Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros ORCID: 0000-0001-9612-7791, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina ORCID: 0000-0003-3670-9399, Power, Christine, Moldovan, Max ORCID: 0000-0001-9680-8474, van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina ORCID: 0000-0003-2029-9102, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan ORCID: 0000-0001-5677-8979, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro ORCID: 0000-0002-4548-8500, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, van der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian'an, Bobak, Martin, Malyutina, Sofia, Pajak, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek ORCID: 0000-0001-5277-4049, Grarup, Niels ORCID: 0000-0001-5526-1070, Pedersen, Oluf ORCID: 0000-0002-3321-3972, Hansen, Torben ORCID: 0000-0001-8748-3831, Linneberg, Allan ORCID: 0000-0002-0994-0184, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., de Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter ORCID: 0000-0001-8298-8590, O'Donnell, Martin ORCID: 0000-0002-7347-7761, Yusuf, Salim, Chong, Michael, Pare, Guillaume, van der Harst, Pim, Said, M. Abdullah ORCID: 0000-0003-2920-7745, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander ORCID: 0000-0002-8309-094X, Baumeister, Sebastian, Doerr, Marcus, Lerch, Markus M. ORCID: 0000-0002-9643-8263, Voelker, Uwe, Voelzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-van der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothee, Roussel, Ronan, Bonnefond, Amelie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha ORCID: 0000-0001-6135-2622, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Bjorn, Goldschmidt, Hartmut, Sud, Amit ORCID: 0000-0002-6133-0164, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P. and Hingorani, Aroon D. (2019). Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. BMC Cardiovasc. Disord., 19 (1). LONDON: BMC. ISSN 1471-2261

Full text not available from this repository.

Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schmidt, Amand F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holmes, Michael V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preiss, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swerdlow, Daniel I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denaxas, SpirosUNSPECIFIEDorcid.org/0000-0001-9612-7791UNSPECIFIED
Fatemifar, GhazalehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faraway, RupertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finan, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valentine, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fairhurst-Hunter, ZammyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartwig, Fernando PiresUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horta, Bernardo LessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hypponen, ElinaUNSPECIFIEDorcid.org/0000-0003-3670-9399UNSPECIFIED
Power, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moldovan, MaxUNSPECIFIEDorcid.org/0000-0001-9680-8474UNSPECIFIED
van Iperen, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hovingh, KeesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demuth, IljaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norman, KristinaUNSPECIFIEDorcid.org/0000-0003-2029-9102UNSPECIFIED
Steinhagen-Thiessen, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demuth, JuriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertram, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lill, Christina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coassin, StefanUNSPECIFIEDorcid.org/0000-0001-5677-8979UNSPECIFIED
Willeit, JohannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiechl, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willeit, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mason, DanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morris, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wanamethee, GoyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whincup, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ben-Shlomo, YoavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McLachlan, StelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Price, Jackie F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kivimaki, MikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welch, CatherineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Galvez, AdelaidaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marques-Vidal, PedroUNSPECIFIEDorcid.org/0000-0002-4548-8500UNSPECIFIED
Nicolaides, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Panayiotou, Andrie G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Onland-Moret, N. CharlotteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Schouw, Yvonne T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matullo, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiorito, GiovanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guarrera, SimonettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sacerdote, CarlottaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wareham, Nicholas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langenberg, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, Robert A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luan, Jian'anUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bobak, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malyutina, SofiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pajak, AndrzejUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubinova, RuzenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tamosiunas, AbdonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pikhart, HynekUNSPECIFIEDorcid.org/0000-0001-5277-4049UNSPECIFIED
Grarup, NielsUNSPECIFIEDorcid.org/0000-0001-5526-1070UNSPECIFIED
Pedersen, OlufUNSPECIFIEDorcid.org/0000-0002-3321-3972UNSPECIFIED
Hansen, TorbenUNSPECIFIEDorcid.org/0000-0001-8748-3831UNSPECIFIED
Linneberg, AllanUNSPECIFIEDorcid.org/0000-0002-0994-0184UNSPECIFIED
Jess, TineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cooper, JackieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Humphries, Steve E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brilliant, MurrayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitchner, TerrieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hakonarson, HakonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrell, David S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCarty, Catherine A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lester, Kirchner H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larson, Eric B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crosslin, David R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Andrade, MarizaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roden, Dan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denny, Joshua C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carty, CaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hancock, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Attia, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holliday, ElizabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, RodneyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schofield, PeterUNSPECIFIEDorcid.org/0000-0001-8298-8590UNSPECIFIED
O'Donnell, MartinUNSPECIFIEDorcid.org/0000-0002-7347-7761UNSPECIFIED
Yusuf, SalimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chong, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pare, GuillaumeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Harst, PimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Said, M. AbdullahUNSPECIFIEDorcid.org/0000-0003-2920-7745UNSPECIFIED
Eppinga, Ruben N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verweij, NiekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Snieder, HaroldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christen, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mook-Kanamori, D. O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gustafsson, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lind, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ingelsson, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pazoki, RahaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franco, OscarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofman, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uitterlinden, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dehghan, AbbasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teumer, AlexanderUNSPECIFIEDorcid.org/0000-0002-8309-094XUNSPECIFIED
Baumeister, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doerr, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerch, Markus M.UNSPECIFIEDorcid.org/0000-0002-9643-8263UNSPECIFIED
Voelker, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voelzke, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ward, JoeyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pell, Jill P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meade, TomUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christophersen, Ingrid E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maitland-van der Zee, Anke H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baranova, Ekaterina V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ford, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, ArchieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Padmanabhan, SandoshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bots, Michiel L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grobbee, Diederick E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Froguel, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thuillier, DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roussel, RonanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonnefond, AmelieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cariou, BertrandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smart, MelissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bao, YanchunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumari, MeenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahajan, AnubhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopewell, Jemma C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seshadri, SudhaUNSPECIFIEDorcid.org/0000-0001-6135-2622UNSPECIFIED
Dale, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Costa, Rui Providencia E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ridker, Paul M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chasman, Daniel I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiner, Alex P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ritchie, Marylyn D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lange, Leslie A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cornish, Alex J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dobbins, Sara E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemminki, KariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kinnersley, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanson, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Labreche, KarimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bondy, MelissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Law, PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speedy, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allan, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, NiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Went, MollyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weinhold, NielsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sonneveld, PieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nilsson, BjornUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldschmidt, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sud, AmitUNSPECIFIEDorcid.org/0000-0002-6133-0164UNSPECIFIED
Engert, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansson, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemingway, HarryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Asselbergs, Folkert W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, Riyaz S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keating, Brendan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sattar, NaveedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlston, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Casas, Juan P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hingorani, Aroon D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-130171
DOI: 10.1186/s12872-019-1187-z
Journal or Publication Title: BMC Cardiovasc. Disord.
Volume: 19
Number: 1
Date: 2019
Publisher: BMC
Place of Publication: LONDON
ISSN: 1471-2261
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CORONARY-HEART-DISEASE; MENDELIAN RANDOMIZATION; STATIN THERAPY; RISK; STROKE; PREVENTION; EZETIMIBE; EFFICACYMultiple languages
Cardiac & Cardiovascular SystemsMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13017

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