Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease
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orcid.org/0000-0002-3921-5805 Journal Title
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Oxford University Press (OUP)
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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.
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Efnisorð
ABCG5/8, Absorption, Dietary cholesterol, Genetics, Phytosterols, Kólesteról, Erfðarannsóknir, Kransæðasjúkdómar
Citation
Anna Helgadottir, Gudmar Thorleifsson, Kristjan F Alexandersson, Vinicius Tragante, Margret Thorsteinsdottir, Finnur F Eiriksson, Solveig Gretarsdottir, Eythór Björnsson, Olafur Magnusson, Gardar Sveinbjornsson, Ingileif Jonsdottir, Valgerdur Steinthorsdottir, Egil Ferkingstad, Brynjar Ö Jensson, Hreinn Stefansson, Isleifur Olafsson, Alex H Christensen, Christian Torp-Pedersen, Lars Køber, Ole B Pedersen, Christian Erikstrup, Erik Sørensen, Søren Brunak, Karina Banasik, Thomas F Hansen, Mette Nyegaard, Gudmundur I Eyjolfssson, Olof Sigurdardottir, Bjorn L Thorarinsson, Stefan E Matthiasson, Thora Steingrimsdottir, Einar S Bjornsson, Ragnar Danielsen, Folkert W Asselbergs, David O Arnar, Henrik Ullum, Henning Bundgaard, Patrick Sulem, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Hilma Holm, Daniel F Gudbjartsson, Kari Stefansson, Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease, European Heart Journal, Volume 41, Issue 28, 21 July 2020, Pages 2618–2628, https://doi.org/10.1093/eurheartj/ehaa531