Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome.
Identifieur interne : 001F44 ( Ncbi/Checkpoint ); précédent : 001F43; suivant : 001F45Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome.
Auteurs : Juliane Winkelmann [Allemagne] ; Peter Lichtner ; Barbara Schormair ; Manfred Uhr ; Stephanie Hauk ; Karin Stiasny-Kolster ; Claudia Trenkwalder ; Walter Paulus ; Ines Peglau ; Ilonka Eisensehr ; Thomas Illig ; H-Erich Wichmann ; Hildegard Pfister ; Jelena Golic ; Thomas Bettecken ; Benno Pütz ; Florian Holsboer ; Thomas Meitinger ; Bertram Müller-MyhsokSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2008.
English descriptors
- KwdEn :
- Adult, Aged, Arginine (genetics), Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, Nitric Oxide Synthase Type I (genetics), Polymorphism, Single Nucleotide (genetics), Restless Legs Syndrome (epidemiology), Restless Legs Syndrome (genetics), Restless Legs Syndrome (physiopathology).
- 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 (P(nominal) = 0.00175, P(Westfall-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.
DOI: 10.1002/mds.21647
PubMed: 18058820
Affiliations:
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last="Lichtner">Peter Lichtner</name></author><author><name sortKey="Schormair, Barbara" sort="Schormair, Barbara" uniqKey="Schormair B" first="Barbara" last="Schormair">Barbara Schormair</name></author><author><name sortKey="Uhr, Manfred" sort="Uhr, Manfred" uniqKey="Uhr M" first="Manfred" last="Uhr">Manfred Uhr</name></author><author><name sortKey="Hauk, Stephanie" sort="Hauk, Stephanie" uniqKey="Hauk S" first="Stephanie" last="Hauk">Stephanie Hauk</name></author><author><name sortKey="Stiasny Kolster, Karin" sort="Stiasny Kolster, Karin" uniqKey="Stiasny Kolster K" first="Karin" last="Stiasny-Kolster">Karin Stiasny-Kolster</name></author><author><name sortKey="Trenkwalder, Claudia" sort="Trenkwalder, Claudia" uniqKey="Trenkwalder C" first="Claudia" last="Trenkwalder">Claudia Trenkwalder</name></author><author><name sortKey="Paulus, Walter" sort="Paulus, Walter" uniqKey="Paulus W" first="Walter" last="Paulus">Walter Paulus</name></author><author><name sortKey="Peglau, Ines" 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Benno" sort="Putz, Benno" uniqKey="Putz B" first="Benno" last="Pütz">Benno Pütz</name></author><author><name sortKey="Holsboer, Florian" sort="Holsboer, Florian" uniqKey="Holsboer F" first="Florian" last="Holsboer">Florian Holsboer</name></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name></author><author><name sortKey="Muller Myhsok, Bertram" sort="Muller Myhsok, Bertram" uniqKey="Muller Myhsok B" first="Bertram" last="Müller-Myhsok">Bertram Müller-Myhsok</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2008">2008</date><idno type="doi">10.1002/mds.21647</idno><idno type="RBID">pubmed:18058820</idno><idno type="pmid">18058820</idno><idno type="wicri:Area/PubMed/Corpus">002415</idno><idno type="wicri:Area/PubMed/Curation">002415</idno><idno type="wicri:Area/PubMed/Checkpoint">002000</idno><idno type="wicri:Area/Ncbi/Merge">001F44</idno><idno type="wicri:Area/Ncbi/Curation">001F44</idno><idno type="wicri:Area/Ncbi/Checkpoint">001F44</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome.</title><author><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Human Genetics, GSF-National Research Center for Environment and Health, Munich, Germany. julianewinkelmann@t-online.de</nlm:affiliation><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></author><author><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name></author><author><name sortKey="Schormair, Barbara" sort="Schormair, Barbara" uniqKey="Schormair B" first="Barbara" last="Schormair">Barbara Schormair</name></author><author><name sortKey="Uhr, Manfred" sort="Uhr, Manfred" uniqKey="Uhr M" first="Manfred" last="Uhr">Manfred Uhr</name></author><author><name sortKey="Hauk, Stephanie" sort="Hauk, Stephanie" uniqKey="Hauk S" first="Stephanie" last="Hauk">Stephanie Hauk</name></author><author><name sortKey="Stiasny Kolster, Karin" sort="Stiasny Kolster, Karin" uniqKey="Stiasny Kolster K" first="Karin" last="Stiasny-Kolster">Karin Stiasny-Kolster</name></author><author><name sortKey="Trenkwalder, Claudia" sort="Trenkwalder, Claudia" uniqKey="Trenkwalder C" first="Claudia" last="Trenkwalder">Claudia Trenkwalder</name></author><author><name sortKey="Paulus, Walter" sort="Paulus, Walter" uniqKey="Paulus W" first="Walter" last="Paulus">Walter Paulus</name></author><author><name sortKey="Peglau, Ines" sort="Peglau, Ines" uniqKey="Peglau I" first="Ines" last="Peglau">Ines Peglau</name></author><author><name sortKey="Eisensehr, Ilonka" sort="Eisensehr, Ilonka" uniqKey="Eisensehr I" first="Ilonka" last="Eisensehr">Ilonka Eisensehr</name></author><author><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name></author><author><name sortKey="Wichmann, H Erich" sort="Wichmann, H Erich" uniqKey="Wichmann H" first="H-Erich" last="Wichmann">H-Erich Wichmann</name></author><author><name sortKey="Pfister, Hildegard" sort="Pfister, Hildegard" uniqKey="Pfister H" first="Hildegard" last="Pfister">Hildegard Pfister</name></author><author><name sortKey="Golic, Jelena" sort="Golic, Jelena" uniqKey="Golic J" first="Jelena" last="Golic">Jelena Golic</name></author><author><name sortKey="Bettecken, Thomas" sort="Bettecken, Thomas" uniqKey="Bettecken T" first="Thomas" last="Bettecken">Thomas Bettecken</name></author><author><name sortKey="Putz, Benno" sort="Putz, Benno" uniqKey="Putz B" first="Benno" last="Pütz">Benno Pütz</name></author><author><name sortKey="Holsboer, Florian" sort="Holsboer, Florian" uniqKey="Holsboer F" first="Florian" last="Holsboer">Florian Holsboer</name></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name></author><author><name sortKey="Muller Myhsok, Bertram" sort="Muller Myhsok, Bertram" uniqKey="Muller Myhsok B" first="Bertram" last="Müller-Myhsok">Bertram Müller-Myhsok</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></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>Nitric Oxide Synthase Type I (genetics)</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></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></textClass></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 (P(nominal) = 0.00175, P(Westfall-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.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bavière</li><li>District de Haute-Bavière</li></region><settlement><li>Munich</li></settlement></list><tree><noCountry><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="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="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><name sortKey="Muller Myhsok, Bertram" sort="Muller Myhsok, Bertram" uniqKey="Muller Myhsok 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="Stiasny Kolster, Karin" sort="Stiasny Kolster, Karin" uniqKey="Stiasny Kolster 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 Erich" sort="Wichmann, H Erich" uniqKey="Wichmann H" first="H-Erich" last="Wichmann">H-Erich Wichmann</name></noCountry><country name="Allemagne"><region name="Bavière"><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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