The incidence of cardiovascular disease increases progressively with age in men and is more common in younger men than in women of similar age. The difference in incidence of cardiovascular disease between the sexes diminishes in the elderly, as the incidence of female cardiovascular disease increases with age in post-menopausal females. This pattern coincides with that of iron stores; in men iron stores increase with age, while menstrual blood loss means that pre-menopausal women have little or no storage of iron with iron only accumulating post-menopause. This link was used by Sullivan1 to propose that excess iron is important to the pathogenesis of atherosclerosis. Blood donation reduces body iron stores and comparing donors and non-donors provides a way of testing this hypothesis. In two studies the incidence of heart disease was found to be reduced in male blood donors, but no such reduction was found in a later, prospective study of 38 000 health professionals2 (and references therein).
Haemochromatosis is characterised by excess accumulation of iron. Most patients of European origin with genetic haemochromatosis are homozygous for the C282Y mutation of the HFE gene. This mutation is particularly common in Northern Europe where between 10–20% of the population are heterozygotes. Heterozygotes have higher transferrin saturations and may accumulate more iron than subjects lacking the mutation3; however, heterozygotes rarely accumulate the concentrations of iron associated with tissue damage in subjects with haemochromatosis who are homozygous for C282Y. However, if even small increases in tissue iron concentration promote the formation of highly reactive oxygen species and lipid peroxidation, a crucial step in atherosclerosis,4 then heterozygosity for C282Y may be a risk factor for cardiac disease.
Two large surveys suggested that possession of the HFE C282Y mutation may predispose to cardiovascular disorders, cardiovascular death in women,5 and acute myocardial infarction in men.6 Since then a number of other studies of HFE mutations and cardiovascular disease have been reported.7 These have included patients with atherosclerosis, coronary heart disease, myocardial infarction, and stroke. These were smaller studies but in all cases the 95% confidence intervals for the odds ratio include 1.0. The aim of the study reported here was to test the hypothesis that HFE C282Y is a risk factor for coronary heart disease and thereby is over-represented in patients with angina.