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Sci Transl Med. 2016 Jun 1;8(341):341ra76. doi: 10.1126/scitranslmed.aad3744.

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

Scott RA1, Freitag DF2, Li L3, Chu AY4, Surendran P5, Young R5, Grarup N6, Stancáková A7, Chen Y8, Varga TV9, Yaghootkar H10, Luan J11, Zhao JH11, Willems SM12, Wessel J13, Wang S8, Maruthur N14, Michailidou K15, Pirie A15, van der Lee SJ16, Gillson C11, Al Olama AA15, Amouyel P17, Arriola L18, Arveiler D19, Aviles-Olmos I20, Balkau B21, Barricarte A22, Barroso I23, Garcia SB15, Bis JC24, Blankenberg S25, Boehnke M26, Boeing H27, Boerwinkle E28, Borecki IB29, Bork-Jensen J6, Bowden S30, Caldas C31, Caslake M32; CVD50 consortium, Cupples LA33, Cruchaga C34, Czajkowski J35, den Hoed M36, Dunn JA37, Earl HM38, Ehret GB39, Ferrannini E40, Ferrieres J41, Foltynie T20, Ford I32, Forouhi NG11, Gianfagna F42, Gonzalez C43, Grioni S44, Hiller L37, Jansson JH45, Jørgensen ME46, Jukema JW47, Kaaks R48, Kee F49, Kerrison ND11, Key TJ50, Kontto J51, Kote-Jarai Z52, Kraja AT35, Kuulasmaa K51, Kuusisto J53, Linneberg A54, Liu C55, Marenne G56, Mohlke KL57, Morris AP58, Muir K59, Müller-Nurasyid M60, Munroe PB61, Navarro C62, Nielsen SF63, Nilsson PM64, Nordestgaard BG63, Packard CJ32, Palli D65, Panico S66, Peloso GM67, Perola M68, Peters A69, Poole CJ70, Quirós JR71, Rolandsson O72, Sacerdote C73, Salomaa V51, Sánchez MJ74, Sattar N32, Sharp SJ11, Sims R75, Slimani N76, Smith JA77, Thompson DJ15, Trompet S47, Tumino R78, van der A DL79, van der Schouw YT80, Virtamo J51, Walker M81, Walter K56; GERAD_EC Consortium; Neurology Working Group of the Cohorts for Heart; Aging Research in Genomic Epidemiology (CHARGE); Alzheimer’s Disease Genetics Consortium; Pancreatic Cancer Cohort Consortium; European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD); EPIC-InterAct, Abraham JE82, Amundadottir LT83, Aponte JL84, Butterworth AS5, Dupuis J8, Easton DF85, Eeles RA86, Erdmann J87, Franks PW88, Frayling TM10, Hansen T6, Howson JM5, Jørgensen T89, Kooner J90, Laakso M91, Langenberg C11, McCarthy MI92, Pankow JS93, Pedersen O6, Riboli E94, Rotter JI95, Saleheen D96, Samani NJ97, Schunkert H98, Vollenweider P99, O'Rahilly S100; CHARGE consortium; CHD Exome+ Consortium; CARDIOGRAM Exome Consortium, Deloukas P101, Danesh J2, Goodarzi MO102, Kathiresan S103, Meigs JB104, Ehm MG84, Wareham NJ1, Waterworth DM105.

Author information

1
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.
2
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.
3
Statistical Genetics, Projects, Clinical Platforms, and Sciences (PCPS), GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
4
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
6
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
7
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
8
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
9
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 Malmö, Sweden.
10
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
11
Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
12
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, Netherlands.
13
Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN 46202, USA. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
14
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 Public Health, Baltimore, MD 21205, USA.
15
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
16
Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands.
17
University of Lille, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, UMR 1167, RID-AGE, F-59000 Lille, France.
18
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.
19
Department of Epidemiology and Public Health (EA3430), University of Strasbourg, 67085 Strasbourg, France.
20
Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
21
INSERM, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), 94807 Villejuif, France. Univeristy of Paris-Sud, F-94805 Villejuif, France.
22
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain. Navarre Public Health Institute (ISPN), Pamplona 31003, Spain.
23
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.
24
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
25
Department of General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany.
26
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109-2029, USA.
27
German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
28
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.
29
Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63108, USA.
30
Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
31
Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK.
32
University of Glasgow, Glasgow G12 8QQ, UK.
33
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.
34
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
35
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.
36
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, SE-752 37 Uppsala, Sweden.
37
Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
38
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.
39
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
40
Consiglio Nazionale delle Ricerche (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy.
41
Department of Epidemiology, UMR 1027, INSERM, Centre Hospitalier Universitaire (CHU) de Toulouse, 31000 Toulouse, France.
42
Department of Clinical and Experimental Medicine, Research Centre in Epidemiology and Preventive Medicine, University of Insubria, 21100 Varese, Italy. Department of Epidemiology and Prevention, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
43
Catalan Institute of Oncology (ICO), Barcelona 08908, Spain.
44
Epidemiology and Prevention Unit, 20133 Milan, Italy.
45
Research Unit, 931 41 Skellefteå, Sweden. Department of Public Health & Clinical Medicine, Umeå University, 901 85 Umeå, Sweden.
46
Steno Diabetes Center, 2820 Gentofte, Denmark. National Institute of Public Health, Southern Denmark University, DK-1353 Odense, Denmark.
47
Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
48
German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
49
UK Clinical Research Collaboration (UKCRC) Centre of Excellence for Public Health, Queen's University Belfast, Northern Ireland, Belfast BT12 6BJ, UK.
50
University of Oxford, Oxford OX1 2JD, UK.
51
National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
52
The Institute of Cancer Research, London SM2 5NG, UK.
53
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland. Kuopio University Hospital, FL 70029 Kuopio, Finland.
54
Research Centre for Prevention and Health, Capital Region, DK-2600 Copenhagen, Denmark. Department of Clinical Experimental Research, Rigshospitalet, 2100 Glostrup, Denmark. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
55
Framingham Heart Study, Population Sciences Branch, NHLBI/National Institutes of Health (NIH), Bethesda, MD 20892, USA.
56
The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
57
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA.
58
Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
59
Centre for Epidemiology, Institute of Population Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK. University of Warwick, Coventry CV4 7AL, UK.
60
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany. Department of Medicine I, Ludwig Maximilians University Munich, 80336 Munich, Germany. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
61
Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
62
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia 30008, Spain.
63
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, 2730 Copenhagen, Denmark.
64
Lund University, 20502 Malmö, Sweden.
65
Cancer Research and Prevention Institute (ISPO), 50141 Florence, Italy.
66
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, 80131 Naples, Italy.
67
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
68
National Institute for Health and Welfare, FI-00271 Helsinki, Finland. Institute of Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014 Helsinki, Finland.
69
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
70
University of Warwick, Coventry CV4 7AL, UK. Department of Medical Oncology, Arden Cancer Centre, University Hospital Coventry and Warwickshire, West Midlands CV2 2DX, UK.
71
Public Health Directorate, 33006 Oviedo, Asturias, Spain.
72
Umeå University, 90187 Umeå, Sweden.
73
Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital, University of Turin, 10126 Torino, Italy. Center for Cancer Prevention (CPO), 10126 Torino, Italy. Human Genetics Foundation, 10126 Torino, Italy.
74
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain. Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada 18012, Spain.
75
Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre, Cardiff University, Cardiff CF24 4HQ, UK.
76
International Agency for Research on Cancer, 69372 Lyon, France.
77
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109-2029, USA.
78
Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospital, ASP Ragusa, 97100 Ragusa, Italy.
79
National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, Netherlands.
80
University Medical Center Utrecht, 3508 GA Utrecht, Netherlands.
81
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
82
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
83
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
84
Genetics, PCPS, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
85
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
86
The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden NHS Foundation Trust, Fulham and Sutton, London and Surrey SW3 6JJ, UK.
87
Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
88
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 Malmö, Sweden. Department of Public Health & Clinical Medicine, Umeå University, 901 85 Umeå, Sweden. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
89
Research Centre for Prevention and Health, DK-2600 Capital Region, Denmark. Department of Public Health, Institute of Health Science, University of Copenhagen, 1014 Copenhagen, Denmark. Faculty of Medicine, Aalborg University, 9220 Aalborg, Denmark.
90
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.
91
Department of Medicine, University of Kuopio, FI-70211 Kuopio, Finland.
92
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.
93
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455-0381, USA.
94
School of Public Health, Imperial College London, London W2 1PG, UK.
95
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.
96
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
97
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.
98
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany. Deutsches Herzzentrum München, Technische Universität München, 80636 Munich, Germany.
99
Department of Internal Medicine, BH10-462, Internal Medicine, Lausanne University Hospital (CHUV), CH-1011 Lausanne, Switzerland.
100
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.
101
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
102
Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
103
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.
104
Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
105
Genetics, PCPS, GlaxoSmithKline, Philadelphia, PA 19104, USA. dawn.m.waterworth@gsk.com robert.scott@mrc-epid.cam.ac.uk nick.wareham@mrc-epid.cam.ac.uk.

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.

PMID:
27252175
PMCID:
PMC5219001
DOI:
10.1126/scitranslmed.aad3744
[Indexed for MEDLINE]
Free PMC Article

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