University of Oulu

Qin Wang, Clare Oliver-Williams, Olli T Raitakari, Jorma Viikari, Terho Lehtimäki, Mika Kähönen, Marjo-Riitta Järvelin, Veikko Salomaa, Markus Perola, John Danesh, Johannes Kettunen, Adam S Butterworth, Michael V Holmes, Mika Ala-Korpela, Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis, European Heart Journal, Volume 42, Issue 12, 21 March 2021, Pages 1160–1169, https://doi.org/10.1093/eurheartj/ehaa972

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition : a drug-target Mendelian randomization analysis

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Author: Wang, Qin1,2,3; Oliver-Williams, Clare4,5; Raitakari, Olli T.6,7,8,9;
Organizations: 1Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
2Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
3Center for Life Course Health Research, University of Oulu, Oulu, Finland
4MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
5Homerton College, University of Cambridge, Cambridge, UK
6Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
7Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
8Centre for Population Health Research, University of Turku, Turku, Finland
9Turku University Hospital, Turku, Finland
10Department of Medicine, University of Turku, Turku, Finland
11Division of Medicine, Turku University Hospital, Turku, Finland
12Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
13Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
14Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland
15Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
16Department of Life Sciences, College of Health and Life Sciences, Brunel University London, UK
17National Institute for Health and Welfare, Helsinki, Finland
18Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
19Estonian Genome Center, University of Tartu, Tartu, Estonia
20National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK
21Wellcome Trust Sanger Institute, Hinxton, UK
22British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK
23Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK
24Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford , Big Data Institute Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK
25National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
26Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
27NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021051229669
Language: English
Published: Oxford University Press, 2021
Publish Date: 2021-05-12
Description:

Abstract

Aims: Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement.

Methods and results: Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function.

Conclusions: Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.

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Series: European heart journal
ISSN: 0195-668X
ISSN-E: 1522-9645
ISSN-L: 0195-668X
Volume: 42
Issue: 12
Pages: 1160 - 1169
DOI: 10.1093/eurheartj/ehaa972
OADOI: https://oadoi.org/10.1093/eurheartj/ehaa972
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
LPL
Funding: The Academy of Finland (grant no. 297338, 307247, 322098, 286284, 134309, 126925, 121584, 124282, 129378, 117787, and 41071), Novo Nordisk foundation (NNF17OC0027034 and NNF17OC0026062), Oulu Health and Wellfare Center, Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, ERDF European Regional Development Fund (grant no. 539/2010: A31592), EU Horizon 2020 (grant no. 633595 and 755320), EU Research Council (grant no. 742927) and following foundations: Sigrid Juselius, Finnish Cardiovascular Research, Juho Vainio, Paavo Nurmi, Finnish Cultural, Tampere Tuberculosis, Emil Aaltonen, Yrjö Jahnsson, Signe and Ane Gyllenberg, and Finnish Diabetes Research. Dr M.V.H. is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre.
Academy of Finland Grant Number: 297338
307247
322098
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
322098 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
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