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


METHODS
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.


METHODS
Odds ratios of the three diseases for a 5 micromol/l increase in serum homocysteine concentration.


RESULTS
There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 micromol/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 results-strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 micromol/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%).
Wald
David S
DS
Department of Cardiology, Southampton General Hospital, Southampton SO16 6YD. davidwald@hotmail.com
Law
Malcolm
M
Morris
Joan K
JK
D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000097:blood*; D006720:Homozygote; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009154:Mutation / Q000235:genetics*; D017202:Myocardial Ischemia / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D016017:Odds Ratio; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D011446:Prospective Studies; D011655:Pulmonary Embolism / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D012307:Risk Factors; D020246:Venous Thrombosis / Q000097:blood / Q000201:enzymology / Q000235:genetics*
D006710:Homocysteine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)