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

• DOI: 10.1126/scitranslmed.aad3744
• Publication Date: 2016-06-02T01:19:13Z
• Authors: 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-Nu...; Patricia B. Munroe; Carmen Navarro; Sune F. Nielsen; Peter M. Nilsson; Børge G. Nordestg...; 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...; Jarmo Virtamo; Mark Walker; Klaudia Walter; ; ; ; ; ; ; ; Jean E. Abraham; Laufey T. Amundad...; 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
• Keywords: genetic association; sequence analysis; CHARGE consortium; RECEPTOR AGONIST LIXISENATIDE; Research & Experimental Medicine; Cardiovascular; PLACEBO-CONTROLLED TRIAL; Receptor, Cannabinoid, CB2; glucagon like peptide 1 receptor; Dipeptidyl Peptidase 4/genetics; Receptor, Serotonin, 5-HT2C; dipeptidyl peptidase IV; 5-HT2C; serotonin 2C receptor; Research & Experimental; 11 Medical And Health Sciences; RANDOMIZED CONTROLLED-TRIAL; CB2; CNR2 protein human; 3. Good health; genetic code; genotyping technique; priority journal; Medicine, Research & Experimental; 5.1 Pharmaceuticals; meta analysis (topic); EPIC-InterAct; Medicine; Type 2; INCRETIN-BASED THERAPIES; Serotonin; RM; Receptors Somatostatin; European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD); EMC NIHES-01-64-01; Genotype; Clinical Trials and Supportive Activities; Medical biotechnology; CB2/genetics; GLP1R gene; 610; TYPE-2 DIABETES-MELLITUS; Article; 03 medical and health sciences; MCHR1 gene; Sodium-Glucose Transporter 1; Clinical Research; 616; Genetics; Diabetes Mellitus; Humans; C720 - Biological chemistry; Sodium-Glucose Transporter 1/genetics; human; glucagon like peptide 1 receptor agonist; Alleles; Science & Technology; Prevention; Alzheimer’s Disease Genetics Consortium; Glucagon-Like Peptide-1 Receptor/genetics; drug targeting; 06 Biological Sciences; ischemic heart disease; R1; Diabetes Mellitus, Type 2; Aging Research in Genomic Epidemiology (CHARGE); GLP1R protein human; genetic variation; RC; Type 2/genetics; 0301 basic medicine; Somatostatin/genetics; Obesity/genetics; Coronary Disease; DPP4 protein human; Receptor Serotonin 5-HT2C; Medical and Health Sciences; F100 - Chemistry; DOUBLE-BLIND; ONCE-DAILY LIXISENATIDE; Receptor Cannabinoid CB2; Receptors; 2.1 Biological and endogenous factors; Receptors, Somatostatin; randomized controlled trial (topic); MCHR1 protein human; GLUCAGON-LIKE PEPTIDE-1; CHD Exome+ Consortium; non insulin dependent diabetes mellitus; Diabetes; Neurology Working Group of the Cohorts for Heart; Pharmacology and Pharmaceutical Sciences; sodium glucose cotransporter 1; Biological Sciences; somatostatin receptor; HTR2C gene; Coronary Disease/genetics; 5-HT2C/genetics; CVD50 consortium; Heart Disease; Somatostatin; Biomedical engineering; Life Sciences & Biomedicine; Receptor; cardiovascular risk; SLC5A1 protein human; Dipeptidyl Peptidase 4; Glucagon-Like Peptide-1 Receptor; heart protection; BETA-CELL FUNCTION; Obesity; gene; CNR2 gene; Cannabinoid; Heart Disease - Coronary Heart Disease; Metabolic and endocrine; Biomedical and Clinical Sciences; Human Genome; GERAD_EC Consortium; Cell Biology; Diabetes Mellitus Type 2; cannabinoid 2 receptor; CARDIOGRAM Exome Consortium; BODY-MASS INDEX; Aging Research in Genomic Epidemiology; Good Health and Well Being; placebo; European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease; DPP4 gene; exome; Pancreatic Cancer Cohort Consortium

A missense variant in GLP1R associated with lower fasting glucose levels and protective against T2D is associated with lower risk of coronary heart disease, suggesting that GLP1R agonists are not associated with an unacceptable increase in cardiovascular risk.