Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
View/ Open
Date
2019-10-29ICR Author
Author
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
Pająk, 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
Lifelines Cohort authors,
Christen, T
Mook-Kanamori, DO
ICBP Consortium,
Gustafsson, S
Lind, L
Ingelsson, E
Pazoki, R
Franco, O
Hofman, A
Uitterlinden, A
Dehghan, A
Teumer, A
Baumeister, S
Dörr, M
Lerch, MM
Völker, U
Völzke, 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
METASTROKE Consortium of the ISGC,
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Lifelines Cohort authors
ICBP Consortium
METASTROKE Consortium of the ISGC
Humans
Brain Ischemia
Myocardial Infarction
Anticholesteremic Agents
Serine Proteinase Inhibitors
Treatment Outcome
Risk Assessment
Risk Factors
Down-Regulation
Polymorphism, Single Nucleotide
Dyslipidemias
Cholesterol, LDL
Randomized Controlled Trials as Topic
Stroke
Genome-Wide Association Study
Biomarkers
Proprotein Convertase 9
Research team
Cancer Genomics
Language
eng
Date accepted
2019-08-19
License start date
2019-10-29
Citation
BMC cardiovascular disorders, 2019, 19 (1), pp. 240 - ?
Publisher
BMC