Cholesterol Not Particle Concentration Mediates the Atherogenic Risk Conferred by Apolipoprotein B Particles: A Mendelian Randomization Analysis

Anna Helgadottir*, Gudmar Thorleifsson, Audunn Snaebjarnarson, Lilja Stefansdottir, Gardar Sveinbjornsson, Vinicius Tragante, Eyþór Björnsson, Valgerdur Steinthorsdottir, Solveig Gretarsdottir, Hannes Helgason, Jona Saemundsdottir, Isleifur Olafsson, Jens Jakob Thune, Anna Axelsson Raja, Jonas Ghouse, Morten Salling Olesen, Alex Christensen, Rikke Louise Jacobsen, Joseph Dowsett, Mie Topholm BruunKaspar René Nielsen, Kirk Knowlton, Lincoln Nadauld, Rafn Benediktsson, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik, Søren Brunak, Henning Bundgaard, Sisse Rye Ostrowski, Patrick Sulem, David O. Arnar, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Kari Stefansson, Hilma Holm, Steffen Andersen, Karina Banasik, Kristoffer Sølvsten Burgdorf, Maria Didriksen, Khoa Manh Dinh, Thomas Folkmann Hansen, Henrik Hjalgrim, Gregor Borut Ernst Jemec, Poul Jennum, Pär Ingemar Johansson, Margit Anita Hørup Larsen, Susan Mikkelsen, Mette Nyegaard, Hreinn Stefánsson, Susanne Sækmose, Erik Sørensen, Henrik Ullum, Thomas Werge, DBDS Genomic Consortium

*Corresponding author for this work

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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 
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.
Original languageEnglish
Article numberzwac219
JournalEuropean Journal of Preventive Cardiology
Number of pages12
ISSN2047-4873
DOIs
Publication statusPublished - 22 Sep 2022

Bibliographical note

Epub ahead of print. Published online: 20 September 2022.

Keywords

  • Apolipoprotein
  • Non-HDL cholesterol
  • Coronary artery disease
  • Mendelian randomization

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