University of Oulu

Kettunen J, Holmes MV, Allara E, Anufrieva O, Ohukainen P, Oliver-Williams C, et al. (2019) Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition. PLoS Biol 17(12): e3000572.

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

Saved in:
Author: Kettunen, Johannes1,2; Holmes, Michael V.3,4,5,6; Allara, Elias7,8;
Organizations: 1Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
2National Institute for Health and Welfare, Helsinki, Finland
3Medical Research Council Population Health Research Unit, University of Oxford, Oxford, United Kingdom
4Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
5National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, United Kingdom
6Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom
7British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
8National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
9Homerton College, University of Cambridge, Cambridge, United Kingdom
10Institute of Cardiovascular Science, University College London, London, United Kingdom
11Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland
12Department of Clinical Chemistry, Fimlab Laboratories, Finnish Cardiovascular Research Center Tampere
13Faculty of Medicine and Health Technologies, University of Tampere, Tampere, Finland
14Department of Medicine, University of Turku, Turku, Finland
15Division of Medicine, Turku University Hospital, Turku, Finland
16Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
17Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
18Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
19Biocenter Oulu, University of Oulu, Oulu, Finland
20Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland
21Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
22Department of Life Sciences, College of Health and Life Sciences, Brunel University London, United Kingdom
23Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland
24Estonian Genome Center, University of Tartu, Tartu, Estonia
25Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom
26Wellcome Trust Sanger Institute, Hinxton, United Kingdom
27British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
28NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
29Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
30Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
Persistent link:
Language: English
Published: Public Library of Science, 2019
Publish Date: 2020-03-25


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.

see all

Series: PLoS biology
ISSN: 1544-9173
ISSN-E: 1545-7885
ISSN-L: 1544-9173
Volume: 17
Issue: 12
Article number: e3000572
DOI: 10.1371/journal.pbio.3000572
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: JK was funded through Academy of Finland (grant numbers 297338 and 307247) and Novo Nordisk Foundation (NNF17OC0026062). MVH works in a Unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512). PO was supported by the Emil Aaltonen Foundation. COW has been awarded prize money by Novartis UK. MAK was supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1158958) and by Sigrid Juselius Foundation. GDS and MAK work in a Unit that receives funds from the University of Bristol and UK Medical Research Council (MC_UU_12013/1). The Northern Finland Birth Cohorts (MRJ) were supported by the Academy of Finland (EGEA-project, 285547), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), ERDF European Regional Development Fund Grant no. 539/2010 A31592, EU H2020--PHC-2014 DynaHEALTH action (No. 633595), EU H2020-HCO-2004 iHEALTH Action (643774), EU H2020-SC1-2016-2017 LifeCycle Action (grant agreement No 733206), and MRC Grant nro MR/M013138/1. The Young Finns Study (OTR) has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. The INTERVAL trial (JD) was funded by NHSBT and the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). The trial’s coordinating centre at the Department of Public Health and Primary Care at the University of Cambridge, Cambridge, UK, has received core support from the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and the NIHR Cambridge Biomedical Research Centre. The NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics is supported by grant NIHR BTRU-2014-10024. Dr Allara was supported by a NIHR BTRU PhD Studentship while this study was performed. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant n° 116074. Investigators at the University of Oxford, Oxford, UK, have been supported by the Research and Development Programme of NHSBT, the NHSBT Howard Ostin Trust Fund, and the NIHR Oxford Biomedical Research Centre through the programme grant NIHR-RP-PG-0310-1004. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(643774) iHealth-T2D - Family-based intervention to improve healthy lifestyle and prevent Type 2 Diabetes amongst South Asians with central obesity and prediabetes
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
Academy of Finland Grant Number: 297338
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
285547 (Academy of Finland Funding decision)
Copyright information: © 2019 Kettunen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.