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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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@article{93d4e0066fff4c99a3d4363c68ebeaac,
title = "APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk: Mediation-and meta-analyses of 137 895 individuals",
abstract = "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.",
keywords = "Cardiovascular diseases, Genetics, Humans, Risk factors, Triglycerides",
author = "Wulff, {Anders B.} and Nordestgaard, {B{\o}rge G.} and Anne Tybja{\ae}rg-Hansen",
year = "2018",
month = "1",
day = "1",
doi = "10.1161/ATVBAHA.117.310473",
language = "English",
volume = "38",
pages = "660--668",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams & Wilkins",
number = "3",

}

RIS

TY - JOUR

T1 - APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk

T2 - Mediation-and meta-analyses of 137 895 individuals

AU - Wulff, Anders B.

AU - Nordestgaard, Børge G.

AU - Tybjaærg-Hansen, Anne

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Cardiovascular diseases

KW - Genetics

KW - Humans

KW - Risk factors

KW - Triglycerides

UR - http://www.scopus.com/inward/record.url?scp=85046675008&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.117.310473

DO - 10.1161/ATVBAHA.117.310473

M3 - Journal article

VL - 38

SP - 660

EP - 668

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 3

ER -

ID: 55696458