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PMID: 26933753 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease.

The New England journal of medicine ·Vol. 374 ·No. 12 ·2016-03-24 ·Pages 1123-33

Dewey FE, Gusarova V, O'Dushlaine C, Gottesman O, Trejos J, Hunt C, Van Hout CV, Habegger L, Buckler D, Lai KM, Leader JB, Murray MF, Ritchie MD, Kirchner HL, Ledbetter DH, Penn J, Lopez A, Borecki IB, Overton JD, Reid JG, Carey DJ, Murphy AJ, Yancopoulos GD, Baras A, Gromada J, Shuldiner AR

Abstract

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. 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. 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. 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.).

MeSH Terms
Aged Angiopoietin-Like Protein 4 Angiopoietins/antagonists & inhibitors,genetics Animals Cholesterol/blood Coronary Artery Disease/genetics Disease Models, Animal Female Gene Silencing Heterozygote Humans Macaca mulatta Male Mice Middle Aged Mutation Risk Factors Triglycerides/blood
Chemicals
ANGPTL4 protein, human Angiopoietin-Like Protein 4 Angiopoietins Triglycerides Cholesterol
Authors & Affiliations
26 authors, click to expand affiliations / ORCID
Dewey Frederick E
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.).
Gusarova Viktoria
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.).
O'Dushlaine Colm
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.).
Gottesman Omri
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.).
Trejos Jesus
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.).
Hunt Charleen
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.).
Van Hout Cristopher V
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.).
Habegger Lukas
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.).
Buckler David
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.).
Lai Ka-Man V
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.).
Leader Joseph B
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.).
Murray Michael F
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.).
Ritchie Marylyn D
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.).
Kirchner H Lester
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.).
Ledbetter David H
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.).
Penn John
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.).
Lopez Alexander
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.).
Borecki Ingrid B
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.).
Overton John D
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.).
Reid Jeffrey G
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.).
Carey David J
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.).
Murphy Andrew J
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.).
Yancopoulos George D
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.).
Baras Aris
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.).
Gromada Jesper
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.).
Shuldiner Alan R
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.).
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Article Info
Journal
The New England journal of medicine
Abbr.
N Engl J Med
ISSN
1533-4406
DOI
10.1056/NEJMoa1510926
Published
2016-03-24
Epub
2016-00-02
Pages
1123-33
Language
English
Region
United States
NLM ID
0255562
PMCID
PMC4900689
Subset
IM
Grants
NIDDK NIH HHS · P30 DK072488 · United States
Corrections
CommentIn
PMID: 26934667
CommentIn
PMID: 27959690
CommentIn
PMID: 27959691
CommentIn
PMID: 27959692
CommentIn
PMID: 28112898
CommentIn
PMID: 28112899
CommentIn
PMID: 28112900
External Links
PubMed source DOI: 10.1056/NEJMoa1510926 PMC Full Text View journal details
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