Joint Associations of APOC3 and LDL-C-Lowering Variants With the Risk of Coronary Heart Disease.

Summary

Using a 2×2 factorial Mendelian randomization in 401,548 UK Biobank participants, genetically lower APOC3 was associated with reduced CHD and T2D risk, with CHD risk reduction per 10 mg/dL ApoB decrease comparable to PCSK9. Combined exposure to APOC3-lowering and LDL-C–lowering variants (PCSK9 or HMGCR) yielded additive reductions in CHD risk.

Key Findings

• Genetically lower APOC3 associated with lower CHD risk (OR 0.96, 95% CI 0.93-0.98) and lower T2D risk (OR 0.97, 95% CI 0.95-0.99).
• Per 10 mg/dL ApoB decrease, CHD risk reduction with APOC3 and PCSK9 variants was comparable (OR 0.70 vs 0.71).
• Combined exposure to APOC3 and PCSK9 or HMGCR variants produced additive CHD risk reduction (e.g., combined APOC3+PCSK9 OR 0.90, 95% CI 0.86-0.93).

Clinical Implications

In high-risk patients who fail to meet ApoB/LDL-C targets, combining APOC3-targeting therapies with established LDL-lowering agents may provide incremental risk reduction. Genetic evidence supports prioritizing ApoB-centric treatment goals.

Limitations

• Predominantly European ancestry limits generalizability to diverse populations.
• Mendelian randomization assumptions (no pleiotropy, linearity) may be violated despite sensitivity analyses.

Future Directions

Prospective trials combining APOC3 inhibitors with PCSK9 or statins in high-risk patients should quantify additive risk reduction and safety, including in diverse ancestries.