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

• Main Authors: Helgadottir, A, Thorleifsson, G, Alexandersson, KF, Tragante, V, Thorsteinsdottir, M, Eiriksson, FF, Gretarsdottir, S, Björnsson, E, Magnusson, O, Sveinbjornsson, G, Jonsdottir, I, Steinthorsdottir, V, Ferkingstad, E, Jensson, BÖ, Stefansson, H, Olafsson, I, Christensen, AH, Torp-Pedersen, C, Køber, L, Pedersen, OB, Erikstrup, C, Sørensen, E, Brunak, S, Banasik, K, Hansen, TF, Nyegaard, M, Eyjolfssson, GI, Sigurdardottir, O, Thorarinsson, BL, Matthiasson, SE, Steingrimsdottir, T, Bjornsson, ES, Danielsen, R, Asselbergs, FW, Arnar, DO, Ullum, H, Bundgaard, H, Sulem, P, Thorsteinsdottir, U, Thorgeirsson, G, Holm, H, Gudbjartsson, DF, Stefansson, K
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2020
• Subjects: ABCG5/8; Absorption; Dietary cholesterol; Genetics; Phytosterols; Iceland
• Online Access: https://discovery.ucl.ac.uk/id/eprint/10106796/1/ehaa531.pdf; https://discovery.ucl.ac.uk/id/eprint/10106796/

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.