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

María Gordillo-Marañón,Andrew Wong,Magdalena Zwierzyna,Fotios Drenos,Anna Gaulton,Sandesh Chopade,Alun D Hughes ,Jorgen Engmann,Mika Kivimäki ,Debbie A Lawlor ,Reecha Sofat,Nish Chaturvedi ,Jackie F Price ,Olia Papacosta,Goya Wannamethee,Tom R Gaunt ,Amand F Schmidt ,Pimphen Charoen,Tina Shah,Aroon D Hingorani ,Chris Finan

doi:10.1038/s41467-021-25731-z

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.

Highlights

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
The OR for coronary heart disease (CHD) per standard deviation (SD) higher concentration of the corresponding blood lipid fraction was 1.50 (95% confidence interval (CI): 1.39–1.63) for low-density lipoprotein cholesterol (LDL-C), 0.95 for HDL-C and 1.10 for TG
These findings were replicated in an independent analysis using summary statistics from a Genome-wide association studies (GWAS) meta-analysis of lipids measured using a nuclear magnetic resonance (NMR) spectroscopy platform[15,16], and genetic associations with CHD risk derived from UK Biobank[17]

Summary

Introduction

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. Genome-wide biomarker MR studies have validated the causal role of elevated low-density lipoprotein cholesterol (LDL-C) on CHD risk, supporting the findings from randomized controlled trials of different LDL-C lowering drug classes[4,5,6,7,8,9]. Such studies have been equivocal on the role of HDL-C and TG in CHD4,5. These observations suggest that other effective as yet unexploited drug targets might exist for the prevention or treatment of CHD that could be identified through their association with blood lipids even though such analyses should not presume that the effect on CHD is mediated through these lipids

Methods

Results

Conclusion