Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies

Background Elevated concentrations of homocyst(e)ine are thought to increase the risk of vascular diseases including coronary heart disease and cerebrovascular disease. Methods We searched MEDLINE (1966-1999), EMBASE (1974-1999), SciSearch (1974-1999), and Dissertation Abstracts (1999) for articles and theses about homocyst(e)ine concentration and coronary heart disease and cerebrovascular disease. Results We included 57 publications (3 cohort studies, 12 nested case-control studies, 42 case-control studies) that reported results on 55 18 people with coronary heart disease (11 068 control subjects) and 1817 people with cerebrovascular disease (4787 control subjects) in our analysis. For coronary heart disease, the summary odds ratios (OR) for a 5-mumol/l increase in homocyst(e)ine concentration were 1.06 (95% CI : 0.99-1.13) for 2 publications of cohort studies, 1.23 (95% CI : 1.07-1.41) for 10 publications of nested case-control studies, and 1.70 (95% CI: 1.50-1.93) for 26 publications of case-control studies. For cerebrovascular disease, the summary OR for a 5-mumol/l increase in homocyst(e)ine concentration were 1.10 (95% CI: 0.94-1.28) for 2 publications of cohort studies, 1.58 (95% CI: 1.35-1.85) for 5 publications of nested case-control studies, and 2.16 (95% CI: 1.65-2.82) for 17 publications of case-control studies. Conclusions Prospective studies offer weaker support than case-control studies for an association between homocyst(e)ine concentration and cardiovascular disease. Although other lines of evidence support a role for homocyst(e)ine in the pathogenesis of cardiovascular disease, more information from prospective epidemiological studies or clinical trials is needed to clarify this role.