title: Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance.
abstract: Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (GR, NR3C1). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression.
authors.affiliation: Institute of Psychobiology, University of Trier, Trier, Germany. robert.kumsta@iop.kcl.ac.uk
authors.forename: Robert
authors.initials: R
authors.lastname: Kumsta
authors.forename: Dirk
authors.initials: D
authors.lastname: Moser
authors.forename: Fabian
authors.initials: F
authors.lastname: Streit
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Koper
authors.forename: Jobst
authors.initials: J
authors.lastname: Meyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Wüst
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000032:analysis / Q000235:genetics; D000483:Alleles; D045744:Cell Line, Tumor; D003865:Major Depressive Disorder / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics; D014162:Transfection
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone