Genetic Variability in the Uptake of Dietary Sterols Affects the Risk of Coronary Artery Disease

Background: The ATP-binding cassette (ABC) G5 and G8 transporters, encoded by the ABCG5 and ABCG8 (ABCG5/8) genes, have a key role in controlling intestinal absorption of cholesterol and other sterols, and in promoting their hepatobiliary secretion. Here, we use novel rare ABCG5/8 variants, together with common variants, to explore whether variability in sterol absorption impacts the risk of coronary artery disease (CAD). Methods: We examined 41 ABCG5/8 coding variants for association with non-high density lipoprotein (non-HDL) cholesterol in data from Iceland and the Global Lipid Genetics Consortium (N up to 472,392 combined). We tested variants for association with CAD in up to 67,130 cases and 700,075 controls from Iceland and the UK Biobank. Findings: We identified several rare ABCG5/8 coding variants with substantial impact on circulating levels of non-HDL cholesterol, and demonstrate that heterozygous carriers are at increased risk of CAD and other related diseases. Consistent with causal effects of other sterols such as phytosterols, on atherosclerotic disease we demonstrate that the degree of CAD risk conferred by both common and rare ABCG5/8 variants is greater than predicted based on their effect on non-HDL cholesterol levels. Interpretation: Our data highlight intestinal absorption as an important mechanism in the regulation of non-HDL /LDL cholesterol levels and CAD risk. Further, the results support the notion that other sterols such as phytosterols contribute to the pathogenesis of CAD. Funding Statement: The study was funded by deCODE genetics/Amgen Inc. Declaration of Interests: The authors who are affiliated with deCODE genetics/AMGEN, declare competing financial interests as employees. The remaining authors declare no competing financial interests. Ethics Approval Statement: The study was approved by The Icelandic Data Protection Authority and the National Bioethics Committee of Iceland (approvals no. VSNb201508003/03.01, VSNb2015010033/03.12 and VSNb2014100020/03.12 with amendments). All participating subjects donating biological samples signed informed consents. Personal identities of the participants and biological samples were encrypted with a third-party system approved and monitored by the Icelandic Data Protection Authority.