RT Journal Article
SR Electronic
T1 Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 295394
DO 10.1101/295394
A1 Johannes Kettunen
A1 Michael V. Holmes
A1 Elias Allara
A1 Olga Anufrieva
A1 Pauli Ohukainen
A1 Clare Oliver-Williams
A1 Therese Tillin
A1 Alun D. Hughes
A1 Mika Kähönen
A1 Terho Lehtimäki
A1 Jorma Viikari
A1 Olli T. Raitakari
A1 Veikko Salomaa
A1 Marjo-Riitta Järvelin
A1 Markus Perola
A1 George Davey Smith
A1 Nish Chaturvedi
A1 John Danesh
A1 Emanuele Di Angelantonio
A1 Adam S. Butterworth
A1 Mika AlaKorpela
YR 2018
UL http://biorxiv.org/content/early/2018/04/05/295394.abstract
AB 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 highdensity 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.