Genetic modelling of triglyceride-rich lipoprotein/remnant lowering mimics APOC3-silencing and predicts clinically relevant coronary heart disease event reductions

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. 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). 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%. 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.