| Title: | Joint Associations of APOC3 and LDL-C-Lowering Variants With the Risk of Coronary Heart Disease |
| Journal: | JAMA Cardiology |
| Published: | 1 May 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40105833/ |
| DOI: | https://doi.org/10.1001/jamacardio.2025.0195 |
Publication 15705
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Abstract
Importance: Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)-lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lowering triglycerides. Multiple clinical trials of small-interfering RNA therapeutics targeting APOC3 are currently underway.</p>
Objective: To investigate whether genetically predicted lower APOC3 is associated with a reduction in cardiovascular risk and if the combined exposure to APOC3 and LDL-C-lowering variants is associated with a reduction in the risk of coronary heart disease (CHD).</p>
Design, Setting, and Participants: This was a population-based genetic association study with 2 × 2 factorial mendelian randomization. Included were participants of European ancestry in the UK Biobank. Data were analyzed from November 2023 to July 2024.</p>
Exposures: Genetic scores were constructed to mimic the effects of APOC3, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors.</p>
Main Outcomes and Measures: Plasma lipid and lipoprotein levels, CHD, and type 2 diabetes (T2D).</p>
Results: This study included 401 548 UK Biobank participants (mean [SD] age, 56.9 [8.0] years; 216 901 female [54.0%]). Genetically predicted lower APOC3 was associated with a lower risk of CHD (odds ratio [OR], 0.96; 95% CI, 0.93-0.98) and T2D (0.97; 95% CI, 0.95-0.99). Genetically lower APOC3 and PCSK9 were associated with a similar magnitude of risk reduction in CHD per 10-mg/dL decrease in apolipoprotein B (ApoB) level (APOC3: 0.70; 95% CI, 0.59-0.83; PCSK9: 0.71; 95% CI, 0.65-0.77). Combined exposure to genetically lower APOC3 and PCSK9 was associated with an additive lower risk of CHD (APOC3: 0.96; 95% CI, 0.92-0.99; PCSK9: 0.93; 95% CI, 0.90-0.97; combined: 0.90; 95% CI, 0.86-0.93). Genetically lower HMGCR was also associated with a lower risk of CHD, and the risk was further reduced when combined with APOC3 (0.93; 95% CI, 0.90-0.97).</p>
Conclusions and Relevance: Genetically predicted lower APOC3 was associated with a reduced risk of CHD that is comparable with that associated with lower PCSK9 per unit decrease in ApoB. Combined exposure to APOC3 and LDL-C-lowering variants was associated with an additive reduction in CHD risk. Future studies are warranted to investigate the therapeutic potential of these combined therapies, particularly among high-risk patients who cannot achieve therapeutic targets with existing lipid-lowering therapies.</p>
12 Keywords
- Aged
- Apolipoprotein C-III
- Cholesterol, LDL
- Coronary Disease
- Female
- Humans
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- United Kingdom
7 Authors
- Wenxiu Wang
- Rui Li
- Zimin Song
- Ninghao Huang
- Tao Huang
- Xinwei Hua
- Yi-Da Tang
1 Application
| Application ID | Title |
|---|---|
| 44430 | Genetic risk, environmental factors and chronic diseases and ageing outcomes |
Enabling scientific discoveries that improve human health