Publication:
Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Issued Date

2021-12-01

Resource Type

Article

ISSN

20411723

DOI

10.1038/s41467-021-25703-3

Other identifier(s)

2-s2.0-85115675591

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Nature Communications. Vol.12, No.1 (2021)

Suggested Citation

Amand F. Schmidt, Nicholas B. Hunt, Maria Gordillo-Marañón, Pimphen Charoen, Fotios Drenos, Mika Kivimaki, Deborah A. Lawlor, Claudia Giambartolomei, Olia Papacosta, Nishi Chaturvedi, Joshua C. Bis, Christopher J. O’Donnell, Goya Wannamethee, Andrew Wong, Jackie F. Price, Alun D. Hughes, Tom R. Gaunt, Nora Franceschini, Dennis O. Mook-Kanamori, Magdalena Zwierzyna, Reecha Sofat, Aroon D. Hingorani, Chris Finan Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease. Nature Communications. Vol.12, No.1 (2021). doi:10.1038/s41467-021-25703-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/75919

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Title

Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Author(s)

Amand F. Schmidt
 Nicholas B. Hunt
 Maria Gordillo-Marañón
 Pimphen Charoen
 Fotios Drenos
 Mika Kivimaki
 Deborah A. Lawlor
 Claudia Giambartolomei
 Olia Papacosta
 Nishi Chaturvedi
 Joshua C. Bis
 Christopher J. O’Donnell
 Goya Wannamethee
 Andrew Wong
 Jackie F. Price
 Alun D. Hughes
 Tom R. Gaunt
 Nora Franceschini
 Dennis O. Mook-Kanamori
 Magdalena Zwierzyna
 Reecha Sofat
 Aroon D. Hingorani
 Chris Finan

Other Contributor(s)

Faculty of Tropical Medicine, Mahidol University
 Bristol Medical School
 NIHR Bristol Biomedical Research Centre
 Edinburgh Medical School
 VA Boston Healthcare System
 Istituto Italiano di Tecnologia
 British Heart Foundation
 Utrechts Instituut voor Farmaceutische Wetenschappen
 University Medical Center Utrecht
 University of Washington School of Medicine
 The University of North Carolina at Chapel Hill
 University College London
 University of Bristol
 Brunel University London
 Medical Research Council
 Leids Universitair Medisch Centrum
 Mahidol University
 Harvard Medical School
 Health Data Research UK

Abstract

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.

Keyword(s)

Biochemistry, Genetics and Molecular Biology
 Chemistry
 Physics and Astronomy

Availability

URI

https://repository.li.mahidol.ac.th/handle/123456789/75919

Collections

Scopus 2021