Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome
Identifieur interne : 002543 ( Main/Exploration ); précédent : 002542; suivant : 002544Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome
Auteurs : Juliane Winkelmann [Allemagne] ; Peter Lichtner [Allemagne] ; Barbara Schormair [Allemagne] ; Manfred Uhr [Allemagne] ; Stephanie Hauk [Allemagne] ; Karin Stiasny-Kolster [Allemagne] ; Claudia Trenkwalder [Allemagne] ; Walter Paulus [Allemagne] ; Ines Peglau [Allemagne] ; Ilonka Eisensehr [Allemagne] ; Thomas Illig [Allemagne] ; H. Rich Wichmann [Allemagne] ; Hildegard Pfister [Allemagne] ; Jelena Golic [Allemagne] ; Thomas Bettecken [Allemagne] ; Benno Pütz [Allemagne] ; Florian Holsboer [Allemagne] ; Thomas Meitinger [Allemagne] ; Bertram Müller-Myhsok [Allemagne]Source :
- Movement Disorders [ 0885-3185 ] ; 2008-02-15.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
- Adult, Aged, Arginine (genetics), Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, NOS, Nervous system diseases, Nitric Oxide Synthase Type I (genetics), Nitric-oxide synthase, Polymorphism, Single Nucleotide (genetics), Restless Legs Syndrome (epidemiology), Restless Legs Syndrome (genetics), Restless Legs Syndrome (physiopathology), Restless legs syndrome, Sleep, association study, genetics, restless legs syndrome, sleep.
- MESH :
- chemical , genetics : Arginine, Nitric Oxide Synthase Type I.
- epidemiology : Restless Legs Syndrome.
- genetics : Polymorphism, Single Nucleotide, Restless Legs Syndrome.
- physiopathology : Restless Legs Syndrome.
- Adult, Aged, Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged.
Abstract
Sixty percent of the patients with restless legs syndrome (RLS) report a positive family history. To date five loci have been mapped on chromosome 12q, 14q, 9p, 2q, and 20p (RLS1‐5) but no gene has been identified so far. To identify genes related to RLS, we performed a three‐stage association study (explorative study, replication study, high‐density mapping) in two Caucasian RLS case‐control samples of altogether 918 independent cases and controls. In the explorative study (367 cases and controls, respectively), we screened 1536 SNPs in 366 genes in a 21 Mb region encompassing the RLS1 critical region on chromosome 12. Armitage trend test revealed three genomic regions that were significant (P < 0.05). In the replication study (551 cases and controls, respectively) we genotyped the most significant SNPs of Stage 1. After correction for multiple testing, association was observed with SNP rs7977109 (Pnominal = 0.00175, PWestfall‐Young = 0.04895, OR = 0.76228, 95% CI = 0.64310–0.90355), which is in the neuronal nitric oxide synthase (NOS1) gene. High‐density mapping using altogether 34 tagging and coding SNPs of the NOS1 gene in both case‐control samples further confirmed the significant association results to NOS1. Ten more SNPs revealed significance with nominal P‐values from 0.0001 to 0.0482 (genotypic test and Armitage test). Altogether, this study provides evidence for an association of variants in the NOS1 gene and RLS, and suggests the involvement of the NO/arginine pathway in the pathogenesis of RLS. Potential usage of NO modulating agents as new treatment options for RLS have become a challenging aspect for future research of this disorder. © 2007 Movement Disorder Society
Url:
DOI: 10.1002/mds.21647
Affiliations:
- Allemagne
- Basse-Saxe, Bavière, Berlin, District de Giessen, District de Haute-Bavière, District de Kassel, Hesse (Land)
- Berlin, Cassel (Hesse), Göttingen, Marbourg, Munich
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Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Eisensehr, Ilonka" sort="Eisensehr, Ilonka" uniqKey="Eisensehr I" first="Ilonka" last="Eisensehr">Ilonka Eisensehr</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Neurologische Praxis Sendlingerstrasse, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology, GSF‐National Research Center for Environment and Health, Munich</wicri:regionArea><placeName><region 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Rich" last="Wichmann">H. Rich Wichmann</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology, GSF‐National Research Center for Environment and Health, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Pfister, Hildegard" sort="Pfister, Hildegard" uniqKey="Pfister H" first="Hildegard" last="Pfister">Hildegard Pfister</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Golic, Jelena" sort="Golic, Jelena" uniqKey="Golic J" first="Jelena" last="Golic">Jelena Golic</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, Technical University, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Bettecken, Thomas" sort="Bettecken, Thomas" uniqKey="Bettecken T" first="Thomas" last="Bettecken">Thomas Bettecken</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Putz, Benno" sort="Putz, Benno" uniqKey="Putz B" first="Benno" last="Pütz">Benno Pütz</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Holsboer, Florian" sort="Holsboer, Florian" uniqKey="Holsboer F" first="Florian" last="Holsboer">Florian Holsboer</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, GSF‐National Research Center for Environment and Health, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, Technical University, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Muller Yhsok, Bertram" sort="Muller Yhsok, Bertram" uniqKey="Muller Yhsok B" first="Bertram" last="Müller-Myhsok">Bertram Müller-Myhsok</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max Planck Institute of Psychiatry, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="sub">Official Journal of the Movement Disorder Society</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2008-02-15">2008-02-15</date><biblScope unit="vol">23</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="350">350</biblScope><biblScope unit="page" to="358">358</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">71FDA7DBF728A3FB0AF66861615DAC0FEC9359C2</idno><idno type="DOI">10.1002/mds.21647</idno><idno type="ArticleID">MDS21647</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Aged</term><term>Arginine (genetics)</term><term>Case-Control Studies</term><term>Female</term><term>Gene Frequency</term><term>Genetic Predisposition to Disease</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>NOS</term><term>Nervous system diseases</term><term>Nitric Oxide Synthase Type I (genetics)</term><term>Nitric-oxide synthase</term><term>Polymorphism, Single Nucleotide (genetics)</term><term>Restless Legs Syndrome (epidemiology)</term><term>Restless Legs Syndrome (genetics)</term><term>Restless Legs Syndrome (physiopathology)</term><term>Restless legs syndrome</term><term>Sleep</term><term>association study</term><term>genetics</term><term>restless legs syndrome</term><term>sleep</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Arginine</term><term>Nitric Oxide Synthase Type I</term></keywords><keywords scheme="MESH" qualifier="epidemiology" xml:lang="en"><term>Restless Legs Syndrome</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Polymorphism, Single Nucleotide</term><term>Restless Legs Syndrome</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Restless Legs Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Case-Control Studies</term><term>Female</term><term>Gene Frequency</term><term>Genetic Predisposition to Disease</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Middle Aged</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Nitric-oxide synthase</term><term>Pathologie du système nerveux</term><term>Sommeil</term><term>Syndrome des jambes sans repos</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Sixty percent of the patients with restless legs syndrome (RLS) report a positive family history. To date five loci have been mapped on chromosome 12q, 14q, 9p, 2q, and 20p (RLS1‐5) but no gene has been identified so far. To identify genes related to RLS, we performed a three‐stage association study (explorative study, replication study, high‐density mapping) in two Caucasian RLS case‐control samples of altogether 918 independent cases and controls. In the explorative study (367 cases and controls, respectively), we screened 1536 SNPs in 366 genes in a 21 Mb region encompassing the RLS1 critical region on chromosome 12. Armitage trend test revealed three genomic regions that were significant (P < 0.05). In the replication study (551 cases and controls, respectively) we genotyped the most significant SNPs of Stage 1. After correction for multiple testing, association was observed with SNP rs7977109 (Pnominal = 0.00175, PWestfall‐Young = 0.04895, OR = 0.76228, 95% CI = 0.64310–0.90355), which is in the neuronal nitric oxide synthase (NOS1) gene. High‐density mapping using altogether 34 tagging and coding SNPs of the NOS1 gene in both case‐control samples further confirmed the significant association results to NOS1. Ten more SNPs revealed significance with nominal P‐values from 0.0001 to 0.0482 (genotypic test and Armitage test). Altogether, this study provides evidence for an association of variants in the NOS1 gene and RLS, and suggests the involvement of the NO/arginine pathway in the pathogenesis of RLS. Potential usage of NO modulating agents as new treatment options for RLS have become a challenging aspect for future research of this disorder. © 2007 Movement Disorder Society</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Basse-Saxe</li><li>Bavière</li><li>Berlin</li><li>District de Giessen</li><li>District de Haute-Bavière</li><li>District de Kassel</li><li>Hesse (Land)</li></region><settlement><li>Berlin</li><li>Cassel (Hesse)</li><li>Göttingen</li><li>Marbourg</li><li>Munich</li></settlement></list><tree><country name="Allemagne"><region name="Bavière"><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name></region><name sortKey="Bettecken, Thomas" sort="Bettecken, Thomas" uniqKey="Bettecken T" first="Thomas" last="Bettecken">Thomas Bettecken</name><name sortKey="Eisensehr, Ilonka" sort="Eisensehr, Ilonka" uniqKey="Eisensehr I" first="Ilonka" last="Eisensehr">Ilonka Eisensehr</name><name sortKey="Golic, Jelena" sort="Golic, Jelena" uniqKey="Golic J" first="Jelena" last="Golic">Jelena Golic</name><name sortKey="Hauk, Stephanie" sort="Hauk, Stephanie" uniqKey="Hauk S" first="Stephanie" last="Hauk">Stephanie Hauk</name><name sortKey="Hauk, Stephanie" sort="Hauk, Stephanie" uniqKey="Hauk S" first="Stephanie" last="Hauk">Stephanie Hauk</name><name sortKey="Holsboer, Florian" sort="Holsboer, Florian" uniqKey="Holsboer F" first="Florian" last="Holsboer">Florian Holsboer</name><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><name sortKey="Muller Yhsok, Bertram" sort="Muller Yhsok, Bertram" uniqKey="Muller Yhsok B" first="Bertram" last="Müller-Myhsok">Bertram Müller-Myhsok</name><name sortKey="Paulus, Walter" sort="Paulus, Walter" uniqKey="Paulus W" first="Walter" last="Paulus">Walter Paulus</name><name sortKey="Peglau, Ines" sort="Peglau, Ines" uniqKey="Peglau I" first="Ines" last="Peglau">Ines Peglau</name><name sortKey="Pfister, Hildegard" sort="Pfister, Hildegard" uniqKey="Pfister H" first="Hildegard" last="Pfister">Hildegard Pfister</name><name sortKey="Putz, Benno" sort="Putz, Benno" uniqKey="Putz B" first="Benno" last="Pütz">Benno Pütz</name><name sortKey="Schormair, Barbara" sort="Schormair, Barbara" uniqKey="Schormair B" first="Barbara" last="Schormair">Barbara Schormair</name><name sortKey="Schormair, Barbara" sort="Schormair, Barbara" uniqKey="Schormair B" first="Barbara" last="Schormair">Barbara Schormair</name><name sortKey="Stiasny Olster, Karin" sort="Stiasny Olster, Karin" uniqKey="Stiasny Olster K" first="Karin" last="Stiasny-Kolster">Karin Stiasny-Kolster</name><name sortKey="Trenkwalder, Claudia" sort="Trenkwalder, Claudia" uniqKey="Trenkwalder C" first="Claudia" last="Trenkwalder">Claudia Trenkwalder</name><name sortKey="Uhr, Manfred" sort="Uhr, Manfred" uniqKey="Uhr M" first="Manfred" last="Uhr">Manfred Uhr</name><name sortKey="Wichmann, H Rich" sort="Wichmann, H Rich" uniqKey="Wichmann H" first="H. Rich" last="Wichmann">H. Rich Wichmann</name><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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