Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Viktoria Gusarova, Colm O’Dushlaine, Tanya M. Teslovich, Peter N. Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V. Van Hout, Michael F. Murray, Anubha Mahajan, Jonas B. Nielsen, Lars Fritsche, Anders Berg Wulff, Daniel F. Gudbjartsson, Marketa Sjögren, Connor A. Emdin, Robert A. Scott, Wen-Jane Lee, Aeron Small, Lydia C. Kwee, Om Prakash Dwivedi, Rashmi B. Prasad, Shannon Bruse, Alexander E. Lopez, John Penn, Anthony Marcketta, Joseph B. Leader, Christopher D. Still, H. Lester Kirchner, Uyenlinh L. Mirshahi, Amr H. Wardeh, Cassandra M. Hartle, Lukas Habegger, Samantha N. Fetterolf, Teresa Tusie-Luna, Andrew P. Morris, Hilma Holm, Valgerdur Steinthorsdottir, Patrick Sulem, Unnur Thorsteinsdottir, Jerome I. Rotter, Lee-Ming Chuang, Scott Damrauer, David Birtwell, Chad M. Brummett, Amit V. Khera, Pradeep Natarajan, Marju Orho-Melander, Jason Flannick, Luca A. Lotta, Cristen J. Willer, Oddgeir L. Holmen, Marylyn D. Ritchie, David H. Ledbetter, Andrew J. Murphy, Ingrid B. Borecki, Jeffrey G. Reid, John D. Overton, Ola Hansson, Leif Groop, Svati H. Shah, William E. Kraus, Daniel J. Rader, Yii- Der I. Chen, Kristian Hveem, Nicholas J. Wareham, Sekar Kathiresan, Olle Melander, Kari Stefansson, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Goncalo R. Abecasis, David Altshuler, Jose C. Florez, Michael Boehnke, Mark I. McCarthy, George D. Yancopoulos, David J. Carey, Alan R. Shuldiner, Aris Baras (), Frederick E. Dewey () and Jesper Gromada ()
Additional contact information
Viktoria Gusarova: Regeneron Pharmaceuticals
Colm O’Dushlaine: Regeneron Genetics Center
Tanya M. Teslovich: Regeneron Genetics Center
Peter N. Benotti: Geisinger
Tooraj Mirshahi: Geisinger
Omri Gottesman: Regeneron Genetics Center
Cristopher V. Van Hout: Regeneron Genetics Center
Michael F. Murray: Geisinger
Anubha Mahajan: University of Oxford
Jonas B. Nielsen: University of Michigan
Lars Fritsche: University of Michigan
Anders Berg Wulff: Copenhagen University Hospital
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Marketa Sjögren: Lund University
Connor A. Emdin: Broad Institute
Robert A. Scott: Addenbrooke’s Hospital
Wen-Jane Lee: Taichung Veterans General Hospital
Aeron Small: University of Pennsylvania
Lydia C. Kwee: Duke University
Om Prakash Dwivedi: Helsinki University
Rashmi B. Prasad: Lund University
Shannon Bruse: Regeneron Genetics Center
Alexander E. Lopez: Regeneron Genetics Center
John Penn: Regeneron Genetics Center
Anthony Marcketta: Regeneron Genetics Center
Joseph B. Leader: Geisinger
Christopher D. Still: Geisinger
H. Lester Kirchner: Geisinger
Uyenlinh L. Mirshahi: Geisinger
Amr H. Wardeh: Geisinger
Cassandra M. Hartle: Geisinger
Lukas Habegger: Regeneron Genetics Center
Samantha N. Fetterolf: Geisinger
Teresa Tusie-Luna: Instituto de Investigaciones Biomédicas, UNAM, Coyoacán
Andrew P. Morris: University of Oxford
Hilma Holm: deCODE Genetics/Amgen, Inc.
Valgerdur Steinthorsdottir: deCODE Genetics/Amgen, Inc.
Patrick Sulem: deCODE Genetics/Amgen, Inc.
Unnur Thorsteinsdottir: deCODE Genetics/Amgen, Inc.
Jerome I. Rotter: LABioMed at Harbor-UCLA Medical Center
Lee-Ming Chuang: National Taiwan University Hospital
Scott Damrauer: University of Pennsylvania
David Birtwell: University of Pennsylvania
Chad M. Brummett: University of Michigan
Amit V. Khera: Broad Institute
Pradeep Natarajan: Broad Institute
Marju Orho-Melander: Lund University
Jason Flannick: Broad Institute
Luca A. Lotta: Addenbrooke’s Hospital
Cristen J. Willer: University of Michigan
Oddgeir L. Holmen: Norwegian University of Science and Technology
Marylyn D. Ritchie: Geisinger
David H. Ledbetter: Geisinger
Andrew J. Murphy: Regeneron Pharmaceuticals
Ingrid B. Borecki: Regeneron Genetics Center
Jeffrey G. Reid: Regeneron Genetics Center
John D. Overton: Regeneron Genetics Center
Ola Hansson: Helsinki University
Leif Groop: Helsinki University
Svati H. Shah: Duke University
William E. Kraus: Duke University
Daniel J. Rader: University of Pennsylvania
Yii- Der I. Chen: LABioMed at Harbor-UCLA Medical Center
Kristian Hveem: Norwegian University of Science and Technology
Nicholas J. Wareham: Addenbrooke’s Hospital
Sekar Kathiresan: Harvard Medical School
Olle Melander: Lund University
Kari Stefansson: deCODE Genetics/Amgen, Inc.
Børge G. Nordestgaard: Copenhagen University Hospital
Anne Tybjærg-Hansen: Copenhagen University Hospital
Goncalo R. Abecasis: University of Michigan
David Altshuler: Broad Institute
Jose C. Florez: Massachusetts General Hospital
Michael Boehnke: University of Michigan
Mark I. McCarthy: University of Oxford
George D. Yancopoulos: Regeneron Pharmaceuticals
David J. Carey: Geisinger
Alan R. Shuldiner: Regeneron Genetics Center
Aris Baras: Regeneron Genetics Center
Frederick E. Dewey: Regeneron Genetics Center
Jesper Gromada: Regeneron Pharmaceuticals

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

Date: 2018
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DOI: 10.1038/s41467-018-04611-z

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