Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

María Gordillo-Marañón (), Magdalena Zwierzyna, Pimphen Charoen, Fotios Drenos, Sandesh Chopade, Tina Shah, Jorgen Engmann, Nishi Chaturvedi, Olia Papacosta, Goya Wannamethee, Andrew Wong, Reecha Sofat, Mika Kivimaki, Jackie F. Price, Alun D. Hughes, Tom R. Gaunt, Deborah A. Lawlor, Anna Gaulton, Aroon D. Hingorani, Amand F. Schmidt and Chris Finan
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María Gordillo-Marañón: University College London
Magdalena Zwierzyna: University College London
Pimphen Charoen: University College London
Fotios Drenos: University College London
Sandesh Chopade: University College London
Tina Shah: University College London
Jorgen Engmann: University College London
Nishi Chaturvedi: University College London
Olia Papacosta: University College London
Goya Wannamethee: University College London
Andrew Wong: University College London
Reecha Sofat: University College London
Mika Kivimaki: University College London
Jackie F. Price: University of Edinburgh
Alun D. Hughes: University College London
Tom R. Gaunt: MRC Integrative Epidemiology Unit at the University of Bristol
Deborah A. Lawlor: MRC Integrative Epidemiology Unit at the University of Bristol
Anna Gaulton: Wellcome Genome Campus, Hinxton
Aroon D. Hingorani: University College London
Amand F. Schmidt: University College London
Chris Finan: University College London

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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 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.

Date: 2021
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DOI: 10.1038/s41467-021-25731-z

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