Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease
Helgadottir, Anna; Thorleifsson, Gudmar; Alexandersson, Kristjan F; Tragante, Vinicius; Thorsteinsdottir, Margret; Eiriksson, Finnur F; Gretarsdottir, Solveig; Björnsson, Eythór; Magnusson, Olafur; Sveinbjornsson, Gardar; Jonsdottir, Ingileif; Steinthorsdottir, Valgerdur; Ferkingstad, Egil; Jensson, Brynjar Ö; Stefansson, Hreinn; Olafsson, Isleifur; Christensen, Alex H; Torp-Pedersen, Christian; Køber, Lars; Pedersen, Ole B; Erikstrup, Christian; Sørensen, Erik; Brunak, Søren; Banasik, Karina; Hansen, Thomas F; Nyegaard, Mette; Eyjolfssson, Gudmundur I; Sigurdardottir, Olof; Thorarinsson, Bjorn L; Matthiasson, Stefan E; Steingrimsdottir, Thora; Bjornsson, Einar S; Danielsen, Ragnar; Asselbergs, Folkert W; Arnar, David O; Ullum, Henrik; Bundgaard, Henning; Sulem, Patrick; Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Holm, Hilma; Gudbjartsson, Daniel F; Stefansson, Kari
(2020) European heart journal, volume 41, issue 28, pp. 2618 - 2628
(Article)
Abstract
AIMS: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols. METHODS AND RESULTS: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL)
... read more
cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4). CONCLUSIONS: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.
show less
Download/Full Text
Keywords: ABCG5/8, Absorption, Dietary cholesterol, Genetics, Phytosterols, Cardiology and Cardiovascular Medicine, Journal Article
ISSN: 0195-668X
Publisher: Oxford University Press
Note: Publisher Copyright: © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
(Peer reviewed)