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

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

Title: Genetic variability in the uptake of dietary sterols affects the risk of coronary artery disease
Author: Eiríksson, Finnur Freyr
Helgadottir, Anna   orcid.org/0000-0002-1806-2467
Thorleifsson, Gudmar   orcid.org/0000-0003-4623-9087
Alexandersson, Kristjan F.
Tragante, Vinicius
Þorsteinsdóttir, Margrét
Grétarsdóttir, Solveig
Björnsson, Eyþór
Magnússon, Ólafur
Sveinbjornsson, Gardar
... 33 more authors Show all authors
Date: 2020
Language: English
Scope: 4889378
School: Health Sciences
Department: Faculty of Pharmaceutical Sciences
Clinical Laboratory Services, Diagnostics and Blood Bank
Faculty of Medicine
Other departments
Series: European Heart Journal; 41(28)
ISSN: 0195-668X
DOI: https://doi.org/10.1093/eurheartj/ehaa531
URI: https://hdl.handle.net/20.500.11815/4033

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Eiríksson , F F , Helgadottir , A , Thorleifsson , G , Alexandersson , K F , Tragante , V , Þorsteinsdóttir , M , Grétarsdóttir , S , Björnsson , E , Magnússon , Ó , Sveinbjornsson , G , Jónsdóttir , I , Steinthorsdottir , V , Ferkingstad , E , Jensson , B Ö , Stefansson , H , Ólafsson , Í , Christensen , A H , Torp-Pedersen , C , Køber , L , Pedersen , O B , Erikstrup , C , Sorensen , E , Brunak , S , Banasik , K , Hansen , T F , Nyegaard , M , Eyjolfssson , G I , Sigurdardottir , O , Thorarinsson , B L , Matthiasson , S E , Steingrimsdottir , T , Bjornsson , E S , Danielsen , R , Asselbergs , F W , Arnar , D O , Ullum , H , Bundgaard , H , sulem , P , Thorsteinsdottir , U , Thorgeirsson , G , Holm , H , Gudbjartsson , D F & Stefansson , K 2020 , ' Genetic variability in the uptake of dietary sterols affects the risk of coronary artery disease ' , European Heart Journal , vol. 41 , no. 28 . https://doi.org/10.1093/eurheartj/ehaa531


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). Conflict of interest: The authors affiliated with deCODE genetics/Amgen, Inc. are employed by the company.

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