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

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Serval ID
serval:BIB_FD7E2A2C6D1C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
Journal
BMC cardiovascular disorders
Author(s)
Schmidt A.F., Holmes M.V., Preiss D., Swerdlow D.I., Denaxas S., Fatemifar G., Faraway R., Finan C., Valentine D., Fairhurst-Hunter Z., Hartwig F.P., Horta B.L., Hypponen E., Power C., Moldovan M., van Iperen E., Hovingh K., Demuth I., Norman K., Steinhagen-Thiessen E., Demuth J., Bertram L., Lill C.M., Coassin S., Willeit J., Kiechl S., Willeit K., Mason D., Wright J., Morris R., Wanamethee G., Whincup P., Ben-Shlomo Y., McLachlan S., Price J.F., Kivimaki M., Welch C., Sanchez-Galvez A., Marques-Vidal P., Nicolaides A., Panayiotou A.G., Onland-Moret N.C., van der Schouw Y.T., Matullo G., Fiorito G., Guarrera S., Sacerdote C., Wareham N.J., Langenberg C., Scott R.A., Luan J., Bobak M., Malyutina S., Pająk A., Kubinova R., Tamosiunas A., Pikhart H., Grarup N., Pedersen O., Hansen T., Linneberg A., Jess T., Cooper J., Humphries S.E., Brilliant M., Kitchner T., Hakonarson H., Carrell D.S., McCarty C.A., Lester K.H., Larson E.B., Crosslin D.R., de Andrade M., Roden D.M., Denny J.C., 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 M.A., Eppinga R.N., Verweij N., Snieder H., Christen T., Mook-Kanamori D.O., Gustafsson S., Lind L., Ingelsson E., Pazoki R., Franco O., Hofman A., Uitterlinden A., Dehghan A., Teumer A., Baumeister S., Dörr M., Lerch M.M., Völker U., Völzke H., Ward J., Pell J.P., Meade T., Christophersen I.E., Maitland-van der Zee A.H., Baranova E.V., Young R., Ford I., Campbell A., Padmanabhan S., Bots M.L., Grobbee D.E., Froguel P., Thuillier D., Roussel R., Bonnefond A., Cariou B., Smart M., Bao Y., Kumari M., Mahajan A., Hopewell J.C., Seshadri S., Dale C., Costa RPE, Ridker P.M., Chasman D.I., Reiner A.P., Ritchie M.D., Lange L.A., Cornish A.J., Dobbins S.E., 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 F.W., Patel R.S., Keating B.J., Sattar N., Houlston R., Casas J.P., Hingorani A.D.
Working group(s)
Lifelines Cohort authors, ICBP Consortium, METASTROKE Consortium of the ISGC
ISSN
1471-2261 (Electronic)
ISSN-L
1471-2261
Publication state
Published
Issued date
29/10/2019
Peer-reviewed
Oui
Volume
19
Number
1
Pages
240
Language
english
Notes
Publication types: Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.
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.
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.
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
Anticholesteremic Agents/adverse effects, Anticholesteremic Agents/therapeutic use, Biomarkers/blood, Brain Ischemia/epidemiology, Brain Ischemia/prevention & control, Cholesterol, LDL/blood, Down-Regulation, Dyslipidemias/blood, Dyslipidemias/drug therapy, Dyslipidemias/epidemiology, Dyslipidemias/genetics, Genome-Wide Association Study, Humans, Myocardial Infarction/epidemiology, Myocardial Infarction/prevention & control, Polymorphism, Single Nucleotide, Proprotein Convertase 9/antagonists & inhibitors, Proprotein Convertase 9/genetics, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Serine Proteinase Inhibitors/adverse effects, Serine Proteinase Inhibitors/therapeutic use, Stroke/epidemiology, Stroke/prevention & control, Treatment Outcome, Genetic association studies, LDL-cholesterol, Mendelian randomisation, Phenome-wide association scan
Pubmed
Web of science
Open Access
Yes
Create date
06/07/2020 15:06
Last modification date
07/07/2021 5:37
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