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Epigenome-wide association study of incident type 2 diabetes in a British population : EPIC-Norfolk study

Cardona, Alexia ; Day, Felix R. ; Perry, John R.B. ; Loh, Marie ; Chu, Audrey Y. ; Lehne, Benjamin ; Paul, Dirk S. ; Lotta, Luca A. ; Stewart, Isobel D. and Kerrison, Nicola D. , et al. (2019) In Diabetes 68(12). p.2315-2326
Abstract

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the populationbased European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs... (More)

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the populationbased European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesityrelated pathways acting before the collection of baseline samples.We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

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published
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Diabetes
volume
68
issue
12
pages
12 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:31506343
  • scopus:85075812967
ISSN
0012-1797
DOI
10.2337/db18-0290
language
English
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yes
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2e29c98f-33ff-4bf3-bf05-bda334b57425
date added to LUP
2019-12-17 08:51:15
date last changed
2020-01-13 02:36:43
@article{2e29c98f-33ff-4bf3-bf05-bda334b57425,
  abstract     = {<p>Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the populationbased European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesityrelated pathways acting before the collection of baseline samples.We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.</p>},
  author       = {Cardona, Alexia and Day, Felix R. and Perry, John R.B. and Loh, Marie and Chu, Audrey Y. and Lehne, Benjamin and Paul, Dirk S. and Lotta, Luca A. and Stewart, Isobel D. and Kerrison, Nicola D. and Scott, Robert A. and Khaw, Kay Tee and Forouhi, Nita G. and Langenberg, Claudia and Liu, Chunyu and Mendelson, Michael M. and Levy, Daniel and Beck, Stephan and Leslie, R. David and Dupuis, Josée and Meigs, James B. and Kooner, Jaspal S. and Pihlajamäki, Jussi and Vaag, Allan and Perfilyev, Alexander and Ling, Charlotte and Hivert, Marie France and Chambers, John C. and Wareham, Nicholas J. and Ong, Ken K.},
  issn         = {0012-1797},
  language     = {eng},
  number       = {12},
  pages        = {2315--2326},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Epigenome-wide association study of incident type 2 diabetes in a British population : EPIC-Norfolk study},
  url          = {http://dx.doi.org/10.2337/db18-0290},
  doi          = {10.2337/db18-0290},
  volume       = {68},
  year         = {2019},
}