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Journal Article

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

Authors

  1. Amand F. Schmidt
  2. Michael V. Holmes
  3. David Preiss
  4. Daniel I. Swerdlow
  5. Spiros Denaxas
  6. Ghazaleh Fatemifar
  7. Rupert Faraway
  8. Chris Finan
  9. Dennis Valentine
  10. Zammy Fairhurst-Hunter
  11. Fernando Pires Hartwig
  12. Bernardo Lessa Horta
  13. Elina Hypponen
  14. Christine Power
  15. Max Moldovan
  16. Erik van Iperen
  17. Kees Hovingh
  18. Ilja Demuth
  19. Kristina Norman
  20. Elisabeth Steinhagen-Thiessen
  21. Juri Demuth
  22. Lars Bertram
  23. Christina M. Lill
  24. Stefan Coassin
  25. Johann Willeit
  26. Stefan Kiechl
  27. Karin Willeit
  28. Dan Mason
  29. John Wright
  30. Richard Morris
  31. Goya Wanamethee
  32. Peter Whincup
  33. Yoav Ben-Shlomo
  34. Stela McLachlan
  35. Jackie F. Price
  36. Mika Kivimaki
  37. Catherine Welch
  38. Adelaida Sanchez-Galvez
  39. Pedro Marques-Vidal
  40. Andrew Nicolaides
  41. Andrie G. Panayiotou
  42. N. Charlotte Onland-Moret
  43. Yvonne T. van der Schouw
  44. Giuseppe Matullo
  45. Giovanni Fiorito
  46. Simonetta Guarrera
  47. Carlotta Sacerdote
  48. Nicholas J. Wareham
  49. Claudia Langenberg
  50. Robert A. Scott
  51. Jian’an Luan
  52. Martin Bobak
  53. Sofia Malyutina
  54. Andrzej Pająk
  55. Ruzena Kubinova
  56. Abdonas Tamosiunas
  57. Hynek Pikhart
  58. Niels Grarup
  59. Oluf Pedersen
  60. Torben Hansen
  61. Allan Linneberg
  62. Tine Jess
  63. Jackie Cooper
  64. Steve E. Humphries
  65. Murray Brilliant
  66. Terrie Kitchner
  67. Hakon Hakonarson
  68. David S. Carrell
  69. Catherine A. McCarty
  70. Kirchner H. Lester
  71. Eric B. Larson
  72. David R. Crosslin
  73. Mariza de Andrade
  74. Dan M. Roden
  75. Joshua C. Denny
  76. Cara Carty
  77. Stephen Hancock
  78. John Attia
  79. Elizabeth Holliday
  80. Rodney Scott
  81. Peter Schofield
  82. Martin O’Donnell
  83. Salim Yusuf
  84. Michael Chong
  85. Guillaume Pare
  86. Pim van der Harst
  87. M. Abdullah Said
  88. Ruben N. Eppinga
  89. Niek Verweij
  90. Harold Snieder
  91. Tim Christen
  92. D.O. Mook-Kanamori
  93. Stefan Gustafsson
  94. Lars Lind
  95. Erik Ingelsson
  96. Raha Pazoki
  97. Oscar Franco
  98. Albert Hofman
  99. Andre Uitterlinden
  100. Abbas Dehghan
  101. Alexander Teumer
  102. Sebastian Baumeister
  103. Marcus Dörr
  104. Markus M. Lerch
  105. Uwe Völker
  106. Henry Völzke
  107. Joey Ward
  108. Jill P. Pell
  109. Tom Meade
  110. Ingrid E. Christophersen
  111. Anke H. Maitland-van der Zee
  112. Ekaterina V. Baranova
  113. Robin Young
  114. Ian Ford
  115. Archie Campbell
  116. Sandosh Padmanabhan
  117. Michiel L. Bots
  118. Diederick E. Grobbee
  119. Philippe Froguel
  120. Dorothée Thuillier
  121. Ronan Roussel
  122. Amélie Bonnefond
  123. Bertrand Cariou
  124. Melissa Smart
  125. Yanchun Bao
  126. Meena Kumari
  127. Anubha Mahajan
  128. Jemma C. Hopewell
  129. Sudha Seshadri
  130. Caroline Dale
  131. Rui Providencia E. Costa
  132. Paul M. Ridker
  133. Daniel I. Chasman
  134. Alex P. Reiner
  135. Marylyn D. Ritchie
  136. Leslie A. Lange
  137. Alex J. Cornish
  138. Sara E. Dobbins
  139. Kari Hemminki
  140. Ben Kinnersley
  141. Marc Sanson
  142. Karim Labreche
  143. Matthias Simon
  144. Melissa Bondy
  145. Philip Law
  146. Helen Speedy
  147. James Allan
  148. Ni Li
  149. Molly Went
  150. Niels Weinhold
  151. Gareth Morgan
  152. Pieter Sonneveld
  153. Björn Nilsson
  154. Hartmut Goldschmidt
  155. Amit Sud
  156. Andreas Engert
  157. Markus Hansson
  158. Harry Hemingway
  159. Folkert W. Asselbergs
  160. Riyaz S. Patel
  161. Brendan J. Keating
  162. Naveed Sattar
  163. Richard Houlston
  164. Juan P. Casas
  165. Aroon D. Hingorani

Publication date

29 Oct 2019

Summary

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.

Published in

BMC Cardiovascular Disorders

Volume

19:240

DOI

https://doi.org/10.1186/s12872-019-1187-z

ISSN

16

Subjects

Health, Biology, and Genetics

Notes

Open Access; This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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