Abstract 16563: 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 hyperlipidemic mouse model of atherosclerosis progression.
Results: We identified nine distinct heterozygous LoF variants in ANGPTL3 sequence data from 212 of 49,178 individuals. Heterozygous LoF variant carriers had ~50% reduction in serum [ANGPTL3] and significantly lower TGs, HDL-C and LDL-C. Thirty-nine of 12,207 (0.32%) individuals with coronary artery disease and 157 of 33,819 controls harbored a LoF variant in ANGPTL3 (0.46%), corresponding to 39% lower odds of coronary artery disease (odds ratio 0.61, 95% confidence interval 0.43-0.88, p = 0.008). In APOE*3-Leiden.CETP mice, inhibition of Angptl3 with a human monoclonal antibody decreased total cholesterol (-52%, p<0.001), triglycerides levels (-84%, p<0.001), atherosclerotic lesion area (-39%, p<0.001) and necrotic content (-45%, p<0.001) as compared with control antibody treatment.
Conclusions: Genetic and therapeutic antagonism of ANGPTL3 in humans and mice was associated with reduction in all lipid fractions and reduced atherosclerotic coronary artery disease risk. ANGPTL3 joins a growing list of promising novel drug targets identified and validated through large-scale studies of rare loss of function variants in humans.
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- © 2016 by American Heart Association, Inc.