TY - JOUR
T1 - Cholesterol Not Particle Concentration Mediates the Atherogenic Risk Conferred by Apolipoprotein B Particles
T2 - A Mendelian Randomization Analysis
AU - Helgadottir, Anna
AU - Thorleifsson, Gudmar
AU - Snaebjarnarson, Audunn
AU - Stefansdottir, Lilja
AU - Sveinbjornsson, Gardar
AU - Tragante, Vinicius
AU - Björnsson, Eyþór
AU - Steinthorsdottir, Valgerdur
AU - Gretarsdottir, Solveig
AU - Helgason, Hannes
AU - Saemundsdottir, Jona
AU - Olafsson, Isleifur
AU - Thune, Jens Jakob
AU - Raja, Anna Axelsson
AU - Ghouse, Jonas
AU - Salling Olesen, Morten
AU - Christensen, Alex
AU - Jacobsen, Rikke Louise
AU - Dowsett, Joseph
AU - Bruun, Mie Topholm
AU - Nielsen, Kaspar René
AU - Knowlton, Kirk
AU - Nadauld, Lincoln
AU - Benediktsson, Rafn
AU - Erikstrup, Christian
AU - Pedersen, Ole Birger
AU - Banasik, Karina
AU - Brunak, Søren
AU - Bundgaard, Henning
AU - Ostrowski, Sisse Rye
AU - Sulem, Patrick
AU - Arnar, David O.
AU - Thorgeirsson, Gudmundur
AU - Thorsteinsdottir, Unnur
AU - Gudbjartsson, Daniel F.
AU - Stefansson, Kari
AU - Holm, Hilma
AU - Andersen, Steffen
AU - Banasik, Karina
AU - Burgdorf, Kristoffer Sølvsten
AU - Didriksen, Maria
AU - Dinh, Khoa Manh
AU - Folkmann Hansen, Thomas
AU - Hjalgrim, Henrik
AU - Jemec, Gregor Borut Ernst
AU - Jennum, Poul
AU - Johansson, Pär Ingemar
AU - Hørup Larsen, Margit Anita
AU - Mikkelsen, Susan
AU - Nyegaard, Mette
AU - Stefánsson, Hreinn
AU - Sækmose, Susanne
AU - Sørensen, Erik
AU - Ullum, Henrik
AU - Werge, Thomas
AU - DBDS Genomic Consortium
N1 - Epub ahead of print. Published online: 20 September 2022.
PY - 2022/9/22
Y1 - 2022/9/22
N2 - 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.
AB - 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.
KW - Apolipoprotein
KW - Non-HDL cholesterol
KW - Coronary artery disease
KW - Mendelian randomization
KW - Apolipoprotein B
KW - Non-HDL cholesterol
KW - Coronary artery disease
KW - Mendelian randomization
U2 - 10.1093/eurjpc/zwac219
DO - 10.1093/eurjpc/zwac219
M3 - Journal article
SN - 2047-4873
JO - European Journal of Preventive Cardiology
JF - European Journal of Preventive Cardiology
M1 - zwac219
ER -