Physicians' Academy for Cardiovascular Education

Remnant cholesterol determines CV risk in APOC3 LOF heterozygotes

APOC3 Loss-of-Function Mutations, Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Cardiovascular Risk: Mediation and Meta-Analyses of 137 895 Individuals

Literature - Wulff AB, Nordestgaard BG and Tybjærg-Hansen A. - Arterioscler Thromb Vasc Biol 2018;38: published online ahead of


//APOC3// loss-of-function (LOF) mutations have been associated with a lower risk of ischemic vascular disease (IVD), as well as with lower triglyceride, apolipoprotein CIII (ApoC3), and very LDL-c levels [1-4].

This study evaluated whether the low IVD risk in APOC3 LOF heterozygotes can be explained by the low plasma remnant cholesterol and low LDL-c levels. For this purpose, the levels of remnant cholesterol and LDL-c were determined in APOC3 LOF heterozygotes versus non-carriers, by means of a meta-analysis of 8 study cohorts including 137,895 individuals.

Moreover, LDL-c levels of APOC3 LOF heterozygotes were compared with those of non-carriers in 75,725 individuals in the two prospective Danish general population cohorts (Copenhagen City Heart Study and Copenhagen General Population Study), and it was assessed whether lipid-lowering therapy masked the associations of LDL cholesterol with IVD. Moreover, the fraction of the observed lower IVD and ischemic heart disease (IHD) risk associated with APOC3 LOF mutations was calculated using mediation analysis by low remnant cholesterol and low LDL-c.

Main results


The lower IVD risk in APOC3 LOF heterozygotes compared with non-carriers is largely due to the significantly lower levels of remnant cholesterol and not due to lower levels of LDL-c, and this observation was not affected by lipid-lowering therapy. These findings might be importantmay point at APOC3 and remnant cholesterol as therapeutic targets for CV prevention.


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