title: Premature aging of leukocyte DNA methylation is associated with type 2 diabetes prevalence.
abstract: BACKGROUND
  Type 2 diabetes mellitus (T2D) is highly prevalent in Middle-Eastern and North African Arab populations, but the molecular basis for this susceptibility is unknown. Altered DNA methylation levels were reported in insulin-secreting and responding tissues, but whether methylation in accessible tissues such as peripheral blood is associated with T2D risk remains an open question. Age-related alteration of DNA methylation level was reported in certain methylation sites, but no association with T2D has been shown. Here we report on a population-based study of 929 men and women representing the East Jerusalem Palestinian (EJP) Arab population and compare with the findings among Israeli Ashkenazi Jews. This is the first reported epigenetic study of an Arab population with a characteristic high prevalence of T2D.
  
  
  RESULTS
  We found that DNA methylation of a prespecified regulatory site in peripheral blood leukocytes (PBLs) is associated with impaired glucose metabolism and T2D independent of sex, body mass index, and white blood cell composition. This CpG site (Chr16: 53,809,231-2; hg19) is located in a region within an intron of the FTO gene, suspected to serve as a tissue-specific enhancer. The association between PBL hypomethylation and T2D varied by age, revealing differential patterns of methylation aging in healthy and diabetic individuals and between ethnic groups: T2D patients displayed prematurely low methylation levels, and this hypomethylation was greater and occurred earlier in life among Palestinian Arabs than Ashkenazi Jews.
  
  
  CONCLUSIONS
  Our study suggests that premature DNA methylation aging is associated with increased risk of T2D. These findings should stimulate the search for more such sites and may pave the way to improved T2D risk prediction within and between human populations.
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel.
authors.forename: Gidon
authors.initials: G
authors.lastname: Toperoff
authors.affiliation: Epidemiology Unit, Braun School of Public Health and Community Medicine, Hebrew University and Hadassah Medical Organization, Jerusalem, Israel.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Kark
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel ; School of Computer Science and Engineering, Hebrew University, Jerusalem, Israel.
authors.forename: Dvir
authors.initials: D
authors.lastname: Aran
authors.affiliation: Cardiology Department, Hadassah-Hebrew University Medical Center, Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel ; St Joseph Hospital (East Jerusalem), Jerusalem, Israel.
authors.forename: Hisham
authors.initials: H
authors.lastname: Nassar
authors.affiliation: Epidemiology Unit, Braun School of Public Health and Community Medicine, Hebrew University and Hadassah Medical Organization, Jerusalem, Israel.
authors.forename: Wiessam Abu
authors.initials: WA
authors.lastname: Ahmad
authors.affiliation: Epidemiology Unit, Braun School of Public Health and Community Medicine, Hebrew University and Hadassah Medical Organization, Jerusalem, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Sinnreich
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel.
authors.forename: Dima
authors.initials: D
authors.lastname: Azaiza
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Hellman
keywords: Ashkenazi Jews; DNA methylation; East Jerusalem Palestinians; Epigenetic aging; Ethnic groups; Leukocytes; Population epigenetics; Type 2 diabetes
references.citation: Diabet Med. 2012 Jun;29(6):748-54
references.pmid: 22050554
references.citation: Epigenetics Chromatin. 2010 May 24;3(1):11
references.pmid: 20497546
references.citation: Lancet. 2000 Oct 21;356(9239):1410-1
references.pmid: 11052588
references.citation: Ann Epidemiol. 2009 Feb;19(2):112-7
references.pmid: 19185804
references.citation: J Biol Chem. 1998 Aug 7;273(32):20175-9
references.pmid: 9685363
references.citation: Mol Psychiatry. 2012 Jul;17(7):728-40
references.pmid: 21647149
references.citation: Lancet. 2011 Jul 2;378(9785):31-40
references.pmid: 21705069
references.citation: Diabetes Care. 1998 Jun;21(6):936-42
references.pmid: 9614611
references.citation: Am J Hum Genet. 2001 Nov;69(5):1095-112
references.pmid: 11573163
references.citation: Diabet Med. 1997 Jul;14(7):595-602
references.pmid: 9223399
references.citation: PLoS One. 2010 Nov 18;5(11):e14040
references.pmid: 21124985
references.citation: Science. 2007 May 11;316(5826):889-94
references.pmid: 17434869
references.citation: Nat Genet. 2008 Jul;40(7):904-8
references.pmid: 18568024
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827
references.citation: Mol Endocrinol. 2012 Jul;26(7):1203-12
references.pmid: 22570331
references.citation: PLoS One. 2012;7(8):e40948
references.pmid: 22905094
references.citation: PLoS One. 2015 Jan 30;10(1):e0116617
references.pmid: 25635396
references.citation: Cell Metab. 2014 Jan 7;19(1):135-45
references.pmid: 24374217
references.citation: PLoS One. 2012;7(12):e51302
references.pmid: 23251491
references.citation: Int J Epidemiol. 2010 Oct;39(5):1324-32
references.pmid: 20534651
references.citation: BMC Public Health. 2012 Jan 30;12:90
references.pmid: 22289260
references.citation: PLoS One. 2010 May 20;5(5):e10521
references.pmid: 20502638
references.citation: EMBO J. 2012 Mar 21;31(6):1405-26
references.pmid: 22293752
references.citation: Am J Hum Genet. 2010 Jun 11;86(6):850-9
references.pmid: 20560205
references.citation: Diabetologia. 2008 Nov;51(11):2078-87
references.pmid: 18758746
references.citation: Int J Endocrinol. 2012;2012:902873
references.pmid: 22851968
references.citation: Trends Genet. 2008 Dec;24(12):613-21
references.pmid: 18952314
references.citation: Diabetes. 2011 May;60(5):1637-44
references.pmid: 21398525
references.citation: Nature. 2014 Mar 20;507(7492):371-5
references.pmid: 24646999
references.citation: Atherosclerosis. 2013 Aug;229(2):363-8
references.pmid: 23880188
references.citation: Am J Hum Genet. 2010 Feb 12;86(2):196-212
references.pmid: 20159110
references.citation: Hum Mol Genet. 2012 Jan 15;21(2):371-83
references.pmid: 21994764
references.citation: Int J Epidemiol. 2006 Apr;35(2):448-57
references.pmid: 16455758