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Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease

Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we...

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Autores principales: Dabin, Luke C., Guntoro, Fernando, Campbell, Tracy, Bélicard, Tony, Smith, Adam R., Smith, Rebecca G., Raybould, Rachel, Schott, Jonathan M., Lunnon, Katie, Sarkies, Peter, Collinge, John, Mead, Simon, Viré, Emmanuelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666287/
https://www.ncbi.nlm.nih.gov/pubmed/32918118
http://dx.doi.org/10.1007/s00401-020-02224-9
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author Dabin, Luke C.
Guntoro, Fernando
Campbell, Tracy
Bélicard, Tony
Smith, Adam R.
Smith, Rebecca G.
Raybould, Rachel
Schott, Jonathan M.
Lunnon, Katie
Sarkies, Peter
Collinge, John
Mead, Simon
Viré, Emmanuelle
author_facet Dabin, Luke C.
Guntoro, Fernando
Campbell, Tracy
Bélicard, Tony
Smith, Adam R.
Smith, Rebecca G.
Raybould, Rachel
Schott, Jonathan M.
Lunnon, Katie
Sarkies, Peter
Collinge, John
Mead, Simon
Viré, Emmanuelle
author_sort Dabin, Luke C.
collection PubMed
description Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt–Jakob disease (sCJD). Our case–control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10(–7)). Nine of these sites were taken forward in a replication study, performed in an independent case–control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case–control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer’s disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-020-02224-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-76662872020-11-17 Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease Dabin, Luke C. Guntoro, Fernando Campbell, Tracy Bélicard, Tony Smith, Adam R. Smith, Rebecca G. Raybould, Rachel Schott, Jonathan M. Lunnon, Katie Sarkies, Peter Collinge, John Mead, Simon Viré, Emmanuelle Acta Neuropathol Original Paper Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt–Jakob disease (sCJD). Our case–control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10(–7)). Nine of these sites were taken forward in a replication study, performed in an independent case–control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case–control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer’s disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-020-02224-9) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-09-12 2020 /pmc/articles/PMC7666287/ /pubmed/32918118 http://dx.doi.org/10.1007/s00401-020-02224-9 Text en © The Author(s) 2020, corrected publication 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Paper
Dabin, Luke C.
Guntoro, Fernando
Campbell, Tracy
Bélicard, Tony
Smith, Adam R.
Smith, Rebecca G.
Raybould, Rachel
Schott, Jonathan M.
Lunnon, Katie
Sarkies, Peter
Collinge, John
Mead, Simon
Viré, Emmanuelle
Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease
title Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease
title_full Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease
title_fullStr Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease
title_full_unstemmed Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease
title_short Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease
title_sort altered dna methylation profiles in blood from patients with sporadic creutzfeldt–jakob disease
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666287/
https://www.ncbi.nlm.nih.gov/pubmed/32918118
http://dx.doi.org/10.1007/s00401-020-02224-9
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