Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
Authors:   Lifelines Cohort authors, Schmidt Amand F. ,   the ICBP Consortium,   the METASTROKE Consortium of the ISGC, Holmes Michael V. , Preiss David , Swerdlow Daniel I. , Denaxas Spiros , Fatemifar Ghazaleh , Faraway Rupert , Finan Chris , Valentine Dennis , Fairhurst-Hunter Zammy , Hartwig Fernando Pires , Horta Bernardo Lessa , Hypponen Elina , Power Christine , Moldovan Max , van Iperen Erik , Hovingh Kees , Demuth Ilja , Norman Kristina , Steinhagen-Thiessen Elisabeth , Demuth Juri , Bertram Lars , Lill Christina M. , Coassin Stefan , Willeit Johann , Kiechl Stefan , Willeit Karin , Mason Dan , Wright John , Morris Richard , Wanamethee Goya , Whincup Peter , Ben-Shlomo Yoav , McLachlan Stela , Price Jackie F. , Kivimaki Mika , Welch Catherine , Sanchez-Galvez Adelaida , Marques-Vidal Pedro , Nicolaides Andrew , Panayiotou Andrie G. , Onland-Moret N. Charlotte , van der Schouw Yvonne T. , Matullo Giuseppe , Fiorito Giovanni , Guarrera Simonetta , Sacerdote Carlotta , Wareham Nicholas J. , Langenberg Claudia , Scott Robert A. , Luan Jian’an , Bobak Martin , Malyutina Sofia , Pająk Andrzej , Kubinova Ruzena , Tamosiunas Abdonas , Pikhart Hynek , Grarup Niels , Pedersen Oluf , Hansen Torben , Linneberg Allan , Jess Tine , Cooper Jackie , Humphries Steve E. , Brilliant Murray , Kitchner Terrie , Hakonarson Hakon , Carrell David S. , McCarty Catherine A. , Lester Kirchner H. , Larson Eric B. , Crosslin David R. , de Andrade Mariza , Roden Dan M. , Denny Joshua C. , Carty Cara , Hancock Stephen , Attia John , Holliday Elizabeth , Scott Rodney , Schofield Peter , O’Donnell Martin , Yusuf Salim , Chong Michael , Pare Guillaume , van der Harst Pim , Said M. Abdullah , Eppinga Ruben N. , Verweij Niek , Snieder Harold , Christen Tim , Mook-Kanamori D. O. , Gustafsson Stefan , Lind Lars , Ingelsson Erik , Pazoki Raha , Franco Oscar , Hofman Albert , Uitterlinden Andre , Dehghan Abbas , Teumer Alexander , Baumeister Sebastian , Dörr Marcus , Lerch Markus M. , Völker Uwe , Völzke Henry , Ward Joey , Pell Jill P. , Meade Tom , Christophersen Ingrid E. , Maitland-van der Zee Anke H. , Baranova Ekaterina V. , Young Robin , Ford Ian , Campbell Archie , Padmanabhan Sandosh , Bots Michiel L. , Grobbee Diederick E. , Froguel Philippe , Thuillier Dorothée , Roussel Ronan , Bonnefond Amélie , Cariou Bertrand , Smart Melissa , Bao Yanchun , Kumari Meena , Mahajan Anubha , Hopewell Jemma C. , Seshadri Sudha , Dale Caroline , Costa Rui Providencia E. , Ridker Paul M. , Chasman Daniel I. , Reiner Alex P. , Ritchie Marylyn D. , Lange Leslie A. , Cornish Alex J. , Dobbins Sara E. , Hemminki Kari , Kinnersley Ben , Sanson Marc , Labreche Karim , Simon Matthias , Bondy Melissa , Law Philip , Speedy Helen , Allan James , Li Ni , Went Molly , Weinhold Niels , Morgan Gareth , Sonneveld Pieter , Nilsson Björn , Goldschmidt Hartmut , Sud Amit , Engert Andreas , Hansson Markus , Hemingway Harry , Asselbergs Folkert W. , Patel Riyaz S. , Keating Brendan J. , Sattar Naveed , Houlston Richard , Casas Juan P. , Hingorani Aroon D. 
Published: October 2019

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 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.