title: Type 2 diabetes and leucocyte DNA methylation: an epigenome-wide association study in over 1,500 older adults.
abstract: OBJECTIVE
  Development of type 2 diabetes depends on environmental and genetic factors. We investigated the epigenome-wide association of prevalent diabetes with DNA methylation (DNAm) in peripheral blood.
  
  
  METHODS
  DNAm was measured in whole blood with the Illumina Infinium HumanMethylation450 BeadChip in two subsamples of participants from the ESTHER cohort study. Cohort 1 included 988 participants, who were consecutively recruited between July and October 2000 and cohort 2 included 527 randomly selected participants. The association of DNAm with prevalent type 2 diabetes at recruitment was estimated using median regression analysis adjusting for sex, age, BMI, smoking behaviour, cell composition and batch at 361,922 CpG sites.
  
  
  RESULTS
  Type 2 diabetes was prevalent in 16% of the participants, and diabetes was poorly controlled in 45% of the diabetic patients. In cohort 1 (discovery) DNAm at 39 CpGs was significantly associated with prevalent diabetes after correction for multiple testing. In cohort 2 (replication) at one of these CpGs, DNAm was still significantly associated. Decreasing methylation levels at cg19693031 with increasing fasting glucose and HbA1c concentrations were observed using restricted cubic spline analysis. In diabetic patients with poorly controlled diabetes, the decrease in estimated DNAm levels was approximately 5% in comparison with participants free of diagnosed diabetes.
  
  
  CONCLUSIONS
  Cg19693031, which is located within the 3'-untranslated region of TXNIP, might play a role in the pathophysiology of type 2 diabetes. This result appears biologically plausible given that thioredoxin-interacting protein is overexpressed in diabetic animals and humans and 3'-untranslated regions are known to play a regulatory role in gene expression.
authors.affiliation: Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. i.florath@gmx.de.
authors.forename: Ines
authors.initials: I
authors.lastname: Florath
authors.affiliation: Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Butterbach
authors.affiliation: Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Heiss
authors.affiliation: Core Facility Genomics & Proteomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bewerunge-Hudler
authors.affiliation: Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Schöttker
authors.affiliation: Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002352:Carrier Proteins / Q000378:metabolism; D015331:Cohort Studies; D018899:CpG Islands; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007962:Leukocytes / Q000166:cytology*; D008297:Male; D008875:Middle Aged; D012907:Smoking; D011795:Surveys and Questionnaires
chemical_list: D020413:3' Untranslated Regions; D001786:Blood Glucose; D002352:Carrier Proteins; C486715:TXNIP protein, human
keywords: 450k array; DNA methylation; Epigenome-wide; Illumina Infinium HumanMethylation450 BeadChip; Peripheral blood; Type 2 diabetes