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

Robert A Scott; Daniel F Freitag; Li Li; Audrey Y Chu; Praveen Surendran; Robin Young; Niels Grarup; Alena Stancáková; Yuning Chen; Tibor V Varga; 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; Peter M Nilsson; 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; Jennifer L Aponte; Adam S Butterworth; Josée Dupuis; Douglas F Easton; Rosalind A Eeles; Jeanette Erdmann; Paul W Franks; Timothy M Frayling; Torben Hansen; Joanna M M Howson; Torben Jørgensen; Jaspal Kooner; Markku Laakso; Claudia Langenberg; 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; CARDIOGRAM Exome Consortium

doi:10.1126/scitranslmed.aad3744

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

Journal article

Peer reviewed

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

Robert A Scott, Daniel F Freitag, Li Li, Audrey Y Chu, Praveen Surendran, Robin Young, Niels Grarup, Alena Stancáková, Yuning Chen, Tibor V Varga, …

Science translational medicine, Vol.8(341), pp.341ra76-341ra76

01/06/2016

DOI: https://doi.org/10.1126/scitranslmed.aad3744

PMCID: PMC5219001

PMID: 27252175

Abstract

Alleles

Coronary Disease - genetics

Diabetes Mellitus, Type 2 - genetics

Dipeptidyl Peptidase 4 - genetics

Genotype

Glucagon-Like Peptide-1 Receptor - genetics

Humans

Obesity - genetics

Receptor, Cannabinoid, CB2 - genetics

Receptor, Serotonin, 5-HT2C - genetics

Receptors, Somatostatin - genetics

Sodium-Glucose Transporter 1 - genetics

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.

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Title: A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
Creators - without role: Robert A Scott - Medical Research Council
Daniel F Freitag - University of Cambridge
Li Li - Research Triangle Park Foundation
Audrey Y Chu - Brigham and Women's Hospital
Praveen Surendran - University of Cambridge
Robin Young - University of Cambridge
Niels Grarup - University of Copenhagen
Alena Stancáková - University of Eastern Finland
Yuning Chen - Boston University
Tibor V Varga - Lund University
Hanieh Yaghootkar - University of Exeter
Jian'an Luan - Medical Research Council
Jing Hua Zhao - Medical Research Council
Sara M Willems - Medical Research Council
Jennifer Wessel - Indiana University
Shuai Wang - Boston University
Nisa Maruthur - Johns Hopkins University
Kyriaki Michailidou - University of Cambridge
Ailith Pirie - University of Cambridge
Sven J van der Lee - Erasmus MC
Christopher Gillson - Medical Research Council
Ali Amin Al Olama - University of Cambridge
Philippe Amouyel - University of Lille
Larraitz Arriola - Basque Government
Dominique Arveiler - University of Strasbourg
Iciar Aviles-Olmos - University College London
Beverley Balkau - Inserm
Aurelio Barricarte - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Inês Barroso - University of Cambridge
Sara Benlloch Garcia - University of Cambridge
Joshua C Bis - University of Washington
Stefan Blankenberg - Department of General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany
Michael Boehnke - University of Michigan–Ann Arbor
Heiner Boeing - German Institute of Human Nutrition
Eric Boerwinkle - Baylor College of Medicine
Ingrid B Borecki - Washington University in St. Louis
Jette Bork-Jensen - University of Copenhagen
Sarah Bowden - University of Birmingham
Carlos Caldas - University of Cambridge
Muriel Caslake - University of Glasgow
L Adrienne Cupples - Boston University
Carlos Cruchaga - Washington University in St. Louis
Jacek Czajkowski - Washington University in St. Louis
Marcel den Hoed - Uppsala University
Janet A Dunn - University of Warwick
Helena M Earl - University of Cambridge
Georg B Ehret - Johns Hopkins University
Ele Ferrannini - Istituto di Fisiologia Clinica
Jean Ferrieres - Inserm
Thomas Foltynie - University College London
Ian Ford - University of Glasgow
Nita G Forouhi - Medical Research Council
Francesco Gianfagna - University of Insubria
Carlos Gonzalez - Catalan Institute of Oncology (ICO), Barcelona 08908, Spain
Sara Grioni - Mylan
Louise Hiller - University of Warwick
Jan-Håkan Jansson - Umeå University
Marit E Jørgensen - University of Southern Denmark
J Wouter Jukema - Leiden University Medical Center
Rudolf Kaaks - Heidelberg
Frank Kee - Queen's University Belfast
Nicola D Kerrison - Medical Research Council
Timothy J Key - University of Oxford
Jukka Kontto - National Institutes of Health
Zsofia Kote-Jarai - Institute of Cancer Research
Aldi T Kraja - Washington University in St. Louis
Kari Kuulasmaa - National Institutes of Health
Johanna Kuusisto - University of Eastern Finland
Allan Linneberg - University of Copenhagen
Chunyu Liu - National Institutes of Health
Gaëlle Marenne - Wellcome Sanger Institute
Karen L Mohlke - University of North Carolina at Chapel Hill
Andrew P Morris - University of Liverpool
Kenneth Muir - University of Manchester
Martina Müller-Nurasyid - Helmholtz Zentrum München
Patricia B Munroe - Queen Mary University of London
Carmen Navarro - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Sune F Nielsen - Copenhagen University Hospital
Peter M Nilsson - Lund University
Børge G Nordestgaard - Copenhagen University Hospital
Chris J Packard - University of Glasgow
Domenico Palli - Prevention Institute
Salvatore Panico - University of Naples Federico II
Gina M Peloso - Broad Institute
Markus Perola - University of Helsinki
Annette Peters - Helmholtz Zentrum München
Christopher J Poole - University of Warwick
J Ramón Quirós - Public Health Directorate, 33006 Oviedo, Asturias, Spain
Olov Rolandsson - Umeå University
Carlotta Sacerdote - University of Turin
Veikko Salomaa - National Institutes of Health
María-José Sánchez - Universidad de Granada
Naveed Sattar - University of Glasgow
Stephen J Sharp - Medical Research Council
Rebecca Sims - Cardiff University
Nadia Slimani - International Agency For Research On Cancer
Jennifer A Smith - University of Michigan–Ann Arbor
Deborah J Thompson - University of Cambridge
Stella Trompet - Leiden University Medical Center
Rosario Tumino - Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospital, ASP Ragusa, 97100 Ragusa, Italy
Daphne L van der A - British Science Association
Yvonne T van der Schouw - University Medical Center Utrecht
Jarmo Virtamo - National Institute for Health and Welfare, FI-00271 Helsinki, Finland
Mark Walker - Newcastle University
Klaudia Walter - Wellcome Sanger Institute
Jean E Abraham - University of Cambridge
Laufey T Amundadottir - Genomics
Jennifer L Aponte - Triangle
Adam S Butterworth - University of Cambridge
Josée Dupuis - Boston University
Douglas F Easton - University of Cambridge
Rosalind A Eeles - Royal Marsden NHS Foundation Trust
Jeanette Erdmann - Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany
Paul W Franks - Umeå University
Timothy M Frayling - University of Exeter
Torben Hansen - University of Copenhagen
Joanna M M Howson - University of Cambridge
Torben Jørgensen - Aalborg University
Jaspal Kooner - Imperial College Healthcare NHS Trust
Markku Laakso - Department of Medicine, University of Kuopio, FI-70211 Kuopio, Finland
Claudia Langenberg - University of Cambridge
Mark I McCarthy - University of Oxford
James S Pankow - University of Minnesota
Oluf Pedersen - University of Copenhagen
Elio Riboli - Imperial College London
Jerome I Rotter - University of California, Los Angeles
Danish Saleheen - University of Pennsylvania
Nilesh J Samani - University of Leicester
Heribert Schunkert - DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany. Deutsches Herzzentrum München, Technische Universität München, 80636 Munich, Germany
Peter Vollenweider - Department of Internal Medicine, BH10-462, Internal Medicine, Lausanne University Hospital (CHUV), CH-1011 Lausanne, Switzerland
Stephen O'Rahilly - University of Cambridge
Panos Deloukas - Queen Mary University of London
John Danesh - University of Cambridge
Mark O Goodarzi - Cedars-Sinai Medical Center
Sekar Kathiresan - Harvard Medical School
James B Meigs - Harvard Medical School
Margaret G Ehm - Triangle
Nicholas J Wareham - University of Cambridge
Dawn M Waterworth - Cambridge in America
CARDIOGRAM Exome Consortium
Publication Details: Science translational medicine, Vol.8(341), pp.341ra76-341ra76
Grant note: MR/L023784/2 / Medical Research Council U01 DK078616 / NIDDK NIH HHS MR/L023784/1 / Medical Research Council HHSN268201100007C / NHLBI NIH HHS R01 DK072193 / NIDDK NIH HHS U01 HG004402 / NHGRI NIH HHS HHSN268201100012C / NHLBI NIH HHS R01 AG033193 / NIA NIH HHS G0800270 / Medical Research Council MR/L010305/1 / Medical Research Council MR/K013041/1 / Medical Research Council MR/L501517/1 / Medical Research Council MR/M008975/1 / Medical Research Council UL1 TR001108 / NCATS NIH HHS HHSN268201100006C / NHLBI NIH HHS HHSN268201100011C / NHLBI NIH HHS UL1 TR000124 / NCATS NIH HHS K24 DK080140 / NIDDK NIH HHS HHSN268201100010C / NHLBI NIH HHS UL1 RR025005 / NCRR NIH HHS HHSN268201100005C / NHLBI NIH HHS R01 HL059367 / NHLBI NIH HHS MC_UU_12015/1 / Medical Research Council R01 DK093757 / NIDDK NIH HHS R01 AG008122 / NIA NIH HHS HHSN268201100008C / NHLBI NIH HHS N01 CN045165 / NCI NIH HHS R01 HL086694 / NHLBI NIH HHS U01 DK062370 / NIDDK NIH HHS U01 AG032984 / NIA NIH HHS P30 DK020572 / NIDDK NIH HHS 9675 / Cancer Research UK R01 HL087641 / NHLBI NIH HHS MC_UU_12012/5 / Medical Research Council HHSN268201100009C / NHLBI NIH HHS N01RC37004 / CCR NIH HHS G0902227 / Medical Research Council R01 DK078616 / NIDDK NIH HHS P30 DK063491 / NIDDK NIH HHS
Identifiers: 9936709508331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article