PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Publication type

Journal Article


  1. Amand F. Schmidt
  2. Daniel I. Swerdlow
  3. Michael V. Holmes
  4. Riyaz S. Patel
  5. Zammy Fairhurst-Hunter
  6. Donald M. Lyall
  7. Fernando Pires Hartwig
  8. Bernardo Lessa Horta
  9. Elina Hyppönen
  10. Christine Power
  11. Max Moldovan
  12. Erik van Iperen
  13. G. Kees Hovingh
  14. Ilja Demuth
  15. Kristina Norman
  16. Elisabeth Steinhagen-Thiessen
  17. Juri Demuth
  18. Lars Bertram
  19. Tian Liu
  20. Stefan Coassin
  21. Johann Willeit
  22. Stefan Kiechl
  23. Karin Willeit
  24. Dan Mason
  25. John Wright
  26. Richard Morris
  27. Goya Wanamethee
  28. Peter Whincup
  29. Yoav Ben-Shlomo
  30. Stela McLachlan
  31. Jackie F. Price
  32. Mika Kivimaki
  33. Catherine Welch
  34. Adelaida Sanchez-Galvez
  35. Pedro Marques-Vidal
  36. Andrew Nicolaides
  37. Andrie G. Panayiotou
  38. N. Charlotte Onland-Moret
  39. Yvonne T. van der Schouw
  40. Giuseppe Matullo
  41. Giovanni Fiorito
  42. Simonetta Guarrera
  43. Carlotta Sacerdote
  44. Nicholas J. Wareham
  45. Claudia Langenberg
  46. Robert Scott
  47. Jian'an Luan
  48. Martin Bobak
  49. Sofia Malyutina
  50. Andrzej Pająk
  51. Ruzena Kubinova
  52. Abdonas Tamosiunas
  53. Hynek Pikhart
  54. Lise Lotte Nystrup Husemoen
  55. Niels Grarup
  56. Oluf Pedersen
  57. Torben Hansen
  58. Allan Linneberg
  59. Kenneth Starup Simonsen
  60. Jackie Cooper
  61. Steve E. Humphries
  62. Murray Brilliant
  63. Terrie Kitchner
  64. Hakon Hakonarson
  65. David S. Carrell
  66. Catherine A. McCarty
  67. H. Lester Kirchner
  68. Eric B. Larson
  69. David R. Crosslin
  70. Mariza de Andrade
  71. Dan M. Roden
  72. Joshua C. Denny
  73. Cara Carty
  74. Stephen Hancock
  75. John Attia
  76. Elizabeth Holliday
  77. Martin O. Donnell
  78. Salim Yusuf
  79. Michael Chong
  80. Guillaume Pare
  81. Pim van der Harst
  82. M. Abdullah Said
  83. Ruben N. Eppinga
  84. Niek Verweij
  85. Harold Snieder
  86. Tim Christen
  87. Dennis O. Mook-Kanamori
  88. Stefan Gustafsson
  89. Lars Lind
  90. Erik Ingelsson
  91. Raha Pazoki
  92. Oscar Franco
  93. Albert Hofman
  94. Andre Uitterlinden
  95. Abbas Dehghan
  96. Alexander Teumer
  97. Sebastian Baumeister
  98. Marcus Dörr
  99. Markus M. Lerch
  100. Uwe Völker
  101. Henry Völzke
  102. Joey Ward
  103. Jill P. Pell
  104. Daniel J. Smith
  105. Tom Meade
  106. Anke H. Maitland-van der Zee
  107. Ekaterina V. Baranova
  108. Robin Young
  109. Ian Ford
  110. Archie Campbell
  111. Sandosh Padmanabhan
  112. Michiel L. Bots
  113. Diederick E. Grobbee
  114. Philippe Froguel
  115. Dorothée Thuillier
  116. Beverley Balkau
  117. Amélie Bonnefond
  118. Bertrand Cariou
  119. Melissa Smart
  120. Yanchun Bao
  121. Meena Kumari
  122. Anubha Mahajan
  123. Paul M. Ridker
  124. Daniel I. Chasman
  125. Alex P. Reiner
  126. Leslie A. Lange
  127. Marylyn D. Ritchie
  128. Folkert W. Asselbergs
  129. Juan-Pablo Casas
  130. Brendan J. Keating
  131. David Preiss
  132. Aroon D. Hingorani
  133. Naveed Sattar

Publication date

February 15, 2017


Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30). Interpretation: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. Funding: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Published in

The Lancet Diabetes and Endocrinology

Volume and page numbers

Volume: 5 , p.97 -105







Open Access

Open Access funded by British Heart Foundation

Under a Creative Commons license



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