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.