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, 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
• Other Authors: 1deCODE genetics/Amgen, Inc., Sturlugata 8, 102 Reykjavik, Iceland. 2Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands. 3ArcticMass, Sturlugata 8, 102 Reykjavik, Iceland. 4Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, 107 Reykjavik, Iceland. 5Department of Internal Medicine, Landspitali - National University Hospital of Iceland, 101 Reykjavik, Iceland. 6Faculty of Medicine, University of Iceland, Vatnsmýrarvegur, 101 Reykjavik, Iceland. 7Department of Clinical Biochemistry, Landspitali -National University Hospital of Iceland, Hringbraut, 101 Reykjavik, Iceland. 8Herlev-Gentofte Hospital, Copenhagen University Hospital, Gentofte Hospitalsvej 1, 2900 Hellerup, Denmark. 9Department of Cardiology and Clinical Research, Nordsjaellands Hospital, Dyrehavevej 29, 3400 Hillerød, Denmark. 10Department of Cardiology, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark. 11The Capital Region's Unit of Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. 12Department of Clinical Immunology, Næstved Hospital, Ringstedgade 61, 4700 Næstved, Denmark. 13Department of Clinical Medicine, Copenhagen University, Blegdamsvej 3B, 2200 Copenhagen, Denmark. 14Department of Clinical Immunology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark. 15Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark. 16Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. 17Department of Neurology, Danish Headache Center, Glostrup, Rigshospitalet, Valdemar Hansens vej 1-23, 2600 Glostrup, Denmark. 18Institute for Biological Psychiatry, Mental Health Center Sct. Hans, Boserupvej 2, 4000 Roskilde, Denmark. 19Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, 8000 Aarhus, Denmark. 20The Laboratory in Mjodd, Thonglabakki 6, 109 Reykjavik, Iceland. 21Department of Clinical Biochemistry, Akureyri Hospital, Eyrarlandsvegur, 600 Akureyri, Iceland. 22Department of Neurology, Landspitali - National University Hospital of Iceland, Hringbraut, 101 Reykjavik, Iceland. 23Laekning, Medical Clinics, Lágmúli 5, 108 Reykjavik, Iceland. 24Department of Obstetrics and Gynecology, Landspitali - National University Hospital, Hringbraut, 101 Reykjavik, Iceland. 25Division of Cardiology, Department of Internal Medicine, Landspitali - National University Hospital of Iceland, Hringbraut, 101 Reykjavik, Iceland. 26Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, Gower Street, London WC1E 6BT, UK. 27Health Data Research UK and Institute of Health Informatics, University College London, Gower Street, London WC1E 6BT, UK. 28School of Engineering and Natural Sciences, University of Iceland, Dunhagi, 101 Reykjavik, Iceland.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Oxford University Press 2020
• Subjects: ABCG5/8; Absorption; Dietary cholesterol; Genetics; Phytosterols; Kólesteról; Kransæðasjúkdómar; Cholesterol; Dietary; Coronary Artery Disease; Iceland
• Online Access: http://hdl.handle.net/2336/621579; https://doi.org/10.1093/eurheartj/ehaa531

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download 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. Keywords: ABCG5/8; Absorption; Dietary cholesterol; Genetics; Phytosterols. Novo Nordisk Foundation University College London Hospital National Institute for Health Research ...