Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles: a Mendelian randomization analysis
Anna Helgadóttir, Guðmar Þorleifsson, Auðunn Skúta Snæbjarnarson, Lilja Stefánsdóttir, Garðar Sveinbjörnsson, Vinicius Tragante, Eyþór Björnsson, Valgerður Steinthórsdóttir, Sólveig Grétarsdóttir, Hannes Helgason, Jona Saemundsdottir, Ísleifur Ólafsson, Jens Jakob Thune, Anna Axelsson Raja, Jonas Ghouse, Morten S. Olesen, Alex Hørby Christensen, Rikke Louise Jacobsen, Joseph Dowsett, Mie Topholm Bruun, Kaspar René Nielsen, Kirk U. Knowlton, Lincoln Nadauld, Rafn Benediktsson, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik, Søren Brunak, Steffen Andersen, Karina Banasik, Søren Brunak, Kristoffer Sølvsten Burgdorf, Maria Didriksen, Khoa Manh Dinh, Christian Erikstrup, Daníel F. Guðbjartsson, Thomas Folkmann Hansen, Henrik Hjalgrim, Gregor B. E. Jemec, Poul Jennum, Pär I. Johansson, Margit Anita Hørup Larsen, Susan Mikkelsen, Kasper Nielsen, Mette Nyegaard, Sisse Rye Ostrowski, Ole Birger Pedersen, Kari Stefansson, Hreinn Stefánsson, Susanne Gjørup Sækmose, Erik Sørensen, Unnur Þorsteinsdóttir, Mie Topholm Brun, Henrik Ullum, Thomas Werge, Henning Bundgaard, Sisse Rye Ostrowski, Patrick Sulem, Davíð O. Arnar, Guðmundur Þorgeirsson, Unnur Þorsteinsdóttir, Daníel F. Guðbjartsson, Kari Stefansson, Hilma Hólm
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.