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

Author

Listed:
  • 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
    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
    Tunghai University)

  • Aeron Small

    (University of Pennsylvania
    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
    UNAM/INCMNSZ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán)

  • Andrew P. Morris

    (University of Oxford
    University of Liverpool
    University of Tartu)

  • 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
    National Taiwan University)

  • Scott Damrauer

    (University of Pennsylvania
    Corporal Michael Crescenz VA Medical Center)

  • David Birtwell

    (University of Pennsylvania
    University of Pennsylvania)

  • Chad M. Brummett

    (University of Michigan)

  • Amit V. Khera

    (Broad Institute
    Harvard Medical School)

  • Pradeep Natarajan

    (Broad Institute
    Harvard Medical School)

  • Marju Orho-Melander

    (Lund University)

  • Jason Flannick

    (Broad Institute
    Harvard Medical School)

  • Luca A. Lotta

    (Addenbrooke’s Hospital)

  • Cristen J. Willer

    (University of Michigan
    University of Michigan
    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
    Lund University)

  • Leif Groop

    (Helsinki University
    Lund University)

  • Svati H. Shah

    (Duke University)

  • William E. Kraus

    (Duke University)

  • Daniel J. Rader

    (University of Pennsylvania
    University of Pennsylvania)

  • Yii-Der I. Chen

    (LABioMed at Harbor-UCLA Medical Center)

  • Kristian Hveem

    (Norwegian University of Science and Technology
    Norwegian University of Science and Technology
    Nord-Trøndelag Health Trust)

  • 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
    Copenhagen University Hospital
    Copenhagen University Hospital
    University of Copenhagen)

  • Anne Tybjærg-Hansen

    (Copenhagen University Hospital
    Copenhagen University Hospital
    Copenhagen University Hospital
    University of Copenhagen)

  • Goncalo R. Abecasis

    (University of Michigan)

  • David Altshuler

    (Broad Institute
    Massachusetts General Hospital
    Harvard Medical School
    Massachusetts Institute of Technology)

  • Jose C. Florez

    (Massachusetts General Hospital
    Broad Institute
    Harvard Medical School)

  • Michael Boehnke

    (University of Michigan)

  • Mark I. McCarthy

    (University of Oxford
    Churchill Hospital
    Churchill Hospital)

  • 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)

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.

Suggested Citation

  • 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 , 2018. "Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04611-z
    DOI: 10.1038/s41467-018-04611-z
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    Cited by:

    1. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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