BMJ 2002;325:1202 ( 23 November )

Papers

Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

David S Wald, specialist registrar in cardiology, ^a Malcolm Law, professor, ^b Joan K Morris, senior lecturer. ^b

^a Department of Cardiology, Southampton General Hospital, Southampton SO16 6YD, ^b Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ

Correspondence to D S Wald davidwald{at}hotmail.com

Objective: To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them.
Design: Meta-analyses of the above three diseases using (a) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and (b) 20 prospective studies (3820 participants) of serum homocysteine and disease risk.
Main outcome measures: Odds ratios of the three diseases for a 5 µmol/l increase in serum homocysteine concentration.
Results: There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 µmol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies.
Conclusions: The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant resultsstrong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 µmol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%).

What is already known on this topic There is an association between serum homocysteine concentration and cardiovascular disease, but it is not known whether the association is causal A common single gene mutation that reduces the activity of an enzyme involved in folate metabolism (MTHFR) is associated with a moderate (20%) increase in serum homocysteine What this study adds A meta-analysis of MTHFR studies shows a significantly higher risk of both ischaemic heart disease and deep vein thrombosis (with or without pulmonary embolism) in people with the MTHFR mutation A meta-analysis of prospective studies shows a significant association between homocysteine concentration and ischaemic heart disease similar in size to that expected from the results of the MTHFR studies and a significant association with stroke The MTHFR studies and the prospective studies do not share the same potential sources of error but both yield similar resultsstrong evidence that the association between homocysteine and cardiovascular disease is causal On this basis a decrease in serum homocysteine of 3 µmol/l (achievable by daily intake of about 0.8 mg folic acid) should reduce the risk of ischaemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24%

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• Undas, A., Brozek, J., Jankowski, M., Siudak, Z., Szczeklik, A., Jakubowski, H. (2006). Plasma Homocysteine Affects Fibrin Clot Permeability and Resistance to Lysis in Human Subjects. Arterioscler. Thromb. Vasc. Bio. 26: 1397-1404 [Abstract] [Full text]  
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• Vasan, R. S. (2006). Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations. Circulation 113: 2335-2362 [Full text]  
• Loscalzo, J. (2006). Homocysteine Trials -- Clear Outcomes for Complex Reasons. NEJM 354: 1629-1632 [Full text]  
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• The Heart Outcomes Prevention Evaluation (HOPE) 2, (2006). Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. NEJM 354: 1567-1577 [Abstract] [Full text]  
• Menon, V., Sarnak, M. J., Greene, T., Wang, X., Pereira, A. A., Beck, G. J., Kusek, J. W., Selhub, J., Collins, A. J., Levey, A. S., Shlipak, M. G. (2006). Relationship Between Homocysteine and Mortality in Chronic Kidney Disease. Circulation 113: 1572-1577 [Abstract] [Full text]  
• Wuerges, J., Garau, G., Geremia, S., Fedosov, S. N., Petersen, T. E., Randaccio, L. (2006). Structural basis for mammalian vitamin B12 transport by transcobalamin. Proc. Natl. Acad. Sci. USA 103: 4386-4391 [Abstract] [Full text]  
• Yang, Q., Botto, L. D., Erickson, J. D., Berry, R. J., Sambell, C., Johansen, H., Friedman, J.M. (2006). Improvement in Stroke Mortality in Canada and the United States, 1990 to 2002. Circulation 113: 1335-1343 [Abstract] [Full text]  
• Devlin, A. M., Lentz, S. R. (2006). ApoA-I: A Missing Link Between Homocysteine and Lipid Metabolism?. Circ. Res. 98: 431-433 [Full text]  
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• Lee, K. W.J., Hill, J. S., Walley, K. R., Frohlich, J. J. (2006). Relative value of multiple plasma biomarkers as risk factors for coronary artery disease and death in an angiography cohort.. CMAJ 174: 461-466 [Abstract] [Full text]  
• Ho, G. Y.-H., Eikelboom, J. W., Hankey, G. J., Wong, C.-R., Tan, S.-L., Chan, J. B.-C., Chen, C. P.L.-H. (2006). Methylenetetrahydrofolate Reductase Polymorphisms and Homocysteine-Lowering Effect of Vitamin Therapy in Singaporean Stroke Patients. Stroke 37: 456-460 [Abstract] [Full text]  
• Kamath, A. F., Chauhan, A. K., Kisucka, J., Dole, V. S., Loscalzo, J., Handy, D. E., Wagner, D. D. (2006). Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 107: 591-593 [Abstract] [Full text]  
• McNulty, H., Dowey, L. R. C., Strain, J.J., Dunne, A., Ward, M., Molloy, A. M., McAnena, L. B., Hughes, J. P., Hannon-Fletcher, M., Scott, J. M. (2006). Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism. Circulation 113: 74-80 [Abstract] [Full text]  
• Minelli, C., Thompson, J. R, Abrams, K. R, Thakkinstian, A., Attia, J. (2005). The choice of a genetic model in the meta-analysis of molecular association studies. Int J Epidemiol 34: 1319-1328 [Abstract] [Full text]  
• Lewis, S. J, Ebrahim, S., Davey Smith, G. (2005). Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?. BMJ 331: 1053- [Abstract] [Full text]  
• Ginsburg, G. S., Donahue, M. P., Newby, L. K. (2005). Prospects for Personalized Cardiovascular Medicine: The Impact of Genomics. J Am Coll Cardiol 46: 1615-1627 [Abstract] [Full text]  
• Chanson, A., Sayd, T., Rock, E., Chambon, C., Sante-Lhoutellier, V., Potier de Courcy, G., Brachet, P. (2005). Proteomic Analysis Reveals Changes in the Liver Protein Pattern of Rats Exposed to Dietary Folate Deficiency. J. Nutr. 135: 2524-2529 [Abstract] [Full text]  
• Spence, J. D., Bang, H., Chambless, L. E., Stampfer, M. J. (2005). Vitamin Intervention for Stroke Prevention Trial: An Efficacy Analysis. Stroke 36: 2404-2409 [Abstract] [Full text]  
• Homocysteine Lowering Trialists' Collaboration, (2005). Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am. J. Clin. Nutr. 82: 806-812 [Abstract] [Full text]  
• Feinbloom, D., Bauer, K. A. (2005). Assessment of Hemostatic Risk Factors in Predicting Arterial Thrombotic Events. Arterioscler. Thromb. Vasc. Bio. 25: 2043-2053 [Abstract] [Full text]  
• Duncan, I. C., Terblanche, J. M. (2005). Spontaneous Isolated Posterior Communicating Artery Dissection in a Young Adult with Hyperhomocysteinemia. Am. J. Neuroradiol. 26: 2030-2032 [Abstract] [Full text]  
• Paraskevas, K. I., Daskalopoulou, S. S., Daskalopoulos, M. E., Liapis, C. D. (2005). Secondary Prevention of Ischemic Cerebrovascular Disease. What Is the Evidence?. ANGIOLOGY 56: 539-552 [Abstract]  
• Liem, A, Reynierse-Buitenwerf, G H, Zwinderman, A H, Jukema, J W, van Veldhuisen, D J (2005). Secondary prevention with folic acid: results of the Goes extension study. Heart 91: 1213-1214 [Full text]  
• Gori, A. M., Corsi, A. M., Fedi, S., Gazzini, A., Sofi, F., Bartali, B., Bandinelli, S., Gensini, G. F., Abbate, R., Ferrucci, L. (2005). A proinflammatory state is associated with hyperhomocysteinemia in the elderly. Am. J. Clin. Nutr. 82: 335-341 [Abstract] [Full text]  
• Pfeiffer, C. M, Caudill, S. P, Gunter, E. W, Osterloh, J., Sampson, E. J (2005). Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am. J. Clin. Nutr. 82: 442-450 [Abstract] [Full text]  
• Dietrich, M., Brown, C. J.P., Block, G. (2005). The Effect of Folate Fortification of Cereal-Grain Products on Blood Folate Status, Dietary Folate Intake, and Dietary Folate Sources among Adult Non-Supplement Users in the United States. J. Am. Coll. Nutr. 24: 266-274 [Abstract] [Full text]  
• Ebbesen, L. S., Ingerslev, J. (2005). Folate Deficiency-Induced Hyperhomocysteinemia Attenuates, and Folic Acid Supplementation Restores, the Functional Activities of Rat Coagulation Factors XII, X, and II. J. Nutr. 135: 1836-1840 [Abstract] [Full text]  
• Weikert, C., Hoffmann, K., Dierkes, J., Zyriax, B.-C., Klipstein-Grobusch, K., Schulze, M. B., Jung, R., Windler, E., Boeing, H. (2005). A Homocysteine Metabolism-Related Dietary Pattern and the Risk of Coronary Heart Disease in Two Independent German Study Populations. J. Nutr. 135: 1981-1988 [Abstract] [Full text]  
• Williams, C., Kingwell, B. A, Burke, K., McPherson, J., Dart, A. M (2005). Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype. Am. J. Clin. Nutr. 82: 26-31 [Abstract] [Full text]  
• Olthof, M. R, Brink, E. J, Katan, M. B, Verhoef, P. (2005). Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am. J. Clin. Nutr. 82: 111-117 [Abstract] [Full text]  
• Dayal, S., Lentz, S. R (2005). ADMA and hyperhomocysteinemia. Vasc Med 10: S27-S33 [Abstract]  
• Van Guelpen, B., Hultdin, J., Johansson, I., Stegmayr, B., Hallmans, G., K. Nilsson, T., Weinehall, L., Witthoft, C., Palmqvist, R., Winkvist, A. (2005). Folate, Vitamin B12, and Risk of Ischemic and Hemorrhagic Stroke: A Prospective, Nested Case-Referent Study of Plasma Concentrations and Dietary Intake. Stroke 36: 1426-1431 [Abstract] [Full text]  
• Ernest, S., Hosack, A., O'Brien, W. E., Rosenblatt, D. S., Nadeau, J. H. (2005). Homocysteine levels in A/J and C57BL/6J mice: genetic, diet, gender, and parental effects. Physiol. Genomics 21: 404-410 [Abstract] [Full text]  

Rapid Responses:

Read all Rapid Responses

MTHFR C677T not valuable thrombophilia test

Joel G Ray
bmj.com, 22 Nov 2002 [Full text]

Diet-induced Folate Deficiency

Bill D. Misner
bmj.com, 23 Nov 2002 [Full text]

Another cardiovascular effect of homocysteine

Serdar KULA
bmj.com, 23 Nov 2002 [Full text]

Minimising the risk of deep venous thrombosis through genetic screening

Maritha J Kotze, et al.
bmj.com, 26 Nov 2002 [Full text]

Homocysteine causes mitochondrial dysfunction

Richard G Fiddian-Green, et al.
bmj.com, 3 Dec 2002 [Full text]

Observational data do not prove homocysteine is causal in cardiovascular disease

Sagar N Doshi, et al.
bmj.com, 6 Dec 2002 [Full text]

Meta-analysis of homocyst(e)ine in CVD

Dan G. Hackam
bmj.com, 15 Dec 2002 [Full text]

Do port and red wine preserve ATP stores?

Richard G Fiddian-Green
bmj.com, 16 Dec 2002 [Full text]

Homocysteine, ATP degradation and free radical release.

Richard G Fiddian-Green
bmj.com, 18 Dec 2002 [Full text]

Homocysteine, folic acid, uric acid, ATP and free radical scavenging

Richard G Fiddian-Green
bmj.com, 19 Dec 2002 [Full text]

Exercise and plasma homocysteine

Harpal S Randeva, et al.
bmj.com, 20 Dec 2002 [Full text]

Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

Miranda B. Keijzer, et al.
bmj.com, 20 Dec 2002 [Full text]

Testing travellers for MTHFR TT is absurd

Joel G Ray
bmj.com, 22 Dec 2002 [Full text]

Pre-travel screening to identify genetic factors predisposing to thrombosis

Maritha J Kotze
bmj.com, 27 Dec 2002 [Full text]

Re: pre-travel screening for thromboembolism

Richard G Fiddian-Green
bmj.com, 30 Dec 2002 [Full text]

Re: Pre-travel screening may be harmful

Joel G Ray
bmj.com, 30 Dec 2002 [Full text]

"Lactic acidosis": the common denominator?

Richard G Fiddian-Green
bmj.com, 3 Jan 2003 [Full text]

Pre-test assessment to determine appropriateness of pre-travel genetic screening for thrombosis risk

Maritha J Kotze
bmj.com, 4 Jan 2003 [Full text]

Role of renal impairment.

Dan Hackam
bmj.com, 7 Jan 2003 [Full text]

Role of renal impairment.

Dan Hackam
bmj.com, 5 Jan 2003 [Full text]

Homocysteine: an adenine nucleotide trap?

Richard G Fiddian-Green
bmj.com, 9 Jan 2003 [Full text]

pH/calcium regulation of homocysteine metabolism

Richard G Fiddian-Green
bmj.com, 10 Jan 2003 [Full text]

Biochemical definitions

Richard G Fiddian-Green
bmj.com, 10 Jan 2003 [Full text]

MTHFR gene mutation, methylmalonic acidosis, and exercise.

Richard G Fiddian-Green
bmj.com, 19 Jan 2003 [Full text]

MTHFR and meta-Analysis

Markus Weih
bmj.com, 16 Jan 2003 [Full text]

The MTHFR poymorphism and screening for deep vein thrombosis

David S Wald, et al.
bmj.com, 31 Jan 2003 [Full text]

Re: Observational data do not prove homocysteine is causal in cardiovascular disease

David S Wald, et al.
bmj.com, 31 Jan 2003 [Full text]

Re: Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

David S Wald, et al.
bmj.com, 31 Jan 2003 [Full text]

Genetic equilibrium suggests no link between MTHFR and ischaemic heart disease.

Gavin Willis, et al.
bmj.com, 7 Apr 2003 [Full text]