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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
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.
Affiliation
  • Schmidt AF; Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. amand.schmidt@ucl.ac.uk.
  • Holmes MV; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. amand.schmidt@ucl.ac.uk.
  • Preiss D; UCL's BHF Research Accelerator Centre, London, UK. amand.schmidt@ucl.ac.uk.
  • Swerdlow DI; Medical Research Council Population Health Research Unit, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • Denaxas S; Medical Research Council Population Health Research Unit, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • Fatemifar G; Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Faraway R; Department of Medicine, Imperial College London, London, UK.
  • Finan C; UCL's BHF Research Accelerator Centre, London, UK.
  • Valentine D; Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Fairhurst-Hunter Z; Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Hartwig FP; The Alan Turing Institute, British Library, 96 Euston Rd, London, NW1 2DB, UK.
  • Horta BL; UCL's BHF Research Accelerator Centre, London, UK.
  • Hypponen E; Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Power C; Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Moldovan M; Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • van Iperen E; Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.
  • Hovingh K; UCL's BHF Research Accelerator Centre, London, UK.
  • Demuth I; UCL's BHF Research Accelerator Centre, London, UK.
  • Norman K; University College London, Farr Institute of Health Informatics, London, UK.
  • Steinhagen-Thiessen E; Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK.
  • Demuth J; Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
  • Bertram L; Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
  • Lill CM; Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
  • Coassin S; Population, Policy and Practice, UCL GOS Institute of Child Health, London, UK.
  • Willeit J; South Australian Health and Medical Research Institute, Adelaide, Australia.
  • Kiechl S; Population, Policy and Practice, UCL GOS Institute of Child Health, London, UK.
  • Willeit K; South Australian Health and Medical Research Institute, Adelaide, Australia.
  • Mason D; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
  • Wright J; Department of Clinical Epidemiology, Biostatistics And Bioinformatics, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
  • Morris R; Department of vascular medicine, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
  • Wanamethee G; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Lipid Clinic at the Interdisciplinary Metabolism Center, Berlin, Germany.
  • Whincup P; Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.
  • Ben-Shlomo Y; Institute of Nutritional Science, University of Potsdam, 14558, Nuthetal, Germany.
  • McLachlan S; Geriatrics Research Group, Charité - Universitätsmedizin Berlin, 13347, Berlin, Germany.
  • Price JF; Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Nuthetal, Germany.
  • Kivimaki M; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Lipid Clinic at the Interdisciplinary Metabolism Center, Berlin, Germany.
  • Welch C; E.CA Economics GmbH, Berlin, Germany.
  • Sanchez-Galvez A; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
  • Marques-Vidal P; Center for Lifespan Changes in Brain and Cognition (LCBC), Dept. Psychology, University of Oslo, Oslo, Norway.
  • Nicolaides A; Genetic and Molecular Epidemiology Group, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck, Germany.
  • Panayiotou AG; Institute of Human Genetics, Lübeck, Germany.
  • Onland-Moret NC; Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, UK.
  • van der Schouw YT; Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, 6020, Innsbruck, Austria.
  • Matullo G; Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
  • Fiorito G; Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
  • Guarrera S; Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
  • Sacerdote C; Department of Neurology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland.
  • Wareham NJ; Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
  • Langenberg C; Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
  • Scott RA; Department Primary Care & Population Health, University College London, London, UK.
BMC Cardiovasc Disord ; 19(1): 240, 2019 10 29.
Article in En | MEDLINE | ID: mdl-31664920
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serine Proteinase Inhibitors / Polymorphism, Single Nucleotide / Dyslipidemias / Proprotein Convertase 9 / PCSK9 Inhibitors / Cholesterol, LDL / Anticholesteremic Agents Type of study: Clinical_trials / Etiology_studies / Risk_factors_studies Limits: Humans Language: En Journal: BMC Cardiovasc Disord Journal subject: ANGIOLOGIA / CARDIOLOGIA Year: 2019 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serine Proteinase Inhibitors / Polymorphism, Single Nucleotide / Dyslipidemias / Proprotein Convertase 9 / PCSK9 Inhibitors / Cholesterol, LDL / Anticholesteremic Agents Type of study: Clinical_trials / Etiology_studies / Risk_factors_studies Limits: Humans Language: En Journal: BMC Cardiovasc Disord Journal subject: ANGIOLOGIA / CARDIOLOGIA Year: 2019 Type: Article