Erschienen in:Arteriosclerosis, Thrombosis, and Vascular Biology
Sprache:
Englisch
DOI:
10.1161/atvbaha.117.310473
ISSN:
1079-5642;
1524-4636
Entstehung:
Anmerkungen:
Beschreibung:
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<jats:title>Objective—</jats:title>
<jats:p>
Loss-of-function mutations in
<jats:italic>APOC3</jats:italic>
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
<jats:italic>APOC3</jats:italic>
loss-of-function heterozygotes. We tested to what extent the low risk of IVD in
<jats:italic>APOC3</jats:italic>
loss-of-function heterozygotes is mediated by low plasma remnant cholesterol and LDL-C.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Approach and Results—</jats:title>
<jats:p>
In
<jats:italic>APOC3</jats:italic>
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 (
<jats:italic>P</jats:italic>
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%.
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</jats:sec>
<jats:sec>
<jats:title>Conclusions—</jats:title>
<jats:p>
The low risk of IVD observed in
<jats:italic>APOC3</jats:italic>
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
<jats:italic>APOC3</jats:italic>
and remnant cholesterol as important new targets for reducing cardiovascular risk.
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</jats:sec>