Recent ABCA1 studies in the general population reveal a genetic mixture of rare alleles with large effects and common alleles with modest effects on common traits. While both common and rare ABCA1 variants influence HDL cholesterol levels and ischemic heart disease (IHD) risk, the association between ABCA1 variants and IHD risk appears independent of plasma HDL cholesterol levels, challenging the causality of isolated low HDL cholesterol in IHD development. This evidence concerns the gene ABCA1 and myocardial ischemia.