CETP inhibition Reduces Cardiovascular Events by Lowering of Cumulative LDL Exposure: Reconciling Evidence from Human Genetics and Clinical Trials

BackgroundSequence variants that disrupt Cholesteryl Ester Transfer Protein (CETP) provide a genetic proxy for therapeutic inhibition, but their association with atherosclerotic vascular events has not been robustly established. ObjectivesTo assess whether protein-disrupting CETP variants conferring lifelong reduced CETP activity lower atherosclerotic vascular event rates. MethodsWe tested associations between protein-disrupting CETP variants and atherosclerotic vascular and coronary artery disease across the All of Us Research Program and the UK Biobank using whole-genome sequences and linked health data. Predicted protein-disrupting variants were identified with LOFTEE and AlphaMissense. Gene-based burden testing used Firths logistic regression via REGENIE. Coronary artery disease was meta-analysed with FinnGen, Biobank Japan, and previous case-control studies. Restricted mean event-free survival to average life expectancy of 81 years was estimated in the UK Biobank. ResultsWe included 1,515-4,575 carriers of CETP protein-disrupting variants and 848,000-1,585,000 non-carriers in combined populations with 126,000 atherosclerotic events and 246,000 coronary artery disease events, respectively. HDL cholesterol was 25% higher (0.35 mmol/L [14 mg/dL], P=4x10-138) and non-HDL cholesterol was 6% lower (0.23 mmol/L [9 mg/dL], P=9x10-8) in carriers. Atherosclerotic vascular event rates were lower in carriers (odds ratio, 0.73, 95% confidence interval, 0.62-0.87, P=3x10-4). Coronary artery disease risk was also lower in carriers (odds ratio, 0.79, 95% confidence interval, 0.72-0.86, P=3x10-7), reaching exome-wide significance. Carriers lived an average 1.0 years longer without atherosclerotic disease (95% confidence interval, 0.5-1.4, P=6x10-5). ConclusionProtein-disrupting CETP variants were associated with reduced atherosclerotic vascular disease risk and longer disease-free survival.