%L discovery10052989 %D 2018 %J bioRxiv %A J Kettunen %A M Holmes %A E Allara %A O Anufrieva %A P Ohukainen %A C Oliver-Williams %A T Tillin %A A Hughes %A M Kahonen %A T Lehtimaki %A J Viikari %A O Raitakari %A V Salomaa %A M-R Jarvinen %A M Perola %A G Davey Smith %A N Chaturvedi %A J Danesh %A E Di Angelantonio %A A Butterworth %A M Ala-Korpela %O The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license. %T Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition %X BACKGROUND: CETP inhibition reduces vascular event rates but confusion surrounds its low-density lipoprotein (LDL)-cholesterol effects. We sought to clarify associations of genetic inhibition of CETP on detailed lipoproteins. METHODS AND RESULTS: We used variants associated with CETP (rs247617) and HMGCR (rs12916) expression in 62,400 Europeans with detailed lipoprotein profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% lower risk of coronary heart disease (CHD). Associations of lipoprotein measures with risk of incident CHD in three population-based cohorts (770 cases) were examined. CETP and HMGCR had near-identical associations with LDL-cholesterol concentration estimated by Friedewald-equation. HMGCR had a relatively consistent effect on cholesterol concentrations across all apolipoprotein B-containing lipoproteins. CETP had stronger effects on remnant and very-low-density lipoprotein cholesterol but no effect on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02SD 95%CI: -0.10, 0.05 for CETP versus -0.24SD, 95%CI -0.30, -0.18 for HMGCR). CETP had profound effects on lipid compositions of lipoproteins, with strong reductions in the triglyceride content of all high-density lipoprotein (HDL) particles. These alterations in triglyceride composition within HDL subclasses were observationally associated with risk of CHD, independently of total cholesterol and triglycerides (strongest HR per 1-SD higher triglyceride composition in very-large HDL 1.35; 95%CI: 1.18, 1.54). CONCLUSION: CETP inhibition does not affect size-specific LDL cholesterol but may lower CHD risk by lowering cholesterol in other apolipoprotein-B containing lipoproteins and lowering triglyceride content of HDL particles. Conventional composite lipid assays may mask heterogeneous effects of lipid-altering therapies.