.70,71

Data Synthesis

Assuming that a prolonged increase in plasma homocysteine of 1 µmol/L (0.14 mg/L) is associated with a 5% increase in CHD risk1,72 and that the average homocysteine concentration is 2.5 µmol/L (0.34 mg/L) higher in TT-genotype patients than CC-genotype patients,8 the expected odds ratio (OR) of CHD for the TT compared with the CC genotype would be about 1.13. With an average prevalence of the TT genotype of 12%,8 more than 9526 cases and an equal number of controls were required to have sufficient statistical power to estimate an OR in the expected range, using a 2-sided α of .05 and 80% power.72

Plasma homocysteine and folate values were log-transformed to improve normality, and geometric means are shown. Differences between cases and controls and between MTHFR 677C→T genotypes were assessed using analysis of variance for continuous data and χ2 tests for categorical data. We assessed whether the frequencies of CC, CT, and TT genotypes among controls in individual studies were consistent with the expected distribution (ie, in Hardy-Weinberg equilibrium) using the Pearson χ2 test.

The OR and 95% confidence interval (CI) of CHD for the TT genotype or for the CT genotype compared with the CC genotype were assessed in each individual study using logistic regression. The analyses ignored matching of cases and controls on age and sex, which had been applied in some studies. The study-specific ORs were then pooled with adjustment for study. Possible heterogeneity between the results of individual studies or in groups defined by continent of origin or by study design was assessed using χ2 tests.

To explore interaction between the MTHFR 677C→T genotype and folate status, 6 subgroups were created whereby folate status was defined as below or above the median serum/plasma folate level. Odds ratios were calculated for all subgroups, with the subgroup with CC genotype and high folate as the reference group.

Complete data on age, sex, smoking, hypertension, and hypercholesterolemia were only available in a subset of studies, and the possible effects of confounding by these risk factors on the relationship between MTHFR and CHD risk were assessed using multivariable logistic regression in this subset.

A funnel plot was created by plotting the OR of CHD for TT vs CC genotype against the number of individuals in each study. A pattern resembling a symmetrical inverted funnel implied absence of significant selection or publication bias. All analyses were performed using SAS, version 6.12 (SAS Institute Inc, Cary, NC).

Characteristics of Included Studies

Table 1 shows the number of cases and controls and selected characteristics for the controls of included studies. About half the data came from studies involving European populations and about a quarter from those of North American populations. The age distribution was similar in all studies. The prevalence of TT genotype among controls varied considerably among studies, ranging from 3.2 (in UK Indians)52 to 30.2 (in an Italian population).42 The MTHFR 677C→T genotype frequencies in controls were in Hardy-Weinberg equilibrium in all but 3 studies.53,54,60

Characteristics of Cases and Controls by Genotype

Table 2 shows the geometric mean plasma concentrations of homocysteine and folate and the presence of established cardiovascular risk factors for cases and controls and within MTHFR 677C→T genotypes. Cases had a higher mean homocysteine concentration and a more adverse cardiovascular risk profile. There were no significant differences in plasma folate concentrations between cases and controls. Among both cases and controls, individuals with the TT and CT genotypes had higher plasma homocysteine concentrations and lower folate concentrations than individuals with the CC genotype. Among controls, individuals with the CT genotype had a lower body mass index and individuals with the TT genotype had lower creatinine concentrations compared with individuals with the CC genotype. Among cases, there were significant differences in the prevalence of male sex, hypercholesterolemia, and smoking among genotypes.

Table Graphic Jump LocationTable 2. Distribution of Homocysteine and Folate Levels and Prevalence of Known Cardiovascular Risk Factors for Cases and Controls and by Subgroup of the MTHFR 677C→T Genotype*
677C→T Polymorphism and Risk of CHD

Figure 1 shows the OR of CHD for the TT genotype compared with the CC genotype in individual studies and a summary estimate for the combined analysis of all studies with adjustment for study. Overall, individuals with the TT genotype had a significantly higher odds of CHD compared with individuals with the CC genotype (OR, 1.16; 95% CI, 1.05-1.28). There was a trend toward an increased risk for the CT genotype compared with the CC genotype (OR, 1.04; 95% CI, 0.98-1.10). There was significant heterogeneity among the results of individual studies (χ239 = 63.8; P<.01). The continent of origin appeared to account for most of this heterogeneity. Continent-specific ORs showed that CHD risk was significantly increased for individuals with the TT genotype compared with those with the CC genotype in Europe (OR, 1.14; 95% CI, 1.01-1.28) but not in North America (OR, 0.87; 95% CI, 0.73-1.05). There was no heterogeneity within European studies (χ221 = 27.1; P = .17) or North American studies (χ29 = 4.2; P = .90), but there was significant heterogeneity between the pooled estimates for Europe and North America (χ21 = 6.6; P = .01). Data on studies from other continents were too sparse to assess a continent-specific OR.

Figure 1. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of Coronary Heart Disease for MTHFR 677 TT vs CC Genotype by Region of Origin
Graphic Jump Location
The size of the data markers is inversely proportional to the variance of the log ORs; horizontal lines represent the 95% CIs. Studies are ordered by the number of cases in each region. The combined ORs and the subtotals for each region and their 95% CIs are indicated by the diamonds.
Effect Modification by Folate Status

The heterogeneity between European and North American studies may be explained by an interaction between MTHFR 677C→T polymorphism and folate status. Table 3 shows ORs of CHD within strata of the MTHFR 677C→T genotype and folate status for a subset of studies for which data on folate status was available. The results show that the TT genotype is associated with increased CHD risk only when folate status is low, which indicates an interaction between the MTHFR 677C→T polymorphism and folate status.

Table Graphic Jump LocationTable 3. Odds Ratios (ORs) of Coronary Heart Disease (CHD) by Strata of the MTHFR 677C→T Polymorphism and Folate Status*
Prospective vs Retrospective Studies

To explore potential differences in the association between prospective and retrospective studies, we assessed pooled ORs for each study design. There was significant heterogeneity between the pooled estimates of prospective and retrospective studies (χ21 = 16.1; P<.001). The pooled OR of CHD for the TT genotype compared with the CC genotype was 0.86 (95% CI, 0.67-1.10) for prospective studies (5 studies involving 1288 cases and 1749 controls) and 1.21 (95% CI, 1.10-1.33) for retrospective studies (35 studies involving 9874 cases and 11 009 controls). However, since 3 of the 5 prospective studies were North American studies, it is likely that this subgroup analysis reflects a continent effect rather than an effect of the prospective study design.

Possible Confounding and Bias

The effect of confounding was explored in a subgroup of studies with available data on age, sex, smoking, hypertension, and hypercholesterolemia. Complete data on these cardiovascular risk factors were available for 5343 cases and 7308 controls. In this subgroup, the crude OR of CHD for the TT genotype vs the CC genotype was 1.15 (95% CI, 1.02-1.30). After adjustment for these confounding factors, the OR of CHD was 1.21 (95% CI, 1.06-1.38), thereby indicating that confounding is of little relevance to the overall results.

Figure 2 shows a funnel plot in which the OR of CHD for TT vs CC genotype was plotted against the number of individuals in each study. The figure includes data from published and unpublished studies and from studies for which data were not available. The shape of the funnel plot suggests that a few small studies finding an inverse association may not have been published. In addition, we calculated the average OR of CHD associated with TT compared with CC genotype among the 12 studies in which individual data were not provided for these analyses. The average OR for these studies was 1.15 (using the inverse of the variance as a weighting factor), suggesting that the present findings were probably not materially altered by the exclusion of studies for which data were unavailable.

Figure 2. Funnel Plot of the Odds Ratios (ORs) of Coronary Heart Disease (CHD) for MTHFR TT vs CC Genotype for Each Study by Number of Individuals Studied
Graphic Jump Location
The plot shows the ORs for the 34 published and 6 unpublished studies and the 12 studies that were unavailable for inclusion in this analysis. Among the unavailable studies, 1 study23 was omitted because the OR could not be abstracted and another study29 was included twice because the data were presented separately in 2 different populations. The summary estimate of the OR of CHD for TT compared with CC is represented by a vertical dotted line.
Importance of the Genetic Association

This study involving 11 162 CHD cases and 12 758 controls from 40 studies demonstrated that individuals with the MTHFR 677 TT genotype have a 16% higher odds of CHD compared with individuals with the CC genotype. The results support the hypothesis that impaired folate metabolism, resulting in high homocysteine concentrations, plays a causal role in the occurrence of CHD. This meta-analysis illustrates the need to study a very large number of cases and controls to provide conclusive evidence for an association between genotype and disease in a setting in which the disease risk associated with a genotype is moderate.

Effect Modification by Folate and Other Factors

The MTHFR 677 TT genotype was significantly associated with a 14% increase in CHD risk in European populations but not in North American populations. Previous studies had shown that the MTHFR 677C→T polymorphism is only associated with high homocysteine levels or increased CHD risk in a setting of low folate status.11,12,43,44,67,73,74 Hence, at higher dietary intakes of folate, the effect of the MTHFR 677C→T genotype has no adverse effect on plasma homocysteine levels or on subsequent risk of CHD. Our results confirm that a positive association between the MTHFR 677 TT genotype and CHD risk is mainly present when folate levels are low. However, we think that these results should be interpreted with caution since they are based on only part of the data and there might be misclassification of folate status because of the different assays used. Therefore, the absolute estimates might not be completely valid.

The average use of vitamin supplements has been consistently higher for several years in North America (25%-40%)57,7578 than in Europe (5%-15%).35,79 While the North American studies were carried out before the enhancement of folate fortification in 1998, fortification of breakfast cereals had been introduced several years before this. Hence, it is very likely that effect modification by dietary intake of folate may account for at least some of the difference in the ORs of CHD obtained for the European and North American populations.44,72,80 In the present study, combined data from both cases and controls for each study showed that the mean homocysteine concentration was higher in European studies (10.9 µmol/L [1.47 mg/L]) than in North American studies (10.5 µmol/L [1.42 mg/L]). Moreover, the differences between MTHFR TT and CC genotypes were greater in European studies compared with North American studies for both homocysteine (2.1 vs 1.3 µmol/L [0.28 vs 0.18 mg/L]) and folate (2.5 vs 1.7 nmol/L [1.1 vs 0.75 ng/mL]) concentrations, respectively.

Additional sources of heterogeneity between Europe and North America may include effect modification by other cardiovascular risk factors65,8083 or linkage disequilibrium with other polymorphisms, such as the MTHFR 1298A→C polymorphism.39,46,84 While the prevalence of hypercholesterolemia, smoking, and alcohol use was higher in European compared with North American studies (data not shown), these data were too sparse to examine possible effect modification by these factors.

Prospective vs Retrospective Studies

Studies on the association between the MTHFR 677C→T polymorphism and mortality or longevity have shown inconsistent results.20,8589 However, if individuals with TT have a higher case-fatality rate, then one might expect that the association in retrospective studies would be attenuated compared with that observed in prospective studies because retrospective studies are restricted to survivors, whereas prospective studies can include fatal and nonfatal outcomes. The present study showed that the TT genotype was associated with increased CHD risk in retrospective studies, but not in prospective studies, but this is likely to reflect differences in populations rather than an effect of prospective studies, considering that 3 of 5 prospective studies were North American studies.

Possible Influence of Bias

Although confounding is generally not anticipated in analyses of an association of a genotype with disease, there may be some imbalance in the distribution of cardiovascular risk factors by the MTHFR genotypes. Adjustment for the possible confounders in a subset of studies with available data did not attenuate the OR of CHD for the TT compared with CC genotype for MTHFR. However, the possibility of residual confounding cannot be completely excluded.

Another potential source of bias might be the inclusion of individuals from heterogeneous ethnic backgrounds. For example, the prevalence of the TT genotype is much lower in blacks (˜1%) than in whites.90 If the distribution of individuals with a specific ethnic background is unequal between cases and controls (so-called population stratification), this may bias an association between a genotype and risk of CHD. In a recent study, however, bias from population stratification in case-control studies was quantified and it was concluded that its impact is likely to be small, even if ethnicity is ignored.91 Furthermore, the risk of population stratification in this meta-analysis is small since adjustment for study ensured that cases from each study were compared with their own controls.

It is unlikely that publication bias accounted for the results obtained; the funnel plot shows that only a few small negative studies may have been missed. Furthermore, selection bias is unlikely to have influenced the results, since the average OR of CHD associated with the TT genotype compared with the CC genotype of 12 studies that were unavailable for inclusion in these analyses was similar to our pooled OR.

Implications for Public Health

An accompanying article in this issue (see p 2015) describes a meta-analysis of 30 studies involving 5000 cases with ischemic heart disease, which showed that among prospective studies, a 25% lower usual homocysteine was associated with 11% (OR, 1.11; 95% CI, 1.04-1.17) lower risk of ischemic heart disease.92 The concordance between the risk estimates obtained in these studies provides support for a causal association between homocysteine and CHD. Several large trials are currently under way to assess if homocysteine lowering by supplementation with folic acid and other B vitamins can reduce the risk of CHD.93 Neither the meta-analyses nor these trials can solve the issue of whether high homocysteine levels per se or the accompanying low folate levels, which may operate via other mechanisms, are the cause of CHD. However, the present study provides some indirect evidence of the likely benefits of increasing population mean levels of folate, as the MTHFR genotype has no adverse effect on cardiovascular risk in the setting of normal folate status. Hence, provided that folate status is adequate, there is little clinical value of screening for MTHFR 677C→T genotype in the general population for prediction of CHD risk.

Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies.  J Cardiovasc Risk.1998;5:229-232.
Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect?  Am J Clin Nutr.2000;72:315-323.
Verhoef P, Stampfer MJ, Rimm EB. Folate and coronary heart disease.  Curr Opin Lipidol.1998;9:17-22.
Folsom AR, Nieto FJ, McGovern PG.  et al.  Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study.  Circulation.1998;98:204-210.
Voutilainen S, Lakka TA, Porkkala SE, Rissanen T, Kaplan GA, Salonen JT. Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study.  Eur J Clin Nutr.2000;54:424-428.
Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Low dietary folate intake is associated with an excess incidence of acute coronary events—the Kuopio Ischemic Heart Disease Risk Factor Study.  Circulation.2001;103:2674-2680.
Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst(e)inaemia: restoration by folic acid.  Clin Sci (Colch).1999;96:235-239.
Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis.  Circulation.1998;98:2520-2526.
van der Put NM, Steegers-Theunissen R, Frosst P.  et al.  Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida.  Lancet.1995;346:1070-1071.
Deloughery TG, Evans A, Sadeghi A.  et al.  Common mutation in methylenetetrahydrofolate reductase: correlation with homocysteine metabolism and late-onset vascular disease.  Circulation.1996;94:3074-3078.
Ma J, Stampfer MJ, Hennekens CH.  et al.  Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians.  Circulation.1996;94:2410-2416.
Schwartz SM, Siscovick DS, Malinow MR.  et al.  Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene.  Circulation.1997;96:412-417.
McQuillan BM, Beilby JP, Nidorf M, Thompson PL, Hung J. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening: the Perth Carotid Ultrasound Disease Assessment Study (CUDAS).  Circulation.1999;99:2383-2388.
Kluijtmans LA, Kastelein JJ, Lindemans J.  et al.  Thermolabile methylenetetrahydrofolate reductase in coronary artery disease.  Circulation.1997;96:2573-2577.
Blom HJ, Verhoef P. Hyperhomocysteinemia, MTHFR, and risk of vascular disease.  Circulation.2000;101:E171.
Araujo F, Lopes M, Goncalves L, Maciel MJ, Cunha RL. Hyperhomocysteinemia, MTHFR C677T genotype and low folate levels: a risk combination for acute coronary disease in a Portuguese population.  Thromb Haemost.2000;83:517-518.
Chao CL, Tsai HH, Lee CM.  et al.  The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis.  Atherosclerosis.1999;147:379-386.
Mager A, Lalezari S, Shohat T.  et al.  Methylenetetrahydrofolate reductase genotypes and early-onset coronary artery disease.  Circulation.1999;100:2406-2410.
Raslova K, Smolkova B, Vohnout B, Gasparovic J, Frohlich JJ. Risk factors for atherosclerosis in survivors of myocardial infarction and their spouses: comparison to controls without personal and family history of atherosclerosis.  Metabolism.2001;50:24-29.
Thuillier L, Chadefaux-Vekemans B, Bonnefont JP.  et al.  Does the polymorphism 677C-T of the 5,10-methylenetetrahydrofolate reductase gene contribute to homocysteine-related vascular disease?  J Inherit Metab Dis.1998;21:812-822.
Roest M, van der Schouw YT, Grobbee DE.  et al.  Methylenetetrahydrofolate reductase 677 C/T genotype and cardiovascular disease mortality in postmenopausal women.  Am J Epidemiol.2001;153:673-679.
Brugada R, Marian AJ. A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction.  Atherosclerosis.1997;128:107-112.
Chen TY, Chen JH, Tsao CJ. Methylenetetrahydrofolate reductase gene polymorphism and coronary artery disease in Taiwan Chinese.  Haematologica.2000;85:445-446.
Goracy I, Goracy J, Suliga M, Ciechanowicz A. Polimorfizm C677T genu reduktazy metylenotetrahydrofolianu (MTHFR) u chorych po przebytym zawale miesnia sercowego [C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in patients with myocardial infarction].  Pol Arch Med Wewn.1999;102:849-854.
Hsu LA, Ko YL, Wang SM.  et al.  The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan.  Hum Hered.2001;51:41-45.
Izumi M, Iwai N, Ohmichi N, Nakamura Y, Shimoike H, Kinoshita M. Molecular variant of 5,10-methylenetetrahydrofolate reductase is a risk factor of ischemic heart disease in the Japanese population.  Atherosclerosis.1996;121:293-294.
Kim CH, Hwang KY, Choi TM, Shin WY, Hong SY. The methylenetetrahydrofolate reductase gene polymorphism in Koreans with coronary artery disease.  Int J Cardiol.2001;78:13-17.
Kostulas K, Crisby M, Huang WX.  et al.  A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis.  Eur J Clin Invest.1998;28:285-289.
Malik NM, Syrris P, Schwartzman R.  et al.  Methylenetetrahydrofolate reductase polymorphism (C-677T) and coronary artery disease.  Clin Sci.1998;95:311-315.
Narang R, Callaghan G, Haider AW, Davies GJ, Tuddenham EG. Methylenetetrahydrofolate reductase mutation and coronary artery disease.  Circulation.1996;94:2322-2323.
Pinto X, Vilaseca MA, Garcia GN.  et al.  Homocysteine and the MTHFR 677C>T allele in premature coronary artery disease: case control and family studies.  Eur J Clin Invest.2001;31:24-30.
Reinhardt D, Sigusch HH, Vogt SF, Farker K, Muller S, Hoffmann A. Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and the risk of coronary artery disease.  Eur J Clin Invest.1998;28:20-23.
Wilcken DE, Wang XL, Sim AS, McCredie RM. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation.  Arterioscler Thromb Vasc Biol.1996;16:878-882.
Zheng YZ, Tong J, Do XP, Pu XQ, Zhou BT. Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population.  Br J Haematol.2000;109:870-874.
Graham IM, Daly LE, Refsum HM.  et al.  Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project.  JAMA.1997;277:1775-1781.
Wu LL, Wu J, Hunt SC.  et al.  Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease.  Clin Chem.1994;40:552-561.
Silberberg JS, Crooks RL, Wlodarczyk JH, Fryer JL. Association between plasma folate and coronary disease independent of homocysteine.  Am J Cardiol.2001;87:1003-1004.
Tanis BC, van den Bosch MA, Kemmeren JM.  et al.  Oral contraceptives and the risk of myocardial infarction.  N Engl J Med.2001;345:1787-1793.
Meisel C, Cascorbi I, Gerloff T.  et al.  Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease.  Atherosclerosis.2001;154:651-658.
Abbate R, Sardi I, Pepe G.  et al.  The high prevalence of thermolabile 5-10 methylenetetrahydrofolate reductase (MTHFR) in Italians is not associated to an increased risk for coronary artery disease (CAD).  Thromb Haemost.1998;79:727-730.
Ardissino D, Mannucci PM, Merlini PA.  et al.  Prothrombotic genetic risk factors in young survivors of myocardial infarction.  Blood.1999;94:46-51.
Gemmati D, Serino ML, Trivellato C, Fiorini S, Scapoli GL. C677T substitution in the methylenetetrahydrofolate reductase gene as a risk factor for venous thrombosis and arterial disease in selected patients.  Haematologica.1999;84:824-828.
Girelli D, Friso S, Trabetti E.  et al.  Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction.  Blood.1998;91:4158-4163.
Verhoef P, Kok FJ, Kluijtmans LA.  et al.  The 677C>T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease.  Atherosclerosis.1997;132:105-113.
Verhoeff BJ, Trip MD, Prins MH, Kastelein JJ, Reitsma PH. The effect of a common methylenetetrahydrofolate reductase mutation on levels of homocysteine, folate, vitamin B12 and on the risk of premature atherosclerosis.  Atherosclerosis.1998;141:161-166.
Szczeklik A, Sanak M, Jankowski M.  et al.  Mutation A1298C of methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia.  Am J Med Genet.2001;101:36-39.
Ferrer AC, Palmeiro A, Morais J, Lourenco M, Freitas M, Providencia L. The mutation C677T in the methylene tetrahydrofolate reductase gene as a risk factor for myocardial infarction in the Portuguese population.  Thromb Haemost.1998;80:521-522.
Fernandez-Arcas N, Dieguez-Lucena JL, Munoz-Moran E.  et al.  The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction.  Atherosclerosis.1999;145:293-300.
Thogersen AM, Nilsson TK, Dahlen G.  et al.  Homozygosity for the C677>T mutation of 5,10-methylenetetrahydrofolate reductase and total plasma homocyst(e) ine are not associated with greater than normal risk of a first myocardial infarction in northern Sweden.  Coron Artery Dis.2001;12:85-90.
Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE. Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age.  Eur J Clin Invest.1999;29:1003-1009.
Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction.  QJM.1996;89:437-444.
Chambers JC, Ireland H, Thompson E.  et al.  Methylenetetrahydrofolate reductase 677 C>T mutation and coronary heart disease risk in UK Indian Asians.  Arterioscler Thromb Vasc Biol.2000;20:2448-2452.
Fowkes FG, Lee AJ, Hau CM, Cooke A, Connor JM, Lowe GD. Methylene tetrahydrofolate reductase (MTHFR) and nitric oxide synthase (ecNOS) genes and risks of peripheral arterial disease and coronary heart disease: Edinburgh Artery Study.  Atherosclerosis.2000;150:179-185.
McDowell IF, Clark ZE, Bowen DJ, Bellamy MF, Burr ML. Heteroduplex analysis for C677T genotyping of methylene tetrahydrofolate: a case-control study in men with angina.  Neth J Med.1998;52:S1-S61.
Christensen B, Frosst P, Lussier CS.  et al.  Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease.  Arterioscler Thromb Vasc Biol.1997;17:569-573.
Anderson JL, King GJ, Thomson MJ.  et al.  A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction.  J Am Coll Cardiol.1997;30:1206-1211.
Malinow MR, Nieto FJ, Kruger WD.  et al.  The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes.  Arterioscler Thromb Vasc Biol.1997;17:1157-1162.
Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infarction: a case-control study.  Circulation.1996;94:1812-1814.
Tsai MY, Welge BG, Hanson NQ.  et al.  Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases.  Atherosclerosis.1999;143:163-170.
Verhoef P, Rimm EB, Hunter DJ.  et al.  A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among US men.  J Am Coll Cardiol.1998;32:353-359.
van Bockxmeer F, Mamotte CD, Vasikaran SD, Taylor RR. Methylenetetrahydrofolate reductase gene and coronary artery disease.  Circulation.1997;95:21-23.
Morita H, Taguchi J, Kurihara H.  et al.  Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease.  Circulation.1997;95:2032-2036.
Nakai K, Fusazaki T, Suzuki T.  et al.  Genetic polymorphism of 5,10-methylenetetrahydrofolate increases risk of myocardial infarction and is correlated to elevated levels of homocysteine in the Japanese general population.  Coron Artery Dis.2000;11:47-51.
Ou T, Yamakawa-Kobayashi K, Arinami T.  et al.  Methylenetetrahydrofolate reductase and apolipoprotein E polymorphisms are independent risk factors for coronary heart disease in Japanese: a case-control study.  Atherosclerosis.1998;137:23-28.
Inbal A, Freimark D, Modan B.  et al.  Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males.  Blood.1999;93:2186-2190.
Gulec S, Aras O, Akar E.  et al.  Methylenetetrahydrofolate reductase gene polymorphism and risk of premature myocardial infarction.  Clin Cardiol.2001;24:281-284.
Tokgozoglu SL, Alikasifoglu M, Unsal I.  et al.  Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate.  Heart.1999;81:518-522.
 Nomenclature and criteria for diagnosis of ischemic heart disease: report of the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature  Circulation.1979;59:607-609.
Frosst P, Blom HJ, Milos R.  et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet.1995;10:111-113.
Clark ZE, Bowen DJ, Whatley SD, Bellamy MF, Collins PW, McDowell FW. Genotyping method for methylenetetrahydrofolate reductase (C677T thermolabile variant) using heteroduplex technology.  Clin Chem.1998;44:2360-2362.
Kozich V, Janosikova B, Kylouskova M. Coronary artery disease (CAD) study. Available at: http://www.lf1.cuni.cz/udmp/cad/. Accessed September 26, 2002.
Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk.  Am J Clin Nutr.2000;72:324-332.
Jacques PF, Bostom AG, Williams RR.  et al.  Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.  Circulation.1996;93:7-9.
Harmon DL, Woodside JV, Yarnell JW.  et al.  The common "thermolabile" variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia.  QJM.1996;89:571-577.
Ma J, Stampfer MJ, Giovannucci E.  et al.  Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer.  Cancer Res.1997;57:1098-1102.
Rimm EB, Willett WC, Hu FB.  et al.  Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.  JAMA.1998;279:359-364.
Tucker KL, Selhub J, Wilson PW, Rosenberg IH. Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study.  J Nutr.1996;126:3025-3031.
Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham offspring cohort.  Am J Clin Nutr.2001;73:613-621.
Amorim-Cruz JA, Moreiras O, Brzozowska A. Longitudinal changes in the intake of vitamins and minerals of elderly Europeans.  Eur J Clin Nutr.1996;50(suppl 2):S77-S85.
Jee SH, Beaty TH, Suh I, Yoon Y, Appel LJ. The methylenetetrahydrofolate reductase gene is associated with increased cardiovascular risk in Japan, but not in other populations.  Atherosclerosis.2000;153:161-168.
Refsum H, Ueland P, Nygard O, Vollset SE. Homocysteine and cardiovascular disease.  Ann Rev Med.1998;49:31-62.
Eikelboom JW, Lonn E, Genest Jr J, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.  Ann Intern Med.1999;131:363-375.
Gardemann A, Weidemann H, Philipp M.  et al.  The TT genotype of the methylenetetrahydrofolate reductase C677T gene polymorphism is associated with the extent of coronary atherosclerosis in patients at high risk for coronary artery disease.  Eur Heart J.1999;20:584-592.
Lievers KJ, Boers GH, Verhoef P.  et al.  A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk.  J Mol Med.2001;79:522-528.
Heijmans BT, Gussekloo J, Kluft C.  et al.  Mortality risk in men is associated with a common mutation in the methylene-tetrahydrofolate reductase gene (MTHFR).  Eur J Hum Genet.1999;7:197-204.
Anderson JL, Muhlestein JB, Horne BD.  et al.  Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease.  Circulation.2000;102:1227-1232.
Brattstrom L, Zhang Y, Hurtig M.  et al.  A common methylenetetrahydrofolate reductase gene mutation and longevity.  Atherosclerosis.1998;141:315-319.
Bladbjerg EM, Andersen RK, de Maat MP.  et al.  Longevity is independent of common variations in genes associated with cardiovascular risk.  Thromb Haemost.1999;82:1100-1105.
Hessner MJ, Dinauer DM, Kwiatkowski R, Neri B, Raife TJ. Age-dependent prevalence of vascular disease-associated polymorphisms among 2689 volunteer blood donors.  Clin Chem.2001;47:1879-1884.
Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review.  Am J Epidemiol.2000;151:862-877.
Wacholder S, Rothman N, Caporaso N. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias.  J Natl Cancer Inst.2000;92:1151-1158.
The Homocysteine Studies Collaboration.  Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA.2002;288:2015-2022.
Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? design of clinical trials to test the homocysteine hypothesis of vascular disease.  J Cardiovasc Risk.1998;5:249-255.

Figures

Figure 1. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of Coronary Heart Disease for MTHFR 677 TT vs CC Genotype by Region of Origin
Graphic Jump Location
The size of the data markers is inversely proportional to the variance of the log ORs; horizontal lines represent the 95% CIs. Studies are ordered by the number of cases in each region. The combined ORs and the subtotals for each region and their 95% CIs are indicated by the diamonds.
Figure 2. Funnel Plot of the Odds Ratios (ORs) of Coronary Heart Disease (CHD) for MTHFR TT vs CC Genotype for Each Study by Number of Individuals Studied
Graphic Jump Location
The plot shows the ORs for the 34 published and 6 unpublished studies and the 12 studies that were unavailable for inclusion in this analysis. Among the unavailable studies, 1 study23 was omitted because the OR could not be abstracted and another study29 was included twice because the data were presented separately in 2 different populations. The summary estimate of the OR of CHD for TT compared with CC is represented by a vertical dotted line.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Included Studies*
Table Graphic Jump LocationTable 2. Distribution of Homocysteine and Folate Levels and Prevalence of Known Cardiovascular Risk Factors for Cases and Controls and by Subgroup of the MTHFR 677C→T Genotype*
Table Graphic Jump LocationTable 3. Odds Ratios (ORs) of Coronary Heart Disease (CHD) by Strata of the MTHFR 677C→T Polymorphism and Folate Status*

References

Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies.  J Cardiovasc Risk.1998;5:229-232.
Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect?  Am J Clin Nutr.2000;72:315-323.
Verhoef P, Stampfer MJ, Rimm EB. Folate and coronary heart disease.  Curr Opin Lipidol.1998;9:17-22.
Folsom AR, Nieto FJ, McGovern PG.  et al.  Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study.  Circulation.1998;98:204-210.
Voutilainen S, Lakka TA, Porkkala SE, Rissanen T, Kaplan GA, Salonen JT. Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study.  Eur J Clin Nutr.2000;54:424-428.
Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Low dietary folate intake is associated with an excess incidence of acute coronary events—the Kuopio Ischemic Heart Disease Risk Factor Study.  Circulation.2001;103:2674-2680.
Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst(e)inaemia: restoration by folic acid.  Clin Sci (Colch).1999;96:235-239.
Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis.  Circulation.1998;98:2520-2526.
van der Put NM, Steegers-Theunissen R, Frosst P.  et al.  Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida.  Lancet.1995;346:1070-1071.
Deloughery TG, Evans A, Sadeghi A.  et al.  Common mutation in methylenetetrahydrofolate reductase: correlation with homocysteine metabolism and late-onset vascular disease.  Circulation.1996;94:3074-3078.
Ma J, Stampfer MJ, Hennekens CH.  et al.  Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians.  Circulation.1996;94:2410-2416.
Schwartz SM, Siscovick DS, Malinow MR.  et al.  Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene.  Circulation.1997;96:412-417.
McQuillan BM, Beilby JP, Nidorf M, Thompson PL, Hung J. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening: the Perth Carotid Ultrasound Disease Assessment Study (CUDAS).  Circulation.1999;99:2383-2388.
Kluijtmans LA, Kastelein JJ, Lindemans J.  et al.  Thermolabile methylenetetrahydrofolate reductase in coronary artery disease.  Circulation.1997;96:2573-2577.
Blom HJ, Verhoef P. Hyperhomocysteinemia, MTHFR, and risk of vascular disease.  Circulation.2000;101:E171.
Araujo F, Lopes M, Goncalves L, Maciel MJ, Cunha RL. Hyperhomocysteinemia, MTHFR C677T genotype and low folate levels: a risk combination for acute coronary disease in a Portuguese population.  Thromb Haemost.2000;83:517-518.
Chao CL, Tsai HH, Lee CM.  et al.  The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis.  Atherosclerosis.1999;147:379-386.
Mager A, Lalezari S, Shohat T.  et al.  Methylenetetrahydrofolate reductase genotypes and early-onset coronary artery disease.  Circulation.1999;100:2406-2410.
Raslova K, Smolkova B, Vohnout B, Gasparovic J, Frohlich JJ. Risk factors for atherosclerosis in survivors of myocardial infarction and their spouses: comparison to controls without personal and family history of atherosclerosis.  Metabolism.2001;50:24-29.
Thuillier L, Chadefaux-Vekemans B, Bonnefont JP.  et al.  Does the polymorphism 677C-T of the 5,10-methylenetetrahydrofolate reductase gene contribute to homocysteine-related vascular disease?  J Inherit Metab Dis.1998;21:812-822.
Roest M, van der Schouw YT, Grobbee DE.  et al.  Methylenetetrahydrofolate reductase 677 C/T genotype and cardiovascular disease mortality in postmenopausal women.  Am J Epidemiol.2001;153:673-679.
Brugada R, Marian AJ. A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction.  Atherosclerosis.1997;128:107-112.
Chen TY, Chen JH, Tsao CJ. Methylenetetrahydrofolate reductase gene polymorphism and coronary artery disease in Taiwan Chinese.  Haematologica.2000;85:445-446.
Goracy I, Goracy J, Suliga M, Ciechanowicz A. Polimorfizm C677T genu reduktazy metylenotetrahydrofolianu (MTHFR) u chorych po przebytym zawale miesnia sercowego [C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in patients with myocardial infarction].  Pol Arch Med Wewn.1999;102:849-854.
Hsu LA, Ko YL, Wang SM.  et al.  The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan.  Hum Hered.2001;51:41-45.
Izumi M, Iwai N, Ohmichi N, Nakamura Y, Shimoike H, Kinoshita M. Molecular variant of 5,10-methylenetetrahydrofolate reductase is a risk factor of ischemic heart disease in the Japanese population.  Atherosclerosis.1996;121:293-294.
Kim CH, Hwang KY, Choi TM, Shin WY, Hong SY. The methylenetetrahydrofolate reductase gene polymorphism in Koreans with coronary artery disease.  Int J Cardiol.2001;78:13-17.
Kostulas K, Crisby M, Huang WX.  et al.  A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis.  Eur J Clin Invest.1998;28:285-289.
Malik NM, Syrris P, Schwartzman R.  et al.  Methylenetetrahydrofolate reductase polymorphism (C-677T) and coronary artery disease.  Clin Sci.1998;95:311-315.
Narang R, Callaghan G, Haider AW, Davies GJ, Tuddenham EG. Methylenetetrahydrofolate reductase mutation and coronary artery disease.  Circulation.1996;94:2322-2323.
Pinto X, Vilaseca MA, Garcia GN.  et al.  Homocysteine and the MTHFR 677C>T allele in premature coronary artery disease: case control and family studies.  Eur J Clin Invest.2001;31:24-30.
Reinhardt D, Sigusch HH, Vogt SF, Farker K, Muller S, Hoffmann A. Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and the risk of coronary artery disease.  Eur J Clin Invest.1998;28:20-23.
Wilcken DE, Wang XL, Sim AS, McCredie RM. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation.  Arterioscler Thromb Vasc Biol.1996;16:878-882.
Zheng YZ, Tong J, Do XP, Pu XQ, Zhou BT. Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population.  Br J Haematol.2000;109:870-874.
Graham IM, Daly LE, Refsum HM.  et al.  Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project.  JAMA.1997;277:1775-1781.
Wu LL, Wu J, Hunt SC.  et al.  Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease.  Clin Chem.1994;40:552-561.
Silberberg JS, Crooks RL, Wlodarczyk JH, Fryer JL. Association between plasma folate and coronary disease independent of homocysteine.  Am J Cardiol.2001;87:1003-1004.
Tanis BC, van den Bosch MA, Kemmeren JM.  et al.  Oral contraceptives and the risk of myocardial infarction.  N Engl J Med.2001;345:1787-1793.
Meisel C, Cascorbi I, Gerloff T.  et al.  Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease.  Atherosclerosis.2001;154:651-658.
Abbate R, Sardi I, Pepe G.  et al.  The high prevalence of thermolabile 5-10 methylenetetrahydrofolate reductase (MTHFR) in Italians is not associated to an increased risk for coronary artery disease (CAD).  Thromb Haemost.1998;79:727-730.
Ardissino D, Mannucci PM, Merlini PA.  et al.  Prothrombotic genetic risk factors in young survivors of myocardial infarction.  Blood.1999;94:46-51.
Gemmati D, Serino ML, Trivellato C, Fiorini S, Scapoli GL. C677T substitution in the methylenetetrahydrofolate reductase gene as a risk factor for venous thrombosis and arterial disease in selected patients.  Haematologica.1999;84:824-828.
Girelli D, Friso S, Trabetti E.  et al.  Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction.  Blood.1998;91:4158-4163.
Verhoef P, Kok FJ, Kluijtmans LA.  et al.  The 677C>T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease.  Atherosclerosis.1997;132:105-113.
Verhoeff BJ, Trip MD, Prins MH, Kastelein JJ, Reitsma PH. The effect of a common methylenetetrahydrofolate reductase mutation on levels of homocysteine, folate, vitamin B12 and on the risk of premature atherosclerosis.  Atherosclerosis.1998;141:161-166.
Szczeklik A, Sanak M, Jankowski M.  et al.  Mutation A1298C of methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia.  Am J Med Genet.2001;101:36-39.
Ferrer AC, Palmeiro A, Morais J, Lourenco M, Freitas M, Providencia L. The mutation C677T in the methylene tetrahydrofolate reductase gene as a risk factor for myocardial infarction in the Portuguese population.  Thromb Haemost.1998;80:521-522.
Fernandez-Arcas N, Dieguez-Lucena JL, Munoz-Moran E.  et al.  The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction.  Atherosclerosis.1999;145:293-300.
Thogersen AM, Nilsson TK, Dahlen G.  et al.  Homozygosity for the C677>T mutation of 5,10-methylenetetrahydrofolate reductase and total plasma homocyst(e) ine are not associated with greater than normal risk of a first myocardial infarction in northern Sweden.  Coron Artery Dis.2001;12:85-90.
Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE. Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age.  Eur J Clin Invest.1999;29:1003-1009.
Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction.  QJM.1996;89:437-444.
Chambers JC, Ireland H, Thompson E.  et al.  Methylenetetrahydrofolate reductase 677 C>T mutation and coronary heart disease risk in UK Indian Asians.  Arterioscler Thromb Vasc Biol.2000;20:2448-2452.
Fowkes FG, Lee AJ, Hau CM, Cooke A, Connor JM, Lowe GD. Methylene tetrahydrofolate reductase (MTHFR) and nitric oxide synthase (ecNOS) genes and risks of peripheral arterial disease and coronary heart disease: Edinburgh Artery Study.  Atherosclerosis.2000;150:179-185.
McDowell IF, Clark ZE, Bowen DJ, Bellamy MF, Burr ML. Heteroduplex analysis for C677T genotyping of methylene tetrahydrofolate: a case-control study in men with angina.  Neth J Med.1998;52:S1-S61.
Christensen B, Frosst P, Lussier CS.  et al.  Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease.  Arterioscler Thromb Vasc Biol.1997;17:569-573.
Anderson JL, King GJ, Thomson MJ.  et al.  A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction.  J Am Coll Cardiol.1997;30:1206-1211.
Malinow MR, Nieto FJ, Kruger WD.  et al.  The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes.  Arterioscler Thromb Vasc Biol.1997;17:1157-1162.
Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infarction: a case-control study.  Circulation.1996;94:1812-1814.
Tsai MY, Welge BG, Hanson NQ.  et al.  Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases.  Atherosclerosis.1999;143:163-170.
Verhoef P, Rimm EB, Hunter DJ.  et al.  A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among US men.  J Am Coll Cardiol.1998;32:353-359.
van Bockxmeer F, Mamotte CD, Vasikaran SD, Taylor RR. Methylenetetrahydrofolate reductase gene and coronary artery disease.  Circulation.1997;95:21-23.
Morita H, Taguchi J, Kurihara H.  et al.  Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease.  Circulation.1997;95:2032-2036.
Nakai K, Fusazaki T, Suzuki T.  et al.  Genetic polymorphism of 5,10-methylenetetrahydrofolate increases risk of myocardial infarction and is correlated to elevated levels of homocysteine in the Japanese general population.  Coron Artery Dis.2000;11:47-51.
Ou T, Yamakawa-Kobayashi K, Arinami T.  et al.  Methylenetetrahydrofolate reductase and apolipoprotein E polymorphisms are independent risk factors for coronary heart disease in Japanese: a case-control study.  Atherosclerosis.1998;137:23-28.
Inbal A, Freimark D, Modan B.  et al.  Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males.  Blood.1999;93:2186-2190.
Gulec S, Aras O, Akar E.  et al.  Methylenetetrahydrofolate reductase gene polymorphism and risk of premature myocardial infarction.  Clin Cardiol.2001;24:281-284.
Tokgozoglu SL, Alikasifoglu M, Unsal I.  et al.  Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate.  Heart.1999;81:518-522.
 Nomenclature and criteria for diagnosis of ischemic heart disease: report of the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature  Circulation.1979;59:607-609.
Frosst P, Blom HJ, Milos R.  et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet.1995;10:111-113.
Clark ZE, Bowen DJ, Whatley SD, Bellamy MF, Collins PW, McDowell FW. Genotyping method for methylenetetrahydrofolate reductase (C677T thermolabile variant) using heteroduplex technology.  Clin Chem.1998;44:2360-2362.
Kozich V, Janosikova B, Kylouskova M. Coronary artery disease (CAD) study. Available at: http://www.lf1.cuni.cz/udmp/cad/. Accessed September 26, 2002.
Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk.  Am J Clin Nutr.2000;72:324-332.
Jacques PF, Bostom AG, Williams RR.  et al.  Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.  Circulation.1996;93:7-9.
Harmon DL, Woodside JV, Yarnell JW.  et al.  The common "thermolabile" variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia.  QJM.1996;89:571-577.
Ma J, Stampfer MJ, Giovannucci E.  et al.  Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer.  Cancer Res.1997;57:1098-1102.
Rimm EB, Willett WC, Hu FB.  et al.  Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.  JAMA.1998;279:359-364.
Tucker KL, Selhub J, Wilson PW, Rosenberg IH. Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study.  J Nutr.1996;126:3025-3031.
Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham offspring cohort.  Am J Clin Nutr.2001;73:613-621.
Amorim-Cruz JA, Moreiras O, Brzozowska A. Longitudinal changes in the intake of vitamins and minerals of elderly Europeans.  Eur J Clin Nutr.1996;50(suppl 2):S77-S85.
Jee SH, Beaty TH, Suh I, Yoon Y, Appel LJ. The methylenetetrahydrofolate reductase gene is associated with increased cardiovascular risk in Japan, but not in other populations.  Atherosclerosis.2000;153:161-168.
Refsum H, Ueland P, Nygard O, Vollset SE. Homocysteine and cardiovascular disease.  Ann Rev Med.1998;49:31-62.
Eikelboom JW, Lonn E, Genest Jr J, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.  Ann Intern Med.1999;131:363-375.
Gardemann A, Weidemann H, Philipp M.  et al.  The TT genotype of the methylenetetrahydrofolate reductase C677T gene polymorphism is associated with the extent of coronary atherosclerosis in patients at high risk for coronary artery disease.  Eur Heart J.1999;20:584-592.
Lievers KJ, Boers GH, Verhoef P.  et al.  A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk.  J Mol Med.2001;79:522-528.
Heijmans BT, Gussekloo J, Kluft C.  et al.  Mortality risk in men is associated with a common mutation in the methylene-tetrahydrofolate reductase gene (MTHFR).  Eur J Hum Genet.1999;7:197-204.
Anderson JL, Muhlestein JB, Horne BD.  et al.  Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease.  Circulation.2000;102:1227-1232.
Brattstrom L, Zhang Y, Hurtig M.  et al.  A common methylenetetrahydrofolate reductase gene mutation and longevity.  Atherosclerosis.1998;141:315-319.
Bladbjerg EM, Andersen RK, de Maat MP.  et al.  Longevity is independent of common variations in genes associated with cardiovascular risk.  Thromb Haemost.1999;82:1100-1105.
Hessner MJ, Dinauer DM, Kwiatkowski R, Neri B, Raife TJ. Age-dependent prevalence of vascular disease-associated polymorphisms among 2689 volunteer blood donors.  Clin Chem.2001;47:1879-1884.
Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review.  Am J Epidemiol.2000;151:862-877.
Wacholder S, Rothman N, Caporaso N. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias.  J Natl Cancer Inst.2000;92:1151-1158.
The Homocysteine Studies Collaboration.  Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA.2002;288:2015-2022.
Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? design of clinical trials to test the homocysteine hypothesis of vascular disease.  J Cardiovasc Risk.1998;5:249-255.
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