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

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.

doi:10.1186/s12872-019-1187-z

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

Details

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State: Public
Version: author
License: CC BY 4.0

Secondary document(s)

Under indefinite embargo.
UNIL restricted access
State: Public
Version: Supplementary document
License: Not specified

Serval ID

serval:BIB_FD7E2A2C6D1C

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

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

Number

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

OAI-PMH

oai:serval.unil.ch:BIB_FD7E2A2C6D1C

DOI

10.1186/s12872-019-1187-z

Pubmed

31664920

Web of science

000503475600002

Open Access

Yes

Create date

06/07/2020 16:06