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Updated: Jun 6, 2026
06:47
Isolation and Analysis of Plasma Lipoproteins by Ultracentrifugation
Published on: January 28, 2021
Translating Lipoprotein Genetics Into New Therapies
1Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Circulation Research
|June 4, 2026
Summary
Human genetics identifies drug targets for lowering lipids, with rare variants proving key for therapeutic success. This approach has led to new drug approvals and informed future cardiovascular disease treatments.
Area of Science:
- Human genetics and pharmacology
- Cardiovascular disease research
- Drug discovery and development
Background:
- Human genetics, particularly rare loss-of-function variants, serves as a powerful tool for identifying lipid-lowering drug targets.
- The 'human knockout' paradigm, observing individuals with genetic variants, provides real-world proof-of-concept for therapeutic targets.
- Previous genetic insights have validated targets like PCSK9, APOC3, and ANGPTL3, leading to approved therapies.
Purpose of the Study:
- To review the role of human genetics in identifying and validating targets for lipid-lowering therapies.
- To discuss the translation of genetic findings into pharmacological interventions, including RNA-based approaches.
- To assess the current landscape and future potential of genetic insights in cardiovascular drug development.
Main Methods:
- Analysis of monogenic family studies and population-based sequencing to identify functional genetic variants.
- Review of Mendelian randomization studies to distinguish causal targets from biomarkers.
- Examination of RNA-based pharmacology (siRNAs, ASOs) and gene-editing technologies for therapeutic translation.
Main Results:
- Genetic validation has driven approvals for drugs targeting PCSK9, APOC3, and ANGPTL3, demonstrating significant clinical benefits.
- Mendelian randomization identified high-density lipoprotein (HDL) cholesterol as a non-causal biomarker, explaining the failure of HDL-raising therapies.
- RNA-based therapies are emerging as a practical platform for translating genetic targets into durable treatments.
Conclusions:
- Human genetics is pivotal in discovering and validating lipid-lowering drug targets, significantly impacting cardiovascular medicine.
- RNA-based pharmacology represents a successful translation of genetic insights into novel therapeutic strategies.
- While GWAS and polygenic scores expand target discovery, rare-variant genetics currently offers greater translational yield.
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