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Organization: METASTROKE Consortium of the ISGC

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Online article

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Schmidt, Amand F
Author Schmidt, Amand F Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. amand.schmidt@ucl.ac.uk. Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. amand.schmidt@ucl.ac.uk. UCL's BHF Research Accelerator Centre, London, UK. amand.schmidt@ucl.ac.uk
Holmes, Michael V
Author Holmes, Michael V 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
Preiss, David
Author Preiss, David 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
Swerdlow, Daniel I
Author Swerdlow, Daniel I Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. Department of Medicine, Imperial College London, London, UK
Denaxas, Spiros
Author Denaxas, Spiros UCL's BHF Research Accelerator Centre, London, UK. Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK. Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK. The Alan Turing Institute, British Library, 96 Euston Rd, London, NW1 2DB, UK
Fatemifar, Ghazaleh
Author Fatemifar, Ghazaleh UCL's BHF Research Accelerator Centre, London, UK. Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK. Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, UK
Faraway, Rupert
Author Faraway, Rupert Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK
Finan, Chris
Author Finan, Chris Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. UCL's BHF Research Accelerator Centre, London, UK
Valentine, Dennis
Author Valentine, Dennis UCL's BHF Research Accelerator Centre, London, UK. University College London, Farr Institute of Health Informatics, London, UK
Fairhurst-Hunter, Zammy
Author Fairhurst-Hunter, Zammy 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

BMC cardiovascular disorders. 2019 ; 19 (1) : 240. [pub] 20191029

BMC Cardiovasc Disord
ISSN 1471-2261
Medvik
Source

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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