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Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

Paul, Dirk S.; Teschendorff, Andrew E.; Dang, Mary A N; Lowe, Robert; Hawa, Mohammed I.; Ecker, Simone; Beyan, Huriya; Cunningham, Stephanie; Fouts, Alexandra R. and Ramelius, Anita LU , et al. (2016) In Nature Communications 7.
Abstract

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell... (More)

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.

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Nature Communications
volume
7
publisher
Nature Publishing Group
external identifiers
  • scopus:84999233015
  • wos:000388992700001
ISSN
2041-1723
DOI
10.1038/ncomms13555
language
English
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yes
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44133c31-2227-4af7-92de-e9f62cf6cd7d
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2016-12-19 09:23:30
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2017-09-24 05:04:49
@article{44133c31-2227-4af7-92de-e9f62cf6cd7d,
  abstract     = {<p>The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.</p>},
  articleno    = {13555},
  author       = {Paul, Dirk S. and Teschendorff, Andrew E. and Dang, Mary A N and Lowe, Robert and Hawa, Mohammed I. and Ecker, Simone and Beyan, Huriya and Cunningham, Stephanie and Fouts, Alexandra R. and Ramelius, Anita and Burden, Frances and Farrow, Samantha and Rowlston, Sophia and Rehnstrom, Karola and Frontini, Mattia and Downes, Kate and Busche, Stephan and Cheung, Warren A. and Ge, Bing and Simon, Marie Michelle and Bujold, David and Kwan, Tony and Bourque, Guillaume and Datta, Avik and Lowy, Ernesto and Clarke, Laura and Flicek, Paul and Libertini, Emanuele and Heath, Simon and Gut, Marta and Gut, Ivo G. and Ouwehand, Willem H. and Pastinen, Tomi and Soranzo, Nicole and Hofer, Sabine E. and Karges, Beate and Meissner, Thomas and Boehm, Bernhard O. and Cilio, Corrado and Larsson, Helena Elding and Lernmark, Åke and Steck, Andrea K. and Rakyan, Vardhman K. and Beck, Stephan and Leslie, R. David},
  issn         = {2041-1723},
  language     = {eng},
  month        = {11},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Increased DNA methylation variability in type 1 diabetes across three immune effector cell types},
  url          = {http://dx.doi.org/10.1038/ncomms13555},
  volume       = {7},
  year         = {2016},
}