Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics

Abstract

Identification of the CETP, LIPG (encoding endothelial lipase) and APOC3 genes, and analysis of rare genetic variants in them, have allowed researchers to increase understanding of HDL metabolism significantly. However, development of cardiovascular risk-reducing therapeutics targeting the proteins encoded by these genes has been less straightforward. The failure of two CETP inhibitors is complex but illustrates a possible over-reliance on HDL cholesterol as a marker of therapeutic efficacy. The case of endothelial lipase exemplifies the importance of utilizing population-wide genetic studies of rare variants in potential therapeutic targets to gain information on cardiovascular disease end points. Similar population-wide studies of cardiovascular end points make apoC-III a potentially attractive target for lipid-related drug discovery. These three cases illustrate the positives and negatives of single-gene studies relating to HDL-related cardiovascular drug discovery; such studies should focus not only on HDL cholesterol and other components of the lipid profile, but also on the effect genetic variants have on cardiovascular end points.

Key Words:

• anacetrapib
• apoC-III
• CETP
• cholesterol
• dalcetrapib
• endothelial lipase
• evacetrapib
• genetics
• HDL
• ISI-APOCIII_rx
• torcetrapib