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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2020
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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. |
format | Online Article Text |
id | pubmed-7666287 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
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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