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

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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.

Original languageEnglish
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number3
Pages (from-to)660-668
Number of pages9
ISSN1079-5642
DOIs
Publication statusPublished - 1 Jan 2018

    Research areas

  • Cardiovascular diseases, Genetics, Humans, Risk factors, Triglycerides

ID: 55696458