Remnant cholesterol concentrations best explain the cardiovascular benefit of APOC3 genetic inhibition: a drug target Mendelian randomization study.

Abstract

Aims: Apolipoprotein C-III (APOC3) inhibitors are approved for hypertriglyceridaemia. Genetic evidence suggests that APOC3 inhibition may also prevent coronary artery disease (CAD), but mechanisms remain unclear.

Methods and results: To clarify how APOC3 inhibition could prevent CAD, we performed two-step cis-Mendelian randomization using genetic variants in the APOC3 gene region associated with plasma levels of APOC3. For comparison, we investigated proprotein convertase subtilisin/kexin type 9 (PCSK9). Potential mediators included apolipoprotein B, triglycerides, LDL-cholesterol, and remnant cholesterol measured by nuclear magnetic resonance spectroscopy in mostly fasting samples from Karjalainen et al., and in non-fasting samples from the UK Biobank. CAD data were from CARDIoGRAMplusC4D. APOC3 associations with apolipoprotein B and remnant cholesterol levels were two-fold larger in the study by Karjalainen et al. (55% fasted individuals) when compared with the UK Biobank study (non-fasted individuals). Genetically predicted lower APOC3 and PCSK9 levels were similarly associated with reduced CAD risk (OR = 0.83, 95% CI = 0.75-0.92, P = 4.6e-04 and 0.76, 95% CI = 0.73-0.80, P = 1.6e-31, respectively). In the two-step cis-Mendelian randomization analysis, the association between genetically predicted APOC3 and CAD was attenuated to null when adjusting for apolipoprotein B, triglycerides, or remnant cholesterol. Multivariable Mendelian randomization using genome-wide variants showed that remnant cholesterol, not triglycerides, was conditionally associated with CAD risk.

Conclusion: Remnant cholesterol best explains the mechanism through which APOC3 inhibition could prevent CAD. APOC3 inhibition may influence fasting remnant cholesterol to a greater extent than non-fasting remnant cholesterol. People with high levels of remnant cholesterol could benefit from APOC3 inhibition.