 |
|
Homocysteine and Risk of Ischemic Heart Disease and Stroke
A Meta-analysis
Homocysteine Studies Collaboration
JAMA. 2002;288:2015-2022.
ABSTRACT
| |
Context It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke.
Objective To assess the relationship of homocysteine concentrations with vascular disease risk.
Data Sources MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators.
Study Selection Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete.
Data Extraction Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression.
Data Synthesis Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 µmol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk.
Conclusions This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.
INTRODUCTION
The hypothesis that elevated blood concentrations of the sulfur-containing amino acid homocysteine may be a risk factor for cardiovascular disease was suggested by the observation that children with homozygous homocystinuria, a rare inborn error of metabolism causing markedly elevated blood total homocysteine concentrations, had a high incidence of premature occlusive vascular disease.1 The initial epidemiological evidence in support of this hypothesis came from retrospective case-control studies.2-4 More recently, however, inconsistent results have been reported from prospective observational studies, including cohort and nested case-control studies, with some showing highly significant associations but others showing none.5
The aim of this collaborative meta-analysis was to combine individual participant data from all relevant observational studies to produce reliable estimates of the associations of total plasma homocysteine with ischemic heart disease (IHD) and stroke, with adjustment for confounding caused by known cardiovascular risk factors and correction for regression dilution caused by random variation in homocysteine measurements.6-7 The chief emphasis in this report is on combined analyses of the prospective studies (which involve the measurement of homocysteine in blood collected before the onset of disease) rather than on the retrospective studies, since the former should be less prone to artifacts produced by any effects of preexisting vascular disease on homocysteine levels (referred to as reverse causality).
METHODS
Study Populations
Relevant studies were identified by systematic searches of the scientific literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations (using the terms coronary heart disease, myocardial infarction, cerebrovascular disease, stroke, cardiovascular disease, homocysteine or homocyst(e)ine, and hyperhomocystinemia). We searched the MEDLINE database for articles published from January 1966 to January 1999 and identified additional studies by hand-searching references of original articles or review articles on this topic and by personal contact with relevant investigators in that period. Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, age at entry (for prospective studies), and age at event (G. S. Omenn, unpublished data, September 2002).8-37 Studies were excluded if they measured only blood concentrations of free homocysteine or of total homocysteine only after a methionine-loading test3, 38-40 or if relevant data were unavailable41-48 or incomplete.49-51 To avoid confounding by disease, prospective studies of participants selected on the basis of existing cardiovascular disease, diabetes mellitus, renal impairment, or some other disease were also excluded,52-56 as were participants with preexisting cardiovascular disease in prospective studies of apparently healthy populations.
Data Collection
Investigators who agreed to collaborate were asked to provide data for each participant on date of birth, sex, blood homocysteine concentration (with the date of blood collection), any nonfatal or fatal myocardial infarction or occlusive coronary artery disease, and any nonfatal or fatal stroke or transient cerebral ischemic attack (with the dates of all such events). If available, data were also collected on history of heart disease event, prior cerebrovascular disease event, diabetes mellitus, smoking (current vs not), alcohol consumption, blood concentrations of total and high-density lipoprotein cholesterol and of creatinine, systolic and diastolic blood pressure, weight, and height. Studies were classified as prospective if the blood sample used to measure homocysteine was collected before the IHD or stroke event (whether homocysteine was measured in all individuals or in a nested manner among cases and matched controls) and as retrospective if the blood sample was collected after the event in cases. Retrospective studies were further classified as population-based if the controls were selected randomly from the same source population as the cases or as other if the controls were spouse controls or patients with some other illness.
Statistical Analyses
Cases and controls were restricted to people who were at least 40 years of age at baseline (ie, when the blood sample for homocysteine measurement was taken) and had measured homocysteine concentrations between 3 and 40 µmol/L (0.41 and 5.41 mg/L). Analyses were conducted for all ages together and for 3 age-at-event bands (40-54, 55-64, and  65 years), with prospective and retrospective studies considered separately to assess the possible impact of reverse causality and of any bias caused by control selection or participation.57 Results from prospective studies in which all participants had had homocysteine measured in a baseline sample were combined with those from prospective studies in which only the cases and a matched random sample of controls had had homocysteine measured in a baseline sample (ie, nested case-control studies). For prospective studies that provided data as nested case-control studies, the controls originally used for each case were retained in this study. For the other prospective studies, up to 8 controls per case were selected in each age-at-event band (matched for sex and age at baseline in 5-year bands), with age at last follow-up having to be greater than the lower limit of the age-at-event band. Controls could be selected only once within an age-at-event band but could be selected again for a later age-at-event band. For anyone experiencing multiple vascular events, only the first event was considered.
All analyses were based on logarithmically transformed homocysteine values because homocysteine values are positively skewed, with log2 used so that a unit increase in log2 of homocysteine is equivalent to a doubling in homocysteine. Conditional logistic regression analyses stratified for study were used 2 ways to describe the dose-response relationships. First, to investigate the shape of the association, the odds ratios (ORs) for groups defined by quintiles of baseline values of homocysteine within each study were calculated, with 95% confidence intervals (CIs) estimated from floated variances reflecting the amount of information underlying each group (including the reference group).58 Second, assuming a log-linear association, regression coefficients were calculated for the percentage of difference in risk associated with a 25% lower homocysteine concentration (which is equivalent to the average change in plasma total homocysteine concentration achieved by folic acid supplementation).59 Heterogeneity between the results of prospective and retrospective study designs and between studies within each type of design was assessed by a  2 statistic. Heterogeneity between the results of prospective studies was investigated with respect to mean age at baseline, percentage of men, percentage of current smokers, mean homocysteine concentrations in controls, and mean time between blood collection and vascular events. Analyses of the prospective studies were adjusted for the effects of smoking (tobacco use vs not), total cholesterol level, and systolic blood pressure by using multivariable logistic regression, with the stepwise change in the 2 statistic after making these adjustments providing a quantitative indication of the potential confounding effects of these factors. All analyses were performed with SAS version 8.1 (SAS Institute Inc, Cary, NC).
Correction for Regression Dilution Bias
The analyses of the prospective studies relate vascular disease risk to the estimated usual concentrations of homocysteine at approximately the time of the event by using remeasurements of homocysteine in samples collected at an appropriate interval after baseline to correct for regression dilution.6-7 Random fluctuations in a measured value of homocysteine will underestimate the strength of the real association between the usual (ie, long-term average) level of homocysteine during a particular exposure period and disease. This so-called regression dilution effect may be caused by measurement error or transient fluctuations in homocysteine levels caused by treatment, disease, age, or changes in diet. Information from repeated homocysteine measurements in a representative sample of individuals can be used to correct for the effects of regression dilution. Most of the studies did not have such repeat measurements of homocysteine, but 3 studies involving a total of 2318 individuals had remeasured participants at 3 to 8 years after baseline,60-62 and 1 other study had done so in 500 individuals at 3, 6, 9, and 12 years.63 Baseline measurements of homocysteine were used to divide people into quintiles, and the ratio of the range between the mean values of the repeat measurements in the top vs the bottom quintile to the range of the baseline measurements was used to estimate regression dilution ratios for various intervals. The regression dilution ratio declined with increasing intervals between measurements,6 with a value of 0.75 for the mean interval of 5 years from the initial homocysteine measurement to IHD events in prospective studies and of 0.77 for the mean interval of 4 years to stroke events. In the retrospective studies, homocysteine was measured at or shortly after the event, so a regression dilution ratio of 0.83 (which makes allowance for short-term variability only) was used for IHD and stroke analyses. The regression coefficient (and its SE) relating risk to usual concentrations of homocysteine was then estimated as the uncorrected regression coefficient (and its SE) that related risk to single measurements of baseline homocysteine concentrations (1 divided by the regression dilution ratio).
RESULTS
Study Populations
Individual participant data were obtained for 30 studies, which include 18 of 28 eligible retrospective studies and 12 of 13 eligible prospective studies (Table 1). Of 5073 IHD events, 1968 came from prospective studies, 2496 from retrospective studies with population controls, and 609 from retrospective studies with other controls. Of 1113 stroke events, 463 came from prospective studies, 344 from retrospective studies with population controls, and 306 from retrospective studies with other controls. The median (and interquartile range [IQR]) (SD) homocysteine level among controls in the different studies varied from 7.8 µmol/L (1.05 mg/L; IQR, 7.0-8.9) to 14.3 µmol/L (1.93 mg/L; IQR, 12.3-17.0), with an overall median of 11.0 µmol/L (1.49 mg/L; IQR, 9.0-13.6) (SD, 4.2 µmol/L [0.57 mg/L]). Eighty-five percent of the participants were men (88% in prospective studies, 83% in retrospective studies with population controls, and 73% in retrospective studies with other controls), and 36% were current smokers (41%, 31%, and 24%, respectively). In the prospective studies, the mean age at IHD was 62 years (SD, 8 years), and these events occurred at an average of 5 years (range, 2-9 years) after baseline. The mean age at stroke was 68 years (SD, 11 years) in prospective studies, and these events occurred at an average of 4 years (range, 2-11 years) after baseline. The mean age of IHD cases in retrospective studies with population controls was 53 years (SD, 7 years); in retrospective studies with other controls, 59 years (SD, 10 years); and of stroke cases, 61 years (SD, 16 years) and 63 years (SD, 9 years), respectively.
|
|
|
|
Table 1. Characteristics of Included Studies*
|
|
|
Risks of IHD in Relation to Differences in Homocysteine Levels
Before correction for regression dilution, the ORs for IHD associated with a 25% lower baseline homocysteine level after adjustment for study, age, and sex were 0.87 (95% CI, 0.82-0.92) in prospective studies, 0.71 (95% CI, 0.68-0.75) in retrospective studies with population controls, and 0.77 (95% CI, 0.69-0.86) in retrospective studies with other controls. There was significant heterogeneity between the results from these study designs (22 = 27; P<.001), which was attenuated only slightly by correction for regression dilution (22 = 21; P<.001). After correction for regression dilution (separately within each study), the adjusted ORs for IHD associated with a 25% lower usual homocysteine level were 0.83 (95% CI, 0.77-0.89) in prospective studies, 0.67 (95% CI, 0.62-0.71) in retrospective studies with population controls, and 0.73 (95% CI, 0.64-0.83) in retrospective studies with other controls (Figure 1). Among the prospective studies, there was only marginally significant heterogeneity between the adjusted ORs for IHD (210 = 21; P = .02) after correction for regression dilution, with a slight trend toward attenuation of the ORs with increasing mean time to event in the studies (test for trend, 21 = 4.1; P = .04). In contrast with previous suggestions,27 however, there was no evidence that the association of homocysteine level with IHD was influenced by age, sex, smoking, levels of blood pressure or blood cholesterol (Figure 2), or mean homocysteine concentrations in controls (or size of study, which might have reflected a tendency not to report small studies with less extreme findings).
|
|
|
|
Figure 1. Odds Ratios of Ischemic Heart Disease for a 25% Lower Usual Homocysteine Level in Individual Studies
Data were adjusted for study, sex, and age at enrollment and were corrected for regression dilution. The size of the square is inversely proportional to the variance of the log odds ratio (OR). The horizontal lines represent the 95% confidence intervals (CIs). The combined ORs in the subtotals for each study design and their 95% CIs are indicated by the diamonds.
|
|
|
|
|
|
|
Figure 2. Odds Ratios of Ischemic Heart Disease for a 25% Lower Usual Homocysteine Level Among People in Prospective Studies
Data were adjusted for study, sex, and age at enrollment. Studies are grouped by age at event, sex, smoking, and quintiles of systolic blood pressure and total cholesterol level. A global test for heterogeneity between all of these subgroups was not significant (216 = 14; P = .60). Symbols and conventions are as for Figure 1. To convert cholesterol to mmol/L, multiply by 0.02586. OR indicates odds ratio; CI, confidence interval.
|
|
|
Homocysteine concentrations were correlated with current smoking, total cholesterol levels, and systolic blood pressure, and the study-, age-, and sex-adjusted ORs for IHD in prospective studies were attenuated after further adjustment for these risk factors in individuals with all relevant data (to 0.89 [95% CI, 0.83-0.96]) (Table 2). The substantial change in the 2 statistic with these adjustments (from 24 to 9) suggests that a large part of the association was due to confounding. Moreover, because these confounding factors will necessarily have been measured with some error, substantial residual confounding will remain.
|
|
|
|
Table 2. Odds Ratios for Ischemic Heart Disease (IHD) and for Stroke Associated With 25% Lower Usual Homocysteine Levels in Prospective Studies
|
|
|
Table 3 compares ORs of IHD in quintiles of homocysteine levels determined separately within each study before combined analyses. The study-, age-, and sex-adjusted ORs of IHD appeared to increase with increasing homocysteine concentrations in a graded relationship, but this pattern was attenuated after further adjustment for current smoking, systolic blood pressure, and total cholesterol levels.
|
|
|
|
Table 3. Odds Ratio (95% Confidence Interval) of Ischemic Heart Disease for Quintiles of Baseline Homocysteine Levels in Prospective Studies*
|
|
|
Risk of Stroke in Relation to Differences in Homocysteine Concentrations
After adjustment for study, age, and sex and correction for regression dilution, the ORs for stroke were 0.77 (95% CI, 0.66-0.90) in prospective studies, 0.86 (95% CI, 0.73-1.01) in retrospective studies with population controls, and 0.46 (95% CI, 0.30-0.70) in retrospective studies with other controls (Figure 3). The heterogeneity between the results from these designs for stroke (22 = 7.4; P = .02) was less extreme than that observed for IHD. Among the prospective studies, there was no significant heterogeneity between the adjusted ORs for stroke (27 = 13; P = .06), and there was no good evidence that the association of homocysteine level with stroke was influenced by age or sex. As for IHD, there was a substantial reduction in the 2 statistic (from 11 to 6) for the association of homocysteine level with stroke risk after further adjustment for current smoking, systolic blood pressure, and cholesterol level (OR, 0.81; 95% CI, 0.69-0.95) (Table 2), suggesting that confounding may have inflated the estimated strength of this association.
|
|
|
|
Figure 3. Odds Ratios of Stroke for a 25% Lower Homocysteine Level in Individual Studies
Data were adjusted for study, sex, and age at enrollment and were corrected for regression dilution. Symbols and conventions are as for Figure 1. OR indicates odds ratio; CI, confidence interval.
|
|
|
COMMENT
This meta-analysis indicates that homocysteine level is less strongly related to IHD and stroke risk in healthy populations than has been suggested.4 The chief strength of this study is that inclusion of data from individual participants has allowed adjustment for possible confounding caused by known cardiovascular risk factors and appropriate correction for regression dilution bias. Data from 1 prospective study of homocysteine and cardiovascular disease (involving 244 cases)48 that fulfilled the inclusion criteria were unavailable, as were data from 5 relevant prospective studies that were completed after January 1999 (involving about 600 IHD cases and 50 stroke cases).64-68 These prospective studies reported results similar to those of the prospective studies that were included in this study (based on 1968 IHD cases and 463 strokes), suggesting that our findings were probably not materially altered by their exclusion.
The risks of IHD and stroke associated with homocysteine level were significantly weaker in the prospective studies than the retrospective studies, which may reflect bias in retrospective studies because of the difficulties of selecting appropriate controls or the effects of changes in treatment, renal function, or other factors after the onset of disease that produce increases in homocysteine concentrations among the cases. To minimize such bias, the chief emphasis in this study was on the results from prospective studies (in which blood for homocysteine measurements had been collected before the clinical onset of disease) among individuals with no recorded history of cardiovascular disease at enrollment. The risks of IHD associated with given differences in homocysteine level observed in the prospective studies of such individuals were remarkably consistent, with the exception of the Multiple Risk Factor Intervention Trial.13 The reasons for the apparent discrepancy in that study are unclear, although the mean time from baseline homocysteine measurement to IHD events was about twice that of the other prospective studies.13 Homocysteine concentrations were strongly correlated with current smoking and systolic blood pressure, and the strength of the association of homocysteine with vascular disease was reduced substantially after adjustment for these known cardiovascular risk factors. Moreover, because these confounding factors will necessarily have been measured with some error, substantial residual confounding may well remain. Indeed, because systolic blood pressure (on remeasurement a few years later) has a self-correlation of only about two-thirds,7 adjustment of the relationship between homocysteine and vascular disease should reduce the 2 value by about two thirds, as full adjustment for usual blood pressure would have done. Hence, the results in Table 2 are also consistent with the suggestion that the relationship of homocysteine to disease is largely due to confounding by the usual blood pressure. Thus, among prospective studies of individuals with no history of cardiovascular disease, and after appropriate adjustment for known cardiovascular risk factors and correction for regression dilution bias, a 25% lower usual homocysteine level was associated with about an 11% lower IHD risk and about a 19% lower stroke risk.
If the modest associations observed in this study are causal, then the implications for public health of decreasing the population mean levels of homocysteine could still be substantial. Studies of genetic variants affecting blood homocysteine concentrations and risk of IHD may well help to assess the nature of this association.69-70 Individuals who have a C-to-T substitution at base 677 (amino acid change alanine 222 valine) of the gene that encodes the methylene-tetrahydrofolate reductase enzyme have reduced enzyme activity and, as a consequence, have homocysteine levels that are about 25% higher than those with the CC genotype.70-71 An accompanying article in THE JOURNAL (2002;288:2023-2031) describes a meta-analysis of 40 studies of this genetic polymorphism in which individuals with the TT polymorphism have a 16% (95% CI, 5%-28%) higher risk of IHD than those with the CC polymorphism.72 The concordance of the IHD risks associated with genetically determined differences in homocysteine and of those observed in the population studies of such homocysteine differences provides support for these associations being causal.69 Results from large randomized trials of the effects on vascular disease of lowering homocysteine with folic acid–based vitamin supplementation should provide further information about the relevance of homocysteine levels to the risks of IHD and stroke.73
AUTHOR INFORMATION
Funding/Support: This project was supported in part by the British Heart Foundation, Medical Research Council, and by European Union BIOMED demonstration grant BMH4-98-3549 (Dr Clarke).
Author Contributions: Study concept and design: Clarke, Hopkins, Omenn, Beresford, Kromhout, Elwood, Whincup, Silberberg.
Acquisition of data: Clarke, Alfthan, Tuomilehto, Arnesen, Bonaa, Blacher, Boers, Bots, Grobbee, Brattström, Breteler, Hofman, Chambers, Kooner, Coull, Evans, Evers, Folsom, Freyburger, Parrot, Genest Jr, Dalery, Graham, Hoogeveen, Stehouwer, Hopkins, Jacques, Selhub, Luft, Jungers, Lindgren, Lolin, Loehrer, Fowler, Mansoor, Malinow, Ducimetiere, Nygard, Refsum, Ueland, Omenn, Roseman, Parving, Gall, Perry, Ebrahim, Shaper, Robinson, Jacobsen, Schwartz, Siscovick, Stampfer, Hennekens, Feskens, Kromhout, Ubbink, Elwood, Verhoef, von Eckardstein, Schulte, Assmann, Wald, Whincup, Wilcken, Sherliker, Linksted, Davey Smith, Silberberg.
Analysis and interpretation of data: Clarke, Collins, Lewington, Donald, Alfthan, Bostom, Brattström, Kuller, Daly, Kostense, Stehouwer, Jacques, Lindgren, Fowler, Vollset, Omenn, Schwartz, Siscovick, Hennekens, Feskens, Kromhout, Pickering, Wald, Law, Silberberg.
Drafting of the manuscript: Clarke, Collins, Lewington, Donald, Bostom, Evans, Genest Jr, Sherliker, Linksted.
Critical revision of the manuscript for important intellectual content: Clarke, Collins, Lewington, Alfthan, Tuomilehto, Bonaa, Blacher, Boers, Bots, Grobbee, Brattström, Breteler, Hofman, Kooner, Coull, Kuller, Evers, Folsom, Freyburger, Parrot, Genest Jr, Graham, Daly, Hoogeveen, Kostense, Stehouwer, Hopkins, Jacques, Selhub, Jungers, Lindgren, Lolin, Loehrer, Fowler, Mansoor, Malinow, Ducimetiere, Nygard, Refsum, Vollset, Ueland, Omenn, Beresford, Roseman, Parving, Gall, Perry, Ebrahim, Shaper, Robinson, Jacobsen, Schwartz, Siscovick, Stampfer, Hennekens, Feskens, Kromhout, Pickering, Verhoef, von Eckardstein, Schulte, Assmann, Wald, Law, Whincup, Wilcken, Davey Smith.
Statistical expertise: Clarke, Collins, Lewington, Donald, Bots, Daly, Hoogeveen, Kostense, Hopkins, Jacques, Ducimetiere, Vollset, Stampfer, Hennekens, Feskens, Pickering, Verhoef, Wald, Sherliker, Silberberg.
Obtained funding: Tuomilehto, Blacher, Bots, Grobbee, Genest Jr, Loehrer, Roseman, Ebrahim, Feskens, Kromhout, Whincup.
Administrative, technical, or material support: Clarke, Tuomilehto, Hofman, Evans, Evers, Genest Jr, Dalery, Hopkins, Luft, Lolin, Refsum, Ueland, Omenn, Parving, Perry, Ebrahim, Stampfer, Hennekens, Feskens, von Eckardstein, Schulte, Assmann, Linksted.
Study supervision: Clarke, Collins, Lewington, Alfthan, Brattström, Hofman, Stehouwer, Luft, Loehrer, Nygard, Kromhout, Whincup, Linksted.
Additional Collaborators of the Homocysteine Studies Collaboration: J. C. M. Witteman; B. Israelsson; G. Sexton; L. L. Wu; R. Joubran; B. Norrving, B. Hultberg, A. Andersson, B. B. Johansson; C. Bergmark, A. M. Svardal; A. E. Evans; N. Pancharuniti, C. A. Lewis; R. Holman, I. Stratton, C. Johnston; and J. Morris.
Corresponding Author and Reprints: Robert Clarke, MD, Clinical Trial Service Unit, Radcliffe Infirmary, Oxford OX2 6HE, England (e-mail: robert.clarke{at}ctsu.ox.ac.uk).
Author Members of the Homocysteine Studies Collaboration: R. Clarke, MD, R. Collins, MB, S. Lewington, DPhil, A. Donald, PhD; G. Alfthan, MD, J. Tuomilehto, MD; E. Arnesen, MD, K. Bonaa, MD; J. Blacher, MD; G. H. J. Boers, MD; A. Bostom, MD; M. L. Bots, MD, D. E. Grobbee, MD; L. Brattström, MD; M. M. B. Breteler, MD, A. Hofman, MD; J. C. Chambers, MRCP, J. S. Kooner, FRCP; B. M. Coull, MD; R. W. Evans, PhD, L. H. Kuller; S. Evers, MD; A. R. Folsom, MD; G. Freyburger, MD, F. Parrot, MD; J. Genest Jr, MD, K. Dalery, MD; I. M. Graham, MD, L. Daly, PhD; E. K. Hoogeveen, MD, P. J. Kostense, PhD, C. D. A. Stehouwer, MD; P. N. Hopkins, MD; P. Jacques, ScD, J. Selhub, PhD; F. C. Luft, MD; P. Jungers, MD; A. Lindgren, MD; Y. I. Lolin, MD; F. Loehrer, MD, B. Fowler, PhD; M. A. Mansoor, MD; M. R. Malinow, MD, P. Ducimetiere, MD; O. Nygard, MD, H. Refsum, MD, S. E. Vollset, MD, P. M. Ueland, MD; G. S. Omenn, MD, S. A. A. Beresford, PhD; J. M. Roseman, MD; H. H. Parving, MD, M. A. Gall, MD; I. J. Perry, MD, S. B. Ebrahim, MD, A. G. Shaper, MD; K. Robinson, MD, D. W. Jacobsen, PhD; S. M. Schwartz, PhD; D. S. Siscovick, MD; M. J. Stampfer, MD, C. H. Hennekens, MD; E. J. M. Feskens, D. Kromhout, PhD; J. Ubbink, MD, P. Elwood, MD, J. Pickering, MSc; P. Verhoef, PhD; A. von Eckardstein, MD, H. Schulte, PhD, G. Assmann, MD; N. Wald, FRCP, M. R. Law, FRCP; P. H. Whincup, FRCP; D. E. L. Wilcken, MD; P. Sherliker, BSc; P. Linksted, MSc; and G. Davey Smith.
REFERENCES
| |
1. McCully KS. Vascular pathology of homocysteinemia. Am J Pathol. 1969;56:111-128.
ISI
| PUBMED
2. Wilcken DE, Wilcken B. The pathogenesis of coronary artery disease. J Clin Invest. 1976;57:1079-1082.
ISI
| PUBMED
3. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia. N Engl J Med. 1991;324:1149-1155.
ABSTRACT
4. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA. 1995;274:1049-1057.
FREE FULL TEXT
5. Danesh J, Lewington S. Plasma homocysteine and coronary heart disease. J Cardiovasc Risk. 1998;5:229-232.
PUBMED
6. Clarke R, Lewington S, Donald A, et al. Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies. J Cardiovasc Risk. 2001;8:363-369.
FULL TEXT
|
ISI
| PUBMED
7. Clarke R, Shipley M, Lewington S, et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 1999;150:341-353.
FREE FULL TEXT
8. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877-881.
FREE FULL TEXT
9. Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke. 1994;25:1924-1930.
ABSTRACT
10. Alfthan G, Pekkanen J, Jauhiainen M, et al. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis. 1994;106:9-19.
FULL TEXT
|
ISI
| PUBMED
11. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995;24:704-709.
FREE FULL TEXT
12. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet. 1995;346:1395-1398.
FULL TEXT
|
ISI
| PUBMED
13. Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol. 1997;17:1947-1953.
FREE FULL TEXT
14. Ubbink JB, Fehily AM, Pickering J, Elwood PC, Vermaak WJ. Homocysteine and ischaemic heart disease in the Caerphilly cohort. Atherosclerosis. 1998;140:349-356.
FULL TEXT
|
ISI
| PUBMED
15. Stehouwer CD, Weijenberg MP, van den Berg M, Jakobs C, Feskens EJ, Kromhout D. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol. 1998;18:1895-1901.
FREE FULL TEXT
16. 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.
FREE FULL TEXT
17. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease. Arch Intern Med. 1998;158:862-867.
FREE FULL TEXT
18. Bots ML, Launer LJ, Lindemans J, et al. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch Intern Med. 1999;159:38-44.
FREE FULL TEXT
19. Whincup PH, Refsum H, Perry IJ, et al. Serum total homocysteine and coronary heart disease: prospective study in middle-aged men. Heart. 1999;82:448-454.
FREE FULL TEXT
20. Genest JJ Jr, McNamara JR, Salem DN, Wilson PW, Schaefer EJ, Malinow MR. Plasma homocyst(e)ine levels in men with premature coronary artery disease. J Am Coll Cardiol. 1990;16:1114-1119.
ABSTRACT
21. Pancharuniti N, Lewis CA, Sauberlich HE, et al. Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr. 1994;59:940-948.
FREE FULL TEXT
22. von Eckardstein A, Malinow MR, Upson B, et al. Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Arterioscler Thromb. 1994;14:460-464.
FREE FULL TEXT
23. Hopkins PN, Wu LL, Wu J, et al. Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol. 1995;15:1314-1320.
FREE FULL TEXT
24. Lindgren A, Brattstrom L, Norrving B, Hultberg B, Andersson A, Johansson BB. Plasma homocysteine in the acute and convalescent phases after stroke. Stroke. 1995;26:795-800.
FREE FULL TEXT
25. Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction. Am J Epidemiol. 1996;143:845-859.
FREE FULL TEXT
26. Malinow MR, Ducimetiere P, Luc G, et al. Plasma homocyst(e)ine levels and graded risk for myocardial infarction. Atherosclerosis. 1996;126:27-34.
FULL TEXT
|
ISI
| PUBMED
27. 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.
FREE FULL TEXT
28. Silberberg J, Crooks R, Fryer J, et al. Gender differences and other determinants of the rise in plasma homocysteine after L-methionine loading. Atherosclerosis. 1997;133:105-110.
FULL TEXT
|
ISI
| PUBMED
29. Verhoef P, Kok FJ, Kruyssen DA, et al. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 1997;17:989-995.
FREE FULL TEXT
30. 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.
FREE FULL TEXT
31. Joubran R, Asmi M, Busjahn A, Vergopoulos A, Luft FC, Jouma M. Homocysteine levels and coronary heart disease in Syria. J Cardiovasc Risk. 1998;5:257-261.
FULL TEXT
| PUBMED
32. Chambers JC, Obeid OA, Refsum H, et al. Plasma homocysteine concentrations and risk of coronary heart disease in UK Indian, Asian and European men. Lancet. 2000;355:523-527.
FULL TEXT
|
ISI
| PUBMED
33. Coull BM, Malinow MR, Beamer N, Sexton G, Nordt F, de Garmo P. Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke. 1990;21:572-576.
FREE FULL TEXT
34. Dalery K, Lussier Cacan S, Selhub J, Davignon J, Latour Y, Genest J Jr. Homocysteine and coronary artery disease in French Canadian subjects. Am J Cardiol. 1995;75:1107-1111.
FULL TEXT
|
ISI
| PUBMED
35. Robinson K, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Circulation. 1995;92:2825-2830.
FREE FULL TEXT
36. Lolin YI, Sanderson JE, Cheng SK, et al. Hyperhomocysteinaemia and premature coronary artery disease in the Chinese. Heart. 1996;76:117-122.
FREE FULL TEXT
37. Evers S, Koch HG, Grotemeyer KH, Lange B, Deufel T, Ringelstein EB. Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia. Arch Neurol. 1997;54:1276-1282.
FREE FULL TEXT
38. Brattstrom LE, Hardebo JE, Hultberg BL. Moderate homocysteinemia: a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke. 1984;15:1012-1016.
FREE FULL TEXT
39. Boers GH, Smals AG, Trijbels FJ, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med. 1985;313:709-715.
ABSTRACT
40. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Arterioscler Thromb. 1993;13:1253-1260.
FREE FULL TEXT
41. Israelsson B, Brattstrom LE, Hultberg BL. Homocysteine and myocardial infarction. Atherosclerosis. 1988;71:227-233.
FULL TEXT
|
ISI
| PUBMED
42. Andersson A, Isaksson A, Brattstrom L, Israelsson B, Hultberg B. Influence of hydrolysis on plasma homocysteine determination in healthy subjects and patients with myocardial infarction. Atherosclerosis. 1991;88:143-151.
FULL TEXT
|
ISI
| PUBMED
43. Landgren F, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattstrom L. Plasma homocysteine in acute myocardial infarction. J Intern Med. 1995;237:381-388.
ISI
| PUBMED
44. Mendis S, Athauda SB, Takashi K. Association between hyperhomocysteinemia and ischemic heart disease in Sri Lankans. Int J Cardiol. 1997;62:221-225.
FULL TEXT
|
ISI
| PUBMED
45. Montalescot G, Ankri A, Chadefaux Vekemans B, et al. Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol. 1997;60:295-300.
FULL TEXT
|
ISI
| PUBMED
46. Chacko KA. Plasma homocysteine levels in patients with coronary heart disease. Indian Heart J. 1998;50:295-299.
PUBMED
47. Dierkes J, Bisse E, Nauck M, et al. The diagnostic value of serum homocysteine concentration as a risk factor for coronary artery disease. Clin Chem Lab Med. 1998;36:453-457.
FULL TEXT
|
ISI
| PUBMED
48. Bostom AG, Silbershatz H, Rosenberg IH, et al. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999;159:1077-1080.
FREE FULL TEXT
49. Blacher J, Montalescot G, Ankri A, et al. Hyperhomocysteinemia in coronary artery diseases. Arch Mal Coeur Vaiss. 1996;89:1241-1246.
ISI
| PUBMED
50. Loehrer FM, Angst CP, Haefeli WE, Jordan PP, Ritz R, Fowler B. Low whole-blood S-adenosylmethionine and correlation between 5-methyltetrahydrofolate and homocysteine in coronary artery disease. Arterioscler Thromb Vasc Biol. 1996;16:727-733.
FREE FULL TEXT
51. Freyburger G, Labrouche S, Sassoust G, Rouanet F, Javorschi S, Parrot F. Mild hyperhomocysteinemia and hemostatic factors in patients with arterial vascular diseases. Thromb Haemost. 1997;77:466-471.
ISI
| PUBMED
52. Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet. 1996;348:1120-1124.
FULL TEXT
|
ISI
| PUBMED
53. Moustapha A, Naso A, Nahlawi M, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation. 1998;97:138-141.
FREE FULL TEXT
54. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230-236.
FREE FULL TEXT
55. Hoogeveen EK, Kostense PJ, Beks PJ, et al. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol. 1998;18:133-138.
FREE FULL TEXT
56. Stehouwer CD, Gall MA, Hougaard P, Jakobs C, Parving HH. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Kidney Int. 1999;55:308-314.
FULL TEXT
|
ISI
| PUBMED
57. Stampfer MA, Colditz G. Estrogen replacement therapy and coronary heart disease. Prev Med. 1991;20:47-63.
FULL TEXT
|
ISI
| PUBMED
58. Easton DF, Peto J, Babiker AG. Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med. 1991;10:1025-1035.
ISI
| PUBMED
59. Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements. BMJ. 1998;316:894-898.
FREE FULL TEXT
60. de Groot JC, de Leeuw FE, Oudkerk M, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol. 2000;47:145-151.
FULL TEXT
|
ISI
| PUBMED
61. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286-291.
FREE FULL TEXT
62. Nygard O, Refsum H, Ueland PM, et al. Coffee consumption and plasma total homocysteine: the Hordaland Homocysteine Study. Am J Clin Nutr. 1997;65:136-143.
FREE FULL TEXT
63. United Kingdom Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
FULL TEXT
|
ISI
| PUBMED
64. Kark JD, Selhub J, Adler B, et al. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999;131:321-330.
FREE FULL TEXT
65. Voutilainen S, Lakka TA, Hamelahti P, Lehtimaki T, Poulsen HE, Salonen JT. Plasma total homocysteine concentration and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. J Intern Med. 2000;248:217-222.
FULL TEXT
|
ISI
| PUBMED
66. Vollset SE, Refsum H, Tverdal A, et al. Plasma total homocysteine and cardiovascular disease and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001;74:130-136.
FREE FULL TEXT
67. Knekt P, Reunanen A, Alfthan G, et al. Hyperhomocysteinemia: a risk factor or consequence of coronary heart disease? Arch Intern Med. 2001;161:1589-1594.
FREE FULL TEXT
68. Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA. 1999;281:1817-1821.
FREE FULL TEXT
69. Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet. 2001;358:1356-1360.
FULL TEXT
|
ISI
| PUBMED
70. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease. Nat Genet. 1995;10:111-113.
FULL TEXT
|
ISI
| PUBMED
71. Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr. 2000;72:315-323.
FREE FULL TEXT
72. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG and the MTHFR Studies Collaboration. MTHFR C677C T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288:2023-2031.
FREE FULL TEXT
73. Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? J Cardiovasc Risk. 1998;5:249-255.
PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLES
MTHFR 677CT Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis
Mariska Klerk, Petra Verhoef, Robert Clarke, Henk J. Blom, Frans J. Kok, Evert G. Schouten, and and the MTHFR Studies Collaboration Group
JAMA. 2002;288(16):2023-2031.
ABSTRACT
| FULL TEXT
Homocysteine and Coronary Heart Disease: How Great Is the Hazard?
Peter W. F. Wilson
JAMA. 2002;288(16):2042-2043.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Preventing dementia: role of vascular risk factors and cerebral emboli
Purandare
Br Med Bull 2009;91:49-59.
ABSTRACT
| FULL TEXT
Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction
Berker et al.
Hum Reprod 2009;24:2293-2302.
ABSTRACT
| FULL TEXT
Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study
Malarstig et al.
Blood 2009;114:1417-1422.
ABSTRACT
| FULL TEXT
Ethnicity Does Not Affect the Homocysteine-Lowering Effect of B-Vitamin Therapy in Singaporean Stroke Patients
Kasiman et al.
Stroke 2009;40:2209-2211.
ABSTRACT
| FULL TEXT
Pre-operative homocysteine levels and morbidity and mortality following cardiac surgery
Ranucci et al.
Eur Heart J 2009;30:995-1004.
ABSTRACT
| FULL TEXT
Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women's Genome Health Study
Pare et al.
Circ Cardiovasc Genet 2009;2:142-150.
ABSTRACT
| FULL TEXT
Does the MTHFR 677C->T variant affect the Recommended Dietary Allowance for folate in the US population?
Robitaille et al.
Am. J. Clin. Nutr. 2009;89:1269-1273.
ABSTRACT
| FULL TEXT
Cardiovascular Risk Factors and Atherosclerosis in Young Women: Atherosclerosis Risk Factors in Female Youngsters (ARFY Study)
Knoflach et al.
Stroke 2009;40:1063-1069.
ABSTRACT
| FULL TEXT
Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women: The Women's Antioxidant and Folic Acid Cardiovascular Study
Christen et al.
Arch Intern Med 2009;169:335-341.
ABSTRACT
| FULL TEXT
Folate, Related B Vitamins, and Homocysteine in Childhood and Adolescence: Potential Implications for Disease Risk in Later Life
Kerr et al.
Pediatrics 2009;123:627-635.
ABSTRACT
| FULL TEXT
Plasma A{beta}, homocysteine, and cognition: The Vitamin Intervention for Stroke Prevention (VISP) trial
Viswanathan et al.
Neurology 2009;72:268-272.
ABSTRACT
| FULL TEXT
Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study
de Ruijter et al.
BMJ 2009;338:a3083-a3083.
ABSTRACT
| FULL TEXT
Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials
Antoniades et al.
Eur Heart J 2009;30:6-15.
ABSTRACT
| FULL TEXT
Folic Acid-Based Intervention in Non-ST Elevation Acute Coronary Syndromes
Imasa et al.
Asian Cardiovasc. Thorac. Ann. 2009;17:13-21.
ABSTRACT
| FULL TEXT
Plasma ADMA Predicts Restenosis of Arteriovenous Fistula
Wu et al.
J. Am. Soc. Nephrol. 2009;20:213-222.
ABSTRACT
| FULL TEXT
Dysregulated RANK Ligand/RANK Axis in Hyperhomocysteinemic Subjects: Effect of Treatment With B-Vitamins
Nenseter et al.
Stroke 2009;40:241-247.
ABSTRACT
| FULL TEXT
Clinical Utility of Genotyping the 677C>T Variant of Methylenetetrahydrofolate Reductase in Humans Is Decreased in the Post-Folic Acid Fortification Era
Tsai et al.
J. Nutr. 2009;139:33-37.
ABSTRACT
| FULL TEXT
Lowering Homocysteine With B Vitamins in Patients With Coronary Artery Disease
Scholl
JAMA 2008;300:2853-2853.
FULL TEXT
Roles of Oxidants, Nitric Oxide, and Asymmetric Dimethylarginine in Endothelial Function
Siekmeier et al.
J CARDIOVASC PHARMACOL THER 2008;13:279-297.
ABSTRACT
Hypercoagulable States in Cardiovascular Disease
Chan et al.
Circulation 2008;118:2286-2297.
FULL TEXT
Correlations between plasma homocysteine and folate concentrations and carotid atherosclerosis in high-risk individuals: baseline data from the Homocysteine and Atherosclerosis Reduction Trial (HART)
Held et al.
Vasc Med 2008;13:245-253.
ABSTRACT
The Antiatherogenic Function of HDL Is Impaired in Hyperhomocysteinemic Subjects
Holven et al.
J. Nutr. 2008;138:2070-2075.
ABSTRACT
| FULL TEXT
Sport-related hyperhomocysteinaemia: a putative marker of muscular demand to be noted for cardiovascular risk
Borrione et al.
Br. J. Sports. Med. 2008;42:894-900.
ABSTRACT
| FULL TEXT
Homocysteine: The Rubik's Cube of Cardiovascular Risk Factors
Milani and Lavie
Mayo Clin Proc. 2008;83:1200-1202.
FULL TEXT
Homocysteine Level and Coronary Heart Disease Incidence: A Systematic Review and Meta-analysis
Humphrey et al.
Mayo Clin Proc. 2008;83:1203-1212.
ABSTRACT
| FULL TEXT
Homocysteine and Its Relationship to Stroke Subtypes in a UK Black Population: The South London Ethnicity and Stroke Study
Khan et al.
Stroke 2008;39:2943-2949.
ABSTRACT
| FULL TEXT
B Vitamins for Prevention of Cognitive Decline: Insufficient Evidence to Justify Treatment
Clarke and Bennett
JAMA 2008;300:1819-1821.
FULL TEXT
Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice
Kitami et al.
Physiol. Genomics 2008;35:182-190.
ABSTRACT
| FULL TEXT
Did national folic acid fortification reduce socioeconomic and racial disparities in folate status in the US?
Dowd and Aiello
Int J Epidemiol 2008;37:1059-1066.
ABSTRACT
| FULL TEXT
Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes
Dayal and Lentz
Arterioscler. Thromb. Vasc. Bio. 2008;28:1596-1605.
ABSTRACT
| FULL TEXT
Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia
Dayal et al.
Am. J. Physiol. Heart Circ. Physiol. 2008;295:H816-H825.
ABSTRACT
| FULL TEXT
Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank
Yang et al.
Am. J. Clin. Nutr. 2008;88:232-246.
ABSTRACT
| FULL TEXT
Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients: A Placebo-Controlled, Double-Blind, Randomized Trial
Urquhart et al.
CJASN 2008;3:1041-1047.
ABSTRACT
| FULL TEXT
The Homocysteine Paradox
Rodionov and Lentz
Arterioscler. Thromb. Vasc. Bio. 2008;28:1031-1033.
FULL TEXT
Methionine-Loading Rapidly Impairs Endothelial Function, by Mechanisms Independent of Endothelin-1: Evidence for an Association of Fasting Total Homocysteine with Plasma Endothelin-1 Levels
Tousoulis et al.
J. Am. Coll. Nutr. 2008;27:379-386.
ABSTRACT
| FULL TEXT
Plasma Homocysteine, but Not Folate or Vitamin B-12, Predicts Mortality in Older People in the United Kingdom
Dangour et al.
J. Nutr. 2008;138:1121-1128.
ABSTRACT
| FULL TEXT
Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease: A Randomized Trial
Albert et al.
JAMA 2008;299:2027-2036.
ABSTRACT
| FULL TEXT
Homocysteine-Lowering B Vitamin Therapy in Cardiovascular Prevention--Wrong Again?
Lonn
JAMA 2008;299:2086-2087.
FULL TEXT
Trends in Circulating Concentrations of Total Homocysteine among US Adolescents and Adults: Findings from the 1991-1994 and 1999-2004 National Health and Nutrition Examination Surveys
Pfeiffer et al.
Clin. Chem. 2008;54:801-813.
ABSTRACT
| FULL TEXT
Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease
Moens et al.
Am. J. Physiol. Heart Circ. Physiol. 2008;294:H1971-H1977.
ABSTRACT
| FULL TEXT
Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation
Chang et al.
Circ. Res. 2008;102:933-941.
ABSTRACT
| FULL TEXT
Folate, Vitamin B6, Vitamin B12, and Methionine Intakes and Risk of Stroke Subtypes in Male Smokers
Larsson et al.
Am J Epidemiol 2008;167:954-961.
ABSTRACT
| FULL TEXT
How Does Folic Acid Cure Heart Attacks?
Tian and Ingwall
Circulation 2008;117:1772-1774.
FULL TEXT
Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression
Kim et al.
Br. J. Psychiatry 2008;192:268-274.
ABSTRACT
| FULL TEXT
Folic Acid and Multivitamin Supplement Use and Risk of Placental Abruption: A Population-based Registry Study
Nilsen et al.
Am J Epidemiol 2008;167:867-874.
ABSTRACT
| FULL TEXT
Dietary and supplementary betaine: acute effects on plasma betaine and homocysteine concentrations under standard and postmethionine load conditions in healthy male subjects
Atkinson et al.
Am. J. Clin. Nutr. 2008;87:577-585.
ABSTRACT
| FULL TEXT
Lowering Plasma Homocysteine Concentrations of Older Men and Women with Folate, Vitamin B-12, and Vitamin B-6 Does Not Affect the Proportion of (n-3) Long Chain Polyunsaturated Fatty Acids in Plasma Phosphatidylcholine
Crowe et al.
J. Nutr. 2008;138:551-555.
ABSTRACT
| FULL TEXT
Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study
Mann et al.
Nephrol Dial Transplant 2008;23:645-653.
ABSTRACT
| FULL TEXT
Homocysteine Induces Monocyte Chemoattractant Protein-1 Expression in Hepatocytes Mediated via Activator Protein-1 Activation
Woo et al.
J. Biol. Chem. 2008;283:1282-1292.
ABSTRACT
| FULL TEXT
Cardiovascular Risk Factors and Venous Thromboembolism: A Meta-Analysis
Ageno et al.
Circulation 2008;117:93-102.
ABSTRACT
| FULL TEXT
Hypermethylation of Fads2 and Altered Hepatic Fatty Acid and Phospholipid Metabolism in Mice with Hyperhomocysteinemia
Devlin et al.
J. Biol. Chem. 2007;282:37082-37090.
ABSTRACT
| FULL TEXT
S-Adenosylhomocysteine a better indicator of vascular disease than homocysteine?
Wagner and Koury
Am. J. Clin. Nutr. 2007;86:1581-1585.
ABSTRACT
| FULL TEXT
The risk of venous and arterial thrombosis in hyperhomocysteinemic subjects may be a result of elevated factor VIII levels
Lijfering et al.
haematol 2007;92:1703-1706.
ABSTRACT
| FULL TEXT
Coronary artery disease risk factors in patients with schizophrenia: effects of short term antipsychotic treatment
Sarandol et al.
J Psychopharmacol 2007;21:857-863.
ABSTRACT
B Vitamin Plasma Levels and the Risk of Ischemic Stroke and Transient Ischemic Attack in a German Cohort
Weikert et al.
Stroke 2007;38:2912-2918.
ABSTRACT
| FULL TEXT
The association between betaine and choline intakes and the plasma concentrations of homocysteine in women
Chiuve et al.
Am. J. Clin. Nutr. 2007;86:1073-1081.
ABSTRACT
| FULL TEXT
Association of blood lead and homocysteine levels among lead exposed subjects in Vietnam and Singapore
Chia et al.
Occup. Environ. Med. 2007;64:688-693.
ABSTRACT
| FULL TEXT
Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial
Ferreira et al.
Rheumatology (Oxford) 2007;46:1560-1565.
ABSTRACT
| FULL TEXT
Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease: A Randomized Controlled Trial
Jamison et al.
JAMA 2007;298:1163-1170.
ABSTRACT
| FULL TEXT
B Vitamins for the Prevention of Vascular Disease: Insufficient Evidence to Justify Treatment
Baigent and Clarke
JAMA 2007;298:1212-1214.
FULL TEXT
Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials
de Bree et al.
Am. J. Clin. Nutr. 2007;86:610-617.
ABSTRACT
| FULL TEXT
Endogenous Sex Hormones as Risk Factors for Dementia in Elderly Men and Women
Ravaglia et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2007;62:1035-1041.
ABSTRACT
| FULL TEXT
The heritability of plasma homocysteine, and the influence of genetic variation in the homocysteine methylation pathway
Siva et al.
QJM 2007;100:495-499.
ABSTRACT
| FULL TEXT
High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia
Zittan et al.
Am. J. Physiol. Heart Circ. Physiol. 2007;293:H860-H865.
ABSTRACT
| FULL TEXT
Homocysteine and cardiovascular disease: a review of the evidence
Wierzbicki
Diabetes and Vascular Disease Research 2007;4:143-149.
ABSTRACT
Homocysteine and Cardiovascular Risk: Considering the Evidence in the Context of Study Design, Folate Fortification, and Statistical Power
Ueland and Clarke
Clin. Chem. 2007;53:807-809.
FULL TEXT
Lowering Homocysteine with B Vitamins Has No Effect on Blood Pressure in Older Adults
McMahon et al.
J. Nutr. 2007;137:1183-1187.
ABSTRACT
| FULL TEXT
Homocysteine, 5,10-Methylenetetrahydrofolate Reductase 677C>T Polymorphism, Nutrient Intake, and Incident Cardiovascular Disease in 24 968 Initially Healthy Women
Zee et al.
Clin. Chem. 2007;53:845-851.
ABSTRACT
| FULL TEXT
Folic Acid Supplementation and Cardiovascular Diseases
Dentali et al.
JAMA 2007;297:1549-1550.
FULL TEXT
A comprehensive view of sex-specific issues related to cardiovascular disease
Pilote et al.
CMAJ 2007;176:S1-S44.
ABSTRACT
| FULL TEXT
Both vitamin B6 and total homocysteine plasma levels predict long-term atherothrombotic events in healthy subjects
Vanuzzo et al.
Eur Heart J 2007;28:484-491.
ABSTRACT
| FULL TEXT
Homocysteine, B vitamins, and the risk of dementia
Clarke
Am. J. Clin. Nutr. 2007;85:329-330.
FULL TEXT
Lowering homocysteine with B vitamins has no effect on biomarkers of bone turnover in older persons: a 2-y randomized controlled trial
Green et al.
Am. J. Clin. Nutr. 2007;85:460-464.
ABSTRACT
| FULL TEXT
Cardiovascular Fitness Is Negatively Associated With Homocysteine Levels in Female Adolescents
Ruiz et al.
Arch Pediatr Adolesc Med 2007;161:166-171.
ABSTRACT
| FULL TEXT
Levels of homocysteine are increased in metabolic syndrome patients but are not associated with an increased cardiovascular risk, in contrast to patients without the metabolic syndrome
Hajer et al.
Heart 2007;93:216-220.
ABSTRACT
| FULL TEXT
Elevated Homocysteine Is Associated With Reduced Regional Left Ventricular Function: The Multi-Ethnic Study of Atherosclerosis
Nasir et al.
Circulation 2007;115:180-187.
ABSTRACT
| FULL TEXT
The reverse epidemiology of plasma total homocysteine as a mortality risk factor is related to the impact of wasting and inflammation
Suliman et al.
Nephrol Dial Transplant 2007;22:209-217.
ABSTRACT
| FULL TEXT
Prothrombotic Effects of Hyperhomocysteinemia and Hypercholesterolemia in ApoE-Deficient Mice
Wilson et al.
Arterioscler. Thromb. Vasc. Bio. 2007;27:233-240.
ABSTRACT
| FULL TEXT
Using Genetic Variation to Optimize Nutritional Preemption
Gillies and Krul
J. Nutr. 2007;137:270S-274S.
ABSTRACT
| FULL TEXT
Effect of Folic Acid Supplementation on Risk of Cardiovascular Diseases: A Meta-analysis of Randomized Controlled Trials
Bazzano et al.
JAMA 2006;296:2720-2726.
ABSTRACT
| FULL TEXT
Methylmalonic acid and cognitive function in the Medical Research Council Cognitive Function and Ageing Study
McCracken et al.
Am. J. Clin. Nutr. 2006;84:1406-1411.
ABSTRACT
| FULL TEXT
Elevated serum S-adenosylhomocysteine in cobalamin-deficient elderly and response to treatment
Stabler et al.
Am. J. Clin. Nutr. 2006;84:1422-1429.
ABSTRACT
| FULL TEXT
Apolipoprotein E e4 allele affects risk of hyperhomocysteinemia in the elderly
Ravaglia et al.
Am. J. Clin. Nutr. 2006;84:1473-1480.
ABSTRACT
| FULL TEXT
|
