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 IndividualsLiterature - Wulff AB, Nordestgaard BG and Tybjærg-Hansen A. - Arterioscler Thromb Vasc Biol 2018;38: published online ahead of
- In the meta-analysis, APOC3 LOF heterozygotes had 43% (95%CI: 40%–47%) lower levels of remnant cholesterol compared with non-carriers in both a fixed and in a random effects model (no heterogeneity between studies (I2=0%; P=0.92)). APOC3 LOF heterozygotes had 4% (95%CI: 1%–6%) lower levels of LDL-c compared with non-carriers in a fixed effects model and 5% (95%CI: 1%–8%) lower levels of LDL-c in a random effects model.
- In the general population, remnant cholesterol was 44% (0.3 mmol/L) lower (P=1×10−51), and LDL-c was 3% (0.1 mmol/L) lower (P=0.06) in APO3 LOF heterozygotes versus non-carriers overall, regardless of lipid-lowering therapy.
- After correcting for lipid-lowering therapy, LOF heterozygotes in the general population had 43% (0.3 mmol/L) lower levels of remnant cholesterol (P=5×10−49) and 4% (0.1 mmol/L) lower levels of LDL-c (P=0.008) compared with non-carriers.
- When excluding participants on lipid-lowering therapy at the time of lipid assessment, remnant cholesterol was 44% (0.3 mmol/L) lower (P=2×10−49), and LDL-c was 3% (0.1 mmol/L) lower (P=0.02) in LOF heterozygotes compared with non-carriers.
- //APOC3// LOF heterozygotes showed significant median reductions of 47% (0.7 mmol/L) in triglycerides, 10% (0.4 mmol/L) in non-HDL-c and 13% (14 mg/dL) in apoB, as compared with noncarriers, and an increase of HDL-c of 33% (0.5 mmol/L).
- The mediation analysis showed that the lower levels of remnant cholesterol in LOF heterozygotes versus non-carriers mediated 37% of the lower IVD risk (P value for the indirect effect, P=6×10−37) and 54% of the lower IHD risk (P value for the indirect effect, P=1×10−37), whereas the 4% lower levels of LDL-c mediated only 1% and 2% of the lower risks.
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.