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
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Creators: |
Creators | Email | ORCID | ORCID Put Code |
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Schmidt, Amand F. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Holmes, Michael V. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Preiss, David | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Swerdlow, Daniel I. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Denaxas, Spiros | UNSPECIFIED | orcid.org/0000-0001-9612-7791 | UNSPECIFIED | Fatemifar, Ghazaleh | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Faraway, Rupert | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Finan, Chris | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Valentine, Dennis | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Fairhurst-Hunter, Zammy | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hartwig, Fernando Pires | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Horta, Bernardo Lessa | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hypponen, Elina | UNSPECIFIED | orcid.org/0000-0003-3670-9399 | UNSPECIFIED | Power, Christine | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Moldovan, Max | UNSPECIFIED | orcid.org/0000-0001-9680-8474 | UNSPECIFIED | van Iperen, Erik | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hovingh, Kees | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Demuth, Ilja | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Norman, Kristina | UNSPECIFIED | orcid.org/0000-0003-2029-9102 | UNSPECIFIED | Steinhagen-Thiessen, Elisabeth | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Demuth, Juri | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bertram, Lars | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lill, Christina M. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Coassin, Stefan | UNSPECIFIED | orcid.org/0000-0001-5677-8979 | UNSPECIFIED | Willeit, Johann | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Kiechl, Stefan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Willeit, Karin | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Mason, Dan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Wright, John | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Morris, Richard | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Wanamethee, Goya | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Whincup, Peter | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Ben-Shlomo, Yoav | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | McLachlan, Stela | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Price, Jackie F. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Kivimaki, Mika | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Welch, Catherine | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Sanchez-Galvez, Adelaida | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Marques-Vidal, Pedro | UNSPECIFIED | orcid.org/0000-0002-4548-8500 | UNSPECIFIED | Nicolaides, Andrew | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Panayiotou, Andrie G. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Onland-Moret, N. Charlotte | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | van der Schouw, Yvonne T. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Matullo, Giuseppe | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Fiorito, Giovanni | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Guarrera, Simonetta | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Sacerdote, Carlotta | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Wareham, Nicholas J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Langenberg, Claudia | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Scott, Robert A. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Luan, Jian'an | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bobak, Martin | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Malyutina, Sofia | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Pajak, Andrzej | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Kubinova, Ruzena | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Tamosiunas, Abdonas | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Pikhart, Hynek | UNSPECIFIED | orcid.org/0000-0001-5277-4049 | UNSPECIFIED | Grarup, Niels | UNSPECIFIED | orcid.org/0000-0001-5526-1070 | UNSPECIFIED | Pedersen, Oluf | UNSPECIFIED | orcid.org/0000-0002-3321-3972 | UNSPECIFIED | Hansen, Torben | UNSPECIFIED | orcid.org/0000-0001-8748-3831 | UNSPECIFIED | Linneberg, Allan | UNSPECIFIED | orcid.org/0000-0002-0994-0184 | UNSPECIFIED | Jess, Tine | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Cooper, Jackie | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Humphries, Steve E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Brilliant, Murray | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Kitchner, Terrie | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hakonarson, Hakon | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Carrell, David S. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | McCarty, Catherine A. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lester, Kirchner H. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Larson, Eric B. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Crosslin, David R. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | de Andrade, Mariza | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Roden, Dan M. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Denny, Joshua C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Carty, Cara | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hancock, Stephen | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Attia, John | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Holliday, Elizabeth | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Scott, Rodney | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Schofield, Peter | UNSPECIFIED | orcid.org/0000-0001-8298-8590 | UNSPECIFIED | O'Donnell, Martin | UNSPECIFIED | orcid.org/0000-0002-7347-7761 | UNSPECIFIED | Yusuf, Salim | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Chong, Michael | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Pare, Guillaume | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | van der Harst, Pim | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Said, M. Abdullah | UNSPECIFIED | orcid.org/0000-0003-2920-7745 | UNSPECIFIED | Eppinga, Ruben N. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Verweij, Niek | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Snieder, Harold | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Christen, Tim | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Mook-Kanamori, D. O. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Gustafsson, Stefan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lind, Lars | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Ingelsson, Erik | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Pazoki, Raha | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Franco, Oscar | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hofman, Albert | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Uitterlinden, Andre | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Dehghan, Abbas | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Teumer, Alexander | UNSPECIFIED | orcid.org/0000-0002-8309-094X | UNSPECIFIED | Baumeister, Sebastian | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Doerr, Marcus | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lerch, Markus M. | UNSPECIFIED | orcid.org/0000-0002-9643-8263 | UNSPECIFIED | Voelker, Uwe | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Voelzke, Henry | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Ward, Joey | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Pell, Jill P. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Meade, Tom | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Christophersen, Ingrid E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Maitland-van der Zee, Anke H. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Baranova, Ekaterina V. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Young, Robin | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Ford, Ian | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Campbell, Archie | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Padmanabhan, Sandosh | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bots, Michiel L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Grobbee, Diederick E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Froguel, Philippe | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Thuillier, Dorothee | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Roussel, Ronan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bonnefond, Amelie | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Cariou, Bertrand | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Smart, Melissa | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bao, Yanchun | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Kumari, Meena | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Mahajan, Anubha | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hopewell, Jemma C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Seshadri, Sudha | UNSPECIFIED | orcid.org/0000-0001-6135-2622 | UNSPECIFIED | Dale, Caroline | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Costa, Rui Providencia E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Ridker, Paul M. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Chasman, Daniel I. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Reiner, Alex P. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Ritchie, Marylyn D. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lange, Leslie A. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Cornish, Alex J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Dobbins, Sara E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hemminki, Kari | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Kinnersley, Ben | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Sanson, Marc | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Labreche, Karim | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Simon, Matthias | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bondy, Melissa | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Law, Philip | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Speedy, Helen | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Allan, James | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Li, Ni | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Went, Molly | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Weinhold, Niels | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Morgan, Gareth | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Sonneveld, Pieter | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Nilsson, Bjorn | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Goldschmidt, Hartmut | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Sud, Amit | UNSPECIFIED | orcid.org/0000-0002-6133-0164 | UNSPECIFIED | Engert, Andreas | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hansson, Markus | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hemingway, Harry | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Asselbergs, Folkert W. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Patel, Riyaz S. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Keating, Brendan J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Sattar, Naveed | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Houlston, Richard | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Casas, Juan P. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hingorani, Aroon D. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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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: |
Keywords | Language |
---|
CORONARY-HEART-DISEASE; MENDELIAN RANDOMIZATION; STATIN THERAPY; RISK; STROKE; PREVENTION; EZETIMIBE; EFFICACY | Multiple languages | Cardiac & Cardiovascular Systems | Multiple languages |
|
Refereed: |
Yes |
URI: |
http://kups.ub.uni-koeln.de/id/eprint/13017 |
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