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Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles : a Mendelian randomization analysis

Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles : a Mendelian randomization analysis


Title: Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles : a Mendelian randomization analysis
Author: DBDS Genomic Consortium
Date: 2022-12-21
Language: English
Scope: 12
School: Health Sciences
Department: Office of Division of Diagnostic and Support Services
Faculty of Physical Sciences
Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Internal Medicine and Emergency Services
Cardio-Vascular Center
Series: European Journal of Preventive Cardiology; 29(18)
ISSN: 2047-4873
DOI: https://doi.org/10.1093/eurjpc/zwac219
Subject: Lífefna- og sameindalíffræði; Innkirtlalæknisfræði; Hjartalæknisfræði; Humans; Mendelian Randomization Analysis; Cholesterol, LDL; Risk Factors; Cholesterol; Apolipoproteins B/genetics; Coronary Artery Disease/genetics; Atherosclerosis; Lipoproteins; Cholesterol, HDL; Apolipoprotein B-100/genetics
URI: https://hdl.handle.net/20.500.11815/3848

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Citation:

DBDS Genomic Consortium 2022 , ' Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles : a Mendelian randomization analysis ' , European Journal of Preventive Cardiology , vol. 29 , no. 18 , pp. 2374-2385 . https://doi.org/10.1093/eurjpc/zwac219

Abstract:

BACKGROUND AND AIMS: The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration. METHOD AND RESULTS: We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N = 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses.In univariate MR analysis, both exposures associated with CAD (βnon-HDL-C = 0.40, P = 2.8 × 10-48 and βapoB = 0.38, P = 1.3 × 10-44). Adding effects on non-HDL-C into a model that already included those on apoB significantly improved the genetically predicted CAD effects (P = 3.9 × 10-5), while adding apoB into the model including non-HDL-C did not (P = 0.69). Thirty-five per cent (82/235) of the variants used as genetic instruments had discordant effects on the exposures, associating with non-HDL-C/apoB ratio at P < 2.1 × 10-4 (0.05/235). Fifty-one variants associated at genome-wide significance. CONCLUSION: Many sequence variants have discordant effects on non-HDL-C and apoB. These variants allowed us to show that the causal mechanism underlying the relationship between apolipoprotein B particles and CAD is more associated with non-HDL-C than apoB particle concentration.

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© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

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