title: Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease.
abstract: BACKGROUND
  Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides.
  
  
  METHODS
  We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys.
  
  
  RESULTS
  We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels.
  
  
  CONCLUSIONS
  Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gusarova
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Colm
authors.initials: C
authors.lastname: O'Dushlaine
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Omri
authors.initials: O
authors.lastname: Gottesman
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Jesus
authors.initials: J
authors.lastname: Trejos
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Charleen
authors.initials: C
authors.lastname: Hunt
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Cristopher V
authors.initials: CV
authors.lastname: Van Hout
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Lukas
authors.initials: L
authors.lastname: Habegger
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: David
authors.initials: D
authors.lastname: Buckler
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Ka-Man V
authors.initials: KM
authors.lastname: Lai
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Leader
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Michael F
authors.initials: MF
authors.lastname: Murray
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: H Lester
authors.initials: HL
authors.lastname: Kirchner
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: John
authors.initials: J
authors.lastname: Penn
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Lopez
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: John D
authors.initials: JD
authors.lastname: Overton
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Aris
authors.initials: A
authors.lastname: Baras
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.affiliation: From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D000368:Aged; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D002784:Cholesterol / Q000097:blood; D003324:Coronary Artery Disease / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006579:Heterozygote; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D014280:Triglycerides; D002784:Cholesterol