APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk: Mediation-and meta-analyses of 137 895 individuals

Objective-Loss-of-function mutations in APOC3 associate with low remnant cholesterol levels and low risk of ischemic vascular disease (IVD). Because some studies show an additional association with low levels of low-density lipoprotein cholesterol (LDL-C), low LDL-C may explain the low risk of IVD in APOC3 loss-of-function heterozygotes. We tested to what extent the low risk of IVD in APOC3 loss-of-function heterozygotes is mediated by low plasma remnant cholesterol and LDL-C. Approach and Results-In APOC3 loss-of-function heterozygotes versus noncarriers, we first determined remnant cholesterol and LDL-C levels in meta-analyses of 137 895 individuals. Second, we determined whether the association with LDL-C was masked by lipid-lowering therapy. Finally, using mediation analysis, we determined the fraction of the low risk of IVD and ischemic heart disease mediated by remnant cholesterol and LDL-C. In meta-analyses, remnant cholesterol was 43%lower (95%confidence interval, 40%-47%), and LDL-C was 4%lower (1%-6%) in loss-of-function heterozygotes (n=776) versus noncarriers. In the general population, LDL-C was 3%lower in loss-of-function heterozygotes versus noncarriers, 4%lower when correcting for lipid-lowering therapy, and 3%lower in untreated individuals (P values, 0.06-0.008). Remnant cholesterol mediated 37%of the observed 41%lower risk of IVD and 54%of the observed 36%lower risk of ischemic heart disease; corresponding values mediated by LDL-C were 1%and 2%. Conclusions-The low risk of IVD observed in APOC3 loss-of-function heterozygotes is mainly mediated by the associated low remnant cholesterol and not by low LDL-C. Furthermore, the contribution of LDL-C to IVD risk was not masked by lipidlowering therapy. This suggests APOC3 and remnant cholesterol as important new targets for reducing cardiovascular risk.