title: A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
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.
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. dawn.m.waterworth@gsk.com robert.scott@mrc-epid.cam.ac.uk nick.wareham@mrc-epid.cam.ac.uk.
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authors.affiliation: National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK. Imperial College Healthcare NHS Trust, London W2 1NY, UK. Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK.
authors.forename: Jaspal
authors.initials: J
authors.lastname: Kooner
authors.affiliation: Department of Medicine, University of Kuopio, FI-70211 Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455-0381, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: School of Public Health, Imperial College London, London W2 1PG, UK.
authors.forename: Elio
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authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, CA 90502, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Danish
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authors.lastname: Saleheen
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK. National Institute for Health Research, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
authors.forename: Nilesh J
authors.initials: NJ
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authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany. Deutsches Herzzentrum München, Technische Universität München, 80636 Munich, Germany.
authors.forename: Heribert
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authors.affiliation: Department of Internal Medicine, BH10-462, Internal Medicine, Lausanne University Hospital (CHUV), CH-1011 Lausanne, Switzerland.
authors.forename: Peter
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authors.lastname: Vollenweider
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK. MRC Metabolic Diseases Unit, Cambridge CB2 0QQ, UK. National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
authors.forename: Stephen
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authors.lastname: O'Rahilly
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
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authors.lastname: Danesh
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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authors.initials: JB
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authors.initials: MG
authors.lastname: Ehm
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. dawn.m.waterworth@gsk.com robert.scott@mrc-epid.cam.ac.uk nick.wareham@mrc-epid.cam.ac.uk.
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authors.lastname: Wareham
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mesh_terms: D000483:Alleles; D003327:Coronary Disease / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics; D005838:Genotype; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics*; D006801:Humans; D009765:Obesity / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics; D017481:Receptors, Somatostatin / Q000235:genetics; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics
chemical_list: C588309:CNR2 protein, human; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; C103263:MCHR1 protein, human; D043885:Receptor, Cannabinoid, CB2; D044405:Receptor, Serotonin, 5-HT2C; D017481:Receptors, Somatostatin; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4