Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9 - Sorbonne Université Access content directly
Journal Articles BMC Cardiovascular Disorders Year : 2019

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

Amand F Schmidt , Michael V Holmes , David Preiss , Daniel I Swerdlow , Spiros Denaxas , Ghazaleh Fatemifar , Rupert Faraway , Chris Finan , Dennis Valentine , Zammy Fairhurst-Hunter , Fernando Pires Hartwig , Bernardo Lessa Horta , Elina Hypponen , Christine Power , Max Moldovan , Erik van Iperen , Kees Hovingh , Ilja Demuth , Kristina Norman , Elisabeth Steinhagen-Thiessen , Juri Demuth , Lars Bertram , Christina M Lill , Stefan Coassin , Johann Willeit , Stefan Kiechl , Karin Willeit , Dan Mason , John Wright , Richard Morris , Goya Wanamethee , Peter Whincup , Yoav Ben-Shlomo , Stela Mclachlan , Jackie F Price , Mika Kivimaki , Catherine Welch , Adelaida Sanchez-Galvez , Pedro Marques-Vidal , Andrew Nicolaides , Andrie G Panayiotou , N Charlotte Onland-Moret , Yvonne T van der Schouw , Giuseppe Matullo , Giovanni Fiorito , Simonetta Guarrera , Carlotta Sacerdote , Nicholas J Wareham , Claudia Langenberg , Robert A Scott , Jian’an Luan , Martin Bobak , Sofia Malyutina , Andrzej Pająk , Ruzena Kubinova , Abdonas Tamosiunas , Hynek Pikhart , Niels Grarup , Oluf Pedersen , Torben Hansen , Allan Linneberg , Tine Jess , Jackie Cooper , Steve E Humphries , Murray Brilliant , Terrie Kitchner , Hakon Hakonarson , David S Carrell , Catherine A Mccarty , Kirchner H Lester , Eric B Larson , David R Crosslin , Mariza de Andrade , Dan M Roden , Joshua C Denny , Cara Carty , Stephen Hancock , John Attia , Elizabeth Holliday , Rodney Scott , Peter Schofield , Martin O’donnell , Salim Yusuf , Michael Chong , Guillaume Pare , Pim Van Der Harst , M Abdullah Said , Ruben N Eppinga , Niek Verweij , Harold Snieder , Tim Christen , D O Mook-Kanamori , Stefan Gustafsson , Lars Lind , Erik Ingelsson , Raha Pazoki , Oscar Franco , Albert Hofman , Andre Uitterlinden , Abbas Dehghan , Alexander Teumer , Sebastian Baumeister , Marcus Dörr , Markus M Lerch , Uwe Völker , Henry Völzke , Joey Ward , Jill P Pell , Tom Meade , Ingrid E Christophersen , Anke H Maitland-van der Zee , Ekaterina V Baranova , Robin Young , Ian Ford , Archie Campbell , Sandosh Padmanabhan , Michiel L Bots , Diederick E Grobbee , Philippe Froguel (1) , Dorothée Thuillier (1) , Ronan Roussel (2, 3) , Amélie Bonnefond (1) , Bertrand Cariou (4, 5) , Melissa Smart , Yanchun Bao , Meena Kumari , Anubha Mahajan , Jemma C Hopewell , Sudha Seshadri , Caroline Dale , Rui Providencia E Costa , Paul M Ridker , Daniel I Chasman , Alex P Reiner , Marylyn D Ritchie , Leslie A Lange , Alex J Cornish , Sara E Dobbins , Kari Hemminki , Ben Kinnersley , Marc Sanson (6) , Karim Labreche (6) , Matthias Simon , Melissa Bondy , Philip Law , Helen Speedy , James Allan , Ni Li , Molly Went , Niels Weinhold , Gareth Morgan , Pieter Sonneveld , Björn Nilsson , Hartmut Goldschmidt , Amit Sud , Andreas Engert , Markus Hansson , Harry Hemingway , Folkert W Asselbergs , Riyaz S Patel , Brendan J Keating , Naveed Sattar , Richard Houlston , Juan P Casas , Aroon D Hingorani
Amand F Schmidt
Michael V Holmes
  • Function : Author
David Preiss
  • Function : Author
Daniel I Swerdlow
  • Function : Author
Spiros Denaxas
  • Function : Author
Ghazaleh Fatemifar
  • Function : Author
Rupert Faraway
  • Function : Author
Chris Finan
  • Function : Author
Dennis Valentine
  • Function : Author
Zammy Fairhurst-Hunter
  • Function : Author
Fernando Pires Hartwig
  • Function : Author
Bernardo Lessa Horta
  • Function : Author
Elina Hypponen
  • Function : Author
Christine Power
  • Function : Author
Max Moldovan
  • Function : Author
Erik van Iperen
  • Function : Author
Kees Hovingh
  • Function : Author
Ilja Demuth
  • Function : Author
Kristina Norman
  • Function : Author
Elisabeth Steinhagen-Thiessen
  • Function : Author
Juri Demuth
  • Function : Author
Lars Bertram
  • Function : Author
Christina M Lill
  • Function : Author
Stefan Coassin
  • Function : Author
Johann Willeit
  • Function : Author
Stefan Kiechl
  • Function : Author
Karin Willeit
  • Function : Author
Dan Mason
  • Function : Author
John Wright
  • Function : Author
Richard Morris
  • Function : Author
Goya Wanamethee
  • Function : Author
Peter Whincup
  • Function : Author
Yoav Ben-Shlomo
  • Function : Author
Stela Mclachlan
  • Function : Author
Jackie F Price
  • Function : Author
Mika Kivimaki
  • Function : Author
Catherine Welch
  • Function : Author
Adelaida Sanchez-Galvez
  • Function : Author
Pedro Marques-Vidal
  • Function : Author
Andrew Nicolaides
  • Function : Author
Andrie G Panayiotou
  • Function : Author
N Charlotte Onland-Moret
  • Function : Author
Yvonne T van der Schouw
  • Function : Author
Giuseppe Matullo
  • Function : Author
Giovanni Fiorito
  • Function : Author
Simonetta Guarrera
  • Function : Author
Carlotta Sacerdote
  • Function : Author
Nicholas J Wareham
  • Function : Author
Claudia Langenberg
  • Function : Author
Robert A Scott
  • Function : Author
Jian’an Luan
  • Function : Author
Martin Bobak
  • Function : Author
Sofia Malyutina
  • Function : Author
Andrzej Pająk
  • Function : Author
Ruzena Kubinova
  • Function : Author
Abdonas Tamosiunas
  • Function : Author
Hynek Pikhart
  • Function : Author
Niels Grarup
  • Function : Author
Oluf Pedersen
  • Function : Author
Torben Hansen
  • Function : Author
Allan Linneberg
  • Function : Author
Tine Jess
  • Function : Author
Jackie Cooper
  • Function : Author
Steve E Humphries
  • Function : Author
Murray Brilliant
  • Function : Author
Terrie Kitchner
  • Function : Author
Hakon Hakonarson
  • Function : Author
David S Carrell
  • Function : Author
Catherine A Mccarty
  • Function : Author
Kirchner H Lester
  • Function : Author
Eric B Larson
  • Function : Author
David R Crosslin
  • Function : Author
Mariza de Andrade
  • Function : Author
Dan M Roden
  • Function : Author
Joshua C Denny
  • Function : Author
Cara Carty
  • Function : Author
Stephen Hancock
  • Function : Author
John Attia
  • Function : Author
Elizabeth Holliday
  • Function : Author
Rodney Scott
  • Function : Author
Peter Schofield
  • Function : Author
Martin O’donnell
  • Function : Author
Salim Yusuf
  • Function : Author
Michael Chong
  • Function : Author
Guillaume Pare
  • Function : Author
Pim Van Der Harst
  • Function : Author
M Abdullah Said
  • Function : Author
Ruben N Eppinga
  • Function : Author
Niek Verweij
  • Function : Author
Harold Snieder
  • Function : Author
Tim Christen
  • Function : Author
D O Mook-Kanamori
  • Function : Author
Stefan Gustafsson
  • Function : Author
Lars Lind
  • Function : Author
Erik Ingelsson
  • Function : Author
Raha Pazoki
  • Function : Author
Oscar Franco
  • Function : Author
Albert Hofman
  • Function : Author
Andre Uitterlinden
  • Function : Author
Abbas Dehghan
  • Function : Author
Alexander Teumer
  • Function : Author
Sebastian Baumeister
  • Function : Author
Marcus Dörr
  • Function : Author
Markus M Lerch
  • Function : Author
Uwe Völker
  • Function : Author
Henry Völzke
  • Function : Author
Joey Ward
  • Function : Author
Jill P Pell
  • Function : Author
Tom Meade
  • Function : Author
Ingrid E Christophersen
  • Function : Author
Anke H Maitland-van der Zee
  • Function : Author
Ekaterina V Baranova
  • Function : Author
Robin Young
  • Function : Author
Ian Ford
  • Function : Author
Archie Campbell
  • Function : Author
Sandosh Padmanabhan
  • Function : Author
Michiel L Bots
  • Function : Author
Diederick E Grobbee
  • Function : Author
Melissa Smart
  • Function : Author
Yanchun Bao
  • Function : Author
Meena Kumari
  • Function : Author
Anubha Mahajan
  • Function : Author
Jemma C Hopewell
  • Function : Author
Sudha Seshadri
  • Function : Author
Caroline Dale
  • Function : Author
Rui Providencia E Costa
  • Function : Author
Paul M Ridker
  • Function : Author
Daniel I Chasman
  • Function : Author
Alex P Reiner
  • Function : Author
Marylyn D Ritchie
  • Function : Author
Leslie A Lange
  • Function : Author
Alex J Cornish
  • Function : Author
Sara E Dobbins
  • Function : Author
Kari Hemminki
  • Function : Author
Ben Kinnersley
  • Function : Author
Matthias Simon
  • Function : Author
Melissa Bondy
  • Function : Author
Philip Law
  • Function : Author
Helen Speedy
  • Function : Author
James Allan
  • Function : Author
Ni Li
  • Function : Author
Molly Went
  • Function : Author
Niels Weinhold
  • Function : Author
Gareth Morgan
  • Function : Author
Pieter Sonneveld
  • Function : Author
Björn Nilsson
  • Function : Author
Hartmut Goldschmidt
  • Function : Author
Amit Sud
  • Function : Author
Andreas Engert
  • Function : Author
Markus Hansson
  • Function : Author
Harry Hemingway
  • Function : Author
Folkert W Asselbergs
  • Function : Author
Riyaz S Patel
  • Function : Author
Brendan J Keating
  • Function : Author
Naveed Sattar
  • Function : Author
Richard Houlston
  • Function : Author
Juan P Casas
  • Function : Author
Aroon D Hingorani
  • Function : Author

Abstract

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 diseaseoutcomes 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.
Fichier principal
Vignette du fichier
s12872-019-1187-z.pdf (901.97 Ko) Télécharger le fichier
Origin : Publication funded by an institution
Licence : CC BY - Attribution

Dates and versions

hal-04479637 , version 1 (27-02-2024)

Identifiers

Cite

Amand F Schmidt, Michael V Holmes, David Preiss, Daniel I Swerdlow, Spiros Denaxas, et al.. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. BMC Cardiovascular Disorders, 2019, 19, ⟨10.1186/s12872-019-1187-z⟩. ⟨hal-04479637⟩
28 View
3 Download

Altmetric

Share

Gmail Facebook X LinkedIn More