A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease-Reference-Cited by-同舟云学术

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

Published:2016-06 Issue:341 Volume:8 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Scott Robert A.¹,Freitag Daniel F.²³,Li Li⁴,Chu Audrey Y.⁵,Surendran Praveen²,Young Robin²,Grarup Niels⁶,Stancáková Alena⁷,Chen Yuning⁸,Varga Tibor V.⁹,Yaghootkar Hanieh¹⁰,Luan Jian’an¹,Zhao Jing Hua¹,Willems Sara M.¹¹¹,Wessel Jennifer¹²¹³,Wang Shuai⁸,Maruthur Nisa¹⁴¹⁵¹⁶,Michailidou Kyriaki¹⁷,Pirie Ailith¹⁷,van der Lee Sven J.¹⁸,Gillson Christopher¹,Al Olama Ali Amin¹⁷,Amouyel Philippe¹⁹,Arriola Larraitz²⁰²¹²²,Arveiler Dominique²³,Aviles-Olmos Iciar²⁴,Balkau Beverley²⁵²⁶,Barricarte Aurelio²²²⁷,Barroso Inês³²⁸,Garcia Sara Benlloch¹⁷,Bis Joshua C.²⁹,Blankenberg Stefan³⁰,Boehnke Michael³¹,Boeing Heiner³²,Boerwinkle Eric³³³⁴,Borecki Ingrid B.³⁵,Bork-Jensen Jette⁶,Bowden Sarah³⁶,Caldas Carlos³⁷,Caslake Muriel³⁸,Cupples L. Adrienne⁸³⁹,Cruchaga Carlos⁴⁰,Czajkowski Jacek⁴¹,den Hoed Marcel⁴²,Dunn Janet A.⁴³,Earl Helena M.⁴⁴,Ehret Georg B.⁴⁵,Ferrannini Ele⁴⁶,Ferrieres Jean⁴⁷,Foltynie Thomas²⁴,Ford Ian³⁸,Forouhi Nita G.¹,Gianfagna Francesco⁴⁸⁴⁹,Gonzalez Carlos⁵⁰,Grioni Sara⁵¹,Hiller Louise⁴³,Jansson Jan-Håkan⁵²⁵³,Jørgensen Marit E.⁵⁴⁵⁵,Jukema J. Wouter⁵⁶,Kaaks Rudolf⁵⁷,Kee Frank⁵⁸,Kerrison Nicola D.¹,Key Timothy J.⁵⁹,Kontto Jukka⁶⁰,Kote-Jarai Zsofia⁶¹,Kraja Aldi T.⁴¹,Kuulasmaa Kari⁶⁰,Kuusisto Johanna⁷⁶²,Linneberg Allan⁶³⁶⁴⁶⁵,Liu Chunyu⁶⁶,Marenne Gaëlle³,Mohlke Karen L.⁶⁷,Morris Andrew P.⁶⁸⁶⁹,Muir Kenneth⁷⁰⁷¹,Müller-Nurasyid Martina⁷²⁷³⁷⁴,Munroe Patricia B.⁷⁵,Navarro Carmen²²⁷⁶,Nielsen Sune F.⁷⁷,Nilsson Peter M.⁷⁸,Nordestgaard Børge G.⁷⁷,Packard Chris J.³⁸,Palli Domenico⁷⁹,Panico Salvatore⁸⁰,Peloso Gina M.⁸¹⁸²⁸³,Perola Markus⁶⁰⁸⁴,Peters Annette⁷⁴⁸⁵,Poole Christopher J.⁷¹⁸⁶,Quirós J. Ramón⁸⁷,Rolandsson Olov⁸⁸,Sacerdote Carlotta⁸⁹⁹⁰⁹¹,Salomaa Veikko⁶⁰,Sánchez María-José²²⁹²,Sattar Naveed³⁸,Sharp Stephen J.¹,Sims Rebecca⁹³,Slimani Nadia⁹⁴,Smith Jennifer A.⁹⁵,Thompson Deborah J.¹⁷,Trompet Stella⁵⁶,Tumino Rosario⁹⁶,van der A Daphne L.⁹⁷,van der Schouw Yvonne T.⁹⁸,Virtamo Jarmo⁶⁰,Walker Mark⁹⁹,Walter Klaudia³,Abraham Jean E.¹⁰⁰,Amundadottir Laufey T.¹⁰¹,Aponte Jennifer L.¹⁰²,Butterworth Adam S.²,Dupuis Josée⁸,Easton Douglas F.¹⁷¹⁰⁰,Eeles Rosalind A.⁶¹¹⁰³,Erdmann Jeanette¹⁰⁴,Franks Paul W.⁹⁵³¹⁰⁵,Frayling Timothy M.¹⁰,Hansen Torben⁶,Howson Joanna M. M.²,Jørgensen Torben¹⁰⁶¹⁰⁷¹⁰⁸,Kooner Jaspal¹⁰⁹¹¹⁰¹¹¹,Laakso Markku¹¹²,Langenberg Claudia¹,McCarthy Mark I.⁶⁹¹¹³,Pankow James S.¹¹⁴,Pedersen Oluf⁶,Riboli Elio¹¹⁵,Rotter Jerome I.¹¹⁶,Saleheen Danish¹¹⁷,Samani Nilesh J.¹¹⁸¹¹⁹,Schunkert Heribert⁷⁴¹²⁰,Vollenweider Peter¹²¹,O’Rahilly Stephen²⁸¹²²¹²³,Deloukas Panos¹²⁴,Danesh John²³,Goodarzi Mark O.¹²⁵,Kathiresan Sekar⁸²¹²⁶¹²⁷,Meigs James B.¹²⁸¹²⁹,Ehm Margaret G.¹⁰²,Wareham Nicholas J.¹,Waterworth Dawn M.¹³⁰, , , , , , , , , , ,

Affiliation:

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.

2. Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.

3. The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.

4. Statistical Genetics, Projects, Clinical Platforms, and Sciences (PCPS), GlaxoSmithKline, Research Triangle Park, NC 27709, USA.

5. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.

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. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3000 CE Rotterdam, Netherlands.

12. Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN 46202, USA.

13. 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.

15. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD 21205, USA.

16. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.

17. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.

18. Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands.

19. University of Lille, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, UMR 1167, RID-AGE, F-59000 Lille, France.

20. Public Health Division of Gipuzkoa, San Sebastian 20013, Spain.

21. Instituto BIO-Donostia, Basque Government, San Sebastian 20014, Spain.

22. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain.

23. Department of Epidemiology and Public Health (EA3430), University of Strasbourg, 67085 Strasbourg, France.

24. Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.

25. INSERM, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), 94807 Villejuif, France.

26. Univeristy of Paris-Sud, F-94805 Villejuif, France.

27. Navarre Public Health Institute (ISPN), Pamplona 31003, Spain.

28. University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.

29. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.

30. Department of General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany.

31. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109–2029, USA.

32. German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.

33. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77025, USA.

34. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

35. Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63108, USA.

36. Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

37. Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK.

38. University of Glasgow, Glasgow G12 8QQ, UK.

39. Framingham Heart Study, National Heart, Lung, and Blood Institute (NHLBI), Framingham, MA 01702–5827, USA.

40. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

41. 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.

42. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, SE-752 37 Uppsala, Sweden.

43. Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.

44. 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.

45. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

46. Consiglio Nazionale delle Ricerche (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy.

47. Department of Epidemiology, UMR 1027, INSERM, Centre Hospitalier Universitaire (CHU) de Toulouse, 31000 Toulouse, France.

48. Department of Clinical and Experimental Medicine, Research Centre in Epidemiology and Preventive Medicine, University of Insubria, 21100 Varese, Italy.

49. Department of Epidemiology and Prevention, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.

50. Catalan Institute of Oncology (ICO), Barcelona 08908, Spain.

51. Epidemiology and Prevention Unit, 20133 Milan, Italy.

52. Research Unit, 931 41 Skellefteå, Sweden.

53. Department of Public Health & Clinical Medicine, Umeå University, 901 85 Umeå, Sweden.

54. Steno Diabetes Center, 2820 Gentofte, Denmark.

55. National Institute of Public Health, Southern Denmark University, DK-1353 Odense, Denmark.

56. Leiden University Medical Center, 2333 ZA Leiden, Netherlands.

57. German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.

58. UK Clinical Research Collaboration (UKCRC) Centre of Excellence for Public Health, Queen’s University Belfast, Northern Ireland, Belfast BT12 6BJ, UK.

59. University of Oxford, Oxford OX1 2JD, UK.

60. National Institute for Health and Welfare, FI-00271 Helsinki, Finland.

61. The Institute of Cancer Research, London SM2 5NG, UK.

62. Kuopio University Hospital, FL 70029 Kuopio, Finland.

63. Research Centre for Prevention and Health, Capital Region, DK-2600 Copenhagen, Denmark.

64. Department of Clinical Experimental Research, Rigshospitalet, 2100 Glostrup, Denmark.

65. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

66. Framingham Heart Study, Population Sciences Branch, NHLBI/National Institutes of Health (NIH), Bethesda, MD 20892, USA.

67. Department of Genetics, University of North Carolina, Chapel Hill, NC 27599–7264, USA.

68. Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.

69. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

70. Centre for Epidemiology, Institute of Population Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

71. University of Warwick, Coventry CV4 7AL, UK.

72. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.

73. Department of Medicine I, Ludwig Maximilians University Munich, 80336 Munich, Germany.

74. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.

75. Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.

76. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia 30008, Spain.

77. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, 2730 Copenhagen, Denmark.

78. Lund University, 20502 Malmö, Sweden.

79. Cancer Research and Prevention Institute (ISPO), 50141 Florence, Italy.

80. Dipartimento di Medicina Clinica e Chirurgia, Federico II University, 80131 Naples, Italy.

81. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.

82. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.

83. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.

84. Institute of Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014 Helsinki, Finland.

85. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.

86. Department of Medical Oncology, Arden Cancer Centre, University Hospital Coventry and Warwickshire, West Midlands CV2 2DX, UK.

87. Public Health Directorate, 33006 Oviedo, Asturias, Spain.

88. Umeå University, 90187 Umeå, Sweden.

89. Unit of Cancer Epidemiology, Citta’ della Salute e della Scienza Hospital, University of Turin, 10126 Torino, Italy.

90. Center for Cancer Prevention (CPO), 10126 Torino, Italy.

91. Human Genetics Foundation, 10126 Torino, Italy.

92. Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada 18012, Spain.

93. Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre, Cardiff University, Cardiff CF24 4HQ, UK.

94. International Agency for Research on Cancer, 69372 Lyon, France.

95. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109–2029, USA.

96. Cancer Registry and Histopathology Unit, “Civic–M.P. Arezzo” Hospital, ASP Ragusa, 97100 Ragusa, Italy.

97. National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, Netherlands.

98. University Medical Center Utrecht, 3508 GA Utrecht, Netherlands.

99. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

100. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.

101. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

102. Genetics, PCPS, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.

103. Royal Marsden NHS Foundation Trust, Fulham and Sutton, London and Surrey SW3 6JJ, UK.

104. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.

105. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.

106. Research Centre for Prevention and Health, DK-2600 Capital Region, Denmark.

107. Department of Public Health, Institute of Health Science, University of Copenhagen, 1014 Copenhagen, Denmark.

108. Faculty of Medicine, Aalborg University, 9220 Aalborg, Denmark.

109. National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.

110. Imperial College Healthcare NHS Trust, London W2 1NY, UK.

111. Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK.

112. Department of Medicine, University of Kuopio, FI-70211 Kuopio, Finland.

113. Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, UK.

114. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455–0381, USA.

115. School of Public Health, Imperial College London, London W2 1PG, UK.

116. 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.

117. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.

118. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.

119. National Institute for Health Research, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.

120. Deutsches Herzzentrum München, Technische Universität München, 80636 Munich, Germany.

121. Department of Internal Medicine, BH10-462, Internal Medicine, Lausanne University Hospital (CHUV), CH-1011 Lausanne, Switzerland.

122. MRC Metabolic Diseases Unit, Cambridge CB2 0QQ, UK.

123. National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.

124. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.

125. Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

126. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

127. Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

128. Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

129. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

130. Genetics, PCPS, GlaxoSmithKline, Philadelphia, PA 19104, USA.

Abstract

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.

Funder

Medical Research Council

Cohorts for Health and Aging Research in Genetic Epidemiology

Alzheimer's Disease Genetics Consortium

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Reference115 articles.

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2. Validating therapeutic targets through human genetics

3. The support of human genetic evidence for approved drug indications

4. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

5. Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease

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