Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition

Johannes Kettunen, Michael V Holmes, Elias Allara, Olga Anufrieva, Pauli Ohukainen, Clare Oliver-Williams, Qin Wang, Therese Tillin, Alun D Hughes, Mika Kähönen, Terho Lehtimäki, Jorma Viikari, Olli T Raitakari, Veikko Salomaa, Marjo-Riitta Järvelin, Markus Perola, George Davey Smith, Nish Chaturvedi, John Danesh, Emanuele Di AngelantonioAdam S Butterworth, Mika Ala-Korpela

Research output: Contribution to journalArticle (Academic Journal)

2 Citations (Scopus)

Abstract

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very LDL (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

Original languageEnglish
Pages (from-to)e3000572
JournalPLoS Biology
Volume17
Issue number12
Early online date20 Dec 2019
DOIs
Publication statusE-pub ahead of print - 20 Dec 2019

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    Kettunen, J., Holmes, M. V., Allara, E., Anufrieva, O., Ohukainen, P., Oliver-Williams, C., Wang, Q., Tillin, T., Hughes, A. D., Kähönen, M., Lehtimäki, T., Viikari, J., Raitakari, O. T., Salomaa, V., Järvelin, M-R., Perola, M., Davey Smith, G., Chaturvedi, N., Danesh, J., ... Ala-Korpela, M. (2019). Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition. PLoS Biology, 17(12), e3000572. https://doi.org/10.1371/journal.pbio.3000572