Anders B Wulff1, Børge G Nordestgaard1, Anne Tybjærg-Hansen2. 1. From the Department of Clinical Biochemistry, Rigshospitalet (A.B.W., A.T.-H.), Department of Clinical Biochemistry, Herlev and Gentofte Hospital (B.G.N.), and Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.), Copenhagen University Hospital, University of Copenhagen, Denmark; Department of Clinical Biochemistry, Zealand University Hospital, Denmark (A.B.W.); and Copenhagen General Population Study, Herlev and Gentofte Hospital, Denmark (B.G.N., A.T.-H.). 2. From the Department of Clinical Biochemistry, Rigshospitalet (A.B.W., A.T.-H.), Department of Clinical Biochemistry, Herlev and Gentofte Hospital (B.G.N.), and Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.), Copenhagen University Hospital, University of Copenhagen, Denmark; Department of Clinical Biochemistry, Zealand University Hospital, Denmark (A.B.W.); and Copenhagen General Population Study, Herlev and Gentofte Hospital, Denmark (B.G.N., A.T.-H.). anne.tybjaerg.hansen@regionh.dk.
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 lipid-lowering therapy. This suggests APOC3 and remnant cholesterol as important new targets for reducing cardiovascular risk.
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.
Authors: Gissette Reyes-Soffer; Carol Sztalryd; Richard B Horenstein; Stephen Holleran; Anastasiya Matveyenko; Tiffany Thomas; Renu Nandakumar; Colleen Ngai; Wahida Karmally; Henry N Ginsberg; Rajasekhar Ramakrishnan; Toni I Pollin Journal: Arterioscler Thromb Vasc Biol Date: 2019-01 Impact factor: 8.311
Authors: Jennifer G Robinson; Kevin Jon Williams; Samuel Gidding; Jan Borén; Ira Tabas; Edward A Fisher; Chris Packard; Michael Pencina; Zahi A Fayad; Venkatesh Mani; Kerry Anne Rye; Børge G Nordestgaard; Anne Tybjærg-Hansen; Pamela S Douglas; Stephen J Nicholls; Neha Pagidipati; Allan Sniderman Journal: J Am Heart Assoc Date: 2018-10-16 Impact factor: 5.501