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


Ressource 1Request a copy Sous embargo indéterminé.
State: Public
Version: author
License: CC BY 4.0
Secondary document(s)
Sous embargo indéterminé.
State: Public
Version: Supplementary document
License: Not specified
Sous embargo indéterminé.
State: Public
Version: Supplementary document
License: Not specified
Serval ID
Article: article from journal or magazin.
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
BMC cardiovascular disorders
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
1471-2261 (Electronic)
Publication state
Issued date
Publication types: Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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.
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
Web of science
Open Access
Create date
06/07/2020 15:06
Last modification date
07/07/2021 5:37
Usage data