title: DNA Methylation Profiling in Inflammatory Bowel Disease Provides New Insights into Disease Pathogenesis.
abstract: OBJECTIVE
  Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity.
  
  
  METHODS
  DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls.
  
  
  RESULTS
  A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients.
  
  
  CONCLUSIONS
  Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: Edel
authors.initials: E
authors.lastname: McDermott
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ryan
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Tosetto
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Gibson
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, Devon, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Burrage
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Denise
authors.initials: D
authors.lastname: Keegan
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Byrne
authors.affiliation: School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland Department of Psychiatry, Psychotherapy & Mental Health Research, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Eimear
authors.initials: E
authors.lastname: Crowe
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Gillian
authors.initials: G
authors.lastname: Sexton
authors.affiliation: School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland Department of Psychiatry, Psychotherapy & Mental Health Research, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Malone
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R Alan
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kellermayer
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, Devon, UK MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: Garret
authors.initials: G
authors.lastname: Cullen
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: Glen A
authors.initials: GA
authors.lastname: Doherty
authors.affiliation: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: Hugh
authors.initials: H
authors.lastname: Mulcahy
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, Devon, UK.
authors.forename: Therese M
authors.initials: TM
authors.lastname: Murphy
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D016022:Case-Control Studies; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics / Q000503:physiopathology; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012016:Reference Values; D018570:Risk Assessment; D012737:Sex Factors; D055815:Young Adult
keywords: DNA methylation; Epigenetics; inflammatory bowel disease