Characterization of Functional Polymorphisms and Glucocorticoid-Responsive Elements in the Promoter of TDO2, a Candidate Gene for Ethanol-Induced Behavioural Disorders
Identifieur interne : 005053 ( Main/Exploration ); précédent : 005052; suivant : 005054Characterization of Functional Polymorphisms and Glucocorticoid-Responsive Elements in the Promoter of TDO2, a Candidate Gene for Ethanol-Induced Behavioural Disorders
Auteurs : Marion Soichot [France] ; Arnaud Vaast [France] ; Jean Vignau [France] ; Gilles J. Guillemin [Australie] ; Michel Lhermitte [France] ; Franck Broly [France] ; Delphine Allorge [France]Source :
- Alcohol and alcoholism : (Oxford) [ 0735-0414 ] ; 2013.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Boisson alcoolisée.
English descriptors
- KwdEn :
Abstract
Aims: In response to acute ethanol consumption, tryptophan 2,3-dioxygenase (TDO) induces the kynurenine pathway (KP) through a glucocorticoid-mediated mechanism, which could lead to a dramatic accumulation of neurotoxic metabolites in association with serotonin depletion. As a result, interindividual variability in ethanol-induced behavioural disorders, such as black-outs and violent impulsive behaviours (BOVIBs) following binge drinking, could be partly explained by genetic polymorphisms affecting the KP. The aim of this study was to identify polymorphisms on the promoter of the TD02 gene that could affect expression and/or activity of TDO through glucocorticoid induction. Methods: Polymorphisms were screened using a PCR-sequencing strategy applied to 31 alcohol-dependent patients and 49 unrelated healthy volunteers, and functionally analysed with bioinformatic prediction tools and gene reporter assays in HepG2 and A549 cell lines. Results: We identified 12 polymorphisms in the human TDO2 promoter region, 2 of them corresponding to previously unknown single-nucleotide polymorphisms (SNPs) and 3 of them located in putative glucocorticoid-responsive elements (GREs). Gene reporter assays using HepG2 and A549 cell lines confirmed the presence of several functional GREs in the promoter region of TDO2 and revealed that some of the identified polymorphisms affect the promoter activity under glucocorticoid receptor over-expression and dexamethasone exposure conditions. Conclusions: Correlational studies in larger samples could help to determine whether these polymorphisms are responsible for variations of expression and/or activity of TDO, in particular under conditions where release of glucocorticoids is increased, such as acute ethanol intake. If confirmed, such results would be of major interest in explaining part of the interindividual variability observed in behavioural responses to acute ethanol consumption.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Characterization of Functional Polymorphisms and Glucocorticoid-Responsive Elements in the Promoter of TDO2, a Candidate Gene for Ethanol-Induced Behavioural Disorders</title><author><name sortKey="Soichot, Marion" sort="Soichot, Marion" uniqKey="Soichot M" first="Marion" last="Soichot">Marion Soichot</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Vaast, Arnaud" sort="Vaast, Arnaud" uniqKey="Vaast A" first="Arnaud" last="Vaast">Arnaud Vaast</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Vignau, Jean" sort="Vignau, Jean" uniqKey="Vignau J" first="Jean" last="Vignau">Jean Vignau</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Service d'Addictologie, Centre Hospitalier Regional Universitaire</s1><s2>Lille</s2><s3>FRA</s3><sZ>3 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Guillemin, Gilles J" sort="Guillemin, Gilles J" uniqKey="Guillemin G" first="Gilles J." last="Guillemin">Gilles J. Guillemin</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Neuroinflammation Group, Department of Pharmacology, University of New South Wales</s1><s2>Sydney, NSW 2052</s2><s3>AUS</s3><sZ>4 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Sydney, NSW 2052</wicri:noRegion></affiliation></author><author><name sortKey="Lhermitte, Michel" sort="Lhermitte, Michel" uniqKey="Lhermitte M" first="Michel" last="Lhermitte">Michel Lhermitte</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Laboratoire de Toxicologie and Génopathies, Centre de Biologie Pathologie, CHRU</s1><s2>Lille</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Broly, Franck" sort="Broly, Franck" uniqKey="Broly F" first="Franck" last="Broly">Franck Broly</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Laboratoire de Toxicologie and Génopathies, Centre de Biologie Pathologie, CHRU</s1><s2>Lille</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Allorge, Delphine" sort="Allorge, Delphine" uniqKey="Allorge D" first="Delphine" last="Allorge">Delphine Allorge</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Laboratoire de Toxicologie and Génopathies, Centre de Biologie Pathologie, CHRU</s1><s2>Lille</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">13-0229663</idno><date when="2013">2013</date><idno type="stanalyst">PASCAL 13-0229663 INIST</idno><idno type="RBID">Pascal:13-0229663</idno><idno type="wicri:Area/PascalFrancis/Corpus">000958</idno><idno type="wicri:Area/PascalFrancis/Curation">005518</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000A61</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000A61</idno><idno type="wicri:doubleKey">0735-0414:2013:Soichot M:characterization:of:functional</idno><idno type="wicri:Area/Main/Merge">005235</idno><idno type="wicri:Area/Main/Curation">005053</idno><idno type="wicri:Area/Main/Exploration">005053</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Characterization of Functional Polymorphisms and Glucocorticoid-Responsive Elements in the Promoter of TDO2, a Candidate Gene for Ethanol-Induced Behavioural Disorders</title><author><name sortKey="Soichot, Marion" sort="Soichot, Marion" uniqKey="Soichot M" first="Marion" last="Soichot">Marion Soichot</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Vaast, Arnaud" sort="Vaast, Arnaud" uniqKey="Vaast A" first="Arnaud" last="Vaast">Arnaud Vaast</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Vignau, Jean" sort="Vignau, Jean" uniqKey="Vignau J" first="Jean" last="Vignau">Jean Vignau</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Service d'Addictologie, Centre Hospitalier Regional Universitaire</s1><s2>Lille</s2><s3>FRA</s3><sZ>3 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Guillemin, Gilles J" sort="Guillemin, Gilles J" uniqKey="Guillemin G" first="Gilles J." last="Guillemin">Gilles J. Guillemin</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Neuroinflammation Group, Department of Pharmacology, University of New South Wales</s1><s2>Sydney, NSW 2052</s2><s3>AUS</s3><sZ>4 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Sydney, NSW 2052</wicri:noRegion></affiliation></author><author><name sortKey="Lhermitte, Michel" sort="Lhermitte, Michel" uniqKey="Lhermitte M" first="Michel" last="Lhermitte">Michel Lhermitte</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Laboratoire de Toxicologie and Génopathies, Centre de Biologie Pathologie, CHRU</s1><s2>Lille</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Broly, Franck" sort="Broly, Franck" uniqKey="Broly F" first="Franck" last="Broly">Franck Broly</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Laboratoire de Toxicologie and Génopathies, Centre de Biologie Pathologie, CHRU</s1><s2>Lille</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Allorge, Delphine" sort="Allorge, Delphine" uniqKey="Allorge D" first="Delphine" last="Allorge">Delphine Allorge</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Equipe d'Accueil 4483, Faculté de Médecine/Pôle Recherche, UDSL, Université Lille-Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Laboratoire de Toxicologie and Génopathies, Centre de Biologie Pathologie, CHRU</s1><s2>Lille</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">Alcohol and alcoholism : (Oxford)</title><title level="j" type="abbreviated">Alcohol alcohol. : (Oxford)</title><idno type="ISSN">0735-0414</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Alcohol and alcoholism : (Oxford)</title><title level="j" type="abbreviated">Alcohol alcohol. : (Oxford)</title><idno type="ISSN">0735-0414</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alcoholic beverage</term><term>Behavioral disorder</term><term>Candidate gene</term><term>Characterization</term><term>Ethanol</term><term>Genetic variability</term><term>Genotype</term><term>Glucocorticoid</term><term>Polymorphism</term><term>Promoter</term><term>Response element</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Boisson alcoolisée</term><term>Caractérisation</term><term>Polymorphisme</term><term>Variabilité génétique</term><term>Génotype</term><term>Glucocorticoïde</term><term>Elément réponse</term><term>Trouble du comportement</term><term>Promoteur</term><term>Gène candidat</term><term>Ethanol</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Boisson alcoolisée</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Aims: In response to acute ethanol consumption, tryptophan 2,3-dioxygenase (TDO) induces the kynurenine pathway (KP) through a glucocorticoid-mediated mechanism, which could lead to a dramatic accumulation of neurotoxic metabolites in association with serotonin depletion. As a result, interindividual variability in ethanol-induced behavioural disorders, such as black-outs and violent impulsive behaviours (BOVIBs) following binge drinking, could be partly explained by genetic polymorphisms affecting the KP. The aim of this study was to identify polymorphisms on the promoter of the TD02 gene that could affect expression and/or activity of TDO through glucocorticoid induction. Methods: Polymorphisms were screened using a PCR-sequencing strategy applied to 31 alcohol-dependent patients and 49 unrelated healthy volunteers, and functionally analysed with bioinformatic prediction tools and gene reporter assays in HepG2 and A549 cell lines. Results: We identified 12 polymorphisms in the human TDO2 promoter region, 2 of them corresponding to previously unknown single-nucleotide polymorphisms (SNPs) and 3 of them located in putative glucocorticoid-responsive elements (GREs). Gene reporter assays using HepG2 and A549 cell lines confirmed the presence of several functional GREs in the promoter region of TDO2 and revealed that some of the identified polymorphisms affect the promoter activity under glucocorticoid receptor over-expression and dexamethasone exposure conditions. Conclusions: Correlational studies in larger samples could help to determine whether these polymorphisms are responsible for variations of expression and/or activity of TDO, in particular under conditions where release of glucocorticoids is increased, such as acute ethanol intake. If confirmed, such results would be of major interest in explaining part of the interindividual variability observed in behavioural responses to acute ethanol consumption.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Hauts-de-France</li><li>Nord-Pas-de-Calais</li></region><settlement><li>Lille</li></settlement></list><tree><country name="France"><region name="Hauts-de-France"><name sortKey="Soichot, Marion" sort="Soichot, Marion" uniqKey="Soichot M" first="Marion" last="Soichot">Marion Soichot</name></region><name sortKey="Allorge, Delphine" sort="Allorge, Delphine" uniqKey="Allorge D" first="Delphine" last="Allorge">Delphine Allorge</name><name sortKey="Allorge, Delphine" sort="Allorge, Delphine" uniqKey="Allorge D" first="Delphine" last="Allorge">Delphine Allorge</name><name sortKey="Broly, Franck" sort="Broly, Franck" uniqKey="Broly F" first="Franck" last="Broly">Franck Broly</name><name sortKey="Broly, Franck" sort="Broly, Franck" uniqKey="Broly F" first="Franck" last="Broly">Franck Broly</name><name sortKey="Lhermitte, Michel" sort="Lhermitte, Michel" uniqKey="Lhermitte M" first="Michel" last="Lhermitte">Michel Lhermitte</name><name sortKey="Vaast, Arnaud" sort="Vaast, Arnaud" uniqKey="Vaast A" first="Arnaud" last="Vaast">Arnaud Vaast</name><name sortKey="Vignau, Jean" sort="Vignau, Jean" uniqKey="Vignau J" first="Jean" last="Vignau">Jean Vignau</name><name sortKey="Vignau, Jean" sort="Vignau, Jean" uniqKey="Vignau J" first="Jean" last="Vignau">Jean Vignau</name></country><country name="Australie"><noRegion><name sortKey="Guillemin, Gilles J" sort="Guillemin, Gilles J" uniqKey="Guillemin G" first="Gilles J." last="Guillemin">Gilles J. 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