title: Chronic Fatigue Syndrome and DNA Hypomethylation of the Glucocorticoid Receptor Gene Promoter 1F Region: Associations With HPA Axis Hypofunction and Childhood Trauma.
abstract: OBJECTIVE
  Chronic fatigue syndrome (CFS) has been associated with hypothalamic-pituitary-adrenal axis hypofunction and enhanced glucocorticoid receptor (GR) sensitivity. In addition, childhood trauma is considered a major risk factor for the syndrome. This study examines DNA methylation of the GR gene (NR3C1) in CFS and associations with childhood sexual and physical trauma.
  
  
  METHODS
  Quantification of DNA methylation within the 1F promoter region of NR3C1 was performed in 76 female patients (46 with no/mild and 30 with moderate/severe childhood trauma) and 19 healthy controls by using Sequenom EpiTYPER. Further, we examined the association of NR3C1-1F promoter methylation with the outcomes of the low-dose (0.5 mg) dexamethasone/corticotropin-releasing factor test in a subset of the study population. Mann-Whitney U tests and Spearman correlations were used for statistical analyses.
  
  
  RESULTS
  Overall NR3C1-1F DNA methylation was lower in patients with CFS than in controls. After cytosine guanine dinucleotide (CpG)-specific analysis, CpG_1.5 remained significant after Bonferroni correction (adjusted p = .0014). Within the CFS group, overall methylation (ρ = 0.477, p = .016) and selective CpG units (CpG_1.5: ρ = 0.538, p = .007; CpG_12.13: ρ = 0.448, p = .025) were positively correlated with salivary cortisol after dexamethasone administration. There was no significant difference in NR3C1-1F methylation between traumatized and nontraumatized patients.
  
  
  CONCLUSIONS
  We found evidence of NR3C1 promoter hypomethylation in female patients with CFS and the functional relevance of these differences was consistent with the hypothalamic-pituitary-adrenalaxis hypofunction hypothesis (GR hypersuppression). However, we found no evidence of an additional effect of childhood trauma on CFS via alterations in NR3C1 methylation.
authors.affiliation: From the Genetic Research About Stress and Psychiatry (GRASP) (Vangeel, Hompes, Claes), University Psychiatric Center (Hompes, Claes), Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (Izzi, Freson), and Laboratory of Translational Genetics, Department of Oncology (Lambrechts), University of Leuven, Leuven, Belgium; University Department of Psychiatry (Van Den Eede), Campus Antwerp University Hospital, Antwerp, Edegem, Belgium; Collaborative Antwerp Psychiatric Research Institute (CAPRI) (Van Den Eede) and Department of Molecular Genetics VIB8 (Del Favero), Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium; Department of Internal Medicine (Moorkens), Antwerp University Hospital, Antwerp, Edegem, Belgium; and Vesalius Research Center (VRC) (Lambrechts), VIB, Leuven, Belgium.
authors.forename: Elise
authors.initials: E
authors.lastname: Vangeel
authors.forename: Filip
authors.initials: F
authors.lastname: Van Den Eede
authors.forename: Titia
authors.initials: T
authors.lastname: Hompes
authors.forename: Benedetta
authors.initials: B
authors.lastname: Izzi
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del Favero
authors.forename: Greta
authors.initials: G
authors.lastname: Moorkens
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
authors.forename: Stephan
authors.initials: S
authors.lastname: Claes
mesh_terms: D000328:Adult; D054523:Adult Survivors of Child Abuse; D018899:CpG Islands; D019175:DNA Methylation; D015673:Fatigue Syndrome, Chronic / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D005260:Female; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid