ANGPTL 3 De fi ciency and Protection Against Coronary Artery Disease

Fro ing Ha Ho bri of Ra Ma In Ca BACKGROUND Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES The study goal was to leverage 3 distinct lines of evidence—a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)—to test whether ANGPTL3 deficiency is associated with lower risk for CAD. METHODS We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. RESULTS The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p 1⁄4 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS ANGPTL3 deficiency is associated with protection from CAD. (J Am Coll Cardiol 2017;69:2054–63) © 2017 by the American College of Cardiology Foundation. m the Cardiovascular Division, Department of Medicine, Department of Genetics, and McDonnell Genome Institute, Washton University School of Medicine, St. Louis, Missouri; Center for Human Genetic Research, Massachusetts General Hospital, rvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General spital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Camdge, Massachusetts; Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Mallinckrodt Institute of diology, Washington University School of Medicine, St. Louis, Missouri; Harvard College, Harvard University, Cambridge, ssachusetts; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; stitute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK (German Centre for rdiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; Deutsches Herzzentrum München, Technische SEE PAGE 2064 AB BR E V I A T I O N S