Low LDL Cholesterol in Individuals of African Descent Resulting From Frequent Nonsense Mutations in PCSK9

If mutations that raise PCSK9 cause high cholesterol, what do mutations that break the gene do? This study answered that question — and in doing so, made the case for an entire drug class.

The investigators found that loss-of-function mutations in PCSK9 occurred in roughly 2 percent of African Americans and were associated with a striking 40 percent reduction in LDL cholesterol. People born with less PCSK9 activity had lifelong low LDL. Follow-up work would show these individuals also had dramatically less coronary heart disease — and, reassuringly, no apparent harm from their naturally low cholesterol.

This was the human “experiment of nature” that validated PCSK9 as a target: nature had already created the equivalent of a PCSK9 inhibitor and shown it to be both protective and safe. The blockbuster injectable PCSK9 inhibitors are, in effect, an attempt to mimic this genotype pharmacologically.

We rate the evidence strong, with very high clinical significance. It is a landmark genetic study that turned a biological curiosity into the rationale for one of the most important drug developments in modern cardiology.