Genetic and Pharmacological Inactivation of ANGPTL3 is Associated With Reduced Atherosclerotic Cardiovascular Disease

Introduction: Loss of function (LoF) variants in ANGPTL3 have been associated with low plasma low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels in family and population studies. It is not known whether the net effect of the lipid changes from such mutations are associated with reduced risk for cardiovascular disease, or whether therapeutic antagonism of ANGPTL3 will replicate these lipid effects and reduce coronary atherosclerosis. Methods: We sequenced the exons of ANGPTL3 in 49,178 participants of European ancestry in the DiscovEHR human genetics study of the Geisinger Health System and the Regeneron Genetics Center. We performed tests of association for loss of function (LoF) variants in ANGPTL3 with lipid levels, and then tested for associations with coronary artery disease (CAD) in 12,207 angiographically-defined cases and 33,819 controls. We also tested the effect of a human monoclonal antibody against ANGPTL3 in an established hyp...