title: Increased methylation of glucocorticoid receptor gene promoter 1Fin peripheral blood of patients with generalized anxiety disorder.
abstract: Previous findings on the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety disorder (GAD) are controversial, and the molecular mechanisms underlying such dysfunction remain unclear. We analyzed the methylation status of the NR3C1 1Fpromoter and the expression of glucocorticoid receptor-α isoform (GRα) in peripheral blood mononuclear cells (PMBCs), the basal cortisol level in serum, and a functional neuroendocrine marker for GR sensitivity in the PMBCs in 64 patients with current GAD and 85 healthy controls. We found that patients with GAD had significantly elevated levels of morning basal serum cortisol (P < 0.0001) and diminished GR sensitivity in the PBMCs (P < 0.0001) compared with healthy controls. The overall methylation levels across NR3C1 1Fpromoter (P < 0.0001) and percent methylation at each of the 5 CpG sites including CpG12, 21, 30, 31, and 32 (P < 0.001) significantly increased. Accordingly, the mRNA levels of GRα significantly decreased (P < 0.0001) in the PBMCs in patients with GAD compared with healthy controls, with the effects specific in patients without childhood traumatic experience. Moreover, both serum basal cortisol levels and GR sensitivity in the PBMCs were negatively correlated with the overall methylation levels of the NR3C1 1Fpromoter (P < 0.0001) and positively correlated with GRα mRNA levels (P = 0.007) in the PBMCs. In sum, our study revealed the increased activity of the HPA axis and diminished peripheral glucocorticoid responsiveness of GR underlying episodes of GAD. Furthermore, such dysfunction of the HPA axis is associated with both increased DNA methylation of NR3C1 1Fpromoter and decreased GRα expression.
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China.
authors.forename: Junqin
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China.
authors.forename: Cui
authors.initials: C
authors.lastname: Ji
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China; Reproductive Medicine Center, Maternal and Child Health Hospital of Shaanxi Province & Northwest Women's and Children's Hospital, No. 73 Houzaimen, Xi'an, 710061, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Mu
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China.
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China.
authors.forename: Ce
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China.
authors.forename: Chengge
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China. Electronic address: maxiancang@163.com.
authors.forename: Xian-Cang
authors.initials: XC
authors.lastname: Ma
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, PR China. Electronic address: zhufeng0714@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
mesh_terms: D000328:Adult; D001008:Anxiety Disorders / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D009113:Muramidase / Q000378:metabolism; D000073222:Patient Health Questionnaire; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism
chemical_list: C497713:NR3C1 protein, human; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D009113:Muramidase; D006854:Hydrocortisone
keywords: Childhood trauma; DNA methylation; Generalized anxiety disorder; Glucocorticoid receptor; Hypothalamic-pituitary-adrenal axis