OBJECTIVES To examine the prospective relation between total homocysteine and major coronary heart disease events.

DESIGN A nested case–control study carried out within the British regional heart study, a prospective investigation of cardiovascular disease in men aged 40–59 years at entry. Serum total homocysteine concentrations were analysed retrospectively and blindly in baseline samples from 386 cases who had a myocardial infarct during 12.8 years of follow up and from 454 controls, frequency matched by age and town.

RESULTS Geometric mean serum total homocysteine was slightly higher in cases (14.2 μmol/l) than in controls (13.5 μmol/l), a proportional difference of 5.5% (95% confidence interval (CI) −0.02% to 10.8%, p = 0.06). Age adjusted risk of myocardial infarction increased weakly with log total homocysteine concentration; a 1 SD increase in log total homocysteine (equivalent to a 47% increase in total homo cysteine) was associated with an increase in odds of myocardial infarction of 1.15 (95% CI 1.00 to 1.32; p = 0.05). The relation was particularly marked in the top fifth of the total homocysteine distribution (values >16.5 μmol/l), which had an odds ratio of 1.77 (95% CI 1.28 to 2.42) compared with lower levels. Adjustment for other risk factors had little effect on these findings. Total homocysteine concentrations more than 16.5 μmol/l accounted for 13% of the attributable risk of myocardial infarction in this study population. Serum total homocysteine among control subjects varied between towns and was correlated with town standardised mortality ratios for coronary heart disease (r = 0.43, p = 0.08).

CONCLUSIONS Serum total homocysteine is prospectively related to increased coronary risk and may also be related to geographical variation in coronary risk within Britain. These results strengthen the case for trials of total homocysteine reduction with folate.