Article open access publication

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

Science Translational Medicine, American Association for the Advancement of Science (AAAS), ISSN 1946-6234

Volume 8, 341, 2016

DOI:10.1126/scitranslmed.aad3744, Dimensions: pub.1062688962, PMC: PMC5219001, PMID: 27252175,

Authors

Li, Li (4)
Willems, Sara M (1) (11)
Wessel, Jennifer (12) (13)
Arriola, Larraitz (16) (17) (18)
Balkau, Beverley (21) (22)
Barroso, Inês (2) (3)
Boerwinkle, Eric (28) (29)
Ford, Ian (32)
Kee, Frank (48)
Linneberg, Allan (6) (53) (54)
Morris, Andrew P. (56) (57)
Muir, Kenneth (35) (58)
Müller-Nurasyid, Martina (59) (60) (61)
Navarro, Carmen (18) (63)
Peloso, Gina M. (67) (68)
Perola, Markus (50) (69)
Peters, Annette (60) (61)
Sacerdote, Carlotta (72) (73) (74)
Eeles, Rosalind A. (51) (83)
Franks, Paul W. (9) (43) (85)
Jørgensen, Torben (6) (54) (86)
Kooner, Jaspal (87) (88) (89)
McCarthy, Mark I. (49) (57)
Samani, Nilesh J. (93) (94)
O'Rahilly, Stephen P (3) (97) (98)
Danesh, John (2) (3)
Kathiresan, Sekar (67) (68)
Meigs, James B (68) (85)

Affiliations

Organisations

  1. (1) Institute of Metabolic Science, grid.470900.a
  2. (2) Wellcome Sanger Institute, grid.10306.34
  3. (3) University of Cambridge, grid.5335.0
  4. (4) GlaxoSmithKline (United States), grid.418019.5
  5. (5) Brigham and Women's Hospital, grid.62560.37
  6. (6) University of Copenhagen, grid.5254.6, KU
  7. (7) University of Eastern Finland, grid.9668.1
  8. (8) Boston University, grid.189504.1
  9. (9) Lund University, grid.4514.4
  10. (10) University of Exeter, grid.8391.3
  11. (11) Erasmus University Medical Center, grid.5645.2
  12. (12) Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN 46202, USA
  13. (13) Indiana University – Purdue University Indianapolis, grid.257413.6
  14. (14) Johns Hopkins University, grid.21107.35
  15. (15) Centre Hospitalier Regional et Universitaire de Lille, grid.410463.4
  16. (16) Biodonostia, grid.432380.e
  17. (17) Public Health Division of Gipuzkoa, San Sebastian 20013, Spain
  18. (18) Institute of Health Carlos III, grid.413448.e
  19. (19) University of Strasbourg, grid.11843.3f
  20. (20) University College London, grid.83440.3b
  21. (21) Centre for research in epidemiology and population health, grid.463845.8
  22. (22) University of Paris-Sud, grid.5842.b
  23. (23) Instituto de Salud Pública de Navarra, grid.419126.9
  24. (24) University of Washington, grid.34477.33
  25. (25) University Medical Center Hamburg-Eppendorf, grid.13648.38
  26. (26) University of Michigan, grid.214458.e
  27. (27) German Institute of Human Nutrition, grid.418213.d
  28. (28) Baylor College of Medicine, grid.39382.33
  29. (29) The University of Texas Health Science Center at Houston, grid.267308.8
  30. (30) Washington University in St. Louis, grid.4367.6
  31. (31) Cancer Research UK Clinical Trials Unit, grid.470294.c
  32. (32) University of Glasgow, grid.8756.c
  33. (33) National Heart Lung and Blood Institute, grid.279885.9
  34. (34) Uppsala University, grid.8993.b
  35. (35) University of Warwick, grid.7372.1
  36. (36) Istituto di Fisiologia Clinica, grid.418529.3
  37. (37) Department of Epidemiology, UMR 1027, INSERM, Centre Hospitalier Universitaire (CHU) de Toulouse, 31000 Toulouse, France
  38. (38) Istituto Neurologico Mediterraneo, grid.419543.e
  39. (39) University of Insubria, grid.18147.3b
  40. (40) Catalan Institute of Oncology, grid.418701.b
  41. (41) Epidemiology and Prevention Unit, 20133 Milan, Italy
  42. (42) Research Unit, 931 41 Skellefteå, Sweden
  43. (43) Umeå University, grid.12650.30
  44. (44) Steno Diabetes Center, grid.419658.7, Capital Region
  45. (45) University of Southern Denmark, grid.10825.3e, SDU
  46. (46) Leiden University Medical Center, grid.10419.3d
  47. (47) German Cancer Research Center, grid.7497.d
  48. (48) Queen's University Belfast, grid.4777.3
  49. (49) University of Oxford, grid.4991.5
  50. (50) National Institute for Health and Welfare, grid.14758.3f
  51. (51) Institute of Cancer Research, grid.18886.3f
  52. (52) Kuopio University Hospital, grid.410705.7
  53. (53) Rigshospitalet, grid.475435.4, Capital Region
  54. (54) Research Centre for Prevention and Health, grid.415878.7, Capital Region
  55. (55) University of North Carolina at Chapel Hill, grid.10698.36
  56. (56) University of Liverpool, grid.10025.36
  57. (57) Wellcome Centre for Human Genetics, grid.270683.8
  58. (58) University of Manchester, grid.5379.8
  59. (59) Ludwig Maximilian University of Munich, grid.5252.0
  60. (60) Helmholtz Zentrum München, grid.4567.0
  61. (61) German Centre for Cardiovascular Research, grid.452396.f
  62. (62) Queen Mary University of London, grid.4868.2
  63. (63) Instituto Murciano de Investigación Biosanitaria, grid.452553.0
  64. (64) Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, 2730 Copenhagen, Denmark
  65. (65) Istituto per lo Studio e la Prevenzione Oncologica, grid.417623.5
  66. (66) University of Naples Federico II, grid.4691.a
  67. (67) Broad Institute, grid.66859.34
  68. (68) Massachusetts General Hospital, grid.32224.35
  69. (69) University of Helsinki, grid.7737.4
  70. (70) University Hospital Coventry, grid.412570.5
  71. (71) Public Health Directorate, 33006 Oviedo, Asturias, Spain
  72. (72) Center for Cancer Prevention (CPO), 10126 Torino, Italy
  73. (73) Human Genetics Foundation, grid.428948.b
  74. (74) University of Turin, grid.7605.4
  75. (75) Andalusian School of Public Health, grid.413740.5
  76. (76) Cardiff University, grid.5600.3
  77. (77) International Agency For Research On Cancer, grid.17703.32
  78. (78) Cancer Registry and Histopathology Unit, “Civic–M.P. Arezzo” Hospital, ASP Ragusa, 97100 Ragusa, Italy
  79. (79) National Institute for Public Health and the Environment, grid.31147.30
  80. (80) University Medical Center Utrecht, grid.7692.a
  81. (81) Newcastle University, grid.1006.7
  82. (82) National Institute of Arthritis and Musculoskeletal and Skin Diseases, grid.420086.8
  83. (83) Royal Marsden NHS Foundation Trust, grid.5072.0
  84. (84) University of Lübeck, grid.4562.5
  85. (85) Harvard University, grid.38142.3c
  86. (86) Aalborg University, grid.5117.2, AAU
  87. (87) Ealing Hospital NHS Trust, grid.412922.e
  88. (88) Imperial College Healthcare NHS Trust, grid.417895.6
  89. (89) Imperial College London, grid.7445.2
  90. (90) University of Minnesota, grid.17635.36
  91. (91) Harbor–UCLA Medical Center, grid.239844.0
  92. (92) University of Pennsylvania, grid.25879.31
  93. (93) Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK
  94. (94) Glenfield Hospital, grid.412925.9
  95. (95) Technical University of Munich, grid.6936.a
  96. (96) University Hospital of Lausanne, grid.8515.9
  97. (97) MRC Metabolic Diseases Unit, Cambridge CB2 0QQ, UK
  98. (98) NIHR Cambridge Dementia Biomedical Research Unit, grid.454369.9
  99. (99) Cedars-Sinai Medical Center, grid.50956.3f

Description

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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NORA University Profiles

University of Copenhagen

University of Southern Denmark

Aalborg University

Dimensions Citation Indicators

Times Cited: 59

Field Citation Ratio (FCR): 14.5

Relative Citation ratio (RCR): 2.81

Open Access Info

Green, Accepted