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BMC Medicine
Published in: BMC Medicine 1/2023

Open Access 01-12-2023 | Cholelithiasis | Research article

Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study

Authors: Guoyi Yang, C. Mary Schooling

Published in: BMC Medicine | Issue 1/2023

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Abstract

Background

Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk. Here, we investigated genetically mimicked ASGR1 inhibitors on all-cause mortality and any possible adverse effects.

Methods

We conducted a drug-target Mendelian randomization study to assess genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and 25 a priori outcomes relevant to lipid traits, CAD, and possible adverse effects, i.e. liver function, cholelithiasis, adiposity and type 2 diabetes. We also performed a phenome-wide association study of 1951 health-related phenotypes to identify any novel effects. Associations found were compared with those for currently used lipid modifiers, assessed using colocalization, and replicated where possible.

Results

Genetically mimicked ASGR1 inhibitors were associated with a longer lifespan (3.31 years per standard deviation reduction in LDL-cholesterol, 95% confidence interval 1.01 to 5.62). Genetically mimicked ASGR1 inhibitors were inversely associated with apolipoprotein B (apoB), triglycerides (TG) and CAD risk. Genetically mimicked ASGR1 inhibitors were positively associated with alkaline phosphatase, gamma glutamyltransferase, erythrocyte traits, insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP), but were inversely associated with albumin and calcium. Genetically mimicked ASGR1 inhibitors were not associated with cholelithiasis, adiposity or type 2 diabetes. Associations with apoB and TG were stronger for ASGR1 inhibitors compared with currently used lipid modifiers, and most non-lipid effects were specific to ASGR1 inhibitors. The probabilities for colocalization were > 0.80 for most of these associations, but were 0.42 for lifespan and 0.30 for CAD. These associations were replicated using alternative genetic instruments and other publicly available genetic summary statistics.

Conclusions

Genetically mimicked ASGR1 inhibitors reduced all-cause mortality. Beyond lipid-lowering, genetically mimicked ASGR1 inhibitors increased liver enzymes, erythrocyte traits, IGF-1 and CRP, but decreased albumin and calcium.
Appendix
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Metadata
Title
Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study
Authors
Guoyi Yang
C. Mary Schooling
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2023
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-023-02903-w

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