Mutations in PCSK9 Cause Autosomal Dominant Hypercholesterolemia

Every blockbuster drug starts somewhere. The PCSK9 inhibitors — the injectable medicines that drive LDL cholesterol to levels statins alone cannot reach — trace directly back to this short 2003 paper.

The French team was studying families with severe inherited high cholesterol in whom the two known culprit genes had been ruled out. By tracking which DNA segments traveled with the disease through these families, they identified a third gene, PCSK9, and showed that specific mutations in it drove LDL cholesterol up. It was the discovery of a previously unknown master regulator of how the body clears LDL from the blood.

The significance only grew with what came next. The same gene turned out to have mutations that work the other way — lowering LDL and protecting against heart disease — and that insight became the rationale for blocking PCSK9 with a drug. A finding in a handful of families became one of the most consequential targets in cardiovascular medicine.

We rate the evidence strong, and its clinical significance among the highest in this library. It is a textbook example of how careful human genetics can reveal a pathway, and how that pathway becomes a treatment.