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Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis

Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis
Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis
Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ?50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P?=?0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P?=?0.001) and at (P?=?0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P?=?0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.
1553-7390
1-9
Rakyan, Vardhman K.
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Beyan, Huriya
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Down, Thomas A.
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Hawa, Mohammed I.
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Maslau, Siarhei
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Aden, Deeqo
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Daunay, Antoine
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Busato, Florence
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Mein, Charles A.
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Manfras, Burkhard
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Dias, Kerith-Rae M.
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Bell, Christopher G.
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Tost, Jörg
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Boehm, Bernhard O.
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Beck, Stephan
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Leslie, R. David
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Rakyan, Vardhman K.
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Beyan, Huriya
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Down, Thomas A.
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Hawa, Mohammed I.
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Maslau, Siarhei
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Aden, Deeqo
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Daunay, Antoine
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Busato, Florence
ce103807-1553-442e-85bf-add52e797acf
Mein, Charles A.
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Manfras, Burkhard
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Dias, Kerith-Rae M.
e9c665d9-8a93-4d74-8109-5f447daad09e
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Tost, Jörg
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Boehm, Bernhard O.
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Beck, Stephan
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Leslie, R. David
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Rakyan, Vardhman K., Beyan, Huriya, Down, Thomas A., Hawa, Mohammed I., Maslau, Siarhei, Aden, Deeqo, Daunay, Antoine, Busato, Florence, Mein, Charles A., Manfras, Burkhard, Dias, Kerith-Rae M., Bell, Christopher G., Tost, Jörg, Boehm, Bernhard O., Beck, Stephan and Leslie, R. David (2011) Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genetics, 7 (9), 1-9. (doi:10.1371/journal.pgen.1002300). (PMID:21980303)

Record type: Article

Abstract

Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ?50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P?=?0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P?=?0.001) and at (P?=?0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P?=?0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.

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Accepted/In Press date: 3 August 2011
Published date: 29 September 2011
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

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Local EPrints ID: 400986
URI: http://eprints.soton.ac.uk/id/eprint/400986
ISSN: 1553-7390
PURE UUID: 24b21d71-79af-43a2-9405-06d67827bc81
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 13:35
Last modified: 14 Sep 2021 18:57

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