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Genetic Variability in the Uptake of Dietary Sterols Affects the Risk of Coronary Artery Disease

32 Pages Posted: 20 Feb 2019

See all articles by Anna Helgadottir

Anna Helgadottir

Amgen, Inc. - deCODE Genetics

Kristjan F. Alexandersson

Amgen, Inc. - deCODE Genetics

Gudmar Thorleifsson

Amgen, Inc. - deCODE Genetics

Vinicius Tragante

Amgen, Inc. - deCODE Genetics; Utrecht University - University Medical Center (Utrecht)

Margret Thorsteinsdottir

University of Iceland; ArcticMass

Finnur F. Eiriksson

ArcticMass

Solveig Gretarsdottir

Amgen, Inc. - deCODE Genetics

Eythor Bjornsson

Amgen, Inc. - deCODE Genetics; Landspitali University Hospital; University of Iceland

Olafur Magnusson

Amgen, Inc. - deCODE Genetics

Gardar Sveinbjornsson

Amgen, Inc. - deCODE Genetics

Ingileif Jonsdottir

Amgen, Inc. - deCODE Genetics; University of Iceland

Isleifur Olafsson

Landspitali University Hospital

Gudmundur I. Eyjolfssson

The Laboratory in Mjodd

Olof Sigurdardottir

Akureyri Hospital

Bjorn L. Thorarinsson

Landspitali University Hospital

Stefan E. Matthiasson

Laekning - Medical Clinics

Thora Steingrimsdottir

University of Iceland; Landspitali University Hospital

Einar S. Bjornsson

Landspitali University Hospital; University of Iceland

Ragnar Danielsen

Landspitali University Hospital

Folkert W. Asselbergs

Utrecht University - University Medical Center (Utrecht); Netherlands Heart Institute; University College London

David O. Arnar

University of Iceland; Landspitali University Hospital

Patrick Sulem

Amgen, Inc. - deCODE Genetics

Unnur Thorsteinsdottir

Amgen, Inc. - deCODE Genetics; University of Iceland

Gudmundur Thorgeirsson

Amgen, Inc. - deCODE Genetics; University of Iceland

Hilma Holm

Amgen, Inc. - deCODE Genetics

Daniel F. Gudbjartsson

Amgen, Inc. - deCODE Genetics; University of Iceland

Kari Stefansson

Amgen, Inc. - deCODE Genetics; University of Iceland - Faculty of Medicine

More...

Abstract

Background: The ATP-binding cassette (ABC) G5 and G8 transporters, encoded by the ABCG5 and ABCG8 (ABCG5/8) genes, have a key role in controlling intestinal absorption of cholesterol and other sterols, and in promoting their hepatobiliary secretion. Here, we use novel rare ABCG5/8 variants, together with common variants, to explore whether variability in sterol absorption impacts the risk of coronary artery disease (CAD).  

Methods: We examined 41 ABCG5/8 coding variants for association with non-high density lipoprotein (non-HDL) cholesterol in data from Iceland and the Global Lipid Genetics Consortium (N up to 472,392 combined). We tested variants for association with CAD in up to 67,130 cases and 700,075 controls from Iceland and the UK Biobank.  

Findings: We identified several rare ABCG5/8 coding variants with substantial impact on circulating levels of non-HDL cholesterol, and demonstrate that heterozygous carriers are at increased risk of CAD and other related diseases.  Consistent with causal effects of other sterols such as phytosterols, on atherosclerotic disease we demonstrate that the degree of CAD risk conferred by both common and rare ABCG5/8 variants is greater than predicted based on their effect on non-HDL cholesterol levels.  

Interpretation: Our data highlight intestinal absorption as an important mechanism in the regulation of non-HDL /LDL cholesterol levels and CAD risk. Further, the results support the notion that other sterols such as phytosterols contribute to the pathogenesis of CAD.  

Funding Statement: The study was funded by deCODE genetics/Amgen Inc.  

Declaration of Interests: The authors who are affiliated with deCODE genetics/AMGEN, declare competing financial interests as employees. The remaining authors declare no competing financial interests.

Ethics Approval Statement: The study was approved by The Icelandic Data Protection Authority and the National Bioethics Committee of Iceland (approvals no. VSNb201508003/03.01, VSNb2015010033/03.12 and VSNb2014100020/03.12 with amendments). All participating subjects donating biological samples signed informed consents. Personal identities of the participants and biological samples were encrypted with a third-party system approved and monitored by the Icelandic Data Protection Authority.

Suggested Citation

Helgadottir, Anna and Alexandersson, Kristjan F. and Thorleifsson, Gudmar and Tragante, Vinicius and Thorsteinsdottir, Margret and Eiriksson, Finnur F. and Gretarsdottir, Solveig and Bjornsson, Eythor and Magnusson, Olafur and Sveinbjornsson, Gardar and Jonsdottir, Ingileif and Olafsson, Isleifur and Eyjolfssson, Gudmundur I. and Sigurdardottir, Olof and Thorarinsson, Bjorn L. and Matthiasson, Stefan E. and Steingrimsdottir, Thora and Bjornsson, Einar S. and Danielsen, Ragnar and Asselbergs, Folkert W. and Arnar, David O. and Sulem, Patrick and Thorsteinsdottir, Unnur and Thorgeirsson, Gudmundur and Holm, Hilma and Gudbjartsson, Daniel F. and Stefansson, Kari, Genetic Variability in the Uptake of Dietary Sterols Affects the Risk of Coronary Artery Disease (02/13/2019 15:56:56). Available at SSRN: https://ssrn.com/abstract=3335863 or http://dx.doi.org/10.2139/ssrn.3335863

Anna Helgadottir (Contact Author)

Amgen, Inc. - deCODE Genetics ( email )

Iceland

Kristjan F. Alexandersson

Amgen, Inc. - deCODE Genetics

Iceland

Gudmar Thorleifsson

Amgen, Inc. - deCODE Genetics

Iceland

Vinicius Tragante

Amgen, Inc. - deCODE Genetics

Iceland

Utrecht University - University Medical Center (Utrecht)

6.119, PO Box 85500
Utrecht, 3508 GA
Netherlands

Margret Thorsteinsdottir

University of Iceland

Iceland

ArcticMass

Iceland

Finnur F. Eiriksson

ArcticMass

Iceland

Solveig Gretarsdottir

Amgen, Inc. - deCODE Genetics

Iceland

Eythor Bjornsson

Amgen, Inc. - deCODE Genetics

Iceland

Landspitali University Hospital

Reykjavik
Iceland

University of Iceland

Iceland

Olafur Magnusson

Amgen, Inc. - deCODE Genetics

Iceland

Gardar Sveinbjornsson

Amgen, Inc. - deCODE Genetics

Iceland

Ingileif Jonsdottir

Amgen, Inc. - deCODE Genetics

Iceland

University of Iceland

Iceland

Isleifur Olafsson

Landspitali University Hospital

Reykjavik
Iceland

Gudmundur I. Eyjolfssson

The Laboratory in Mjodd

Iceland

Olof Sigurdardottir

Akureyri Hospital

Iceland

Bjorn L. Thorarinsson

Landspitali University Hospital

Reykjavik
Iceland

Stefan E. Matthiasson

Laekning - Medical Clinics

Iceland

Thora Steingrimsdottir

University of Iceland

Iceland

Landspitali University Hospital

Reykjavik
Iceland

Einar S. Bjornsson

Landspitali University Hospital

Reykjavik
Iceland

University of Iceland

Iceland

Ragnar Danielsen

Landspitali University Hospital

Reykjavik
Iceland

Folkert W. Asselbergs

Utrecht University - University Medical Center (Utrecht)

6.119, PO Box 85500
Utrecht, 3508 GA
Netherlands

Netherlands Heart Institute

Netherlands

University College London

Gower Street
London, WC1E 6BT
United Kingdom

David O. Arnar

University of Iceland

Iceland

Landspitali University Hospital

Reykjavik
Iceland

Patrick Sulem

Amgen, Inc. - deCODE Genetics

Iceland

Unnur Thorsteinsdottir

Amgen, Inc. - deCODE Genetics

Iceland

University of Iceland

Iceland

Gudmundur Thorgeirsson

Amgen, Inc. - deCODE Genetics

Iceland

University of Iceland

Iceland

Hilma Holm

Amgen, Inc. - deCODE Genetics

Iceland

Daniel F. Gudbjartsson

Amgen, Inc. - deCODE Genetics

Iceland

University of Iceland

Iceland

Kari Stefansson

Amgen, Inc. - deCODE Genetics ( email )

Iceland

University of Iceland - Faculty of Medicine ( email )

Iceland

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