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Original Investigation |

Homocysteine and Ischemic Heart Disease:  Results of a Prospective Study With Implications Regarding Prevention FREE

Nicholas J. Wald, DSc(Med), FRCP:; Hilary C. Watt, MSc; Malcolm R. Law, FRCP; Donald G. Weir, FRCP; Joseph McPartlin, PhD; John M. Scott, ScD
[+] Author Affiliations

From the Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, England (Drs Wald and Law and Ms Watt), and the Departments of Clinical Medicine (Drs Weir and McPartlin) and Biochemistry (Dr Scott), Trinity College, St James's Hospital, Dublin, Ireland.


Arch Intern Med. 1998;158(8):862-867. doi:10.1001/archinte.158.8.862.
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Published online

Background  Results from prospective studies of serum homocysteine levels and ischemic heart disease (IHD) are inconclusive. We carried out a further prospective study to help clarify the position.

Methods  In the British United Provident Association (BUPA) prospective study of 21520 men aged 35 to 64 years, we measured homocysteine levels in stored serum samples and analyzed data from 229 men without a history of IHD at study entry who subsequently died of IHD and 1126 age-matched control subjects (nested case-control design).

Results  Serum homocysteine levels were significantly higher in men who died of IHD than in men who did not (mean, 13.1 vs 11.8 µmol/L; P<.001). The risk of IHD among men in the highest quartile of serum homocysteine levels was 3.7 times (or 2.9 times after adjusting for other risk factors) the risk among men in the lowest quartile (95% confidence interval [CI], 1.8-4.7). There was a continuous dose-response relationship, with risk increasing by 41% (95% CI, 20%-65%) for each 5-µmol/L increase in the serum homocysteine level. After adjustment for apolipoprotein B levels and blood pressure, this estimate was 33% (95% CI, 22%-59%). In a meta-analysis of the retrospective studies of homocysteine level and myocardial infarction, the age-adjusted association was stronger: an 84% (95% CI, 52%-123%) increase in risk for a 5-µmol/L increase in the homocysteine level, possibly because the participants were younger; the relationship between serum homocysteine level and IHD seems to be stronger in younger persons than in older persons.

Conclusions  Our positive results help resolve the uncertainty that resulted from previous prospective studies. The epidemiological, genetic, and animal evidence together indicate that the association between serum homocysteine level and IHD is likely to be causal. A general increase in consumption of the vitamin folic acid (which reduces serum homocysteine levels) would, therefore, be expected to reduce mortality from IHD.

THE LINK between high levels of serum homocysteine and atherosclerotic disease has been suspected since 1969,1 but several unresolved questions remain. Retrospective case-control studies show a clear relationship with ischemic heart disease (IHD),210 and there is an association across countries,11 but prospective cohort studies, which in general provide the most rigorous evidence, have yielded inconclusive results.1215 Studies from Finland14 and America15 showed no association between homocysteine level and IHD. The US Physicians' Health Study13 reported an association that was limited to persons in the top 5% of the homocysteine distribution (the relative risk compared with those in the lowest 90% was 3.1).15 In 2 of these studies,13,14 there was also no association with stroke14,16 and (in one) no association with the development of angina.17 Results of a fourth prospective study,12 from Norway, showed a positive association between homocysteine levels and IHD, as did cohort studies of patients with peripheral arterial disease18 and a prospective study19 of mortality in patients with coronary artery disease. Other prospective studies showed associations with stroke20,21 and arterial thrombotic events.21 Therefore, an inconsistency exists among the prospective study results: some are negative, whereas others support the association with IHD, stroke, and other thrombotic events demonstrated in retrospective studies.

To help clarify the position, we examined the relationship between homocysteine level and IHD in the prospective British United Provident Association (BUPA) study. We collated results from all the prospective studies and the retrospective studies to make an overall assessment of the evidence. We sought to determine whether any association is continuous and present over the whole range of homocysteine values found in Western poplations.

Our prospective study consists of 21520 men aged 35 to 64 years who were seen at the BUPA medical center in London, England, for a routine medical examination between 1975 and 1982. The study has been described previously.22 Serum samples were stored at −40°C. We were notified of all subsequent deaths with the assistance of the Office of National Statistics (formerly Office of Population Censuses and Surveys), London. This analysis is based on the 229 men who died of IHD (International Classification of Diseases, Ninth Revision, codes 410-414) by the end of 1987 and who had no history of IHD (angina pectoris or myocardial infarction) on study entry (cases). The mean length of follow-up was 8.7 years. For each case, 5 control subjects (who did not die of IHD and who did not have a history of IHD on study entry) were selected; they were matched for age and duration of storage of the serum sample, both to 1 year. The serum cholesterol level, apolipoprotein A-I and B levels, smoking history, blood pressure, weight, and height of cases and controls were known.22

Serum samples from these men were retrieved and assayed for homocysteine concentration using the sampling and extraction methods of Araki and Sako23 and quantitative estimation by high-performance liquid chromatography according to the method of Ubbink et al.24 Measurements were performed without knowledge of whether the samples were from cases or controls. There were 8 cases and 25 controls with technically unsatisfactory results; the 8 cases were retested with their 40 controls (which included 6 of the 25 controls with unsatisfactory results), so data on all the cases were available. The statistical analysis was based on 229 cases and 1126 controls. Odds ratio estimates were calculated using a conditional logistic regression model. Median homocysteine levels in the controls increased 0.75 µmol/L (95% confidence interval [CI], 0.45-1.06 µmol/L) per 10 years of age; the matching of cases and controls by age allowed for this. Using multiple regression analysis, the odds ratio was adjusted for the weak associations of homocysteine with systolic blood pressure (r=0.11, P<.001) and serum apolipoprotein B (r=0.09, P=.003). The odds ratios were not adjusted for serum apolipoprotein A-I level, smoking, or duration of storage of the serum sample because none of these were significantly associated with serum homocysteine level.

We compared our results with those of other epidemiological studies of homocysteine levels and cardiovascular disease, identifying studies from the review by Boushey and colleagues10 and (subsequent to this) from MEDLINE. Four retrospective studies were omitted because an age-adjusted odds ratio for a specified homocysteine difference was not given or could not be derived from the published results,2528 and studies that measured homocysteine level only after methionine loading were not included. We combined the estimates of the average increase in the risk of IHD with increasing homocysteine levels from different studies (in which an estimated odds ratio was reported or could be calculated from the published data) using the method of Dersimonian and Laird.29 We also analyzed the odds ratios of risk at different homocysteine levels to determine whether the relationship between homocysteine level and risk was continuous across the range of values in Western populations. To calculate CIs on the odds ratios, we used the technique of floating absolute risk.30

Table 1 shows the distribution of IHD risk factors in men who later died of IHD (cases) and men who did not (controls) in the BUPA prospective study; risk factors other than homocysteine level have been reported previously.22 The mean serum homocysteine concentration was higher in cases than in controls (13.1 and 11.8 µmol/L, respectively; P<.001).

Table Graphic Jump LocationTable 1. Serum Homocysteine Level and Other Ischemic Heart Disease (IHD) Risk Factors in Men Who Died of IHD (Cases) and Men Who Did Not (Controls)*

Table 2 shows the distribution of homocysteine values in cases and controls; the association with IHD was present across the entire range of homocysteine levels.

Table Graphic Jump LocationTable 2. Distribution of Serum Homocysteine Levels in Men Who Died of Ischemic Heart Disease (229 Cases) and Men Who Did Not (1126 Controls)

Table 3 shows the estimated odds ratio of death from IHD according to quartile group of homocysteine level. Among men in the top quartile group, IHD mortality was an estimated 3.7 times that among men in the bottom quartile group, or 2.9 times after adjustment for serum apolipoprotein B levels and systolic blood pressure.

Table Graphic Jump LocationTable 3. Odds Ratio of Death From Ischemic Heart Disease According to Homocysteine Quartile Group, Unadjusted and Adjusted for Apolipoprotein B and Systolic Blood Pressure (Matched Design Allowed for Age)

From the continuous logistic regression analysis, an increase in homocysteine concentration of 5 µmol/L (the difference previously used to quantify the dose-response effect10) was associated with an increase in the risk of IHD of 41% (odds ratio, 1.41; 95% CI, 1.20-1.65; P=.001) before and 33% (odds ratio, 1.33; 95% CI, 1.22-1.59) after adjustment for serum apolipoprotein B level and blood pressure. The dose-response relationship between serum homocysteine level and risk of IHD (adjusted) is given by the following equation:

Odds of IHD Death = exp(0.0576 × Increase in Serum Homocysteine Concentration [in micromoles per liter]).

So, for example, a 5-µmol/L increase in serum homocysteine levels increases risk by exp(0.0576 × 5) or 1.33.

EPIDEMIOLOGICAL STUDIES

Our data yield 2 main results: (1) a prospective association exists between homocysteine level and risk of IHD and (2) the dose-response relationship is continuous.

Our results help resolve the uncertainty from the previous prospective studies of major IHD events1215 insofar as they corroborate the results of the Norwegian study12 and the study of patients with peripheral arterial disease and are consistent with the US Physician's Study.13,18Table 4 shows a summary of the 5 prospective studies of homocysteine level and death from IHD or nonfatal myocardial infarction among persons without clinical disease at study entry. The reason for the apparent variation in results, with some studies negative and others positive, is unknown, but the heterogeneity between study results (P=.002) is too large for the overall average to be taken; this would be statistically inappropriate. It is likely that one set is correct and the other is incorrect.

Table Graphic Jump LocationTable 4. Odds Ratio of Ischemic Heart Disease (IHD) Events for a 5-µmol/L Increase in Serum Homocysteine Levels: Results From 5 Prospective Studies (Nested Case-Control Analysis) of Persons Without Disease at Study Entry

We judge that the positive results are correct for 3 reasons. First, these results are supported by the genetic and animal evidence, as discussed below. Second, measurement error could mask a positive result but could not create one (with case and control samples assayed in the same batches and not distinguished). Third, the retrospective studies of homocysteine level and myocardial infarction (which differed from the prospective studies in that the blood samples were collected after the IHD events)29 show an association, as summarized in Table 5. Further supportive evidence comes from studies showing associations between homocysteine level and carotid artery disease31,32 and mortality (in patients with coronary artery stenosis).19 The association shown in the retrospective studies (Table 5) was even stronger than that in the 3 prospective studies with positive results; the combined odds ratio for the 8 retrospective studies was 1.84 (95% CI, 1.52-2.23) for a 5-µmol/L increase in serum homocysteine concentration (or 1.65 excluding 1 atypically high estimate7), significantly higher than the estimate of 1.41 (95% CI, 1.20-1.65) from the prospective BUPA study. There may be reason to expect a stronger relationship in the retrospective studies because the average age of sustaining an IHD event was, on average, about 10 years younger than that in the prospective studies. There is an indication (albeit not statistically significant) in our data and in other data33 that the association between serum homocysteine level and IHD is stronger at younger ages, and the same phenomenon is found with other IHD risk factors, such as serum cholesterol level,34 smoking,35 and blood pressure.36

Table Graphic Jump LocationTable 5. Odds Ratio of Ischemic Heart Disease (IHD) for a 5-µmol/L Increase in Serum Homocysteine Levels: Results From 8 Retrospective Studies

Table 6 shows the estimates from the 8 retrospective studies combined and from the BUPA prospective study of the risk of IHD according to homocysteine level, with homocysteine levels divided into 4 groups (<10, 11-20, 21-30, and 31-60 µmol/L). There is a continuous dose-response relationship across the entire range of homocysteine levels, strong evidence against the view that only greatly elevated levels of homocysteine increase the risk of IHD.

Table Graphic Jump LocationTable 6. Odds Ratio of Ischemic Heart Disease According to Level of Serum Homocysteine: Results From 8 Retrospective Studies and the Prospective BUPA Study
GENETIC AND EXPERIMENTAL STUDIES

There are 3 distinct autosomal-recessive inborn errors of metabolism in which homozygotes have very high serum homocysteine levels (about 10-50 times higher than the general population) and very high risk of premature cardiovascular disease: (1) cystathionine β-synthase deficiency, (2) 5,10-methylenetetrahydrofolate reductase deficiency, and (3) the cobalamin metabolic defects that result in impaired methionine synthase activity.37 Heterozygotes for these 3 disorders have serum homocysteine levels about 3 times the population average and high risk of cardiovascular disease.4 The only biochemical change in common among these 3 inborn errors of metabolism is a high homocysteine level; no other metabolite is consistently high or low in all 3. Given that cardiovascular disease is also common to all 3 genetic disorders, it follows that it is the homocysteine or a metabolite derived from it that is the cause of the IHD and not that homocysteine is merely a marker of some other cause.

Another genetic defect, affecting about 10% of the population (homozygous for a thermolabile form of 5,10-methylenetetrahydrofolate reductase), also offers a useful natural experiment. This genetic variant leads to moderately raised homocysteine levels (increased by about 50% but with wide variation between studies3842). In individuals thought to be homozygous on the basis of their phenotype (thermolabile form of 5,10-methylenetetrahydrofolate reductase),38,4345 the risk of IHD is moderately increased; the combined odds ratio of the 4 cited studies is 3.33 (95% CI, 2.01-5.53). Surprisingly, this is not found in the studies in which cases were defined by the genotype (C677T mutation); the combined odds ratio for the 6 cited studies is 1.10 (95% CI, 0.71-1.69).4651 The difference between the 2 sets of studies suggests that there may be other, as yet unidentified, genetic defects affecting the enzyme activity, as well as a genetic-environmental interaction causing IHD. In those with the genetic variant, homocysteine levels tend to be more elevated if blood folate levels are low39,40; thus, variation in folate intake may contribute to the variation between studies. Results of these phenotypic studies corroborate the epidemiological evidence in Table 6, showing that the dose-response relationship extends down to so-called normal homocysteine levels.

Results of animal and in vitro experimental studies show that increases in blood homocysteine levels increase the extent of vascular and platelet damage,5255 further supporting the causal interpretation. Taken together, the epidemiological, genetic, and experimental evidence make a compelling case for a causal relationship between homocysteine and IHD across the range of serum homocysteine levels found in the general population.

IMPLICATIONS FOR PREVENTION

Once the relationship between homocysteine level and IHD is judged to be causal, it follows that reducing serum homocysteine levels will reduce the risk of IHD. This can be achieved by increasing consumption of the vitamin folic acid.5663

A folic acid supplement of 0.4 mg/d has been shown by Ward and colleagues61 to reduce average homocysteine levels in middle-aged patients by 1.9 µmol/L. Assuming this to be accurate, our result (adjusted for other IHD risk factors) indicates that it is equivalent to a 10% reduction in IHD mortality, exp(0.0576 × −1.9) = 0.90, with 95% CIs of 4% to 16%. The true reduction would be somewhat greater than 10% because of the effect of regression dilution bias (the dilution of the effect of a risk factor when based on single measurements that fluctuate in an individual over time). The bias could be allowed for using data from a study recording homocysteine measurements on 2 occasions in the same individuals. There is a need to confirm the size of the effect of folic acid supplementation on serum homocysteine levels and to determine whether there is a dose of folic acid that confers a maximal effect or a homocysteine threshold below which folic acid ceases to reduce serum homocysteine concentration further; this can be accomplished by a relatively small and short-term randomized study of folic acid supplementation.

The existing data together with data from the 2 additional studies proposed would provide the information needed to refine the estimate of the size of the effect of folic acid in the prevention of death from IHD. At present, the magnitude of the benefit remains uncertain, but the evidence shows that an increase in folic acid intake among the general population will lead to a worthwhile reduction in mortality from IHD.

Accepted for publication August 29, 1997.

We thank the BUPA Medical Foundation for supporting the BUPA Epidemiological Research Group in the Department of Environmental and Preventive Medicine.

Corresponding author: Nicholas J. Wald, DSc (Med), FRCP, Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, England.

McCully  KS Vascular pathology of homocyst(e)inemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56111- 128
Israelsson  BBrattstrom  LEHultberg  BL Homocysteine and myocardial infarction. Atherosclerosis. 1988;71227- 233
Link to Article
Genest  JJMcNamara  JRSalem  DNWilson  PWFSchaefer  EJMalinow  MR Plasma homocyst(e)ine levels in men with premature coronary artery disease. J Am Coll Cardiol. 1990;161114- 1119
Link to Article
Clarke  RDaly  LRobinson  K  et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;3241149- 1155
Link to Article
Ubbink  JBVermaak  WJHBennett  JMBecker  PJvan Staden  DABissbort  S The prevalence of homocysteinemia and hypercholesterolemia in angiographically defined coronary heart disease. Klin Wochenschr. 1991;69527- 534
Link to Article
Pancharuniti  NLewis  CASauberlich  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;59940- 948
Wu  LLWu  JHunt  SC  et al.  Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem. 1994;40552- 561
Dalery  KLussier-Cocan  SSelhub  JDavignon  JLatour  YGenest  J Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol. 1995;751107- 1111
Link to Article
Verhoef  PStampfer  MJBuring  JE  et al.  Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996;143845- 859
Link to Article
Boushey  CJBeresford  SAAOmenn  GSMotulsky  AG A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA. 1995;2741049- 1057
Link to Article
Alfthan  GAro  AGey  KF Plasma homocysteine and cardiovascular disease mortality. Lancet. 1997;349397
Link to Article
Arnesen  ERefsum  HBonaa  KHUeland  PMForde  OHNordrehaug  JE Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995;24704- 709
Link to Article
Stampfer  MJMalinow  MRWillett  WC  et al.  A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA. 1992;268877- 881
Link to Article
Alfthan  GPekkanen  JJuahianen  M  et al.  Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis. 1994;1069- 19
Link to Article
Evans  RWShaten  JHempel  JDCutler  JAKuller  LH Homocysteine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol. 1997;171947- 1953
Link to Article
Verhoef  PHennekens  CHMalinow  MRKok  FJWillett  WCStampfer  MJ A prospective study of plasma homocysteine and risk of ischemic stroke. Stroke. 1994;251924- 1930
Link to Article
Verhoef  PHennekens  CHAllen  RHStabler  SPWillett  WCStampfer  MJ Plasma homocysteine and risk of angina pectoris: results from a prospective study. Ir J Med Sci. 1995;164 ((suppl 15)) 26
Link to Article
Taylor  LMDeFrang  RDHarris  EJPorter  JM The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg. 1991;13128- 136
Link to Article
Nygard  ONordrehaug  JERefsum  HUeland  PMFarstad  MVollset  SE Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337230- 236
Link to Article
Perry  IJRefseum  HMorrise  RWEbrahim  SBUeland  PMShaper  AC Prospective study of serum total homocysteine concentrations and risk of stroke in middle aged British men. Lancet. 1995;3461395- 1398
Link to Article
Petri  MRoubenoff  RDallal  GENadeau  MRSelhub  JRosenberg  IH Plasma homocysteine as a risk factor for atherothrombotic events in systematic lupus erythematosus. Lancet. 1996;3481120- 1124
Link to Article
Wald  NJLaw  MWatt  H  et al.  Apolipoproteins and ischaemic heart disease: implications for screening. Lancet. 1994;34375- 79
Link to Article
Araki  ASako  Y Determination of free and total homocysteine in human plasma by high performance chromatography with fluorescent detection. J Chromatogr. 1987;42243- 52
Link to Article
Ubbink  JBVermaak  WJHBissbort  S Rapid high performance liquid chromatography assay for total homocysteine levels in human serum. J Chromatogr. 1991;565441- 446
Link to Article
von Eckardstein  AManilow  MRUpson  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;14460- 464
Link to Article
Malinow  MRSexton  GAverbuch  MGrossman  MWilson  DUpson  B Homocyst(e)inemia in daily practice: levels in coronary artery disease. Coron Artery Dis. 1990;1215- 220
Link to Article
Lolin  YISanderson  JECheng  SK  et al.  Hyperhomocysteinaemia and premature coronary artery disease in the Chinese. Heart. 1996;76117- 122
Link to Article
Graham  IMDaly  LERefsum  HM  et al.  Plasma homocysteine as a risk factor for vascular disease. JAMA. 1997;2771775- 1781
Link to Article
Dersimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials. 1986;7177- 188
Link to Article
Easton  DFPeto  JBabiker  AGAG Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med. 1991;101025- 1035
Link to Article
Malinow  MRNieto  FJSzklo  MChambless  LEBond  G Carotid artery intimal medial thickening and plasma homocysteine in asymptomatic adults: the Atherosclerosis Risk in Communities Study. Circulation. 1993;871107- 1113
Link to Article
Selhub  JJacques  PFBoston  AG  et al.  Association between plasma homocysteine concentration and extracranial carotid artery stenosis. N Engl J Med. 1995;332286- 291
Link to Article
Verhoef  PStampfer  MJ Prospective studies of homocysteine and cardiovascular disease. Nutr Rev. 1995;33283- 288
Law  MRWald  NJThompson  SG By how much and how quickly does reducing serum cholesterol lower the risk of ischaemic heart disease? BMJ. 1994;308367- 372
Link to Article
Kahn  HA The Dorn study of smoking and mortality among US veterans: report on eight and one-half years of observation. Natl Cancer Inst Monogr. 1966;191- 125
Neaton  JDWentworth  D Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Arch Intern Med. 1992;15256- 64
Link to Article
Green  RJacobsen  DW Clinical implications of hyperhomocysteinemia. Bailey  Led.Folate in Health and Disease. New York, NY Marcel Decker1995;75- 122
Kang  SSWong  PWKSusmando  ASora  JNorusis  MRuggie  N Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991;48536- 545
Frosst  PBlom  HJMilos  R  et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofoate reductase. Nat Genet. 1995;10111- 113
Link to Article
Van der Put  NMJSteegers-Theunissen  RPMFrosst  P  et al.  Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995;3461070- 1071
Link to Article
Jacques  PFBostom  AGWilliams  RR  et al.  Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;937- 9
Link to Article
Harmon  DLWoodside  JVYarrell  JWG  et al.  The common "thermo-labile" variant of methylene-tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM. 1996;89571- 577
Link to Article
Kang  SSWong  PWKZhou  JSora  JLessick  MGrcevich  G Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism. 1988;37611- 613
Link to Article
Kang  SSPassen  ELRuggie  NWong  PWKSora  H Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1993;881463- 1469
Link to Article
Engbersen  AMTFranken  DGBoers  HGStevens  EMBTrijbels  FJMBlom  HK Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet. 1995;56142- 150
Gallagher  PMMeleady  RShields  DS  et al.  Homocysteine and risk of premature coronary heart disease: evidence for a common gene mutation. Circulation. 1996;942154- 2158
Link to Article
Adams  MSmith  PDMartin  DThompson  JRLodwick  DSamani  NJ Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. QJM. 1996;89437- 444
Link to Article
Ma  JStampfer  MJHennekens  CH  et al.  Methylenetetrahydrofolate reductase, polymorphism, plasma folate, homocysteine and risk of myocardial infarction in US physicians. Circulation. 1996;942410- 2416
Link to Article
Kluijtmans  LAJvan den Heuvel  LPWJBoers  GHJ  et al.  Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;5835- 41
Deloughery  TGEvans  ASadeghi  A  et al.  Common mutation in methylenetetrahydrofolate reductase. Circulation. 1996;943074- 3078
Link to Article
Wilcken  DELWang  XLSim  ASMcCredie  RM Distribution in healthy and coronary populations of the methylenetetrahydrofolate reducatase (MTHFR) C677 T mutation. Arterioscler Thromb Vasc Biol. 1996;16878- 882
Link to Article
Harker  LASlighter  SJScott  CRRoss  R Homocystinemia: vascular injury and arterial thrombosis. N Engl J Med. 1974;291537- 543
Link to Article
McCully  KSWilson  RB Homocysteine theory of arteriosclerosis. Arteriosclerosis. 1975;22215- 227
Link to Article
Harker  LARoss  RSlichter  SJScott  CR Homocysteine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976;58731- 741
Link to Article
Wall  RTHarlan  JMHarker  LAStriker  GE Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res. 1980;18113- 121
Link to Article
Brattstrom  LIsraelsson  BNorrving  B  et al.  Impaired homocysteine metabolism in early onset cerebral and peripheral occlusive arterial disease: effect of pyridoxine and folic acid treatment. Atherosclerosis. 1990;8151- 60
Link to Article
Brattstrom  LEIsraelsson  BJeppsson  JOHultberg  BL Folic acid: an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest. 1988;48215- 221
Link to Article
Ubbink  JBHayward Vermaak  WJvan der Merwe  ABecker  PJDelport  RPotgieter  HC Vitamin requirements for the treatment of hypercysteinemia in humans. J Nutr. 1994;1241927- 1933
Naurath  HJJoosten  ERiezler  RStabler  SPAllen  RHLindenbaum  J Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet. 1995;34685- 89
Link to Article
Landgren  PIsraelsson  BLindgren  AHultberg  BAndersson  ABrattstrom  L Plasma homocysteine in acute myocardial infarction: homocysteine lowering effect of folic acid. J Intern Med. 1995;237381- 388
Link to Article
Ward  MMcNulty  HMcPartlin  JStrain  JJWeir  DGScott  JM Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM. 1997;90519- 524
Link to Article
Cuskelly  GJMcNulty  HMcPartlin  JMStrain  JJScott  JM Plasma homocysteine response to folate intervention in young women. Ir J Med Sci. 1995;1643
Link to Article
Selhub  JJacques  PFWilson  PWFRush  DRosenberg  IH Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;2702693- 2698
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Serum Homocysteine Level and Other Ischemic Heart Disease (IHD) Risk Factors in Men Who Died of IHD (Cases) and Men Who Did Not (Controls)*
Table Graphic Jump LocationTable 2. Distribution of Serum Homocysteine Levels in Men Who Died of Ischemic Heart Disease (229 Cases) and Men Who Did Not (1126 Controls)
Table Graphic Jump LocationTable 3. Odds Ratio of Death From Ischemic Heart Disease According to Homocysteine Quartile Group, Unadjusted and Adjusted for Apolipoprotein B and Systolic Blood Pressure (Matched Design Allowed for Age)
Table Graphic Jump LocationTable 4. Odds Ratio of Ischemic Heart Disease (IHD) Events for a 5-µmol/L Increase in Serum Homocysteine Levels: Results From 5 Prospective Studies (Nested Case-Control Analysis) of Persons Without Disease at Study Entry
Table Graphic Jump LocationTable 5. Odds Ratio of Ischemic Heart Disease (IHD) for a 5-µmol/L Increase in Serum Homocysteine Levels: Results From 8 Retrospective Studies
Table Graphic Jump LocationTable 6. Odds Ratio of Ischemic Heart Disease According to Level of Serum Homocysteine: Results From 8 Retrospective Studies and the Prospective BUPA Study

References

McCully  KS Vascular pathology of homocyst(e)inemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56111- 128
Israelsson  BBrattstrom  LEHultberg  BL Homocysteine and myocardial infarction. Atherosclerosis. 1988;71227- 233
Link to Article
Genest  JJMcNamara  JRSalem  DNWilson  PWFSchaefer  EJMalinow  MR Plasma homocyst(e)ine levels in men with premature coronary artery disease. J Am Coll Cardiol. 1990;161114- 1119
Link to Article
Clarke  RDaly  LRobinson  K  et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;3241149- 1155
Link to Article
Ubbink  JBVermaak  WJHBennett  JMBecker  PJvan Staden  DABissbort  S The prevalence of homocysteinemia and hypercholesterolemia in angiographically defined coronary heart disease. Klin Wochenschr. 1991;69527- 534
Link to Article
Pancharuniti  NLewis  CASauberlich  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;59940- 948
Wu  LLWu  JHunt  SC  et al.  Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem. 1994;40552- 561
Dalery  KLussier-Cocan  SSelhub  JDavignon  JLatour  YGenest  J Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol. 1995;751107- 1111
Link to Article
Verhoef  PStampfer  MJBuring  JE  et al.  Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996;143845- 859
Link to Article
Boushey  CJBeresford  SAAOmenn  GSMotulsky  AG A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA. 1995;2741049- 1057
Link to Article
Alfthan  GAro  AGey  KF Plasma homocysteine and cardiovascular disease mortality. Lancet. 1997;349397
Link to Article
Arnesen  ERefsum  HBonaa  KHUeland  PMForde  OHNordrehaug  JE Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995;24704- 709
Link to Article
Stampfer  MJMalinow  MRWillett  WC  et al.  A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA. 1992;268877- 881
Link to Article
Alfthan  GPekkanen  JJuahianen  M  et al.  Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis. 1994;1069- 19
Link to Article
Evans  RWShaten  JHempel  JDCutler  JAKuller  LH Homocysteine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol. 1997;171947- 1953
Link to Article
Verhoef  PHennekens  CHMalinow  MRKok  FJWillett  WCStampfer  MJ A prospective study of plasma homocysteine and risk of ischemic stroke. Stroke. 1994;251924- 1930
Link to Article
Verhoef  PHennekens  CHAllen  RHStabler  SPWillett  WCStampfer  MJ Plasma homocysteine and risk of angina pectoris: results from a prospective study. Ir J Med Sci. 1995;164 ((suppl 15)) 26
Link to Article
Taylor  LMDeFrang  RDHarris  EJPorter  JM The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg. 1991;13128- 136
Link to Article
Nygard  ONordrehaug  JERefsum  HUeland  PMFarstad  MVollset  SE Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337230- 236
Link to Article
Perry  IJRefseum  HMorrise  RWEbrahim  SBUeland  PMShaper  AC Prospective study of serum total homocysteine concentrations and risk of stroke in middle aged British men. Lancet. 1995;3461395- 1398
Link to Article
Petri  MRoubenoff  RDallal  GENadeau  MRSelhub  JRosenberg  IH Plasma homocysteine as a risk factor for atherothrombotic events in systematic lupus erythematosus. Lancet. 1996;3481120- 1124
Link to Article
Wald  NJLaw  MWatt  H  et al.  Apolipoproteins and ischaemic heart disease: implications for screening. Lancet. 1994;34375- 79
Link to Article
Araki  ASako  Y Determination of free and total homocysteine in human plasma by high performance chromatography with fluorescent detection. J Chromatogr. 1987;42243- 52
Link to Article
Ubbink  JBVermaak  WJHBissbort  S Rapid high performance liquid chromatography assay for total homocysteine levels in human serum. J Chromatogr. 1991;565441- 446
Link to Article
von Eckardstein  AManilow  MRUpson  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;14460- 464
Link to Article
Malinow  MRSexton  GAverbuch  MGrossman  MWilson  DUpson  B Homocyst(e)inemia in daily practice: levels in coronary artery disease. Coron Artery Dis. 1990;1215- 220
Link to Article
Lolin  YISanderson  JECheng  SK  et al.  Hyperhomocysteinaemia and premature coronary artery disease in the Chinese. Heart. 1996;76117- 122
Link to Article
Graham  IMDaly  LERefsum  HM  et al.  Plasma homocysteine as a risk factor for vascular disease. JAMA. 1997;2771775- 1781
Link to Article
Dersimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials. 1986;7177- 188
Link to Article
Easton  DFPeto  JBabiker  AGAG Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med. 1991;101025- 1035
Link to Article
Malinow  MRNieto  FJSzklo  MChambless  LEBond  G Carotid artery intimal medial thickening and plasma homocysteine in asymptomatic adults: the Atherosclerosis Risk in Communities Study. Circulation. 1993;871107- 1113
Link to Article
Selhub  JJacques  PFBoston  AG  et al.  Association between plasma homocysteine concentration and extracranial carotid artery stenosis. N Engl J Med. 1995;332286- 291
Link to Article
Verhoef  PStampfer  MJ Prospective studies of homocysteine and cardiovascular disease. Nutr Rev. 1995;33283- 288
Law  MRWald  NJThompson  SG By how much and how quickly does reducing serum cholesterol lower the risk of ischaemic heart disease? BMJ. 1994;308367- 372
Link to Article
Kahn  HA The Dorn study of smoking and mortality among US veterans: report on eight and one-half years of observation. Natl Cancer Inst Monogr. 1966;191- 125
Neaton  JDWentworth  D Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Arch Intern Med. 1992;15256- 64
Link to Article
Green  RJacobsen  DW Clinical implications of hyperhomocysteinemia. Bailey  Led.Folate in Health and Disease. New York, NY Marcel Decker1995;75- 122
Kang  SSWong  PWKSusmando  ASora  JNorusis  MRuggie  N Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991;48536- 545
Frosst  PBlom  HJMilos  R  et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofoate reductase. Nat Genet. 1995;10111- 113
Link to Article
Van der Put  NMJSteegers-Theunissen  RPMFrosst  P  et al.  Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995;3461070- 1071
Link to Article
Jacques  PFBostom  AGWilliams  RR  et al.  Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;937- 9
Link to Article
Harmon  DLWoodside  JVYarrell  JWG  et al.  The common "thermo-labile" variant of methylene-tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM. 1996;89571- 577
Link to Article
Kang  SSWong  PWKZhou  JSora  JLessick  MGrcevich  G Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism. 1988;37611- 613
Link to Article
Kang  SSPassen  ELRuggie  NWong  PWKSora  H Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1993;881463- 1469
Link to Article
Engbersen  AMTFranken  DGBoers  HGStevens  EMBTrijbels  FJMBlom  HK Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet. 1995;56142- 150
Gallagher  PMMeleady  RShields  DS  et al.  Homocysteine and risk of premature coronary heart disease: evidence for a common gene mutation. Circulation. 1996;942154- 2158
Link to Article
Adams  MSmith  PDMartin  DThompson  JRLodwick  DSamani  NJ Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. QJM. 1996;89437- 444
Link to Article
Ma  JStampfer  MJHennekens  CH  et al.  Methylenetetrahydrofolate reductase, polymorphism, plasma folate, homocysteine and risk of myocardial infarction in US physicians. Circulation. 1996;942410- 2416
Link to Article
Kluijtmans  LAJvan den Heuvel  LPWJBoers  GHJ  et al.  Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;5835- 41
Deloughery  TGEvans  ASadeghi  A  et al.  Common mutation in methylenetetrahydrofolate reductase. Circulation. 1996;943074- 3078
Link to Article
Wilcken  DELWang  XLSim  ASMcCredie  RM Distribution in healthy and coronary populations of the methylenetetrahydrofolate reducatase (MTHFR) C677 T mutation. Arterioscler Thromb Vasc Biol. 1996;16878- 882
Link to Article
Harker  LASlighter  SJScott  CRRoss  R Homocystinemia: vascular injury and arterial thrombosis. N Engl J Med. 1974;291537- 543
Link to Article
McCully  KSWilson  RB Homocysteine theory of arteriosclerosis. Arteriosclerosis. 1975;22215- 227
Link to Article
Harker  LARoss  RSlichter  SJScott  CR Homocysteine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976;58731- 741
Link to Article
Wall  RTHarlan  JMHarker  LAStriker  GE Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res. 1980;18113- 121
Link to Article
Brattstrom  LIsraelsson  BNorrving  B  et al.  Impaired homocysteine metabolism in early onset cerebral and peripheral occlusive arterial disease: effect of pyridoxine and folic acid treatment. Atherosclerosis. 1990;8151- 60
Link to Article
Brattstrom  LEIsraelsson  BJeppsson  JOHultberg  BL Folic acid: an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest. 1988;48215- 221
Link to Article
Ubbink  JBHayward Vermaak  WJvan der Merwe  ABecker  PJDelport  RPotgieter  HC Vitamin requirements for the treatment of hypercysteinemia in humans. J Nutr. 1994;1241927- 1933
Naurath  HJJoosten  ERiezler  RStabler  SPAllen  RHLindenbaum  J Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet. 1995;34685- 89
Link to Article
Landgren  PIsraelsson  BLindgren  AHultberg  BAndersson  ABrattstrom  L Plasma homocysteine in acute myocardial infarction: homocysteine lowering effect of folic acid. J Intern Med. 1995;237381- 388
Link to Article
Ward  MMcNulty  HMcPartlin  JStrain  JJWeir  DGScott  JM Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM. 1997;90519- 524
Link to Article
Cuskelly  GJMcNulty  HMcPartlin  JMStrain  JJScott  JM Plasma homocysteine response to folate intervention in young women. Ir J Med Sci. 1995;1643
Link to Article
Selhub  JJacques  PFWilson  PWFRush  DRosenberg  IH Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;2702693- 2698
Link to Article

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