PCSK9 and the Road Less Traveled: How an Unconventional Approach Led to a Major Discovery

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A gene with a remarkable translational research story is leading the way in becoming potentially the next blockbuster drug in heart disease. This “gene of rare effect,” proprotein convertase subtilisin/kexin type 9 ( PCSK9 ),2 was found to be a contributing factor to profoundly low cholesterol concentrations in some individuals and has made its way from unknown factor to headline grabber, as detailed in a recent Nature news feature (1). In the postgenome era, the prevailing “common variant hypothesis” was that genetic variants present at approximately 5% frequencies were expected to contribute importantly to complex disease (such as heart disease). However, subsequent genome-wide association studies proved disappointing, finding that common variants actually have a very small effect on disease. On the contrary, a decade before the Human Genome Project, Helen Hobbs and Jonathan Cohen and their colleagues from the University of Texas Southwestern approached this problem in a divergent manner, by hypothesizing that many different rare variants were likely to have a big effect in complex disorders. They reasoned that common variants with a major impact on complex disorders would be weeded out by natural selection. The Dallas Heart Study (DHS) was a large multiethnic (>50% …