This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (240)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Cardiovascular Disease/ Myocardial Infarction  • Alert me on articles by topic

Results of a Prospective Study With Implications Regarding Prevention

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

Arch Intern Med. 1998;158:862-867.

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.

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.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

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  

Effect of Homocysteine Concentration in Early Pregnancy on Gestational Hypertensive Disorders and Other Pregnancy Outcomes
Dodds et al.
Clin. Chem. 2008;54:326-334.
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  

The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease
Refsum et al.
J. Nutr. 2006;136:1731S-1740S.
ABSTRACT | FULL TEXT  

Folate Deficiency-Induced Hyperhomocysteinemia Attenuates, and Folic Acid Supplementation Restores, the Functional Activities of Rat Coagulation Factors XII, X, and II
Ebbesen and Ingerslev
J. Nutr. 2005;135:1836-1840.
ABSTRACT | FULL TEXT  

Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system
Nakano et al.
J. Lipid Res. 2005;46:484-493.
ABSTRACT | FULL TEXT  

Intermittent rises in plasma homocysteine in patients with rheumatoid arthritis treated with higher dose methotrexate
Hoekstra et al.
Ann Rheum Dis 2005;64:141-143.
ABSTRACT | FULL TEXT  

Association of Serum Total Homocysteine with the Extent of Ischemic Heart Disease in a Mediterranean Cohort
Vrentzos et al.
ANGIOLOGY 2004;55:517-524.
ABSTRACT  

Supplementation with Mixed Fruit and Vegetable Juice Concentrates Increased Serum Antioxidants and Folate in Healthy Adults
Kiefer et al.
J. Am. Coll. Nutr. 2004;23:205-211.
ABSTRACT | FULL TEXT  

Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial
Tucker et al.
Am. J. Clin. Nutr. 2004;79:805-811.
ABSTRACT | FULL TEXT  

Plasma C-Reactive Protein and Homocysteine Concentrations Are Related to Frequent Fruit and Vegetable Intake in Hispanic and Non-Hispanic White Elders
Gao et al.
J. Nutr. 2004;134:913-918.
ABSTRACT | FULL TEXT  

Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion
Refsum et al.
Clin. Chem. 2004;50:3-32.
ABSTRACT | FULL TEXT  

Association of Elevated Homocysteine Levels With a Higher Risk of Recurrent Coronary Events and Mortality in Patients With Acute Myocardial Infarction
Matetzky et al.
Arch Intern Med 2003;163:1933-1937.
ABSTRACT | FULL TEXT  

Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project
Meleady et al.
Am. J. Clin. Nutr. 2003;77:63-70.
ABSTRACT | FULL TEXT  

Homocysteine and Blood Pressure in the Third National Health and Nutrition Examination Survey, 1988-1994
Lim and Cassano
Am J Epidemiol 2002;156:1105-1113.
ABSTRACT | FULL TEXT  

Homocysteine Determinants and the Evidence to What Extent Homocysteine Determines the Risk of Coronary Heart Disease
De Bree et al.
Pharmacol. Rev. 2002;54:599-618.
ABSTRACT | FULL TEXT  

Homocysteine and coronary heart disease: the importance of a distinction between low and high risk subjects
De Bree et al.
Int J Epidemiol 2002;31:1268-1272.
FULL TEXT  

Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis
Wald et al.
BMJ 2002;325:1202-1206.
ABSTRACT | FULL TEXT  

Coronary atherogenic risk factors in women
Stangl et al.
Eur Heart J 2002;23:1738-1752.
FULL TEXT  

Homocysteine and Risk of Ischemic Heart Disease and Stroke: A Meta-analysis
Homocysteine Studies Collaboration
JAMA 2002;288:2015-2022.
ABSTRACT | FULL TEXT  

Smoking and plasma homocysteine
O'Callaghan et al.
Eur Heart J 2002;23:1580-1586.
ABSTRACT | FULL TEXT  

Polymorphisms in the Transcobalamin Gene: Association with Plasma Homocysteine in Healthy Individuals and Vascular Disease Patients
Lievers et al.
Clin. Chem. 2002;48:1383-1389.
ABSTRACT | FULL TEXT  

Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia
Weiss et al.
Vasc Med 2002;7:227-239.
ABSTRACT  

Serum homocysteine level is increased and correlated with endothelin-1 and nitric oxide in Behcet's disease
Er et al.
Br. J. Ophthalmol. 2002;86:653-657.
ABSTRACT | FULL TEXT  

Dietary Intake of Folate and Risk of Stroke in US Men and Women: NHANES I Epidemiologic Follow-Up Study * Editorial Comment: NHANES I Epidemiologic Follow-Up Study
Bazzano et al.
Stroke 2002;33:1183-1189.
ABSTRACT | FULL TEXT  

Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies
Ford et al.
Int J Epidemiol 2002;31:59-70.
ABSTRACT | FULL TEXT  

The Effects of Estrogen and Selective Estrogen Receptor Modulators on Cardiovascular Risk Factors
WALSH
Ann. N. Y. Acad. Sci. 2001;949:163-167.
ABSTRACT | FULL TEXT  

Cost-effectiveness of Vitamin Therapy to Lower Plasma Homocysteine Levels for the Prevention of Coronary Heart Disease: Effect of Grain Fortification and Beyond
Tice et al.
JAMA 2001;286:936-943.
ABSTRACT | FULL TEXT  

Hyperhomocystinemia: A Risk Factor or a Consequence of Coronary Heart Disease?
Knekt et al.
Arch Intern Med 2001;161:1589-1594.
ABSTRACT | FULL TEXT  

Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study
Vollset et al.
Am. J. Clin. Nutr. 2001;74:130-136.
ABSTRACT | FULL TEXT  

Homocysteine modulation as a reason for continuous folic acid supplementation in methotrexate-treated rheumatoid arthritis patients
Erb and Kitas
Rheumatology (Oxford) 2001;40:715-716.
FULL TEXT  

Moderate alcohol consumption as a cardiovascular risk factor: the role of homocysteine and the need to re-explain the 'French Paradox'
Badawy
Alcohol Alcohol 2001;36:185-188.
FULL TEXT  

An Update on Hypercoagulable Disorders
Federman and Kirsner
Arch Intern Med 2001;161:1051-1056.
ABSTRACT | FULL TEXT  

Effects of Growth Hormone (GH) Administration on Homocyst(e)ine Levels in Men with GH Deficiency: A Randomized Controlled Trial
Sesmilo et al.
J. Clin. Endocrinol. Metab. 2001;86:1518-1524.
ABSTRACT | FULL TEXT  

Randomized Trial of Folic Acid Supplementation and Serum Homocysteine Levels
Wald et al.
Arch Intern Med 2001;161:695-700.
ABSTRACT | FULL TEXT  

Homocysteine and ischaemic stroke in men: the Caerphilly study
Fallon et al.
J. Epidemiol. Community Health 2001;55:91-96.
ABSTRACT | FULL TEXT  

Homocysteine and coronary heart disease in the Caerphilly cohort: a 10 year follow up
Fallon et al.
Heart 2001;85:153-158.
ABSTRACT | FULL TEXT  

Plasma Homocysteine Concentrations in the Acute and Convalescent Periods of Atherothrombotic Stroke
Meiklejohn et al.
Stroke 2001;32:57-62.
ABSTRACT | FULL TEXT  

Potential Clinical and Economic Effects of Homocyst(e)ine Lowering
Nallamothu et al.
Arch Intern Med 2000;160:3406-3412.
ABSTRACT | FULL TEXT  

Serum Total Homocysteine Concentration Is Related to Self-Reported Heart Attack or Stroke History among Men and Women in the NHANES III
Morris et al.
J. Nutr. 2000;130:3073-3076.
ABSTRACT | FULL TEXT  

The controversy over homocysteine and cardiovascular risk
Ueland et al.
Am. J. Clin. Nutr. 2000;72:324-332.
ABSTRACT | FULL TEXT  

Multivitamin Use and Mortality in a Large Prospective Study
Watkins et al.
Am J Epidemiol 2000;152:149-162.
FULL TEXT  

Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events
Booth et al.
CMAJ 2000;163:21-29.
ABSTRACT | FULL TEXT  

Blood Levels of Homocysteine and Increased Risks of Cardiovascular Disease: Causal or Casual?
Christen et al.
Arch Intern Med 2000;160:422-434.
ABSTRACT | FULL TEXT  

The Effects of Hormone Replacement Therapy and Raloxifene on C-Reactive Protein and Homocysteine in Healthy Postmenopausal Women: A Randomized, Controlled Trial
Walsh et al.
J. Clin. Endocrinol. Metab. 2000;85:214-218.
ABSTRACT | FULL TEXT  

Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis
Fonseca et al.
Endocr. Rev. 1999;20:738-759.
ABSTRACT | FULL TEXT  

Serum total homocysteine and coronary heart disease: prospective study in middle aged men
Whincup et al.
Heart 1999;82:448-454.
ABSTRACT | FULL TEXT  

Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence
Eikelboom et al.
ANN INTERN MED 1999;131:363-375.
ABSTRACT | FULL TEXT  

Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications
Mahmud et al.
Gut 1999;45:389-394.
ABSTRACT | FULL TEXT  

Evaluating Novel Cardiovascular Risk Factors: Can We Better Predict Heart Attacks?
Ridker
ANN INTERN MED 1999;130:933-937.
ABSTRACT | FULL TEXT  

Homocysteine and endothelial function
Doshi et al.
Cardiovasc Res 1999;42:578-582.
FULL TEXT  

Homocysteine and Risk of Cardiovascular Disease Among Postmenopausal Women
Ridker et al.
JAMA 1999;281:1817-1821.
ABSTRACT | FULL TEXT  

Homocysteine and Arteriosclerosis : Subclinical and Clinical Disease Associations
Bostom and Selhub
Circulation 1999;99:2361-2363.
FULL TEXT  

Distribution of and Factors Associated With Serum Homocysteine Levels in Children: Child and Adolescent Trial for Cardiovascular Health
Osganian et al.
JAMA 1999;281:1189-1196.
ABSTRACT | FULL TEXT  

Hyperhomocysteinemia in Chronic Renal Disease
BOSTOM and CULLETON
J. Am. Soc. Nephrol. 1999;10:891-900.
FULL TEXT  

Homocyst(e)ine, Diet, and Cardiovascular Diseases : A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association
Malinow et al.
Circulation 1999;99:178-182.
FULL TEXT  

Homocysteine and Ischemic Heart Disease Revisited
Journal Watch Cardiology 1998;1998:4-4.
FULL TEXT  

More on Homocysteine Levels and Ischemic Heart Disease
JWatch General 1998;1998:10-10.
FULL TEXT