| Title: | Genetic modelling of triglyceride-rich lipoprotein/remnant lowering mimics APOC3 silencing and predicts clinically relevant coronary heart disease event reductions |
| Journal: | European Journal of Preventive Cardiology |
| Published: | 14 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41092100/ |
| DOI: | https://doi.org/10.1093/eurjpc/zwaf657 |
Publication 19182
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Abstract
AIMS: Triglyceride-rich lipoproteins (TRLs) and remnants are established causal risk factors for coronary heart disease (CHD). APOC3 gene-silencing agents reduce TRL/remnant concentrations but the consequent quantitative effect on CHD risk is not yet defined. We used a polygenic score (PGS)-based model to investigate if the degree of TRL/remnant reduction seen on APOC3 silencing would lead to a meaningful reduction in CHD risk.</p>
METHODS: A TRL/remnant-specific PGS was used to select two groups (each >4,150 individuals) from the UK Biobank. CHD event rates were compared between the group with the highest PGS with genetically higher TRL/remnant levels (mimicking placebo) and the group with the lowest PGS with lower levels (mimicking APOC3 silencing).</p>
RESULTS: Compared with the high PGS group, the low PGS group had lower plasma triglycerides (-34%), TRL/remnant cholesterol (-22.5%), non-HDL cholesterol (-7.5%) and apolipoprotein B (-6.0%), with a small reduction in LDL cholesterol (-3.9%) and a 15.3% increase in HDL cholesterol. These differences were similar to those seen with APOC3 silencing agents, but with about a third of the absolute effect size. The low PGS group had a 28% lower lifetime CHD event rate (HR = 0.72, 95% CI:0.56-0.91). Extrapolating to a 5-year trial, an APOC3 silencing agent achieving a 16-23 mg/dL decrease in TRL/remnant cholesterol is predicted to reduce CHD risk by approximately 25%.</p>
CONCLUSIONS: Based on our genetic modelling, the degree of TRL/remnant lowering seen on APOC3 silencing would produce a meaningful CHD risk reduction of around 25 % over a 5-year outcomes trial.</p>
8 Authors
- Elias Björnson
- Chris Packard
- Martin Adiels
- Nicholas J Leeper
- Jennifer Hellawell
- Anders Gummesson
- Steven E Nissen
- Jan Borén
1 Application
| Application ID | Title |
|---|---|
| 82018 | Improved biomarkers of cardiovascular disease |
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