APOC3 Loss-of-Function Mutations, Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Cardiovascular Risk: Mediation- and Meta-Analyses of 137 895 Individuals
Wulff AB, Nordestgaard BG, Tybjærg-Hansen A
Arteriosclerosis, thrombosis, and vascular biology · 94 citas
Etiquetas de revisión
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Cómo se estudió
- Diseño
- Metaanálisis (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Eventos clínicos como enfermedad o muerte
Quién lo pagó
- Financiación
- Financiación no declarada
Publicación
- Publicado
- 2018-01-18 · Arterioscler Thromb Vasc Biol · vol. 38 · número 3 · págs. 660–668
- Editorial
- Lippincott Williams & Wilkins
- Citado
- 112 citas · más que el 99% de estudios similares · 9.4× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 32 trabajos
- Acceso
- Lectura gratuita
- Áreas de investigación
- Lipoproteins and Cardiovascular Health · Lipid metabolism and disorders · Paraoxonase enzyme and polymorphisms
- Palabras clave
- apolipoprotein C-III, loss-of-function mutations, remnant cholesterol, LDL cholesterol, ischemic vascular disease, ischemic heart disease, cardiovascular risk, mediation analysis, lipid-lowering therapy, genetic variants
- MeSH
- humans, cardiovascular diseases, genetic predisposition to disease, risk assessment, risk factors, heterozygote, phenotype, adult, aged, middle aged, denmark, female, male, dyslipidemias, cholesterol, ldl, apolipoprotein c-iii, chylomicron remnants, loss of function mutation
3 autores
- Anders Berg Wulff🇩🇰University of Copenhagen; Frederiksberg Hospital; Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital; Rigshospitalet; Zealand University Hospital
- Børge Grønne Nordestgaard🇩🇰University of Copenhagen; Frederiksberg Hospital; Copenhagen University Hospital; Gentofte Hospital; Rigshospitalet; Zealand University Hospital
- Anne Tybjærg‐Hansen🇩🇰University of Copenhagen; Frederiksberg Hospital; Copenhagen University Hospital; Gentofte Hospital; Rigshospitalet; Zealand University Hospital
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
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