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; Dorothée Thuillier; Ronan Roussel; Amélie Bonnefond; Bertrand Cariou; 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; Karim Labreche; 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

doi:10.1186/s12872-019-1187-z

Journal Articles BMC Cardiovascular Disorders Year : 2019

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

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (1) , (1) , (2, 3) , (1) , (4, 5) , , , , , , , , , , , , , , , , , , (6) , (6) , , , , , , , , , , , , , , , , , , , , , , ,

1
2
3
4
5
6

Amand F Schmidt

Function : Author
PersonId : 1357389
ORCID : 0000-0003-1327-0424

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

Philippe Froguel

Function : Author

Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508

Dorothée Thuillier

Function : Author

Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508

Ronan Roussel

Function : Author

Centre de Recherche des Cordeliers

Université Sorbonne Paris Cité

Amélie Bonnefond

Function : Author

Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508

Bertrand Cariou

Function : Author

Institut du Thorax [Nantes]

Centre Hospitalier Universitaire de Nantes = Nantes University Hospital

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

Marc Sanson

Function : Author

Institut du Cerveau = Paris Brain Institute

Karim Labreche

Function : Author

Institut du Cerveau = Paris Brain Institute

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.

Keywords

Genetic association studies Mendelian randomisation LDL-cholesterol Phenome-wide association scan Genetic association studies Mendelian randomisation LDL-cholesterol Phenome-wide association scan

Domains

Human health and pathology

Fichier principal

s12872-019-1187-z.pdf (901.97 Ko)

Origin	Publication funded by an institution
Licence	Attribution

Gestionnaire HAL 5 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04479637

Submitted on : Tuesday, February 27, 2024-12:07:22 PM

Last modification on : Thursday, November 7, 2024-2:22:29 PM

Long-term archiving on : Tuesday, May 28, 2024-6:36:16 PM

Dates and versions

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

Licence

Attribution

Identifiers

HAL Id : hal-04479637 , version 1
DOI : 10.1186/s12872-019-1187-z

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⟩

Export

BibTeX XML-TEI Dublin Core DC Terms EndNote DataCite

Collections

RIIP EPHE CNRS CORDELIERS ICM PSL UNIV-LILLE SORBONNE-UNIVERSITE SU-MEDECINE SU-SCIENCES UP-SANTE ANR

47 View

7 Download

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

Abstract

Keywords

Domains

Dates and versions

Licence

Identifiers

Cite

Export

Collections

Altmetric

Share