OBJECTIVE Prospective assessment of the risk of coronary heart disease associated with total serum homocyst(e)ine (homocysteine) concentration.

DESIGN Nested case-control study.

SETTING Caerphilly and surrounding villages in south Wales, UK.

PARTICIPANTS 2290 men who participated in phase II of the study in 1984. After a mean follow up of 10 years, 312 men developed coronary heart disease and were compared with 1248 randomly selected, age frequency matched controls.

MAIN OUTCOME MEASURE Acute myocardial infarction or death from coronary heart disease.

RESULTS The geometric mean serum homocysteine concentration was higher in cases (12.2 μmol/l, 95% confidence interval (CI) 11.8 to 12.6 μmol/l) than in controls (11.8 μmol/l, 95% CI 11.3 to 12.5 μmol/l) (p = 0.09). There was a graded increase in the odds ratio of coronary heart disease across quintiles of the homocysteine concentration distribution compared with the first (p = 0.04), which was attenuated when adjusted for confounding variables (p = 0.4). There was a small but non-significant increase in the adjusted odds ratio of coronary heart disease per standard deviation change in the log distribution of homocysteine concentration (OR = 1.07 (95% CI .93 to 1.24), p = 0.34). Comparing the top quintile of the homocysteine concentration with the remaining 80%, the adjusted odds ratio of coronary heart disease was 1.03 (95% CI 0.73 to 1.45) (p = 0.8) and comparing the top 5% with the remaining 95% it was 1.05 (95% CI 0.56 to 1.95) (p = 0.9).

CONCLUSIONS These findings do not support the hypothesis that a raised homocysteine concentration is a strong independent risk factor for coronary heart disease. Randomised controlled trials of homocysteine lowering treatment such as folic acid are needed before generalising the early positive results of observational studies.