Rakyan, VK;
Beyan, H;
Down, TA;
Hawa, MI;
Maslau, S;
Aden, D;
Daunay, A;
... Leslie, RD; + view all
(2011)
Identification of Type 1 Diabetes-Associated DNA Methylation Variable Positions That Precede Disease Diagnosis.
PLOS GENET
, 7
(9)
, Article e1002300. 10.1371/journal.pgen.1002300.
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Abstract
Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is similar to 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.
| Type: | Article |
|---|---|
| Title: | Identification of Type 1 Diabetes-Associated DNA Methylation Variable Positions That Precede Disease Diagnosis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1002300 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1002300 |
| Language: | English |
| Additional information: | © 2011 Rakyan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Juvenile Diabetes Research Foundation International, the British Diabetic Twin Trust, the National Institute for Health Research Cambridge Biomedical Centre, and the Mary Kinross Trust. VKR was supported by a NHMRC of Australia CJ Martin Fellowship and the Barts and The London Charity. HB was supported by a Wellcome Trust (VIP) award. TAD is supported by a Wellcome Trust Research Career Development Fellowship (083563). The CIMR is in receipt of a Wellcome Trust Strategic Award (079895). CGB and SB were supported by the Wellcome Trust (084071), and SB is recipient of a Royal Society Wolfson Research Merit Award. BM and BOB were supported by DFG (GrK1041) and Center of Excellence. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | MONOZYGOTIC TWINS, AUTOIMMUNITY, EXPRESSION, AGE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1326499 |
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