Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease.
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Alexandersson, Kristjan F
Eiriksson, Finnur F
Jensson, Brynjar Ö
Christensen, Alex H
Pedersen, Ole B
Hansen, Thomas F
Eyjolfssson, Gudmundur I
Thorarinsson, Bjorn L
Matthiasson, Stefan E
Bjornsson, Einar S
Asselbergs, Folkert W
Arnar, David O
Gudbjartsson, Daniel F
MetadataShow full item record
CitationHelgadottir A, Thorleifsson G, Alexandersson KF, Tragante V, Thorsteinsdottir M, Eiriksson FF, et al. Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease. Eur Heart J. 2020 Jul 21;41(28):2618-2628. doi: 10.1093/eurheartj/ehaa531
AbstractAims: 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.
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Rights© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
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