RT Journal Article
SR Electronic
T1 Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 2315
OP 2326
DO 10.2337/db18-0290
VO 68
IS 12
A1 Cardona, Alexia
A1 Day, Felix R.
A1 Perry, John R.B.
A1 Loh, Marie
A1 Chu, Audrey Y.
A1 Lehne, Benjamin
A1 Paul, Dirk S.
A1 Lotta, Luca A.
A1 Stewart, Isobel D.
A1 Kerrison, Nicola D.
A1 Scott, Robert A.
A1 Khaw, Kay-Tee
A1 Forouhi, Nita G.
A1 Langenberg, Claudia
A1 Liu, Chunyu
A1 Mendelson, Michael M.
A1 Levy, Daniel
A1 Beck, Stephan
A1 Leslie, R. David
A1 Dupuis, Josée
A1 Meigs, James B.
A1 Kooner, Jaspal S.
A1 Pihlajamäki, Jussi
A1 Vaag, Allan
A1 Perfilyev, Alexander
A1 Ling, Charlotte
A1 Hivert, Marie-France
A1 Chambers, John C.
A1 Wareham, Nicholas J.
A1 Ong, Ken K.
YR 2019
UL http://diabetes.diabetesjournals.org/content/68/12/2315.abstract
AB 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 population-based 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 obesity-related 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.