Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics
Gordillo-Marañón, María; Zwierzyna, Magdalena; Charoen, Pimphen; Drenos, Fotios; Chopade, Sandesh; Shah, Tina; Engmann, Jorgen; Chaturvedi, Nishi; Papacosta, Olia; Wannamethee, Goya; Wong, Andrew; Sofat, Reecha; Kivimaki, Mika; Price, Jackie F.; Hughes, Alun D.; Gaunt, Tom R.; Lawlor, Deborah A.; Gaulton, Anna; Hingorani, Aroon D.; Schmidt, Amand F.; Finan, Chris
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 12
(Article)
Abstract
Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter the target’s expression or function, as a tool to anticipate the effect of drug action on the same target. Here we apply MR to prioritize drug targets for their
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causal relevance for coronary heart disease (CHD). The targets are further prioritized using independent replication, co-localization, protein expression profiles and data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with blood lipids (HDL-C, LDL-C and triglycerides), we robustly prioritize 30 targets that might elicit beneficial effects in the prevention or treatment of CHD, including NPC1L1 and PCSK9, the targets of drugs used in CHD prevention. We discuss how this approach can be generalized to other targets, disease biomarkers and endpoints to help prioritize and validate targets during the drug development process.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: The authors are grateful to the studies and consortia that provided summary association results and to the participants of the biobanks and research cohorts. This research has been conducted using the UK Biobank Resource under Application Number 12113. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation. M.G.M. is supported by a BHF Fellowship FS/17/70/ 33482. A.F.S. is supported by BHF grant PG/18/5033837 and the UCL BHF Research Accelerator AA/18/6/34223. C.F. and A.F.S. received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A.D.H. is an NIHR Senior Investigator. We further acknowledge support from the Rosetrees Trust. The UCLEB Consortium is supported by a British Heart Foundation Program Grant (RG/10/12/28456). M.K. was supported by grants from the Wellcome Trust, UK (221854/Z/20/Z), the UK Medical Research Council (R024227 and S011676), the National Institute on Aging, NIH (R01AG056477 and RF1AG062553), and the Academy of Finland (311492). AH receives support from the British Heart Foundation, the Economic and Social Research Council (ESRC), the Horizon 2020 Framework Program of the European Union, the National Institute on Aging, the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the UK Medical Research Council and works in a unit that receives support from the UK Medical Research Council. A.G. is funded by the Member States of EMBL. P.C. is supported by the Thailand Research Fund (MRG6280088). D.A.L. is supported by a British Heart Foundation Chair (CH/F/20/90003) and British Heart Foundation grant (AA/18/7/34219), is a National Institute of Health Research Senior Investigator (NF-0616-10102) and works in a Unit that receives support from the University of Bristol and UK Medical Research Council (MC_UU_00011/6). This work was funded in part by the UKRI and NIHR through the Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1). Publisher Copyright: © 2021, The Author(s).
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