The apolipoprotein(a) [APO(a)] gene encodes a protein component of lipoprotein(a) [LP(a)], whose plasma levels vary among individuals. To study the implications of LP(a), we examined plasma LP(a) levels and molecular weights of APO(a) in patients with cerebrovascular disease (CVD) or diabetes mellitus (DM). Mean LP(a) concentrations were higher in the CVD patients with atherothrombotic brain infarction than in those with brain hemorrhage and lacunar infarction. LP(a) levels were lower in the DM cases on diet therapy alone than in those treated with insulin or oral hypoglycemic agents. These results suggest that LP(a) is thrombogenic and atherogenic and that insulin may modulate LP(a) levels. We subclassified the APO(a) gene into four types (A to D) by polymorphisms in the 5'-flanking region. We also measured plasma LP(a) concentrations and examined expression of the gene by an in vitro assay. Homozygotes of type C had higher LP(a) levels than those of type D, and the relative expression of type C was higher than that of type D in vitro. Thus, LP(a) concentrations are genetically determined, and hyper-LP(a)-nemia is related to atherosclerosis and thrombosis.