A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Research output: Contribution to journalArticle

Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Details

Authors
  • Robert A. Scott
  • Daniel F. Freitag
  • Li Li
  • Audrey Y. Chu
  • Praveen Surendran
  • Robin Young
  • Niels Grarup
  • Alena Stancáková
  • Yuning Chen
  • Hanieh Yaghootkar
  • Jian'an Luan
  • Jing Hua Zhao
  • Sara M. Willems
  • Jennifer Wessel
  • Shuai Wang
  • Nisa Maruthur
  • Kyriaki Michailidou
  • Ailith Pirie
  • Sven J. Van Der Lee
  • Christopher Gillson
  • Ali Amin Al Olama
  • Philippe Amouyel
  • Larraitz Arriola
  • Dominique Arveiler
  • Iciar Aviles-Olmos
  • Beverley Balkau
  • Aurelio Barricarte
  • Inês Barroso
  • Sara Benlloch Garcia
  • Joshua C. Bis
  • Stefan Blankenberg
  • Michael Boehnke
  • Heiner Boeing
  • Eric Boerwinkle
  • Ingrid B. Borecki
  • Jette Bork-Jensen
  • Sarah Bowden
  • Carlos Caldas
  • Muriel Caslake
  • L. Adrienne Cupples
  • Carlos Cruchaga
  • Jacek Czajkowski
  • Marcel Den Hoed
  • Janet A. Dunn
  • Helena M. Earl
  • Georg B. Ehret
  • Ele Ferrannini
  • Jean Ferrieres
  • Thomas Foltynie
  • Ian Ford
  • Nita G. Forouhi
  • Francesco Gianfagna
  • Carlos Gonzalez
  • Sara Grioni
  • Louise Hiller
  • Jan Håkan Jansson
  • Marit E. Jørgensen
  • J. Wouter Jukema
  • Rudolf Kaaks
  • Frank Kee
  • Nicola D. Kerrison
  • Timothy J. Key
  • Jukka Kontto
  • Zsofia Kote-Jarai
  • Aldi T. Kraja
  • Kari Kuulasmaa
  • Johanna Kuusisto
  • Allan Linneberg
  • Chunyu Liu
  • Gaëlle Marenne
  • Karen L. Mohlke
  • Andrew P. Morris
  • Kenneth Muir
  • Martina Müller-Nurasyid
  • Patricia B. Munroe
  • Carmen Navarro
  • Sune F. Nielsen
  • Børge G. Nordestgaard
  • Chris J. Packard
  • Domenico Palli
  • Salvatore Panico
  • Gina M. Peloso
  • Markus Perola
  • Annette Peters
  • Christopher J. Poole
  • J. Ramón Quirós
  • Olov Rolandsson
  • Carlotta Sacerdote
  • Veikko Salomaa
  • María José Sánchez
  • Naveed Sattar
  • Stephen J. Sharp
  • Rebecca Sims
  • Nadia Slimani
  • Jennifer A. Smith
  • Deborah J. Thompson
  • Stella Trompet
  • Rosario Tumino
  • Daphne L. Van Der A
  • Yvonne T. Van Der Schouw
  • Jarmo Virtamo
  • Mark Walker
  • Klaudia Walter
  • Jean E. Abraham
  • Laufey T. Amundadottir
  • Adam S. Butterworth
  • Jennifer L. Aponte
  • Josée Dupuis
  • Douglas F. Easton
  • Rosalind A. Eeles
  • Jeanette Erdmann
  • Timothy M. Frayling
  • Torben Hansen
  • Joanna M M Howson
  • Torben Jørgensen
  • Jaspal Kooner
  • Markku Laakso
  • Mark I. McCarthy
  • James S. Pankow
  • Oluf Pedersen
  • Elio Riboli
  • Jerome I. Rotter
  • Danish Saleheen
  • Nilesh J. Samani
  • Heribert Schunkert
  • Peter Vollenweider
  • Stephen O'Rahilly
  • Panos Deloukas
  • John Danesh
  • Mark O. Goodarzi
  • Sekar Kathiresan
  • James B. Meigs
  • Margaret G. Ehm
  • Nicholas J. Wareham
  • Dawn M. Waterworth
Organisations
External organisations
  • University of Cambridge
  • University of Strasbourg
  • GlaxoSmithKline
  • Brigham and Women's Hospital / Harvard Medical School
  • University of Copenhagen
  • University of Eastern Finland
  • Boston University
  • University of Exeter
  • Erasmus University Medical Center
  • Indiana University
  • Johns Hopkins University
  • University of Lille Nord de France
  • CIBER Epidemiology and Public Health (CIBERESP)
  • University College London
  • University of Paris-Sud
  • Health Research Institute of Navarra (IDISNA)
  • University of Washington
  • University Medical Center Hamburg-Eppendorf
  • University of Michigan
  • German Institute of Human Nutrition
  • Baylor College of Medicine
  • Washington University in St. Louis
  • University of Birmingham
  • University of Glasgow
  • Framingham Heart Study
  • Uppsala University
  • University of Warwick
  • CNR Istituto per le Tecnologie Applicate ai Beni Culturali (CNR-ITABC)
  • National Institute for Health and Medical Research, France
  • Istituto Neurologico Mediterraneo Neuromed
  • Catalan Institute of Oncology
  • Istituto Nazionale dei Tumori
  • Umeå University
  • University of Southern Denmark
  • Leiden University Medical Centre
  • German Cancer Research Centre
  • Queen's University Belfast
  • University of Oxford
  • Finnish National Institute for Health and Welfare
  • Institute of Cancer Research London
  • Kuopio University Hospital
  • Wellcome Trust Sanger Institute
  • University of North Carolina
  • German Centre for Cardiovascular Research
  • Queen Mary University
  • Murcia Regional Health Council
  • Cancer Research and Prevention Institute (ISPO)
  • University of Naples Federico II
  • Institute for Molecular Medicine Finland (FIMM)
  • University of Helsinki
  • Helmholtz Zentrum München
  • University Hospital Coventry and Warwickshire
  • Public Health Directorate
  • Human Genetics Foundation (HuGeF)
  • Instituto de Investigación Biosanitaria de Granada (Granada.ibs)
  • Cardiff University
  • International Agency for Research on Cancer, World Health Organization
  • Civic and M.P Arezzo Hospital
  • National Institute for Public Health and the Environment (RIVM)
  • University Medical Center Utrecht
  • University of Newcastle upon Tyne
  • National Cancer Institute, USA
  • Royal Marsden NHS Foundation Trust
  • British Columbia Children's Hospital
  • Aalborg University
  • Ealing Hospital
  • University of Minnesota system
  • Imperial College London
  • Broad Institute
  • University of Pennsylvania
  • Glenfield Hospital
  • Technical University of Munich
  • Lausanne University Hospital
  • National Institute for Health Research, United Kingdom
  • Cedars-Sinai Medical Center
  • Massachusetts General Hospital
  • Harvard University
  • Helsinki University Central Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems
Original languageEnglish
Article number341ra76
JournalScience Translational Medicine
Volume8
Issue number341
Publication statusPublished - 2016 Jun 1
Publication categoryResearch
Peer-reviewedYes