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@article{Schmidt:2019:10.1186/s12872-019-1187-z,
author = {Schmidt, AF and Holmes, MV and Preiss, D and Swerdlow, DI and Denaxas, S and Fatemifar, G and Faraway, R and Finan, C and Valentine, D and Fairhurst-Hunter, Z and Hartwig, FP and Horta, BL and Hypponen, E and Power, C and Moldovan, M and van, Iperen E and Hovingh, K and Demuth, I and Norman, K and Steinhagen-Thiessen, E and Demuth, J and Bertram, L and Lill, CM and Coassin, S and Willeit, J and Kiechl, S and Willeit, K and Mason, D and Wright, J and Morris, R and Wanamethee, G and Whincup, P and Ben-Shlomo, Y and McLachlan, S and Price, JF and Kivimaki, M and Welch, C and Sanchez-Galvez, A and Marques-Vidal, P and Nicolaides, A and Panayiotou, AG and Onland-Moret, NC and van, der Schouw YT and Matullo, G and Fiorito, G and Guarrera, S and Sacerdote, C and Wareham, NJ and Langenberg, C and Scott, RA and Luan, J and Bobak, M and Malyutina, S and Pajk, A and Kubinova, R and Tamosiunas, A and Pikhart, H and Grarup, N and Pedersen, O and Hansen, T and Linneberg, A and Jess, T and Cooper, J },
doi = {10.1186/s12872-019-1187-z},
journal = {BMC Cardiovascular Disorders},
title = {Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9},
url = {http://dx.doi.org/10.1186/s12872-019-1187-z},
volume = {19},
year = {2019}
}

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TY  - JOUR
AB  - 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.
AU  - Schmidt,AF
AU  - Holmes,MV
AU  - Preiss,D
AU  - Swerdlow,DI
AU  - Denaxas,S
AU  - Fatemifar,G
AU  - Faraway,R
AU  - Finan,C
AU  - Valentine,D
AU  - Fairhurst-Hunter,Z
AU  - Hartwig,FP
AU  - Horta,BL
AU  - Hypponen,E
AU  - Power,C
AU  - Moldovan,M
AU  - van,Iperen E
AU  - Hovingh,K
AU  - Demuth,I
AU  - Norman,K
AU  - Steinhagen-Thiessen,E
AU  - Demuth,J
AU  - Bertram,L
AU  - Lill,CM
AU  - Coassin,S
AU  - Willeit,J
AU  - Kiechl,S
AU  - Willeit,K
AU  - Mason,D
AU  - Wright,J
AU  - Morris,R
AU  - Wanamethee,G
AU  - Whincup,P
AU  - Ben-Shlomo,Y
AU  - McLachlan,S
AU  - Price,JF
AU  - Kivimaki,M
AU  - Welch,C
AU  - Sanchez-Galvez,A
AU  - Marques-Vidal,P
AU  - Nicolaides,A
AU  - Panayiotou,AG
AU  - Onland-Moret,NC
AU  - van,der Schouw YT
AU  - Matullo,G
AU  - Fiorito,G
AU  - Guarrera,S
AU  - Sacerdote,C
AU  - Wareham,NJ
AU  - Langenberg,C
AU  - Scott,RA
AU  - Luan,J
AU  - Bobak,M
AU  - Malyutina,S
AU  - Pajk,A
AU  - Kubinova,R
AU  - Tamosiunas,A
AU  - Pikhart,H
AU  - Grarup,N
AU  - Pedersen,O
AU  - Hansen,T
AU  - Linneberg,A
AU  - Jess,T
AU  - Cooper,J
AU  - Humphries,SE
AU  - Brilliant,M
AU  - Kitchner,T
AU  - Hakonarson,H
AU  - Carrell,DS
AU  - McCarty,CA
AU  - Lester,KH
AU  - Larson,EB
AU  - Crosslin,DR
AU  - de,Andrade M
AU  - Roden,DM
AU  - Denny,JC
AU  - Carty,C
AU  - Hancock,S
AU  - Attia,J
AU  - Holliday,E
AU  - Scott,R
AU  - Schofield,P
AU  - O'Donnell,M
AU  - Yusuf,S
AU  - Chong,M
AU  - Pare,G
AU  - van,der Harst P
AU  - Said,MA
AU  - Eppinga,RN
AU  - Verweij,N
AU  - Snieder,H
AU  - Lifelines,Cohort authors
AU  - Christen,T
AU  - Mook-Kanamori,DO
AU  - ICBP,Consortium
AU  - Gustafsson,S
AU  - Lind,L
AU  - Ingelsson,E
AU  - Pazoki,R
AU  - Franco,O
AU  - Hofman,A
AU  - Uitterlinden,A
AU  - Dehghan,A
AU  - Teumer,A
AU  - Baumeister,S
AU  - Dörr,M
AU  - Lerch,MM
AU  - Völker,U
AU  - Völzke,H
AU  - Ward,J
AU  - Pell,JP
AU  - Meade,T
AU  - Christophersen,IE
AU  - Maitland-van,der Zee AH
AU  - Baranova,EV
AU  - Young,R
AU  - Ford,I
AU  - Campbell,A
AU  - Padmanabhan,S
AU  - Bots,ML
AU  - Grobbee,DE
AU  - Froguel,P
AU  - Thuillier,D
AU  - Roussel,R
AU  - Bonnefond,A
AU  - Cariou,B
AU  - Smart,M
AU  - Bao,Y
AU  - Kumari,M
AU  - Mahajan,A
AU  - Hopewell,JC
AU  - Seshadri,S
AU  - METASTROKE,Consortium of the ISGC
AU  - Dale,C
AU  - Costa,RPE
AU  - Ridker,PM
AU  - Chasman,DI
AU  - Reiner,AP
AU  - Ritchie,MD
AU  - Lange,LA
AU  - Cornish,AJ
AU  - Dobbins,SE
AU  - Hemminki,K
AU  - Kinnersley,B
AU  - Sanson,M
AU  - Labreche,K
AU  - Simon,M
AU  - Bondy,M
AU  - Law,P
AU  - Speedy,H
AU  - Allan,J
AU  - Li,N
AU  - Went,M
AU  - Weinhold,N
AU  - Morgan,G
AU  - Sonneveld,P
AU  - Nilsson,B
AU  - Goldschmidt,H
AU  - Sud,A
AU  - Engert,A
AU  - Hansson,M
AU  - Hemingway,H
AU  - Asselbergs,FW
AU  - Patel,RS
AU  - Keating,BJ
AU  - Sattar,N
AU  - Houlston,R
AU  - Casas,JP
AU  - Hingorani,AD
DO  - 10.1186/s12872-019-1187-z
PY  - 2019///
SN  - 1471-2261
TI  - Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
T2  - BMC Cardiovascular Disorders
UR  - http://dx.doi.org/10.1186/s12872-019-1187-z
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31664920
UR  - http://hdl.handle.net/10044/1/75100
VL  - 19
ER  -

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