Article open access publication

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

BMC Cardiovascular Disorders, Springer Nature, ISSN 1471-2261

Volume 19, 1, 2019

DOI:10.1186/s12872-019-1187-z, Dimensions: pub.1122170724, PMC: PMC6820948, PMID: 31664920,

Authors

Schmidt, Amand F. * (1) (2)
Denaxas, Spiros (2) (5)
Hypponen, Elina (2) (7) (8)
van Iperen, Erik (9) (10)
Demuth, Ilja (11) (12)
Norman, Kristina (11) (13) (14)
Bertram, Lars (16) (17)
Lill, Christina M. (4) (17) (18)
Willeit, Karin (19) (20)
Mason, Dan (21)
Matullo, Giuseppe (28) (29)
Fiorito, Giovanni (28) (29)
Malyutina, Sofia (32) (33)
Linneberg, Allan (37) (38)
Jess, Tine (38)
Attia, John (48) (49)
van der Harst, Pim (9) (10) (52)
Lind, Lars (54) (55)
Ingelsson, Erik (54) (55)
Pazoki, Raha (4) (56)
Teumer, Alexander (57) (58)
Dörr, Marcus (57) (58)
Völker, Uwe (57) (58)
Völzke, Henry (57) (58)
Ward, Joey (60)
Meade, Tom (61)
Ford, Ian (60)
Roussel, Ronan (66) (67) (68)
Hemminki, Kari (78) (79)
Sanson, Marc (80) (81)
Labreche, Karim (80) (81)
Li, Ni (77)
Sud, Amit (77)
Hansson, Markus (86) (89)
Hemingway, Harry (2) (90)
Asselbergs, Folkert W. (1) (2) (91)
Patel, Riyaz S. (2) (92)

* Corresponding author

Affiliations

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  1. (1) Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  2. (2) University College London, grid.83440.3b
  3. (3) University of Oxford, grid.4991.5
  4. (4) Imperial College London, grid.7445.2
  5. (5) The Alan Turing Institute, British Library, 96 Euston Rd, NW1 2DB, London, UK
  6. (6) Federal University of Pelotas, grid.411221.5
  7. (7) University of South Australia, grid.1026.5
  8. (8) South Australian Health and Medical Research Institute, grid.430453.5
  9. (9) Academic Medical Center, grid.5650.6
  10. (10) Netherlands Heart Institute, grid.411737.7
  11. (11) Charité, grid.6363.0
  12. (12) Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Lipid Clinic at the Interdisciplinary Metabolism Center, Berlin, Germany
  13. (13) German Institute of Human Nutrition, grid.418213.d
  14. (14) University of Potsdam, grid.11348.3f
  15. (15) E.CA Economics GmbH, Berlin, Germany
  16. (16) Center for Lifespan Changes in Brain and Cognition (LCBC), Dept. Psychology, University of Oslo, Oslo, Norway
  17. (17) University of Lübeck, grid.4562.5
  18. (18) University of Bonn, grid.10388.32
  19. (19) Innsbruck Medical University, grid.5361.1
  20. (20) Department of Neurology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
  21. (21) Bradford Royal Infirmary, grid.418447.a
  22. (22) University of Bristol, grid.5337.2
  23. (23) University of Edinburgh, grid.4305.2
  24. (24) University Hospital of Lausanne, grid.8515.9
  25. (25) University of Nicosia, grid.413056.5
  26. (26) Cyprus University of Technology, grid.15810.3d
  27. (27) Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  28. (28) Italian Institute for Genomic Medicine (IIGM), Turin, Italy
  29. (29) University of Turin, grid.7605.4
  30. (30) Unit of Cancer Epidemiology, Città della Salute e della Scienza University Hospital and Center for Cancer Prevention (CPO), Turin, Italy
  31. (31) Institute of Metabolic Science, grid.470900.a
  32. (32) Novosibirsk State Medical University, grid.445341.3
  33. (33) Siberian Branch of the Russian Academy of Sciences, grid.415877.8
  34. (34) Jagiellonian University, grid.5522.0
  35. (35) National Institute of Public Health, grid.425485.a
  36. (36) Lithuanian University of Health Sciences, grid.45083.3a
  37. (37) University of Copenhagen, grid.5254.6, KU
  38. (38) Bispebjerg Hospital, grid.411702.1, Capital Region
  39. (39) Center for Human Genetics, grid.492411.b
  40. (40) Children's Hospital of Philadelphia, grid.239552.a
  41. (41) Kaiser Permanente Washington Health Research Institute, grid.488833.c
  42. (42) University of Minnesota, grid.17635.36
  43. (43) Geisinger, Danville, USA
  44. (44) University of Washington, grid.34477.33
  45. (45) Mayo Clinic, grid.66875.3a
  46. (46) Vanderbilt University, grid.152326.1
  47. (47) Women's Health Initiative, grid.453840.e
  48. (48) University of Newcastle Australia, grid.266842.c
  49. (49) Hunter Medical Research Institute, grid.413648.c
  50. (50) Hunter New England Health, grid.3006.5
  51. (51) Population Health Research Institute, grid.415102.3
  52. (52) University Medical Center Groningen, grid.4494.d
  53. (53) Leiden University Medical Center, grid.10419.3d
  54. (54) Uppsala University, grid.8993.b
  55. (55) Stanford University, grid.168010.e
  56. (56) Erasmus University Medical Center, grid.5645.2
  57. (57) University of Greifswald, grid.5603.0
  58. (58) German Centre for Cardiovascular Research, grid.452396.f
  59. (59) Ludwig Maximilian University of Munich, grid.5252.0
  60. (60) University of Glasgow, grid.8756.c
  61. (61) London School of Hygiene & Tropical Medicine, grid.8991.9
  62. (62) Bærum sykehus, grid.414168.e
  63. (63) Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
  64. (64) Utrecht University, grid.5477.1
  65. (65) Integrated Genomics and Metabolic Diseases Modeling, grid.463858.4
  66. (66) Assistance Publique -Hopitaux De Paris, grid.50550.35
  67. (67) Centre de Recherche des Cordeliers, grid.417925.c
  68. (68) Paris Diderot University, grid.7452.4
  69. (69) Centre Hospitalier Universitaire de Nantes, grid.277151.7
  70. (70) University of Essex, grid.8356.8
  71. (71) Wellcome Centre for Human Genetics, grid.270683.8
  72. (72) Boston University School of Medicine, grid.475010.7
  73. (73) Brigham and Women's Hospital, grid.62560.37
  74. (74) UWash, Seattle, USA
  75. (75) Pennsylvania State University, grid.29857.31
  76. (76) University of Colorado Denver, grid.241116.1
  77. (77) Institute of Cancer Research, grid.18886.3f
  78. (78) Div. Molecular Genetic Epidemiology German Cancer Research Center, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
  79. (79) German Cancer Research Center, grid.7497.d
  80. (80) Institut du Cerveau et de la Moelle Épinière, grid.425274.2
  81. (81) Sorbonne University, grid.462844.8
  82. (82) Department of Neurosurgery, Bethel Clinic, Kantensiek 11, 33617, Bielefeld, Germany
  83. (83) Baylor College of Medicine, grid.39382.33
  84. (84) Newcastle University, grid.1006.7
  85. (85) University of Arkansas for Medical Sciences, grid.241054.6
  86. (86) Lund University, grid.4514.4
  87. (87) University Hospital Heidelberg, grid.5253.1
  88. (88) University Hospital Cologne, grid.411097.a
  89. (89) Skåne University Hospital, grid.411843.b
  90. (90) UCL Biomedical Research Centre, grid.485385.7
  91. (91) Health Data Research UK, grid.507332.0
  92. (92) St Bartholomew's Hospital, grid.416353.6
  93. (93) University of Pennsylvania, grid.25879.31
  94. (94) VA Boston Healthcare System, grid.410370.1

Description

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

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