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Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis
David S Wald1, Malcolm Law, Joan K Morris
1Department of Cardiology, Southampton General Hospital, Southampton SO16 6YD. davidwald@hotmail.com
Insights
High homocysteine levels causally increase the risk of heart disease, deep vein thrombosis, and stroke. Lowering homocysteine through folic acid can significantly reduce these risks.
Area of Science:
- Cardiovascular epidemiology
- Genetic epidemiology
- Nutritional science
Background:
- Elevated serum homocysteine is associated with cardiovascular diseases.
- The causal relationship and potential for intervention remain under investigation.
Purpose of the Study:
- To determine if serum homocysteine concentration is causally linked to ischemic heart disease, deep vein thrombosis, and stroke.
- To quantify the preventative effect of reducing homocysteine levels on these conditions.
Main Methods:
- Meta-analyses of 72 genetic studies (MTHFR gene mutation) and 20 prospective studies on homocysteine and disease risk.
- Calculated odds ratios for a 5 micromol/l increase in serum homocysteine for the three diseases.
Main Results:
- Significant associations were found between homocysteine and all three diseases in both genetic and prospective studies.
- Odds ratios for a 5 micromol/l homocysteine increase ranged from 1.32 to 1.65 across the diseases and study types.
- Genetic and prospective studies, with different potential biases, yielded consistent, highly significant results.
Conclusions:
- Strong evidence supports a causal association between homocysteine and cardiovascular disease.
- Reducing homocysteine by 3 micromol/l (achievable with folic acid) could decrease ischemic heart disease risk by 16%, deep vein thrombosis by 25%, and stroke by 24%.
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 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%).