Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
Identifieur interne : 001675 ( Istex/Corpus ); précédent : 001674; suivant : 001676Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
Auteurs : Robert Kumsta ; Dirk Moser ; Fabian Streit ; Jan Willem Koper ; Jobst Meyer ; Stefan WüstSource :
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics [ 1552-4841 ] ; 2009-06-05.
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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.
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DOI: 10.1002/ajmg.b.30837
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ISTEX:3EA171A39AB591A587C5B953EDB9CD363C617A28Le document en format XML
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University of Trier, Trier, Germany</mods:affiliation></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><mods:affiliation>Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Meyer, Jobst" sort="Meyer, Jobst" uniqKey="Meyer J" first="Jobst" last="Meyer">Jobst Meyer</name><affiliation><mods:affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</mods:affiliation></affiliation></author><author><name sortKey="Wust, Stefan" sort="Wust, Stefan" uniqKey="Wust S" first="Stefan" last="Wüst">Stefan Wüst</name><affiliation><mods:affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Central Institute of Mental Health, Mannheim, Germany</mods:affiliation></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. 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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>gene expression</term><term>hypothalamus–pituitary–adrenal (HPA) axis</term><term>major depression</term><term>single nucleotide polymorphism (SNP)</term><term>stress</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><corpusName>wiley</corpusName><author><json:item><name>Robert Kumsta</name><affiliations><json:string>Institute of Psychobiology, University of Trier, Trier, Germany</json:string><json:string>SGDP Centre, Institute of Psychiatry, King's College London, UK</json:string><json:string>Institute of Psychiatry, PO 80, MRC SGDP Centre, De Crespigny Park, London SE5 9AF, UK.</json:string></affiliations></json:item><json:item><name>Dirk Moser</name><affiliations><json:string>Institute of Psychobiology, University of Trier, Trier, Germany</json:string></affiliations></json:item><json:item><name>Fabian Streit</name><affiliations><json:string>Institute of Psychobiology, University of Trier, Trier, Germany</json:string></affiliations></json:item><json:item><name>Jan Willem Koper</name><affiliations><json:string>Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands</json:string></affiliations></json:item><json:item><name>Jobst Meyer</name><affiliations><json:string>Institute of Psychobiology, University of Trier, Trier, Germany</json:string></affiliations></json:item><json:item><name>Stefan Wüst</name><affiliations><json:string>Institute of Psychobiology, University of Trier, Trier, Germany</json:string><json:string>Central Institute of Mental Health, Mannheim, Germany</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>gene expression</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>single nucleotide polymorphism (SNP)</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>hypothalamus–pituitary–adrenal (HPA) axis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>stress</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>major depression</value></json:item></subject><articleId><json:string>AJMG30837</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><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.</abstract><qualityIndicators><score>7.135</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1472</abstractCharCount><pdfWordCount>4711</pdfWordCount><pdfCharCount>30910</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>202</abstractWordCount></qualityIndicators><title>Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance</title><refBibs><json:item><author><json:item><name>M Bartels</name></json:item><json:item><name>M Van den Berg</name></json:item><json:item><name>F Sluyter</name></json:item><json:item><name>DI Boomsma</name></json:item><json:item><name>EJ de 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gene</title></json:item></refBibs><genre><json:string>article</json:string></genre><host><volume>150B</volume><publisherId><json:string>AJMG</json:string></publisherId><pages><total>7</total><last>482</last><first>476</first></pages><issn><json:string>1552-4841</json:string></issn><issue>4</issue><subject><json:item><value>Research Article</value></json:item></subject><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1552-485X</json:string></eissn><title>American Journal of Medical Genetics Part B: Neuropsychiatric Genetics</title><doi><json:string>10.1002/(ISSN)1552-485X</json:string></doi></host><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1002/ajmg.b.30837</json:string></doi><id>3EA171A39AB591A587C5B953EDB9CD363C617A28</id><score>1.5027006</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/3EA171A39AB591A587C5B953EDB9CD363C617A28/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/3EA171A39AB591A587C5B953EDB9CD363C617A28/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/3EA171A39AB591A587C5B953EDB9CD363C617A28/fulltext/tei"><teiHeader><fileDesc><titleStmt><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></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>Copyright © 2008 Wiley‐Liss, Inc.</p></availability><date>2009</date></publicationStmt><notesStmt><note type="content">*Please cite this article as follows: Kumsta R, Moser D, Streit F, Koper JW, Meyer J, Wüst S. 2008. Characterization of a Glucocorticoid Receptor Gene (GR, NR3C1) Promoter Polymorphism Reveals Functionality and Extends a Haplotype With Putative Clinical Relevance. Am J Med Genet Part B 150B:476–482.</note><note type="content">*Robert Kumsta and Dirk Moser contributed equally to this work.</note><note>German Research Foundation (DFG) - No. WU 324/3‐(1‐3); No. GRK 1389/1;</note></notesStmt><sourceDesc><biblStruct type="inbook"><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 xml:id="author-1"><persName><forename type="first">Robert</forename><surname>Kumsta</surname></persName><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation><affiliation>SGDP Centre, Institute of Psychiatry, King's College London, UK</affiliation><affiliation>Institute of Psychiatry, PO 80, MRC SGDP Centre, De Crespigny Park, London SE5 9AF, UK.</affiliation></author><author xml:id="author-2"><persName><forename type="first">Dirk</forename><surname>Moser</surname></persName><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation></author><author xml:id="author-3"><persName><forename type="first">Fabian</forename><surname>Streit</surname></persName><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation></author><author xml:id="author-4"><persName><forename type="first">Jan Willem</forename><surname>Koper</surname></persName><affiliation>Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands</affiliation></author><author xml:id="author-5"><persName><forename type="first">Jobst</forename><surname>Meyer</surname></persName><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation></author><author xml:id="author-6"><persName><forename type="first">Stefan</forename><surname>Wüst</surname></persName><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation><affiliation>Central Institute of Mental Health, Mannheim, Germany</affiliation></author></analytic><monogr><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="pISSN">1552-4841</idno><idno type="eISSN">1552-485X</idno><idno type="DOI">10.1002/(ISSN)1552-485X</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="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></monogr><idno type="istex">3EA171A39AB591A587C5B953EDB9CD363C617A28</idno><idno type="DOI">10.1002/ajmg.b.30837</idno><idno type="ArticleID">AJMG30837</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>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.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>gene expression</term></item><item><term>single nucleotide polymorphism (SNP)</term></item><item><term>hypothalamus–pituitary–adrenal (HPA) axis</term></item><item><term>stress</term></item><item><term>major depression</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2008-03-10">Received</change><change when="2008-06-26">Registration</change><change when="2009-06-05">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/3EA171A39AB591A587C5B953EDB9CD363C617A28/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1552-485X</doi><issn type="print">1552-4841</issn><issn type="electronic">1552-485X</issn><idGroup><id type="product" value="AJMG"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="AMERICAN JOURNAL OF MEDICAL GENETICS PART B: NEUROPSYCHIATRIC GENETICS">American Journal of Medical Genetics Part B: Neuropsychiatric Genetics</title><title type="short">Am. 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type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2008 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="2008-03-10"></event><event type="manuscriptAccepted" date="2008-06-26"></event><event type="publishedOnlineEarlyUnpaginated" date="2008-07-28"></event><event type="firstOnline" date="2008-07-28"></event><event type="publishedOnlineFinalForm" date="2009-05-18"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.6 mode:FullText source:FullText result:FullText" date="2010-05-07"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-02"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst">476</numbering><numbering type="pageLast">482</numbering></numberingGroup><correspondenceTo>Institute of Psychiatry, PO 80, MRC SGDP Centre, De Crespigny Park, London SE5 9AF, UK.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:AJMG.AJMG30837.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="2"></count><count type="referenceTotal" number="43"></count><count type="wordTotal" number="5197"></count></countGroup><titleGroup><title type="main" xml:lang="en">Characterization of a glucocorticoid receptor gene (<i>GR</i>, <i>NR3C1</i>) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance<link href="#fn1"></link><link href="#fn2"></link></title><title type="short" xml:lang="en">Functionality of a Glucocorticoid Receptor Gene SNP</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Robert</givenNames><familyName>Kumsta</familyName></personName><contactDetails><email>robert.kumsta@iop.kcl.ac.uk</email></contactDetails></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Dirk</givenNames><familyName>Moser</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Fabian</givenNames><familyName>Streit</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Jan Willem</givenNames><familyName>Koper</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Jobst</givenNames><familyName>Meyer</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1 #af3"><personName><givenNames>Stefan</givenNames><familyName>Wüst</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="DE" type="organization"><unparsedAffiliation>Institute of Psychobiology, University of Trier, Trier, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="GB" type="organization"><unparsedAffiliation>SGDP Centre, Institute of Psychiatry, King's College London, UK</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="DE" type="organization"><unparsedAffiliation>Central Institute of Mental Health, Mannheim, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="NL" type="organization"><unparsedAffiliation>Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">gene expression</keyword><keyword xml:id="kwd2">single nucleotide polymorphism (SNP)</keyword><keyword xml:id="kwd3">hypothalamus–pituitary–adrenal (HPA) axis</keyword><keyword xml:id="kwd4">stress</keyword><keyword xml:id="kwd5">major depression</keyword></keywordGroup><fundingInfo><fundingAgency>German Research Foundation (DFG)</fundingAgency><fundingNumber>WU 324/3‐(1‐3)</fundingNumber><fundingNumber>GRK 1389/1</fundingNumber></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>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 (<i>GR</i>, <i>NR3C1</i>). <i>GR</i> polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common <i>GR</i> 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 <i>GR</i> SNPs to further characterize <i>GR</i> 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 <i>GR</i> SNPs in linkage disequilibrium are responsible for both regulation of <i>GR</i> 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.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Please cite this article as follows: Kumsta R, Moser D, Streit F, Koper JW, Meyer J, Wüst S. 2008. Characterization of a Glucocorticoid Receptor Gene (<i>GR</i>, <i>NR3C1</i>) Promoter Polymorphism Reveals Functionality and Extends a Haplotype With Putative Clinical Relevance. Am J Med Genet Part B 150B:476–482.</p></note><note xml:id="fn2"><p>Robert Kumsta and Dirk Moser contributed equally to this work.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Functionality of a Glucocorticoid Receptor Gene SNP</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance</title></titleInfo><name type="personal"><namePart type="given">Robert</namePart><namePart type="family">Kumsta</namePart><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation><affiliation>SGDP Centre, Institute of Psychiatry, King's College London, UK</affiliation><affiliation>Institute of Psychiatry, PO 80, MRC SGDP Centre, De Crespigny Park, London SE5 9AF, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dirk</namePart><namePart type="family">Moser</namePart><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fabian</namePart><namePart type="family">Streit</namePart><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan Willem</namePart><namePart type="family">Koper</namePart><affiliation>Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jobst</namePart><namePart type="family">Meyer</namePart><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stefan</namePart><namePart type="family">Wüst</namePart><affiliation>Institute of Psychobiology, University of Trier, Trier, Germany</affiliation><affiliation>Central Institute of Mental Health, Mannheim, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2009-06-05</dateIssued><dateCaptured encoding="w3cdtf">2008-03-10</dateCaptured><dateValid encoding="w3cdtf">2008-06-26</dateValid><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">3</extent><extent unit="tables">2</extent><extent unit="references">43</extent><extent unit="words">5197</extent></physicalDescription><abstract 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.</abstract><note type="content">*Please cite this article as follows: Kumsta R, Moser D, Streit F, Koper JW, Meyer J, Wüst S. 2008. Characterization of a Glucocorticoid Receptor Gene (GR, NR3C1) Promoter Polymorphism Reveals Functionality and Extends a Haplotype With Putative Clinical Relevance. Am J Med Genet Part B 150B:476–482.</note><note type="content">*Robert Kumsta and Dirk Moser contributed equally to this work.</note><note type="funding">German Research Foundation (DFG) - No. WU 324/3‐(1‐3); No. GRK 1389/1; </note><subject lang="en"><genre>keywords</genre><topic>gene expression</topic><topic>single nucleotide polymorphism (SNP)</topic><topic>hypothalamus–pituitary–adrenal (HPA) axis</topic><topic>stress</topic><topic>major depression</topic></subject><relatedItem type="host"><titleInfo><title>American Journal of Medical Genetics Part B: Neuropsychiatric Genetics</title></titleInfo><titleInfo type="abbreviated"><title>Am. J. Med. Genet.</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>Research Article</topic></subject><identifier type="ISSN">1552-4841</identifier><identifier type="eISSN">1552-485X</identifier><identifier type="DOI">10.1002/(ISSN)1552-485X</identifier><identifier type="PublisherID">AJMG</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>150B</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>476</start><end>482</end><total>7</total></extent></part></relatedItem><relatedItem type="preceding"><titleInfo><title>American Journal of Medical Genetics</title></titleInfo><identifier type="ISSN">0148-7299</identifier><identifier type="ISSN">1096-8628</identifier><part><date point="end">2004</date></part></relatedItem><identifier type="istex">3EA171A39AB591A587C5B953EDB9CD363C617A28</identifier><identifier type="DOI">10.1002/ajmg.b.30837</identifier><identifier type="ArticleID">AJMG30837</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2008 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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