NOS2A and the modulating effect of cigarette smoking in Parkinson's disease
Identifieur interne : 000671 ( Main/Corpus ); précédent : 000670; suivant : 000672NOS2A and the modulating effect of cigarette smoking in Parkinson's disease
Auteurs : Dana B. Hancock ; Eden R. Martin ; Kenichiro Fujiwara ; Mark A. Stacy ; Burton L. Scott ; Jeffrey M. Stajich ; Rita Jewett ; Yi-Ju Li ; Michael A. Hauser ; Jeffery M. Vance ; William K. ScottSource :
- Annals of Neurology [ 0364-5134 ] ; 2006-09.
Abstract
Objective: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. Methods: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. Results: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two‐SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. Interpretation: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006
Url:
DOI: 10.1002/ana.20915
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Martin</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Fujiwara, Kenichiro" sort="Fujiwara, Kenichiro" uniqKey="Fujiwara K" first="Kenichiro" last="Fujiwara">Kenichiro Fujiwara</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Stacy, Mark A" sort="Stacy, Mark A" uniqKey="Stacy M" first="Mark A." last="Stacy">Mark A. 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Hancock</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Martin, Eden R" sort="Martin, Eden R" uniqKey="Martin E" first="Eden R." last="Martin">Eden R. Martin</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Fujiwara, Kenichiro" sort="Fujiwara, Kenichiro" uniqKey="Fujiwara K" first="Kenichiro" last="Fujiwara">Kenichiro Fujiwara</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Stacy, Mark A" sort="Stacy, Mark A" uniqKey="Stacy M" first="Mark A." last="Stacy">Mark A. Stacy</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Scott, Burton L" sort="Scott, Burton L" uniqKey="Scott B" first="Burton L." last="Scott">Burton L. Scott</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Stajich, Jeffrey M" sort="Stajich, Jeffrey M" uniqKey="Stajich J" first="Jeffrey M." last="Stajich">Jeffrey M. Stajich</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Jewett, Rita" sort="Jewett, Rita" uniqKey="Jewett R" first="Rita" last="Jewett">Rita Jewett</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Li, Yi U" sort="Li, Yi U" uniqKey="Li Y" first="Yi-Ju" last="Li">Yi-Ju Li</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Hauser, Michael A" sort="Hauser, Michael A" uniqKey="Hauser M" first="Michael A." last="Hauser">Michael A. Hauser</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Vance, Jeffery M" sort="Vance, Jeffery M" uniqKey="Vance J" first="Jeffery M." last="Vance">Jeffery M. Vance</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Scott, William K" sort="Scott, William K" uniqKey="Scott W" first="William K." last="Scott">William K. Scott</name><affiliation><mods:affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2006-09">2006-09</date><biblScope unit="volume">60</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="366">366</biblScope><biblScope unit="page" to="373">373</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">FC31CE7498F30D2C79B964393B2654D929B20D1A</idno><idno type="DOI">10.1002/ana.20915</idno><idno type="ArticleID">ANA20915</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. Methods: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. Results: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two‐SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. Interpretation: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Dana B. Hancock BS</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Eden R. Martin PhD</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string><json:string>Department of Medicine, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Kenichiro Fujiwara BS</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Mark A. Stacy MD</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string><json:string>Department of Medicine, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Burton L. Scott PhD, MD</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string><json:string>Department of Medicine, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Jeffrey M. Stajich PA‐C</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Rita Jewett RN</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Yi‐Ju Li PhD</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string><json:string>Department of Medicine, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Michael A. Hauser PhD</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string><json:string>Department of Medicine, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Jeffery M. Vance PhD, MD</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string><json:string>Department of Medicine, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>William K. Scott PhD</name><affiliations><json:string>Center for Human Genetics, Duke University Medical Center, Durham, NC</json:string><json:string>Department of Medicine, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item></author><articleId><json:string>ANA20915</json:string></articleId><language><json:string>eng</json:string></language><abstract>Objective: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. Methods: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. Results: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two‐SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p > 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. Interpretation: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006</abstract><qualityIndicators><score>7.711</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1614</abstractCharCount><pdfWordCount>4903</pdfWordCount><pdfCharCount>33957</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>234</abstractWordCount></qualityIndicators><title>NOS2A and the modulating effect of cigarette smoking in Parkinson's disease</title><genre><json:string>article</json:string></genre><host><volume>60</volume><publisherId><json:string>ANA</json:string></publisherId><pages><total>8</total><last>373</last><first>366</first></pages><issn><json:string>0364-5134</json:string></issn><issue>3</issue><subject><json:item><value>Original Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8249</json:string></eissn><title>Annals of Neurology</title><doi><json:string>10.1002/(ISSN)1531-8249</json:string></doi></host><publicationDate>2006</publicationDate><copyrightDate>2006</copyrightDate><doi><json:string>10.1002/ana.20915</json:string></doi><id>FC31CE7498F30D2C79B964393B2654D929B20D1A</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/FC31CE7498F30D2C79B964393B2654D929B20D1A/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/FC31CE7498F30D2C79B964393B2654D929B20D1A/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/FC31CE7498F30D2C79B964393B2654D929B20D1A/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">NOS2A and the modulating effect of cigarette smoking in Parkinson's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2006</date></publicationStmt><notesStmt><note>NIH (National Institute on Neurological Disorders and Stroke - No. P50 NS39764‐03;</note><note>Duke University Graduate School</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">NOS2A and the modulating effect of cigarette smoking in Parkinson's disease</title><author><persName><forename type="first">Dana B.</forename><surname>Hancock</surname></persName><roleName type="degree">BS</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Eden R.</forename><surname>Martin</surname></persName><roleName type="degree">PhD</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Kenichiro</forename><surname>Fujiwara</surname></persName><roleName type="degree">BS</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Mark A.</forename><surname>Stacy</surname></persName><roleName type="degree">MD</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Burton L.</forename><surname>Scott</surname></persName><roleName type="degree">PhD, MD</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Jeffrey M.</forename><surname>Stajich</surname></persName><roleName type="degree">PA‐C</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Rita</forename><surname>Jewett</surname></persName><roleName type="degree">RN</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Yi‐Ju</forename><surname>Li</surname></persName><roleName type="degree">PhD</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Michael A.</forename><surname>Hauser</surname></persName><roleName type="degree">PhD</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Jeffery M.</forename><surname>Vance</surname></persName><roleName type="degree">PhD, MD</roleName><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">William K.</forename><surname>Scott</surname></persName><roleName type="degree">PhD</roleName><note type="correspondence"><p>Correspondence: Center for Human Genetics, Duke University Medical Center, Box 3445, Durham, NC 27710</p></note><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2006-09"></date><biblScope unit="volume">60</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="366">366</biblScope><biblScope unit="page" to="373">373</biblScope></imprint></monogr><idno type="istex">FC31CE7498F30D2C79B964393B2654D929B20D1A</idno><idno type="DOI">10.1002/ana.20915</idno><idno type="ArticleID">ANA20915</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2006</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Objective: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. Methods: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. Results: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two‐SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. Interpretation: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006</p></abstract><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Original Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2006-01-19">Received</change><change when="2006-05-09">Registration</change><change when="2006-09">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/FC31CE7498F30D2C79B964393B2654D929B20D1A/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 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registered="yes">10.1002/ana.20915</doi><idGroup><id type="unit" value="ANA20915"></id></idGroup><countGroup><count type="pageTotal" number="8"></count></countGroup><titleGroup><title type="articleCategory">Original Article</title><title type="tocHeading1">Original Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2006 American Neurological Association</copyright><eventGroup><event type="manuscriptReceived" date="2006-01-19"></event><event type="manuscriptRevised" date="2006-04-17"></event><event type="manuscriptAccepted" date="2006-05-09"></event><event type="publishedOnlineEarlyUnpaginated" date="2006-07-05"></event><event type="firstOnline" date="2006-07-05"></event><event type="publishedOnlineFinalForm" date="2006-09-18"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.3 mode:FullText source:FullText result:FullText" date="2010-03-19"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-03"></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">366</numbering><numbering type="pageLast">373</numbering></numberingGroup><correspondenceTo>Center for Human Genetics, Duke University Medical Center, Box 3445, Durham, NC 27710</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:ANA.ANA20915.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="1"></count><count type="tableTotal" number="5"></count><count type="referenceTotal" number="35"></count><count type="wordTotal" number="5832"></count></countGroup><titleGroup><title type="main" xml:lang="en"><i>NOS2A</i> and the modulating effect of cigarette smoking in Parkinson's disease</title><title type="short" xml:lang="en"><fi>NOS2A</fi> and Smoking in PD</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Dana B.</givenNames><familyName>Hancock</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Eden R.</givenNames><familyName>Martin</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Kenichiro</givenNames><familyName>Fujiwara</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Mark A.</givenNames><familyName>Stacy</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Burton L.</givenNames><familyName>Scott</familyName><degrees>PhD, MD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Jeffrey M.</givenNames><familyName>Stajich</familyName><degrees>PA‐C</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Rita</givenNames><familyName>Jewett</familyName><degrees>RN</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Yi‐Ju</givenNames><familyName>Li</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Michael A.</givenNames><familyName>Hauser</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Jeffery M.</givenNames><familyName>Vance</familyName><degrees>PhD, MD</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>William K.</givenNames><familyName>Scott</familyName><degrees>PhD</degrees></personName><contactDetails><email>bill.scott@duke.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Department of Medicine, Duke University Medical Center, Durham, NC</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>NIH (National Institute on Neurological Disorders and Stroke</fundingAgency><fundingNumber>P50 NS39764‐03</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Duke University Graduate School</fundingAgency></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><section xml:id="abs1-1"><title type="main">Objective</title><p>Inducible nitric oxide synthase, a protein product of <i>NOS2A,</i> generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. <i>NOS2A</i> is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined <i>NOS2A</i> for association with PD risk and age at onset (AAO) and for interaction with smoking.</p></section><section xml:id="abs1-2"><title type="main">Methods</title><p>We genotyped 13 <i>NOS2A</i> single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations.</p></section><section xml:id="abs1-3"><title type="main">Results</title><p>Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (<i>p</i> = 0.000059 and 0.0062, respectively) and genotypic (<i>p</i> = 0.0039 and 0.0014, respectively) associations with risk and AAO (<i>p</i> = 0.00070 and 0.0073, respectively); the two‐SNP haplotype generated even stronger association with PD (<i>p</i> = 0.000013). Significant interactions with smoking (<i>p</i> = 0.0015 for rs 2255929 and <i>p</i> < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers.</p></section><section xml:id="abs1-4"><title type="main">Interpretation</title><p>Our findings support <i>NOS2A</i> as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006</p></section></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>NOS2A and the modulating effect of cigarette smoking in Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>NOS2A and Smoking in PD</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>and the modulating effect of cigarette smoking in Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Dana B.</namePart><namePart type="family">Hancock</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eden R.</namePart><namePart type="family">Martin</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kenichiro</namePart><namePart type="family">Fujiwara</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark A.</namePart><namePart type="family">Stacy</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Burton L.</namePart><namePart type="family">Scott</namePart><namePart type="termsOfAddress">PhD, MD</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeffrey M.</namePart><namePart type="family">Stajich</namePart><namePart type="termsOfAddress">PA‐C</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rita</namePart><namePart type="family">Jewett</namePart><namePart type="termsOfAddress">RN</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yi‐Ju</namePart><namePart type="family">Li</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael A.</namePart><namePart type="family">Hauser</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeffery M.</namePart><namePart type="family">Vance</namePart><namePart type="termsOfAddress">PhD, MD</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William K.</namePart><namePart type="family">Scott</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Human Genetics, Duke University Medical Center, Durham, NC</affiliation><affiliation>Department of Medicine, Duke University Medical Center, Durham, NC</affiliation><description>Correspondence: Center for Human Genetics, Duke University Medical Center, Box 3445, Durham, NC 27710</description><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">2006-09</dateIssued><dateCaptured encoding="w3cdtf">2006-01-19</dateCaptured><dateValid encoding="w3cdtf">2006-05-09</dateValid><copyrightDate encoding="w3cdtf">2006</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">1</extent><extent unit="tables">5</extent><extent unit="references">35</extent><extent unit="words">5832</extent></physicalDescription><abstract lang="en">Objective: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. Methods: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. Results: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two‐SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. Interpretation: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006</abstract><note type="funding">NIH (National Institute on Neurological Disorders and Stroke - No. P50 NS39764‐03; </note><note type="funding">Duke University Graduate School</note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title><subTitle>Official Journal of the American Neurological Association and the Child Neurology Society</subTitle></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>60</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>366</start><end>373</end><total>8</total></extent></part></relatedItem><identifier type="istex">FC31CE7498F30D2C79B964393B2654D929B20D1A</identifier><identifier type="DOI">10.1002/ana.20915</identifier><identifier type="ArticleID">ANA20915</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2006 American Neurological Association</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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