The dose-response relation between serum homocysteine and cardiovascular disease: implications for treatment and screening

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Abstract
With the recognition that serum homocysteine may cause cardiovascular disease there is clinical interest in homocysteine measurement to guide treatment with folic acid. It is uncertain whether treatment is best directed at those with high homocysteine or those at high risk irrespective of initial homocysteine. Dose-response plots of the associations between serum homocysteine and ischaemic heart disease and deep vein thrombosis were determined from retrospective (case-control) studies (a meta-analysis of 12 age-matched studies) prospective studies and studies of the C677T MTHFR polymorphism (a comparison of risk in three genotypes in a meta-analysis of 72 studies). The value of serum homocysteine as a screening test was assessed from distributions of serum homocysteine in men who did and did not die from ischaemic heart disease in a large prospective study. There were straight-line relationships between serum homocysteine and disease events in the three types of study; a given decrease in homocysteine would produce a similar proportional risk reduction from any pre-treatment level. There was substantial overlap between the distributions of serum homocysteine in men who did and did not die of ischaemic heart disease, indicating poor screening performance; there was no serum homocysteine cut-off that concentrated the majority of disease events into a small minority of the population. Interventions to lower serum homocysteine, if judged to be worthwhile, should not be limited to people with a high homocysteine but should be offered to everyone at high risk, regardless of pre-treatment homocysteine.