التفاصيل البيبلوغرافية
| العنوان: |
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. |
| المؤلفون: |
Schmidt, Amand F, Holmes, Michael V, Preiss, David, Swerdlow, Daniel I, Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M, Coassin, Stefan, 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, 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, Pająk, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, 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, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, van der Harst, Pim, Said, M Abdullah, Eppinga, Ruben N, Verweij, Niek, Snieder, Harold, Lifelines Cohort authors, Christen, Tim, Mook-Kanamori, DO, ICBP Consortium, Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M, Völker, Uwe, Völzke, 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, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C, Seshadri, Sudha, METASTROKE Consortium of the ISGC, 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, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W, Patel, Riyaz S, Keating, Brendan J, Sattar, Naveed, Houlston, Richard, Casas, Juan P, Hingorani, Aroon D |
| بيانات النشر: |
Springer Science and Business Media LLC
//dx.doi.org/10.1186/s12872-019-1187-z
BMC Cardiovasc Disord |
| سنة النشر: |
2019 |
| المجموعة: |
Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: |
Genetic association studies, LDL-cholesterol, Mendelian randomisation, Phenome-wide association scan, Anticholesteremic Agents, Biomarkers, Brain Ischemia, Cholesterol, LDL, Down-Regulation, Dyslipidemias, Genome-Wide Association Study, Humans, Myocardial Infarction, PCSK9 Inhibitors, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Serine Proteinase Inhibitors, Stroke, Treatment Outcome |
| الوصف: |
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. ; Dr Schmidt is supported by BHF grant PG/18/5033837. This research has been funded by the British Heart Foundation (SP/13/6/30554, RG/10/12/28456). The work was also supported by UCL Hospitals NIHR Biomedical Research Centre and by the Rosetrees and Stoneygate Trusts. This research has been conducted using the UK Biobank Resource under Application Number 12113. The authors are grateful to UK Biobank participants. UK Biobank was established by the Wellcome ... |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
Electronic; application/vnd.openxmlformats-officedocument.wordprocessingml.document; application/pdf |
| اللغة: |
English |
| العلاقة: |
https://www.repository.cam.ac.uk/handle/1810/296156Test |
| DOI: |
10.17863/CAM.43205 |
| الإتاحة: |
https://doi.org/10.17863/CAM.43205Test
https://www.repository.cam.ac.uk/handle/1810/296156Test |
| حقوق: |
All rights reserved |
| رقم الانضمام: |
edsbas.ADC86C26 |
| قاعدة البيانات: |
BASE |
