Cardiovascular disease is also known to cluster in families, and this may be related to the clustering of lipid and lipoprotein levels among family members. A review suggested that the familial aggregation of heart disease may be primarily a reflection of the familial aggregation of known risk factors, including cholesterol levels. The work of Goldstein and Brown on familial hypercholesterolemia demonstrated that genetic control of lipoprotein metabolism can play a causative role in the development of atherosclerosis. However, familial hypercholesterolemia is a relatively rare disorder: the prevalence of heterozygotes is estimated to be 1 in 500, homozygotes 1 in a million. In 1987, little was understood about more common genetic contributions to lipid and lipoprotein abnormalities leading to the familial aggregation of coronary heart disease.