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MTHFR 677C T Polymorphism and Risk of Coronary Heart Disease
A Meta-analysis
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
JAMA. 2002;288:2023-2031.
ABSTRACT
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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 677CT 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 677CT 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 Data were obtained from 40 (34 published and 6 unpublished) observational studies involving a total of 11 162 cases and 12 758 controls.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 677CT 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 677CT 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 677CT 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.
INTRODUCTION
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 677CT 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.
METHODS
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 677CT 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 677CT polymorphism and CHD risk, 6 studies were not included because they did not have a proper case-control design16-20 or they studied cardiovascular mortality21 only. Data on 13 further studies were unavailable because the investigators were unable or unwilling to collaborate.22-34 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,35-38 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, 39-67 and 6 unpublished35-38) involving 11 162 cases and 12 758 controls (Table 1).
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Table 1. Characteristics of Included Studies*
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Data Extraction
Data were collected on MTHFR 677CT 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 677CT 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  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 677CT genotypes were assessed using analysis of variance for continuous data and  2 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 2 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 2 tests.
To explore interaction between the MTHFR 677CT 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).
RESULTS
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 677CT 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 677CT 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.
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Table 2. Distribution of Homocysteine and Folate Levels and Prevalence of Known Cardiovascular Risk Factors for Cases and Controls and by Subgroup of the MTHFR 677CT Genotype*
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MTHFR 677CT 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 (239 = 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 (221 = 27.1; P = .17) or North American studies (29 = 4.2; P = .90), but there was significant heterogeneity between the pooled estimates for Europe and North America (21 = 6.6; P = .01). Data on studies from other continents were too sparse to assess a continent-specific OR.
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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
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.
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Effect Modification by Folate Status
The heterogeneity between European and North American studies may be explained by an interaction between MTHFR 677CT polymorphism and folate status. Table 3 shows ORs of CHD within strata of the MTHFR 677CT 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 677CT polymorphism and folate status.
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Table 3. Odds Ratios (ORs) of Coronary Heart Disease (CHD) by Strata of the MTHFR 677CT Polymorphism and Folate Status*
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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 (21 = 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.
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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
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.
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COMMENT
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 677CT 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 677CT 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, 75-78 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, 80-83 or linkage disequilibrium with other polymorphisms, such as the MTHFR 1298AC 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 677CT polymorphism and mortality or longevity have shown inconsistent results.20, 85-89 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 677CT genotype in the general population for prediction of CHD risk.
AUTHOR INFORMATION
Author Contributions: Study concept and design: Klerk, Verhoef, Clarke, Blom, Kok, Schouten.
Acquisition of data: Klerk.
Analysis and interpretation of data: Klerk, Verhoef, Clarke, Blom, Kok, Schouten.
Drafting of the manuscript: Klerk, Verhoef, Blom, Schouten.
Critical revision of the manuscript for important intellectual content: Verhoef, Clarke, Blom, Kok, Shouten.
Statistical expertise: Klerk, Verhoef, Clarke, Schouten.
Obtained funding: Verhoef, Blom, Kok, Schouten.
Administrative, technical, or material support: Klerk, Blom.
Study supervision: Verhoef, Clarke, Blom, Kok, Schouten.
Author Contributions for the MTHFR Studies Collaboration Group: Study concept and design: Hopkins, Jukema.
Acquisition of data: Abbate, Marcucci, Samani, Anderson, Zebrack, Ardissino, Merlini, van Bockxmeer, Brownrigg, Chambers, Kooner, Genest, Rozen, Ferrer-Antunes, Palmeiro, Fernandez-Arcas, Reyes-Engel, Folsom, Fowkes, Lee, Gemmati, Scapoli, Girelli, Corrocher, Gulec, Hopkins, Inbal, Selighson, Kluijtmans, Jukema, Kozich, Janosikova, Ma, Stampfer, Malinow, Ashfield-Watt, Clark, Meisel, Stangl, Graham, Morita, Nagai, Nakai, Yamakawa-Kobayashi, Hamaguchi, Gaziano, Schwartz, Siscovick, Silberberg, Szczeklik, Domagala, Tanis, Rosendaal, Thogersen, Nilsson, Todesco, Litynski, Tokgozoglu, Tsai, Hanson, Rimm, Verhoeff, Trip.
Analysis and interpretation of data: Genest, Fernandez-Arcas, Reyes-Engel, Fowkes, Gulec, Hopkins, Kluijtmans, Ma, Stampfer, Malinow, Schwartz, Siscovick, Tanis, Thogersen, Nilsson, Todesco.
Drafting of the manuscript: Kooner, Rozen, Jukema, Clark, Szczeklik, Domagala.
Critical revision of the manuscript for important intellectual content: Abbate, Marcucci, Samani, Anderson, Zebrack, Ardissino, Merlini, van Bockxmeer, Brownrigg, Chambers, Kooner, Genest, Rozen, Ferrer-Antunes, Palmeiro, Fernandez-Arcas, Reyes-Engel, Folsom, Fowkes, Lee, Gemmati, Scapoli, Girelli, Corrocher, Gulec, Hopkins, Inbal, Selighson, Kluijtmans, Kozich, Janosikova, Ma, Stampfer, Malinow, Ashfield-Watt, Meisel, Stangl, Graham, Morita, Nagai, Nakai, Yamakawa-Kobayashi, Hamaguchi, Gaziano, Schwartz, Siscovick, Silberberg, Szczeklik, Tanis, Rosendaal, Thogersen, Nilsson, Todesco, Litynski, Tokgozoglu, Tsai, Hanson, Rimm, Verhoeff, Trip.
Statistical expertise: Hopkins, Inbal, Jukema, Stampfer, Meisel, Szczeklik, Rosendaal.
Obtained funding: Genest, Rozen, Fowkes, Girelli, Corrocher, Tokgozoglu, Rimm.
Administrative, technical, or material support: Samani, Ardissino, Merlini, van Bockxmeer, Folsom, Gulec, Hopkins, Kluijtmans, Jukema, Ashfield-Watt, Clark, Stangl, Gaziano, Szczeklik, Domagala, Tanis, Thogersen.
Study supervision: Fernandez-Arcas, Reyes-Engel, Fowkes, Selighson, Kluijtmans, Jukema.
Members of the MTHFR Studies Collaboration Group: R. Abbate, R. Marcucci, Instituto di Clinica Medica Generale e Cardiologia, University of Florence, Florence, Italy; N. J. Samani, Department of Cardiology, Glenfield Hospital, Leicester, England; J. L. Anderson, J. S. Zebrack, University of Utah, Salt Lake City; D. Ardissino, F. M. Merlini, Angelo Bianchi Bonomi, Hemophilia and Thrombosis Center, Milan, Italy; F. M. van Bockxmeer, L. Brownrigg, Department of Biochemistry, Royal Perth Hospital, Perth, Australia; J. Chambers, J. S. Kooner, National Heart and Lung Institute, Hammersmith Hospital Campus, London, England; J. Genest, Department of Cardiology, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec; R. Rozen, Montreal Children's Hospital, Montreal, Quebec; C. Ferrer-Antunes, A. Palmeiro, Lab. de Hematologia, Hospitais da Universidade de Coimbra, Coimbra, Portugal; N. Fernandez-Arcas, A. Reyes-Engel, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Malaga, Spain; A. R. Folsom, Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis; F. G. R. Fowkes, A. J. Lee, Wolfson Unit for Prevention of Peripheral Vascular Disease, Community Health Sciences, University of Edinburgh, Edinburgh, Scotland; D. Gemmati, G. L. Scapoli, Center for Study of Haemostasis and Thrombosis, University of Ferrara, Ferrara, Italy; D. Girelli, R. Corrocher, Department of Clinical and Experimental Medicine, Policlinico G. B. Rossi, Verona, Italy; S. Gulec, Medical School of Ankara University, Ankara, Turkey; P. N. Hopkins, Cardiovascular Genetics, Salt Lake City, Utah; A. Inbal, U. Selighson, Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; L. A. J. Kluijtmans, Laboratory of Paediatrics and Neurlogy, University Medical Center Nijmegen, Nijmegen, the Netherlands; J. W. Jukema, Division of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; V. Kozich, B. Janosikova, Institute of IMD, Charles University, First Faculty of Medicine, Prague, Czech Republic; J. Ma, M. J. Stampfer, Channing Laboratory, Boston, Mass; M. R. Malinow, Oregon Regional Primate Research Center, Bearerton; P. A. L. Ashfield-Watt, Z. E. Clark, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff; C. Meisel, K. Stangl, Institut fur Klinische Pharmakologie, Universitätsklinikum Charite, Berlin, Germany; I. M. Graham, Department of Cardiology, the Adelaide and Meath Hospital, Dublin, Ireland; H. Morita, Department of Genetics, Harvard Medical School, Boston, Mass; R. Nagai, Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan; K. Nakai, Laboratory Medicine, Iwate Medical University, Morioka, Japan; K. Yamakawa-Kobayashi, H. Hamaguchi, Department of Medical Genetics, University of Tsukuba, Institute of Basic Medical Science, Tsukuba, Japan; M. Gaziano, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Mass; S. M. Schwartz, D. S. Siscovick, Cardiovascular Health Unit, Seattle, Wash; J. S. Silberberg, Cardiovascular Unit, John Hunter Hospital, New Castle, Australia; A. Szczeklik, B. Domagala Teresa, Department of Medicine, Jagiellonian University School of Medicine, Krakow, Poland; B. C. Tanis, F. M. Rosendaal, Division of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; A. M. Thogersen, T. K. Nilsson, Department of Medicine, Umea University Hospital, Umea, Sweden; L. Todesco, Division of Clinical Pharmacology, University of Basel, Basel, Switzerland; P. Litynsky, University Children's Hospital Basel, Basel, Swizerland; S. L. Tokgozoglu, Department of Cardiology, Hacettepe University Faculty Medicine, Ankara, Turkey; M. Y. Tsai, N. Q. Hanson, Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis; E. B. Rimm, Epidemiology and Nutrition, Harvard School of Public Health, Boston, Mass; B. J. Verhoeff, and M. D. Trip, Division of Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
Funding/Support: This work was financially supported by grants from the Dutch Organization for Scientific Research and the Wageningen Centre for Food Sciences. Henk Blom is an established investigator of the Netherlands Heart Foundation (D97.021).
Acknowledgment: We thank Sarah Lewington and Martijn Katan for their helpful comments on the protocol and manuscript and Paul Sherliker for graphic production.
Corresponding Author and Reprints: Petra Verhoef, PhD, Wageningen Centre for Food Sciences and Division of Human Nutrition and Epidemiology, Wageningen University, PO Box 8129, 6700 EV Wageningen, the Netherlands (e-mail: petra.verhoef{at}staff.nutepi.wau.nl).
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).
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Response to Letter Regarding Article, "Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism"
McNulty et al.
Circulation 2006;114:e66-e66.
FULL TEXT
Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: A randomized controlled study
Postuma et al.
Neurology 2006;66:1941-1943.
ABSTRACT
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The Many Facets of Hyperhomocysteinemia: Studies from the Framingham Cohorts
Selhub
J. Nutr. 2006;136:1726S-1730S.
ABSTRACT
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The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease
Refsum et al.
J. Nutr. 2006;136:1731S-1740S.
ABSTRACT
| FULL TEXT
Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease
The Heart Outcomes Prevention Evaluation (HOPE) 2
NEJM 2006;354:1567-1577.
ABSTRACT
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Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation
van Beynum et al.
Eur Heart J 2006;27:981-987.
ABSTRACT
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Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population
Devlin et al.
Am. J. Clin. Nutr. 2006;83:708-713.
ABSTRACT
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Methylenetetrahydrofolate Reductase Polymorphisms and Homocysteine-Lowering Effect of Vitamin Therapy in Singaporean Stroke Patients
Ho et al.
Stroke 2006;37:456-460.
ABSTRACT
| FULL TEXT
Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism
McNulty et al.
Circulation 2006;113:74-80.
ABSTRACT
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The Glycine N-Methyltransferase (GNMT) 1289 C->T Variant Influences Plasma Total Homocysteine Concentrations in Young Women after Restricting Folate Intake
Beagle et al.
J. Nutr. 2005;135:2780-2785.
ABSTRACT
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The choice of a genetic model in the meta-analysis of molecular association studies
Minelli et al.
Int J Epidemiol 2005;34:1319-1328.
ABSTRACT
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JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice
Prepared by: British Cardiac Society, British Hype
Heart 2005;91:v1-v52.
FULL TEXT
Homocysteine and Its Effects on In-Stent Restenosis
De Luca et al.
Circulation 2005;112:e307-e311.
FULL TEXT
Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?
Lewis et al.
BMJ 2005;331:1053.
ABSTRACT
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Assessment of Hemostatic Risk Factors in Predicting Arterial Thrombotic Events
Feinbloom and Bauer
Arterioscler. Thromb. Vasc. Bio. 2005;25:2043-2053.
ABSTRACT
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A high-protein diet increases postprandial but not fasting plasma total homocysteine concentrations: a dietary controlled, crossover trial in healthy volunteers
Verhoef et al.
Am. J. Clin. Nutr. 2005;82:553-558.
ABSTRACT
| FULL TEXT
Review: Diabetes and cardiac disease in South Asians
Mukhopadhyay et al.
British Journal of Diabetes & Vascular Disease 2005;5:253-259.
ABSTRACT
Cerebral Vascular Dysfunction in Methionine Synthase-Deficient Mice
Dayal et al.
Circulation 2005;112:737-744.
ABSTRACT
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Polymorphisms in Cytoplasmic Serine Hydroxymethyltransferase and Methylenetetrahydrofolate Reductase Affect the Risk of Cardiovascular Disease in Men
Lim et al.
J. Nutr. 2005;135:1989-1994.
ABSTRACT
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Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine
Chiuve et al.
Am. J. Clin. Nutr. 2005;82:155-162.
ABSTRACT
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Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease
Varga et al.
Circulation 2005;111:e289-e293.
FULL TEXT
Conditional Risk Factors for Atherosclerosis
Kullo and Ballantyne
Mayo Clin Proc. 2005;80:219-230.
ABSTRACT
Hyperhomocysteinemic Diabetic Cardiomyopathy: Oxidative Stress, Remodeling, and Endothelial-Myocyte Uncoupling
Tyagi et al.
J CARDIOVASC PHARMACOL THER 2005;10:1-10.
ABSTRACT
Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study
Frederiksen et al.
Blood 2004;104:3046-3051.
ABSTRACT
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Folate levels determine effect of antioxidant supplementation on micronuclei in subjects with cardiovascular risk
Smolkova et al.
Mutagenesis 2004;19:469-476.
ABSTRACT
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Meta-analysis of Genetic Studies in Ischemic Stroke: Thirty-two Genes Involving Approximately 18 000 Cases and 58 000 Controls
Casas et al.
Arch Neurol 2004;61:1652-1661.
ABSTRACT
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Genetic Basis of Atherosclerosis: Part II: Clinical Implications
Lusis et al.
Circulation 2004;110:2066-2071.
FULL TEXT
Phenotypic expression of the methylenetetrahydrofolate reductase 677C->T polymorphism and flavin cofactor availability in thyroid dysfunction
Hustad et al.
Am. J. Clin. Nutr. 2004;80:1050-1057.
ABSTRACT
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Homocysteine and levodopa: Should Parkinson disease patients receive preventative therapy?
Postuma and Lang
Neurology 2004;63:886-891.
ABSTRACT
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Dietary serine and cystine attenuate the homocysteine-raising effect of dietary methionine: a randomized crossover trial in humans
Verhoef et al.
Am. J. Clin. Nutr. 2004;80:674-679.
ABSTRACT
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Bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid in subjects with different genotypes of the glutamate carboxypeptidase II gene
Melse-Boonstra et al.
Am. J. Clin. Nutr. 2004;80:700-704.
ABSTRACT
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An Integrated Approach to the Meta-Analysis of Genetic Association Studies using Mendelian Randomization
Minelli et al.
Am J Epidemiol 2004;160:445-452.
ABSTRACT
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Hyperhomocysteinemia in Patients with Cushing's Syndrome
Terzolo et al.
J. Clin. Endocrinol. Metab. 2004;89:3745-3751.
ABSTRACT
| FULL TEXT
Folic Acid-Based Multivitamin Therapy to Prevent Stroke: The Jury Is Still Out
Hankey and Eikelboom
Stroke 2004;35:1995-1998.
FULL TEXT
Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events
Ridker et al.
Circulation 2004;109:IV-6-IV-19.
FULL TEXT
5,10-methylenetetrahydrofolate reductase (MTHFR) 677C->T and 1298A->C mutations are associated with DNA hypomethylation
Castro et al.
J. Med. Genet. 2004;41:454-458.
FULL TEXT
A healthy lifestyle lowers homocysteine, but should we care?
Verhoef and Katan
Am. J. Clin. Nutr. 2004;79:713-714.
FULL TEXT
Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice
Devlin et al.
Blood 2004;103:2624-2629.
ABSTRACT
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Cross-talk between Cys34 and Lysine Residues in Human Serum Albumin Revealed by N-Homocysteinylation
Glowacki and Jakubowski
J. Biol. Chem. 2004;279:10864-10871.
ABSTRACT
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Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: A HuGE Review
Sharp and Little
Am J Epidemiol 2004;159:423-443.
ABSTRACT
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Commentary: Mendelian randomization, 18 years on
Katan
Int J Epidemiol 2004;33:10-11.
FULL TEXT
Mendelian randomization: prospects, potentials, and limitations
Smith and Ebrahim
Int J Epidemiol 2004;33:30-42.
FULL TEXT
Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion
Refsum et al.
Clin. Chem. 2004;50:3-32.
ABSTRACT
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Red cell N5-methyltetrahydrofolate concentrations and C677T methylenetetrahydrofolate reductase genotype in patients with stroke
Icke et al.
J. Clin. Pathol. 2004;57:54-57.
ABSTRACT
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The atherogenic effect of excess methionine intake
Troen et al.
Proc. Natl. Acad. Sci. USA 2003;100:15089-15094.
ABSTRACT
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Controlled Modulation of Folate Polyglutamyl Tail Length by Metabolic Engineering of Lactococcus lactis
Sybesma et al.
Appl. Environ. Microbiol. 2003;69:7101-7107.
ABSTRACT
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Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women
Olthof et al.
J. Nutr. 2003;133:4135-4138.
ABSTRACT
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Homocysteine Status and Polymorphisms of Methylenetetrahydrofolate Reductase Are Not Associated With Restenosis After Stenting in Coronary Arteries
Koch et al.
Arterioscler. Thromb. Vasc. Bio. 2003;23:2229-2234.
ABSTRACT
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Age and Gender Affect the Relation between Methylenetetrahydrofolate Reductase C677T Genotype and Fasting Plasma Homocysteine Concentrations in the Framingham Offspring Study Cohort
Russo et al.
J. Nutr. 2003;133:3416-3421.
ABSTRACT
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Colon Cancer and Genetic Variation in Folate Metabolism: The Clinical Bottom Line
Little et al.
J. Nutr. 2003;133:3758S-3766.
ABSTRACT
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Homocysteine and the Risk of Intrauterine Growth Retardation
Cattaneo
Clin. Chem. 2003;49:1432-1433.
FULL TEXT
The Use of B Vitamin Supplements and Peripheral Arterial Disease Risk in Men Are Inversely Related
Merchant et al.
J. Nutr. 2003;133:2863-2867.
ABSTRACT
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Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke: A Multicenter Case-Control Study in China
Li et al.
Stroke 2003;34:2085-2090.
ABSTRACT
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Emerging Risk Factors for Atherosclerotic Vascular Disease: A Critical Review of the Evidence
Hackam and Anand
JAMA 2003;290:932-940.
ABSTRACT
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Influence of Centrifugation Temperature on the Plasma Total Homocysteine Concentration
de Bree et al.
Clin. Chem. 2003;49:1026-1027.
FULL TEXT
Folate and risk of cardiovascular disease
Wald et al.
BMJ 2003;326:1035-1035.
FULL TEXT
ADDITIONAL ARTICLES ABSTRACTED IN ACP JOURNAL CLUB
Evid. Based Med. 2003;8:67-67.
FULL TEXT
Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study
van Oort et al.
Am. J. Clin. Nutr. 2003;77:1318-1323.
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