Homocysteine and prediction of coronary heart disease and stroke

Background: Elevated homocysteine levels have been associated with an increased risk of ischemic heart disease (IHD) and stroke, but whether these associations are causal is uncertain. Methods: We reviewed the evidence from a meta-analysis of 30 population studies of differences in homocysteine concentrations (involving 5000 IHD and 1100 stroke events in apparently healthy people), and from a meta-analysis of 40 studies (involving 11,000 IHD events) that examined the association of TT genotype for methylene-tetrahydrofolate reductase (MTHFR) with risk of IHD. Results: Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies of individuals who had no history of cardiovascular disease when blood was collected. Among prospective studies, a 25% lower blood homocysteine was associated with about 10% lower risk of IHD and about 20% lower risk of stroke, after adjustment for known cardiovascular risk factors. About 10% of the population have a genetic defect in the methylene tetrahydrofolate reductase (MTHFR) enzyme and have about 25% higher homocysteine levels. We showed that individuals who have TT genotype have a 16% higher risk of IHD compared with the CC genotype. Conclusions: These results suggest that elevated homocysteine is a modest independent predictor of risk of IHD and stroke. The results obtained for genetically determined differences in homocysteine suggest that these associations are causal. Randomized trials of folic acid-based vitamins in people at "high-risk" of vascular disease are currently underway to assess if lowering homocysteine might reduce risk of vascular disease.