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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
Scott, Robert A; Freitag, Daniel F; Li, Li; Chu, Audrey Y; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning; Varga, Tibor V; Yaghootkar, Hanieh; Luan, Jian'an; Zhao, Jing Hua; Willems, Sara M; Wessel, Jennifer; Wang, Shuai; Maruthur, Nisa; Michailidou, Kyriaki; Pirie, Ailith; van der Lee, Sven J; Gillson, Christopher; Al Olama, Ali Amin; Amouyel, Philippe; Arriola, Larraitz; Arveiler, Dominique; Aviles-Olmos, Iciar; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Garcia, Sara Benlloch; Bis, Joshua C; Blankenberg, Stefan; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Borecki, Ingrid B; Bork-Jensen, Jette; Bowden, Sarah; Caldas, Carlos; Caslake, Muriel; Cupples, L Adrienne; Cruchaga, Carlos; Czajkowski, Jacek; den Hoed, Marcel; Dunn, Janet A; Earl, Helena M; Ehret, Georg B; Ferrannini, Ele; Ferrieres, Jean; Foltynie, Thomas.
Afiliação
  • Scott RA; 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.
  • Freitag DF; Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK. The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
  • Li L; Statistical Genetics, Projects, Clinical Platforms, and Sciences (PCPS), GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
  • Chu AY; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Surendran P; Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
  • Young R; Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
  • Grarup N; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Stancáková A; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
  • Chen Y; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
  • Varga TV; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 Malmö, Sweden.
  • Yaghootkar H; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
  • Luan J; Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Zhao JH; Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Willems SM; Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3000 CE Rotterdam, Neth
  • Wessel J; Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN 46202, USA. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Wang S; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
  • Maruthur N; Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD 21205, USA. Department of Epidemiology, Johns Hopkins University Bloomberg School of
  • Michailidou K; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
  • Pirie A; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
  • van der Lee SJ; Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands.
  • Gillson C; Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Al Olama AA; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
  • Amouyel P; University of Lille, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, UMR 1167, RID-AGE, F-59000 Lille, France.
  • Arriola L; Public Health Division of Gipuzkoa, San Sebastian 20013, Spain. Instituto BIO-Donostia, Basque Government, San Sebastian 20014, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain.
  • Arveiler D; Department of Epidemiology and Public Health (EA3430), University of Strasbourg, 67085 Strasbourg, France.
  • Aviles-Olmos I; Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
  • Balkau B; INSERM, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), 94807 Villejuif, France. Univeristy of Paris-Sud, F-94805 Villejuif, France.
  • Barricarte A; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain. Navarre Public Health Institute (ISPN), Pamplona 31003, Spain.
  • Barroso I; The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK. University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
  • Garcia SB; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
  • Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
  • Blankenberg S; Department of General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany.
  • Boehnke M; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109-2029, USA.
  • Boeing H; German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
  • Boerwinkle E; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77025, USA. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Borecki IB; Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63108, USA.
  • Bork-Jensen J; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Bowden S; Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
  • Caldas C; Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK.
  • Caslake M; University of Glasgow, Glasgow G12 8QQ, UK.
  • Cupples LA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. Framingham Heart Study, National Heart, Lung, and Blood Institute (NHLBI), Framingham, MA 01702-5827, USA.
  • Cruchaga C; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Czajkowski J; Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
  • den Hoed M; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, SE-752 37 Uppsala, Sweden.
  • Dunn JA; Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
  • Earl HM; University of Cambridge and National Institute of Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, UK.
  • Ehret GB; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Ferrannini E; Consiglio Nazionale delle Ricerche (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy.
  • Ferrieres J; Department of Epidemiology, UMR 1027, INSERM, Centre Hospitalier Universitaire (CHU) de Toulouse, 31000 Toulouse, France.
  • Foltynie T; Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Sci Transl Med ; 8(341): 341ra76, 2016 06 01.
Article em En | MEDLINE | ID: mdl-27252175
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença das Coronárias / Receptor do Peptídeo Semelhante ao Glucagon 1 Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença das Coronárias / Receptor do Peptídeo Semelhante ao Glucagon 1 Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2016 Tipo de documento: Article