CETP I405V variant

Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl esters from HDL for triglycerides in VLDL and LDL, effectively lowering HDL-cholesterol. The I405V variant (rs5882) in the CETP gene reduces CETP activity and is enriched in Ashkenazi Jewish centenarians and their offspring relative to controls in the Einstein Aging Study (Barzilai et al., 2003), accompanying notably high HDL and large HDL particle size. Large HDL particles are more effective in reverse cholesterol transport and are associated with reduced cardiovascular and cognitive disease risk. The variant illustrates how a naturally occurring loss-of-function polymorphism can phenocopy the cardiovascular benefit sought by pharmacological CETP inhibitors, several of which failed in trials despite HDL elevation — suggesting particle quality over quantity matters.