Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
Authors: Schmidt Amand F , Holmes Michael V , Preiss David , Swerdlow Daniel , Denaxas Spiros , Fatemifar Ghazaleh , Faraway Rupert , Finan Chris , Lumbers Tom , Henry Albert , 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 , Pajak 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. , Andrade Mariza de , 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 Amelie , 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 , Hemminki Kari , 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: May 2018

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). Fourteen 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. Apparent discordance between genetic associations and trial outcome for T2DM might be explained lack by a of statistical precision, or differences in the nature and duration of genetic versus pharmacological perturbation of PCSK9.

Funding

This research was funded by the British Heart Foundation (SP/13/6/30554, RG/10/12/28456, FS/18/23/33512), UCL Hospitals NIHR Biomedical Research Centre, by the Rosetrees and Stoneygate Trusts.

Condensed abstract

Evidence on the long-term efficacy and safety of therapeutic inhibition of PCSK9 is lacking. To explore potential long-term effects of PCSK9 inhibition, we characterised the phenotypic consequence of LDL-cholesterol lowering variants at the PCSK9 locus. A PCSK9 gene score comprising 4 SNPs recapitulated the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and risk of myocardial infarction, and was associated with an increased risk of type 2 diabetes. No associations with safety outcomes such as cancer, COPD, Alzheimer’s disease or atrial fibrillation were identified. Our findings suggest PCSK9 inhibition may be safe and effective during prolonged use.