Low density lipoprotein (LDL), the major cholesterol-carrying lipoprotein in human plasma, is the offending agent in coronary heart disease, which causes one-third of all deaths in the United States. Originally, LDL was implicated in heart disease through epidemiologic and genetic observations in humans and animal models (1). Its involvement has been confirmed by the recent and repeated demonstration that LDL-lowering drugs, called statins, reduce heart attacks and prolong life (2).

What determines the amount of LDL in plasma, and why do so many people have enough LDL to cause heart attacks? In medicine, common problems are often solved by studies of uncommon genetic diseases. In the case of LDL, answers have emerged from unraveling the aberrant genes underlying four disorders that elevate plasma LDL and cause premature heart attacks. The final two molecular defects of this quartet have been described within the last 6 months (3–5), and one of them is reported on page 1394 of this week's Science (5). Remarkably, all four defects raise the amount of plasma LDL by impairing the activity of hepatic LDL receptors (LDLRs), which normally clear LDL from plasma.