@article{discovery10052989,
            note = {The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.},
            year = {2018},
           month = {April},
         journal = {bioRxiv},
           title = {Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition},
             url = {https://doi.org/10.1101/295394},
          author = {Kettunen, J and Holmes, M and Allara, E and Anufrieva, O and Ohukainen, P and Oliver-Williams, C and Tillin, T and Hughes, A and Kahonen, M and Lehtimaki, T and Viikari, J and Raitakari, O and Salomaa, V and Jarvinen, M-R and Perola, M and Davey Smith, G and Chaturvedi, N and Danesh, J and Di Angelantonio, E and Butterworth, A and Ala-Korpela, M},
        abstract = {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.}
}