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

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.

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.

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.