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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
  • Connor A Emdin
  • Robert A Scott
  • Wen-Jane Lee
  • Aeron Small
  • Lydia C Kwee
  • Om Prakash Dwivedi
  • 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
  • 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
  • Svati Shah
  • William E Kraus
  • Daniel J Rader
  • Yii-Der Ida Chen
  • Kristian Hveem
  • Nicolas J Wareham
  • Sekar Kathiresan
  • Kari Stefansson
  • Børge G Nordestgaard
  • Anne Tybjaerg-Hansen
  • Goncalo R. Abecasis
  • David Altshuler
  • Jose C. Florez
  • Michael Boehnke
  • Mark McCarthy
  • George D Yancopoulos
  • David J. Carey
  • Alan R Shuldiner
  • Aris Baras
  • Frederick E Dewey
  • Jesper Gromada
Organisations
External organisations
  • University of Oxford
  • University of Pennsylvania
  • University of Michigan
  • Regeneron Pharmaceuticals, Inc.
  • Geisinger Health System
  • Copenhagen University Hospital
  • Duke University
  • Tunghai University
  • University of Tartu
  • deCODE Genetics, Amgen, Inc.
  • National Taiwan University
  • Massachusetts General Hospital
  • University of Helsinki
  • University of Cambridge
  • Norwegian University of Science and Technology
  • Broad Institute
  • Harvard Medical School
  • Nord-Trøndelag Health Trust
  • University of Copenhagen
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Endocrinology and Diabetes
Original languageEnglish
Article number2252
Pages (from-to)1-11
JournalNature Communications
Volume9
Publication statusPublished - 2018 Jun 13
Publication categoryResearch
Peer-reviewedYes