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

Lookup NU author(s): Professor James Allan

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


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Author(s): Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, Faraway R, Finan C, Valentine D, Fairhurst-Hunter Z, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh K, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Lill CM, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott RA, Luan J, Bobak M, Malyutina S, Pajak A, Kubinova R, Tamosiunas A, Pikhart H, Grarup N, Pedersen O, Hansen T, Linneberg A, Jess T, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Lester KH, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Scott R, Schofield P, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dorr M, Lerch MM, Volker U, Volzke H, Ward J, Pell JP, Meade T, Christophersen IE, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Roussel R, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Hopewell JC, Seshadri S, Dale C, Costa RPE, Ridker PM, Chasman DI, Reiner AP, Ritchie MD, Lange LA, Cornish AJ, Dobbins SE, Hemminki K, Kinnersley B, Sanson M, Labreche K, Simon M, Bondy M, Law P, Speedy H, Allan J, Li N, Went M, Weinhold N, Morgan G, Sonneveld P, Nilsson B, Goldschmidt H, Sud A, Engert A, Hansson M, Hemingway H, Asselbergs FW, Patel RS, Keating BJ, Sattar N, Houlston R, Casas JP, Hingorani AD

Publication type: Article

Publication status: Published

Journal: BMC Cardiovascular Disorders

Year: 2019

Volume: 19

Issue: 1

Online publication date: 29/10/2019

Acceptance date: 19/08/2019

Date deposited: 11/11/2019

ISSN (electronic): 1471-2261

Publisher: BioMed Central Ltd.

URL: https://doi.org/10.1186/s12872-019-1187-z

DOI: 10.1186/s12872-019-1187-z

PubMed id: 31664920


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