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

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

doi:10.1093/eurheartj/ehaa972

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

Eur Heart J. 2021 Mar 21;42(12):1160-1169. doi: 10.1093/eurheartj/ehaa972.

Authors

Qin Wang^{1

2

3}, Clare Oliver-Williams^{4

5}, Olli T Raitakari^{6

7

8

9}, Jorma Viikari^{10

11}, Terho Lehtimäki¹², Mika Kähönen¹³, Marjo-Riitta Järvelin^{3

14

15

16}, Veikko Salomaa¹⁷, Markus Perola^{17

18

19}, John Danesh^{4

20

21

22}, Johannes Kettunen^{2

3

17}, Adam S Butterworth^{4

20}, Michael V Holmes^{23

24

25

26}, Mika Ala-Korpela^{2

3

27}

Affiliations

¹ Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
² Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
³ Center for Life Course Health Research, University of Oulu, Oulu, Finland.
⁴ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Homerton College, University of Cambridge, Cambridge, UK.
⁶ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁷ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁸ Centre for Population Health Research, University of Turku, Turku, Finland.
⁹ Turku University Hospital, Turku, Finland.
¹⁰ Department of Medicine, University of Turku, Turku, Finland.
¹¹ Division of Medicine, Turku University Hospital, Turku, Finland.
¹² Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
¹³ Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
¹⁴ Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
¹⁵ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
¹⁶ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, UK.
¹⁷ National Institute for Health and Welfare, Helsinki, Finland.
¹⁸ Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.
¹⁹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
²⁰ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
²¹ Wellcome Trust Sanger Institute, Hinxton, UK.
²² British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK.
²³ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
²⁴ Clinical 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.
²⁵ National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.
²⁶ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
²⁷ NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.

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.

Keywords: ANGPTL3; ANGPTL4; Amino acids; Drug targets; Glycoprotein acetyls; LPL; Lipoprotein lipids; Lipoprotein subclasses; Mendelian randomization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiopoietin-Like Protein 3
Angiopoietin-Like Protein 4 / genetics
Angiopoietin-like Proteins / genetics
Angiopoietins / genetics
Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / genetics
Humans
Mendelian Randomization Analysis
Pharmaceutical Preparations*

Substances

ANGPTL3 protein, human
ANGPTL4 protein, human
Angiopoietin-Like Protein 3
Angiopoietin-Like Protein 4
Angiopoietin-like Proteins
Angiopoietins
Pharmaceutical Preparations

Grants and funding

FS/18/23/33512/BHF_/British Heart Foundation/United Kingdom