Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease. (23rd July 2020)

• Record Type: Journal Article
• Authors: Helgadottir, Anna; Thorleifsson, Gudmar; Alexandersson, Kristjan F; Tragante, Vinicius; Thorsteinsdottir, Margret; Eiriksson, Finnur F; Gretarsdottir, Solveig; Björnsson, Eythór; Magnusson, Olafur; Sveinbjornsson, Gardar; Jonsdottir, Ingileif; Steinthorsdottir, Valgerdur; Ferkingstad, Egil; Jensson, Brynjar Ö; Stefansson, Hreinn; Olafsson, Isleifur; Christensen, Alex H; Torp-Pedersen, Christian; Køber, Lars; Pedersen, Ole B; Erikstrup, Christian; Sørensen, Erik; Brunak, Søren; Banasik, Karina; Hansen, Thomas F; Nyegaard, Mette; Eyjolfssson, Gudmundur I; Sigurdardottir, Olof; Thorarinsson, Bjorn L; Matthiasson, Stefan E; Steingrimsdottir, Thora; Bjornsson, Einar S; Danielsen, Ragnar; Asselbergs, Folkert W; Arnar, David O; Ullum, Henrik; Bundgaard, Henning; Sulem, Patrick; Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Holm, Hilma; Gudbjartsson, Daniel F; Stefansson, Kari;
• Is Part Of: European heart journal. Volume 41:Number 28(2020)
• Page Start: 2618
• Page End: 2628
• Publication Date: 2020-07-23
• Subjects: Dietary cholesterol -- Phytosterols -- Absorption -- Genetics -- ABCG5/8; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehaa531
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: 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.