Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition
Year: 2019
Type: preprint
Study design: Observational Study
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-low-density lipoprotein (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.
DOI: 10.17863/cam.47645
Authors: Kettunen, Johannes, Holmes, Michael V., Allara, Elias, Anufrieva, Olga, Ohukainen, Pauli, Oliver-Williams, Clare, Wang, Qin, Tillin, Therese, Hughes, Alun D., Kähönen, Mika, Lehtimäki, Terho, Viikari, Jorma, Raitakari, Olli T., Salomaa, Veikko, Järvelin, Marjo-Riitta, Perola, Markus, Davey Smith, George, Chaturvedi, Nish, Danesh, John, Di Angelantonio, Emanuele, Butterworth, Adam S., Ala-Korpela, Mika
Institutions: Finnish Institute for Health and Welfare, University of Oulu, University of Oxford, MRC Population Health Research Unit, University of Cambridge, National Institute for Health and Care Research, University College London, Tampere University Hospital, University of Tampere, Tampere University, Fimlab (Finland), University of Turku, Turku University Hospital, University of Helsinki, University of Tartu, University of Bristol
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: NHS Blood and Transplant, European Federation of Pharmaceutical Industries and Associations, National Institute for Health and Care Research, British Heart Foundation, University of Cambridge, University of Oxford, Signe ja Ane Gyllenbergin Säätiö, Diabetesliitto, Novo Nordisk Fonden, Medical Research Council, National Health and Medical Research Council, Terveyden Tutkimuksen Toimikunta, NIHR Cambridge Biomedical Research Centre
Awards: G1386524577, G2259971274, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), Methods and tools for structural models integrating multiple high-throughput omics data sets in genetic epidemiology, G3488911319, G3521192838, G385907487, G4194769985, Extensive molecular profiling of systemic metabolism to understand and prevent cardiometabolic diseases, G4584873075, Methods and tools for structural models integrating multiple high-throughput omics data sets in genetic epidemiology, G567453067, G587296758, Erythropoiesis in Health and Disease
OpenAlex ID: W3080585323