Article open access publication

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

The Lancet Diabetes & Endocrinology, Elsevier, ISSN 2213-8587

Volume 5, 2, 2017

DOI:10.1016/s2213-8587(16)30396-5, Dimensions: pub.1037967448, PMC: PMC5266795, PMID: 27908689,

Authors

Patel, Riyaz S (1) (4)
Hyppönen, Elina (1) (8) (9)
Moldovan, Max (9) (10)
van Iperen, Erik (11) (12)
Bertram, Lars (2) (15)
Liu, Tian (16) (17)
Mason, Dan (19)
Matullo, Giuseppe (26) (27)
Fiorito, Giovanni (26) (27)
Linneberg, Allan (36) (37) (38)
van der Harst, Pim (12) (49) (50)
Lind, Lars (53)
Ingelsson, Erik (53) (54)
Dehghan, Abbas (2) (55)
Teumer, Alexander (56) (57)
Dörr, Marcus (56) (57)
Völker, Uwe (56) (57)
Völzke, Henry (56) (57)
Meade, Tom (59)
Ford, Ian (6)
Ritchie, Marylyn D (68) (69)
Asselbergs, Folkert W (1) (12) (25)

* Corresponding author

Affiliations

Organisations

  1. (1) University College London, grid.83440.3b
  2. (2) Imperial College London, grid.7445.2
  3. (3) University of Oxford, grid.4991.5
  4. (4) St Bartholomew's Hospital, grid.416353.6
  5. (5) Wellcome Centre for Human Genetics, grid.270683.8
  6. (6) University of Glasgow, grid.8756.c
  7. (7) Federal University of Pelotas, grid.411221.5
  8. (8) South Australian Health and Medical Research Institute, grid.430453.5
  9. (9) University of South Australia, grid.1026.5
  10. (10) South Australian Health, grid.437961.e
  11. (11) Academic Medical Center, grid.5650.6
  12. (12) Netherlands Heart Institute, grid.411737.7
  13. (13) Charité, grid.6363.0
  14. (14) E.CA Economics GmbH, Berlin, Germany
  15. (15) University of Lübeck, grid.4562.5
  16. (16) Max Planck Institute for Human Development, grid.419526.d
  17. (17) Max Planck Institute for Molecular Genetics, grid.419538.2
  18. (18) Innsbruck Medical University, grid.5361.1
  19. (19) Bradford Royal Infirmary, grid.418447.a
  20. (20) University of Bristol, grid.5337.2
  21. (21) University of Edinburgh, grid.4305.2
  22. (22) University Hospital of Lausanne, grid.8515.9
  23. (23) University of Nicosia, grid.413056.5
  24. (24) Cyprus University of Technology, grid.15810.3d
  25. (25) University Medical Center Utrecht, grid.7692.a
  26. (26) Human Genetics Foundation, grid.428948.b
  27. (27) University of Turin, grid.7605.4
  28. (28) Azienda Ospedaliero Universitaria San Giovanni Battista, grid.413005.3
  29. (29) Piedmont Reference Center for Epidemiology and Cancer Prevention, grid.420240.0
  30. (30) Institute of Metabolic Science, grid.470900.a
  31. (31) Novosibirsk State Medical University, grid.445341.3
  32. (32) Siberian Branch of the Russian Academy of Sciences, grid.415877.8
  33. (33) Jagiellonian University, grid.5522.0
  34. (34) National Institute of Public Health, grid.425485.a
  35. (35) Lithuanian University of Health Sciences, grid.45083.3a
  36. (36) Research Centre for Prevention and Health, Capital Region of Denmark, Denmark
  37. (37) University of Copenhagen, grid.5254.6, KU
  38. (38) Rigshospitalet, grid.475435.4, Capital Region
  39. (39) Marshfield Clinic, grid.280718.4
  40. (40) Children's Hospital of Philadelphia, grid.239552.a
  41. (41) Group Health Cooperative, grid.280243.f
  42. (42) Essentia Health, grid.428919.f
  43. (43) Geisinger Medical Center, grid.415341.6
  44. (44) Mayo Clinic, grid.66875.3a
  45. (45) Vanderbilt University, grid.152326.1
  46. (46) George Washington University, grid.253615.6
  47. (47) University of Newcastle Australia, grid.266842.c
  48. (48) Population Health Research Institute, grid.415102.3
  49. (49) Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
  50. (50) Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
  51. (51) Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
  52. (52) Leiden University Medical Center, grid.10419.3d
  53. (53) Uppsala University, grid.8993.b
  54. (54) Stanford University, grid.168010.e
  55. (55) Erasmus University Medical Center, grid.5645.2
  56. (56) University of Greifswald, grid.5603.0
  57. (57) German Centre for Cardiovascular Research, grid.452396.f
  58. (58) University of Regensburg, grid.7727.5
  59. (59) London School of Hygiene & Tropical Medicine, grid.8991.9
  60. (60) Utrecht University, grid.5477.1
  61. (61) Integrated Genomics and Metabolic Diseases Modeling, grid.463858.4
  62. (62) Centre for research in epidemiology and population health, grid.463845.8
  63. (63) Centre Hospitalier Universitaire de Nantes, grid.277151.7
  64. (64) University of Essex, grid.8356.8
  65. (65) Brigham and Women's Hospital, grid.62560.37
  66. (66) Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA
  67. (67) University of Colorado Denver, grid.241116.1
  68. (68) Geisinger Health System, grid.280776.c
  69. (69) Pennsylvania State University, grid.29857.31
  70. (70) University of Pennsylvania, grid.25879.31

Description

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.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Copenhagen

Dimensions Citation Indicators

Times Cited: 178

Field Citation Ratio (FCR): 97.85

Relative Citation ratio (RCR): 14.41

Open Access Info

Hybrid