Abstract
According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (µg/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 × 10–22) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 × 10–6). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n ~20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.
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Acknowledgements
We express our gratitude to all individuals who participate in the NEO study. We are grateful to all participating general practitioners for inviting eligible participants. We furthermore thank Pat van Beelen and all research nurses for collecting the data, Petra Noordijk and her team for laboratory management and DNA isolation, and Ingeborg de Jonge for all data management of the NEO study. We sincerely thank Chris van der Bent for performing the serum CETP concentration measurements. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. This work was supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area ‘Vascular and Regenerative Medicine; a grant from the Board of Directors of the Leiden University Medical Center to LLB; the Dutch Science Organization (ZonMW-VENI Grant 91617027 to YW); the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757 to DvH); the Dutch Science Organization (ZonMW-VENI Grant 91614023 to DOM-K); the Academy of Finland (312476 and 312477 to PW); the Novo Nordisk Foundation (15998 to PW); and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-9).
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SS and PW are employees of Nightingale Health Ltd, a company offering NMR-based metabolite profiling. PW is a shareholder of Nightingale Health Ltd. All other authors declare that they have no conflict of interest.
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Blauw, L.L., Noordam, R., Soidinsalo, S. et al. Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile. Eur J Hum Genet 27, 422–431 (2019). https://doi.org/10.1038/s41431-018-0301-5
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DOI: https://doi.org/10.1038/s41431-018-0301-5
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