Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease

• Published in: European Heart Journal
• Main Authors: Helgadottir, Anna, Thorleifsson, Gudmar, Alexandersson, Kristjan F, Tragante, Vinicius, Þorsteinsdóttir, Margrét, Eiriksson, Finnur Freyr, Grétarsdóttir, Sólveig, Björnsson, Eyþór, Magnússon, Ólafur, 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, Eyjólfsson, Guðmundur I., Sigurdardottir, Olof, Þórarinsson, Björn L, Matthíasson, Stefán E., Steingrimsdottir, Thora, Björnsson, Einar Stefán, Danielsen, Ragnar, Asselbergs, Folkert W., Arnar, David O, Ullum, Henrik, Bundgaard, Henning, sulem, patrick, Thorsteinsdottir, Unnur, Thorgeirsson, Gudmundur, Holm, Hilma, Gudbjartsson, Daniel, Stefansson, Kari
• Other Authors: Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, University of Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: Oxford University Press (OUP) 2020
• Subjects: ABCG5/8; Absorption; Dietary cholesterol; Genetics; Phytosterols; Kólesteról; Erfðarannsóknir; Kransæðasjúkdómar; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/2448; https://doi.org/10.1093/eurheartj/ehaa531

Publisher's version (útgefin grein) 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) 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. This work was supported by deCODE genetics/Amgen. S.B. is supported by the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). F.W.A. is supported by University College London Hospital National Institute for Health Research Biomedical Research Centre (BRC288A). Peer Reviewed