PMID- 31506343
OWN - NLM
STAT- MEDLINE
DCOM- 20200316
LR  - 20240214
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 68
IP  - 12
DP  - 2019 Dec
TI  - Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British 
      Population: EPIC-Norfolk Study.
PG  - 2315-2326
LID - 10.2337/db18-0290 [doi]
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.
CI  - (c) 2019 by the American Diabetes Association.
FAU - Cardona, Alexia
AU  - Cardona A
AUID- ORCID: 0000-0002-7877-5565
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K. 
      alexia.cardona@mrc-epid.cam.ac.uk ken.ong@mrc-epid.cam.ac.uk.
AD  - Department of Genetics, University of Cambridge, Cambridge, U.K.
FAU - Day, Felix R
AU  - Day FR
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Perry, John R B
AU  - Perry JRB
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Loh, Marie
AU  - Loh M
AD  - Department of Epidemiology and Biostatistics, Imperial College London, London, 
      U.K.
AD  - Translational Laboratory in Genetic Medicine, Agency for Science, Technology and 
      Research, Singapore.
AD  - Department of Biochemistry, National University of Singapore, Singapore.
FAU - Chu, Audrey Y
AU  - Chu AY
AD  - Population Sciences Branch, Division of Intramural Research, National Heart, 
      Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
FAU - Lehne, Benjamin
AU  - Lehne B
AD  - Department of Epidemiology and Biostatistics, Imperial College London, London, 
      U.K.
FAU - Paul, Dirk S
AU  - Paul DS
AD  - MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary 
      Care, University of Cambridge, Cambridge, U.K.
FAU - Lotta, Luca A
AU  - Lotta LA
AUID- ORCID: 0000-0002-2619-5956
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Stewart, Isobel D
AU  - Stewart ID
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Kerrison, Nicola D
AU  - Kerrison ND
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Scott, Robert A
AU  - Scott RA
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Khaw, Kay-Tee
AU  - Khaw KT
AUID- ORCID: 0000-0002-8802-2903
AD  - Department of Public Health and Primary Care, University of Cambridge, Cambridge, 
      U.K.
FAU - Forouhi, Nita G
AU  - Forouhi NG
AUID- ORCID: 0000-0002-5041-248X
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Langenberg, Claudia
AU  - Langenberg C
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Liu, Chunyu
AU  - Liu C
AD  - Population Sciences Branch, Division of Intramural Research, National Heart, 
      Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
AD  - Department of Biostatistics, School of Public Health, Boston University, Boston, 
      MA.
FAU - Mendelson, Michael M
AU  - Mendelson MM
AD  - Population Sciences Branch, Division of Intramural Research, National Heart, 
      Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
AD  - Department of Biostatistics, School of Public Health, Boston University, Boston, 
      MA.
AD  - Department of Cardiology, Boston Children's Hospital, Boston, MA.
FAU - Levy, Daniel
AU  - Levy D
AD  - Population Sciences Branch, Division of Intramural Research, National Heart, 
      Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
FAU - Beck, Stephan
AU  - Beck S
AD  - Medical Genomics, UCL Cancer Institute, University College London, London, U.K.
FAU - Leslie, R David
AU  - Leslie RD
AUID- ORCID: 0000-0002-1786-1531
AD  - The Blizard Institute, Barts and The London School of Medicine and Dentistry, 
      Queen Mary University of London, London, U.K.
FAU - Dupuis, Josee
AU  - Dupuis J
AD  - Department of Biostatistics, School of Public Health, Boston University, Boston, 
      MA.
FAU - Meigs, James B
AU  - Meigs JB
AD  - Division of General Internal Medicine, Massachusetts General Hospital, Boston, 
      MA.
AD  - Harvard Medical School, Boston, MA.
AD  - Programs in Metabolism and Medical and Population Genetics, Broad Institute, 
      Cambridge, MA.
FAU - Kooner, Jaspal S
AU  - Kooner JS
AD  - Department of Cardiology, Ealing Hospital, Middlesex, U.K.
AD  - Imperial College Healthcare NHS Trust, London, U.K.
AD  - MRC-PHE Centre for Environment and Health, Imperial College London, London, U.K.
AD  - National Heart and Lung Institute, Imperial College London, London, U.K.
FAU - Pihlajamaki, Jussi
AU  - Pihlajamaki J
AD  - Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 
      Joensuu, Finland.
AD  - Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, 
      Finland.
FAU - Vaag, Allan
AU  - Vaag A
AD  - Cardiovascular and Metabolic Disease Translational Medicine Unit, Early Clinical 
      Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
FAU - Perfilyev, Alexander
AU  - Perfilyev A
AD  - Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University 
      Diabetes Centre, Scania University Hospital, Malmo, Sweden.
FAU - Ling, Charlotte
AU  - Ling C
AUID- ORCID: 0000-0003-0587-7154
AD  - Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University 
      Diabetes Centre, Scania University Hospital, Malmo, Sweden.
FAU - Hivert, Marie-France
AU  - Hivert MF
AUID- ORCID: 0000-0001-7752-2585
AD  - Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard 
      Medical School, Boston, MA.
AD  - Massachusetts General Hospital, Boston, MA.
FAU - Chambers, John C
AU  - Chambers JC
AD  - Department of Epidemiology and Biostatistics, Imperial College London, London, 
      U.K.
AD  - Department of Cardiology, Ealing Hospital, Middlesex, U.K.
AD  - Imperial College Healthcare NHS Trust, London, U.K.
AD  - MRC-PHE Centre for Environment and Health, Imperial College London, London, U.K.
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
FAU - Wareham, Nicholas J
AU  - Wareham NJ
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K.
FAU - Ong, Ken K
AU  - Ong KK
AD  - MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical 
      Medicine, University of Cambridge, Cambridge, U.K. 
      alexia.cardona@mrc-epid.cam.ac.uk ken.ong@mrc-epid.cam.ac.uk.
LA  - eng
GR  - 212945/Z/18/Z/WT_/Wellcome Trust/United Kingdom
GR  - MR/N003284/1/MRC_/Medical Research Council/United Kingdom
GR  - G9502233/MRC_/Medical Research Council/United Kingdom
GR  - G0401527/MRC_/Medical Research Council/United Kingdom
GR  - MR/L00002/1/MRC_/Medical Research Council/United Kingdom
GR  - G1000143/MRC_/Medical Research Council/United Kingdom
GR  - U01 DK078616/DK/NIDDK NIH HHS/United States
GR  - 090532/WT_/Wellcome Trust/United Kingdom
GR  - 14136/CRUK_/Cancer Research UK/United Kingdom
GR  - N01HC25195/HL/NHLBI NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - UM1 DK078616/DK/NIDDK NIH HHS/United States
GR  - K99 HL136875/HL/NHLBI NIH HHS/United States
GR  - G0700931/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_12015/2/MRC_/Medical Research Council/United Kingdom
GR  - MR/L003120/1/MRC_/Medical Research Council/United Kingdom
GR  - G0601966/MRC_/Medical Research Council/United Kingdom
GR  - 098381/WT_/Wellcome Trust/United Kingdom
GR  - HHSN268201500001C/HL/NHLBI NIH HHS/United States
GR  - SP/04/002/BHF_/British Heart Foundation/United Kingdom
GR  - MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom
GR  - C864/A8257/CRUK_/Cancer Research UK/United Kingdom
GR  - HHSN268201500001I/HL/NHLBI NIH HHS/United States
GR  - K24 DK080140/DK/NIDDK NIH HHS/United States
GR  - MC_UU_12015/5/MRC_/Medical Research Council/United Kingdom
GR  - RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom
GR  - RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom
GR  - 084723/Z/08/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190910
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Blood Glucose)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Blood Glucose
MH  - *DNA Methylation
MH  - Diabetes Mellitus, Type 2/epidemiology/*genetics
MH  - England/epidemiology
MH  - *Epigenome
MH  - Epigenomics
MH  - Female
MH  - Genetic Association Studies
MH  - Humans
MH  - Incidence
MH  - Male
MH  - Middle Aged
PMC - PMC6868468
EDAT- 2019/09/12 06:00
MHDA- 2020/03/17 06:00
PMCR- 2020/12/01
CRDT- 2019/09/12 06:00
PHST- 2018/03/12 00:00 [received]
PHST- 2019/08/25 00:00 [accepted]
PHST- 2019/09/12 06:00 [pubmed]
PHST- 2020/03/17 06:00 [medline]
PHST- 2019/09/12 06:00 [entrez]
PHST- 2020/12/01 00:00 [pmc-release]
AID - db18-0290 [pii]
AID - 0290 [pii]
AID - 10.2337/db18-0290 [doi]
PST - ppublish
SO  - Diabetes. 2019 Dec;68(12):2315-2326. doi: 10.2337/db18-0290. Epub 2019 Sep 10.