Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
Identifieur interne : 000E99 ( Main/Curation ); précédent : 000E98; suivant : 000F00Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
Auteurs : Robert Kumsta [Allemagne, Royaume-Uni] ; Dirk Moser [Allemagne] ; Fabian Streit [Allemagne] ; Jan Willem Koper [Pays-Bas] ; Jobst Meyer [Allemagne] ; Stefan Wüst [Allemagne]Source :
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics [ 1552-4841 ] ; 2009-06-05.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
- Adrenal glands, Adrenocorticotropic Hormone (analysis), Adrenocorticotropic Hormone (genetics), Alleles, Axis, Cell Line, Tumor, Characterization, Depression, Depressive Disorder, Major (genetics), Gene, Gene expression, Haplotype, Haplotypes (genetics), Humans, Hydrocortisone (analysis), Hydrocortisone (genetics), Hypothalamus, Linkage Disequilibrium (genetics), Pituitary gland, Polymorphism, Single Nucleotide (genetics), Promoter, Promoter Regions, Genetic, Receptors, Glucocorticoid (genetics), Relevance, Single nucleotide polymorphism, Stress, Stress, Psychological (genetics), Transfection, gene expression, hypothalamus–pituitary–adrenal (HPA) axis, major depression, single nucleotide polymorphism (SNP), stress.
- MESH :
- chemical , analysis : Adrenocorticotropic Hormone, Hydrocortisone.
- chemical , genetics : Adrenocorticotropic Hormone, Hydrocortisone, Receptors, Glucocorticoid.
- genetics : Depressive Disorder, Major, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Stress, Psychological.
- Alleles, Cell Line, Tumor, Humans, Promoter Regions, Genetic, Transfection.
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. © 2008 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/ajmg.b.30837
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Genet.</title><idno type="ISSN">1552-4841</idno><idno type="eISSN">1552-485X</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-06-05">2009-06-05</date><biblScope unit="volume">150B</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="476">476</biblScope><biblScope unit="page" to="482">482</biblScope></imprint><idno type="ISSN">1552-4841</idno></series><idno type="istex">3EA171A39AB591A587C5B953EDB9CD363C617A28</idno><idno type="DOI">10.1002/ajmg.b.30837</idno><idno type="ArticleID">AJMG30837</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1552-4841</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adrenal glands</term><term>Adrenocorticotropic Hormone (analysis)</term><term>Adrenocorticotropic Hormone (genetics)</term><term>Alleles</term><term>Axis</term><term>Cell Line, Tumor</term><term>Characterization</term><term>Depression</term><term>Depressive Disorder, Major (genetics)</term><term>Gene</term><term>Gene expression</term><term>Haplotype</term><term>Haplotypes (genetics)</term><term>Humans</term><term>Hydrocortisone (analysis)</term><term>Hydrocortisone (genetics)</term><term>Hypothalamus</term><term>Linkage Disequilibrium (genetics)</term><term>Pituitary gland</term><term>Polymorphism, Single Nucleotide (genetics)</term><term>Promoter</term><term>Promoter Regions, Genetic</term><term>Receptors, Glucocorticoid (genetics)</term><term>Relevance</term><term>Single nucleotide polymorphism</term><term>Stress</term><term>Stress, Psychological (genetics)</term><term>Transfection</term><term>gene expression</term><term>hypothalamus–pituitary–adrenal (HPA) axis</term><term>major depression</term><term>single nucleotide polymorphism (SNP)</term><term>stress</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Adrenocorticotropic Hormone</term><term>Hydrocortisone</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Adrenocorticotropic Hormone</term><term>Hydrocortisone</term><term>Receptors, Glucocorticoid</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Depressive Disorder, Major</term><term>Haplotypes</term><term>Linkage Disequilibrium</term><term>Polymorphism, Single Nucleotide</term><term>Stress, Psychological</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Alleles</term><term>Cell Line, Tumor</term><term>Humans</term><term>Promoter Regions, Genetic</term><term>Transfection</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Axe</term><term>Caractérisation</term><term>Etat dépressif</term><term>Expression génique</term><term>Gène</term><term>Haplotype</term><term>Hypophyse</term><term>Hypothalamus</term><term>Pertinence</term><term>Polymorphisme mononucléotide</term><term>Promoteur</term><term>Récepteur de glucocorticoïde</term><term>Stress</term><term>Surrénale</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. © 2008 Wiley‐Liss, Inc.</div></front></TEI><double idat="1552-4841:2009:Kumsta R:characterization:of:a"><INIST><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Characterization of a Glucocorticoid Receptor Gene (GR, NR3C1) Promoter Polymorphism Reveals Functionality and Extends a Haplotype With Putative Clinical Relevance</title><author><name sortKey="Kumsta, Robert" sort="Kumsta, Robert" uniqKey="Kumsta R" first="Robert" last="Kumsta">Robert Kumsta</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Psychobiology, University of Trier</s1><s2>Trier</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Trier</wicri:noRegion><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" 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Trèves</orgName></affiliation></author><author><name sortKey="Streit, Fabian" sort="Streit, Fabian" uniqKey="Streit F" first="Fabian" last="Streit">Fabian Streit</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Psychobiology, University of Trier</s1><s2>Trier</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Trier</wicri:noRegion><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName><orgName type="university">Université de Trèves</orgName></affiliation></author><author><name sortKey="Koper, Jan Willem" sort="Koper, Jan Willem" uniqKey="Koper J" first="Jan Willem" last="Koper">Jan Willem Koper</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Department of Internal Medicine, Erasmus MC</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>4 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wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Psychobiology, University of Trier</s1><s2>Trier</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Trier</wicri:noRegion><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName><orgName type="university">Université de Trèves</orgName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>SGDP Centre, Institute of Psychiatry, King's College London</s1><s3>GBR</s3><sZ>1 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>SGDP Centre, Institute of Psychiatry, King's College London</wicri:noRegion></affiliation></author><author><name sortKey="Moser, Dirk" sort="Moser, Dirk" uniqKey="Moser D" first="Dirk" last="Moser">Dirk Moser</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Psychobiology, University of Trier</s1><s2>Trier</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Trier</wicri:noRegion><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName><orgName type="university">Université de Trèves</orgName></affiliation></author><author><name sortKey="Streit, Fabian" sort="Streit, Fabian" uniqKey="Streit F" first="Fabian" last="Streit">Fabian Streit</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Psychobiology, University of Trier</s1><s2>Trier</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Trier</wicri:noRegion><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName><orgName type="university">Université de Trèves</orgName></affiliation></author><author><name sortKey="Koper, Jan Willem" sort="Koper, Jan Willem" uniqKey="Koper J" first="Jan Willem" last="Koper">Jan Willem Koper</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Department of Internal Medicine, Erasmus MC</s1><s2>Rotterdam</s2><s3>NLD</s3><sZ>4 aut.</sZ></inist:fA14><country>Pays-Bas</country><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Meyer, Jobst" sort="Meyer, Jobst" uniqKey="Meyer J" first="Jobst" last="Meyer">Jobst Meyer</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Psychobiology, University of Trier</s1><s2>Trier</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Trier</wicri:noRegion><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName><orgName type="university">Université de Trèves</orgName></affiliation></author><author><name sortKey="Wust, Stefan" sort="Wust, Stefan" uniqKey="Wust S" first="Stefan" last="Wüst">Stefan Wüst</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Psychobiology, University of Trier</s1><s2>Trier</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Trier</wicri:noRegion><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName><orgName type="university">Université de Trèves</orgName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Central Institute of Mental Health</s1><s2>Mannheim</s2><s3>DEU</s3><sZ>6 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Mannheim</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">American journal of medical genetics. Part B, Neuropsychiatric genetics</title><title level="j" type="abbreviated">Am. j. med. genet., Part B Neuropsychiatr. genet.</title><idno type="ISSN">1552-4841</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of medical genetics. Part B, Neuropsychiatric genetics</title><title level="j" type="abbreviated">Am. j. med. genet., Part B Neuropsychiatr. genet.</title><idno type="ISSN">1552-4841</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adrenal glands</term><term>Axis</term><term>Characterization</term><term>Depression</term><term>Gene</term><term>Gene expression</term><term>Haplotype</term><term>Hypothalamus</term><term>Pituitary gland</term><term>Promoter</term><term>Relevance</term><term>Single nucleotide polymorphism</term><term>Stress</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Etat dépressif</term><term>Caractérisation</term><term>Gène</term><term>Promoteur</term><term>Polymorphisme mononucléotide</term><term>Haplotype</term><term>Pertinence</term><term>Expression génique</term><term>Hypothalamus</term><term>Hypophyse</term><term>Surrénale</term><term>Axe</term><term>Stress</term><term>Récepteur de glucocorticoïde</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. © 2008 Wiley-Liss, Inc.</div></front></TEI></INIST><ISTEX><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance</title><author><name sortKey="Kumsta, Robert" sort="Kumsta, Robert" uniqKey="Kumsta R" first="Robert" last="Kumsta">Robert Kumsta</name></author><author><name sortKey="Moser, Dirk" sort="Moser, Dirk" uniqKey="Moser D" first="Dirk" last="Moser">Dirk Moser</name></author><author><name sortKey="Streit, Fabian" sort="Streit, Fabian" uniqKey="Streit F" first="Fabian" last="Streit">Fabian Streit</name></author><author><name sortKey="Koper, Jan Willem" sort="Koper, Jan Willem" uniqKey="Koper J" first="Jan Willem" last="Koper">Jan Willem Koper</name></author><author><name sortKey="Meyer, Jobst" sort="Meyer, Jobst" uniqKey="Meyer J" first="Jobst" last="Meyer">Jobst Meyer</name></author><author><name sortKey="Wust, Stefan" sort="Wust, Stefan" uniqKey="Wust S" first="Stefan" last="Wüst">Stefan Wüst</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:3EA171A39AB591A587C5B953EDB9CD363C617A28</idno><date when="2009" year="2009">2009</date><idno type="doi">10.1002/ajmg.b.30837</idno><idno type="url">https://api.istex.fr/document/3EA171A39AB591A587C5B953EDB9CD363C617A28/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001675</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001675</idno><idno type="wicri:Area/Istex/Curation">001563</idno><idno type="wicri:Area/Istex/Checkpoint">000446</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000446</idno><idno type="wicri:doubleKey">1552-4841:2009:Kumsta R:characterization:of:a</idno><idno type="wicri:source">PubMed</idno><idno type="RBID">pubmed:18663733</idno><idno type="wicri:Area/PubMed/Corpus">000572</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000572</idno><idno type="wicri:Area/PubMed/Curation">000572</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000572</idno><idno type="wicri:Area/PubMed/Checkpoint">000572</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000572</idno><idno type="wicri:Area/Ncbi/Merge">000323</idno><idno type="wicri:Area/Ncbi/Curation">000323</idno><idno type="wicri:Area/Ncbi/Checkpoint">000323</idno><idno type="wicri:Area/Main/Merge">000F73</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance</title><author><name sortKey="Kumsta, Robert" sort="Kumsta, Robert" uniqKey="Kumsta R" first="Robert" last="Kumsta">Robert Kumsta</name><affiliation wicri:level="4"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Psychobiology, University of Trier, Trier</wicri:regionArea><orgName type="university">Université de Trèves</orgName><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>SGDP Centre, Institute of Psychiatry, King's College London</wicri:regionArea><wicri:noRegion>King's College London</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country><wicri:regionArea>Institute of Psychiatry, PO 80, MRC SGDP Centre, De Crespigny Park, London SE5 9AF</wicri:regionArea><wicri:noRegion>London SE5 9AF</wicri:noRegion></affiliation></author><author><name sortKey="Moser, Dirk" sort="Moser, Dirk" uniqKey="Moser D" first="Dirk" last="Moser">Dirk Moser</name><affiliation wicri:level="4"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Psychobiology, University of Trier, Trier</wicri:regionArea><orgName type="university">Université de Trèves</orgName><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName></affiliation></author><author><name sortKey="Streit, Fabian" sort="Streit, Fabian" uniqKey="Streit F" first="Fabian" last="Streit">Fabian Streit</name><affiliation wicri:level="4"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Psychobiology, University of Trier, Trier</wicri:regionArea><orgName type="university">Université de Trèves</orgName><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName></affiliation></author><author><name sortKey="Koper, Jan Willem" sort="Koper, Jan Willem" uniqKey="Koper J" first="Jan Willem" last="Koper">Jan Willem Koper</name><affiliation wicri:level="3"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus MC, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Meyer, Jobst" sort="Meyer, Jobst" uniqKey="Meyer J" first="Jobst" last="Meyer">Jobst Meyer</name><affiliation wicri:level="4"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Psychobiology, University of Trier, Trier</wicri:regionArea><orgName type="university">Université de Trèves</orgName><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName></affiliation></author><author><name sortKey="Wust, Stefan" sort="Wust, Stefan" uniqKey="Wust S" first="Stefan" last="Wüst">Stefan Wüst</name><affiliation wicri:level="4"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Psychobiology, University of Trier, Trier</wicri:regionArea><orgName type="university">Université de Trèves</orgName><placeName><settlement type="city">Trèves (Allemagne)</settlement><region type="land" nuts="1">Rhénanie-Palatinat</region></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Central Institute of Mental Health, Mannheim</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Mannheim</settlement></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">American Journal of Medical Genetics Part B: Neuropsychiatric Genetics</title><title level="j" type="abbrev">Am. J. Med. Genet.</title><idno type="ISSN">1552-4841</idno><idno type="eISSN">1552-485X</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-06-05">2009-06-05</date><biblScope unit="volume">150B</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="476">476</biblScope><biblScope unit="page" to="482">482</biblScope></imprint><idno type="ISSN">1552-4841</idno></series><idno type="istex">3EA171A39AB591A587C5B953EDB9CD363C617A28</idno><idno type="DOI">10.1002/ajmg.b.30837</idno><idno type="ArticleID">AJMG30837</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1552-4841</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adrenocorticotropic Hormone (analysis)</term><term>Adrenocorticotropic Hormone (genetics)</term><term>Alleles</term><term>Cell Line, Tumor</term><term>Depressive Disorder, Major (genetics)</term><term>Haplotypes (genetics)</term><term>Humans</term><term>Hydrocortisone (analysis)</term><term>Hydrocortisone (genetics)</term><term>Linkage Disequilibrium (genetics)</term><term>Polymorphism, Single Nucleotide (genetics)</term><term>Promoter Regions, Genetic</term><term>Receptors, Glucocorticoid (genetics)</term><term>Stress, Psychological (genetics)</term><term>Transfection</term><term>gene expression</term><term>hypothalamus–pituitary–adrenal (HPA) axis</term><term>major depression</term><term>single nucleotide polymorphism (SNP)</term><term>stress</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Adrenocorticotropic Hormone</term><term>Hydrocortisone</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Adrenocorticotropic Hormone</term><term>Hydrocortisone</term><term>Receptors, Glucocorticoid</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Depressive Disorder, Major</term><term>Haplotypes</term><term>Linkage Disequilibrium</term><term>Polymorphism, Single Nucleotide</term><term>Stress, Psychological</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Alleles</term><term>Cell Line, Tumor</term><term>Humans</term><term>Promoter Regions, Genetic</term><term>Transfection</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. © 2008 Wiley‐Liss, Inc.</div></front></TEI></ISTEX></double></record>Pour manipuler ce document sous Unix (Dilib)
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