Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
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.
gene expression, single nucleotide polymorphism (SNP), hypothalamus-pituitary-adrenal (HPA) axis, stress, major depression
476-482
Kumsta, Robert
88285030-6a7c-4ef1-ba75-b78e09cd2f1e
Moser, Dirk
8345e744-f2e2-407c-9f5b-cd6685091923
Streit, Fabian
32e2452d-2adb-4f53-b1c8-879445769c95
Koper, Jan-Willem
a72a8ce9-6ccb-4f34-b6bb-40231eb2174b
Meyer, Jobst
ffc0f18e-a569-454e-b6f6-b2ab7c963c65
Wüst, Stefan
530861ea-05ba-4a73-8030-9735f1759d5b
5 June 2009
Kumsta, Robert
88285030-6a7c-4ef1-ba75-b78e09cd2f1e
Moser, Dirk
8345e744-f2e2-407c-9f5b-cd6685091923
Streit, Fabian
32e2452d-2adb-4f53-b1c8-879445769c95
Koper, Jan-Willem
a72a8ce9-6ccb-4f34-b6bb-40231eb2174b
Meyer, Jobst
ffc0f18e-a569-454e-b6f6-b2ab7c963c65
Wüst, Stefan
530861ea-05ba-4a73-8030-9735f1759d5b
Kumsta, Robert, Moser, Dirk, Streit, Fabian, Koper, Jan-Willem, Meyer, Jobst and Wüst, Stefan
(2009)
Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance.
American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 150B (4), .
(doi:10.1002/ajmg.b.30837).
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.
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Submitted date: 10 March 2008
Published date: 5 June 2009
Keywords:
gene expression, single nucleotide polymorphism (SNP), hypothalamus-pituitary-adrenal (HPA) axis, stress, major depression
Identifiers
Local EPrints ID: 66662
URI: http://eprints.soton.ac.uk/id/eprint/66662
ISSN: 1552-4841
PURE UUID: 890236c7-bbef-483c-9263-16230a850a23
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Date deposited: 12 Aug 2009
Last modified: 13 Mar 2024 18:28
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Contributors
Author:
Robert Kumsta
Author:
Dirk Moser
Author:
Fabian Streit
Author:
Jan-Willem Koper
Author:
Jobst Meyer
Author:
Stefan Wüst
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