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

Authors:
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

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019
1 Read
1.500 Impact Factor

Publication Analysis

Top Keywords

pcsk9 inhibitor
12
pcsk9
9
inhibitor trials
8
genetic variation
8
pcsk9 locus
8
variation pcsk9
8
95%
6
057 122
4
122 compared
4
compared 085
4
95% 057
4
085 95%
4
084 95%
4
093 ischemic
4
ischemic stroke
4
stroke ors
4
ors 084
4
95% 078
4
078 093
4
diabetes mellitus
4

Similar Publications