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

Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):660-668. doi: 10.1161/ATVBAHA.117.310473. Epub 2018 Jan 18.


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 lipid-lowering therapy. This suggests APOC3 and remnant cholesterol as important new targets for reducing cardiovascular risk.

Keywords: cardiovascular diseases; genetics; humans; risk factors; triglycerides.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Aged
  • Apolipoprotein C-III / genetics*
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / genetics*
  • Cholesterol, LDL / blood*
  • Chylomicron Remnants / blood*
  • Denmark / epidemiology
  • Dyslipidemias / blood
  • Dyslipidemias / diagnosis
  • Dyslipidemias / epidemiology
  • Dyslipidemias / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Loss of Function Mutation*
  • Male
  • Middle Aged
  • Phenotype
  • Risk Assessment
  • Risk Factors


  • Apolipoprotein C-III
  • Cholesterol, LDL
  • Chylomicron Remnants