Multiple LRRK2 variants modulate risk of Parkinson disease: a chinese multicenter study
Identifieur interne : 000636 ( Main/Exploration ); précédent : 000635; suivant : 000637Multiple LRRK2 variants modulate risk of Parkinson disease: a chinese multicenter study
Auteurs : Eng-King Tan [Singapour, Taïwan] ; Rong Peng [République populaire de Chine] ; Yik-Ying Teo [Singapour] ; Louis C. Tan [Singapour] ; Dario Angeles [Singapour] ; Patrick Ho [Singapour] ; Meng-Ling Chen [Taïwan] ; Chin-Hsien Lin [Taïwan] ; Xue-Ye Mao [République populaire de Chine] ; Xue-Li Chang [République populaire de Chine] ; Kumar M. Prakash [Singapour] ; Jian-Jun Liu [Singapour] ; Wing-Lok Au [Singapour] ; Wei-Dong Le [États-Unis] ; Joseph Jankovic [États-Unis] ; Jean-Marc Burgunder [République populaire de Chine, Suisse] ; Yi Zhao [Singapour] ; Ruey-Meei Wu [Taïwan]Source :
- Human Mutation [ 1059-7794 ] ; 2010-05.
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Abstract
We and others found two polymorphic LRRK2 (leucine‐rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5–1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese. Hum Mutat 31:561–568, 2010. © 2010 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/humu.21225
Affiliations:
- République populaire de Chine, Singapour, Suisse, Taïwan, États-Unis
- Canton de Berne, Texas
- Berne, Houston
- Baylor College of Medicine, Université de Berne, Université nationale de Singapour
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Prakash</name><affiliation wicri:level="1"><country xml:lang="fr">Singapour</country><wicri:regionArea>Departments of Neurology, Singapore General Hospital</wicri:regionArea><wicri:noRegion>Singapore General Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Jian Un" sort="Liu, Jian Un" uniqKey="Liu J" first="Jian-Jun" last="Liu">Jian-Jun Liu</name><affiliation wicri:level="1"><country xml:lang="fr">Singapour</country><wicri:regionArea>Human Genetics, Genome Institute of Singapore, A*STAR</wicri:regionArea><wicri:noRegion>A*STAR</wicri:noRegion></affiliation></author><author><name sortKey="Au, Wing Ok" sort="Au, Wing Ok" uniqKey="Au W" first="Wing-Lok" last="Au">Wing-Lok Au</name><affiliation wicri:level="1"><country xml:lang="fr">Singapour</country><wicri:regionArea>National Neuroscience Institute</wicri:regionArea></affiliation></author><author><name sortKey="Le, Wei Ong" sort="Le, Wei Ong" uniqKey="Le W" first="Wei-Dong" last="Le">Wei-Dong Le</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Neurology, Baylor College of Medicine, Houston</wicri:cityArea></affiliation></author><author><name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Neurology, Baylor College of Medicine, Houston</wicri:cityArea><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university" n="3">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Burgunder, Jean Arc" sort="Burgunder, Jean Arc" uniqKey="Burgunder J" first="Jean-Marc" last="Burgunder">Jean-Marc Burgunder</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Neurology, West China Hospital, Sichuan University, Chengdu</wicri:regionArea><wicri:noRegion>Chengdu</wicri:noRegion></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Neurology, University of Bern, Bern</wicri:regionArea><placeName><settlement type="city">Berne</settlement><region type="région" nuts="3">Canton de Berne</region></placeName><orgName type="university">Université de Berne</orgName></affiliation></author><author><name sortKey="Zhao, Yi" sort="Zhao, Yi" uniqKey="Zhao Y" first="Yi" last="Zhao">Yi Zhao</name><affiliation wicri:level="1"><country xml:lang="fr">Singapour</country><wicri:regionArea>Clinical Research, Singapore General Hospital</wicri:regionArea><wicri:noRegion>Singapore General Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Ruey Eei" sort="Wu, Ruey Eei" uniqKey="Wu R" first="Ruey-Meei" last="Wu">Ruey-Meei Wu</name><affiliation wicri:level="1"><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Neurology, National Taiwan University Hospital, National Taiwan University, Taipei</wicri:regionArea><wicri:noRegion>Taipei</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Taïwan</country><wicri:regionArea>Eng‐King Tan, Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169108Ruey‐Meei Wu, Department of Neurology, National Taiwan University Hospital, National Taiwan University, Taipei</wicri:regionArea><wicri:noRegion>Taipei</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Mutation</title><title level="j" type="abbrev">Hum. Mutat.</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-05">2010-05</date><biblScope unit="volume">31</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="561">561</biblScope><biblScope unit="page" to="568">568</biblScope></imprint><idno type="ISSN">1059-7794</idno></series><idno type="istex">3EE7DBF3D18D5DBD5BDE0DD45A47620505FDC4FF</idno><idno type="DOI">10.1002/humu.21225</idno><idno type="ArticleID">HUMU21225</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Chinese</term><term>Han</term><term>LRRK2</term><term>Parkinson disease</term><term>kinase</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We and others found two polymorphic LRRK2 (leucine‐rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5–1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese. Hum Mutat 31:561–568, 2010. © 2010 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li><li>Singapour</li><li>Suisse</li><li>Taïwan</li><li>États-Unis</li></country><region><li>Canton de Berne</li><li>Texas</li></region><settlement><li>Berne</li><li>Houston</li></settlement><orgName><li>Baylor College of Medicine</li><li>Université de Berne</li><li>Université nationale de Singapour</li></orgName></list><tree><country name="Singapour"><noRegion><name sortKey="Tan, Eng Ing" sort="Tan, Eng Ing" uniqKey="Tan E" first="Eng-King" last="Tan">Eng-King Tan</name></noRegion><name sortKey="Angeles, Dario" sort="Angeles, Dario" uniqKey="Angeles D" first="Dario" last="Angeles">Dario Angeles</name><name sortKey="Au, Wing Ok" sort="Au, Wing Ok" uniqKey="Au W" first="Wing-Lok" last="Au">Wing-Lok Au</name><name sortKey="C Tan, Louis" sort="C Tan, Louis" uniqKey="C Tan L" first="Louis" last="C. Tan">Louis C. Tan</name><name sortKey="Ho, Patrick" sort="Ho, Patrick" uniqKey="Ho P" first="Patrick" last="Ho">Patrick Ho</name><name sortKey="Liu, Jian Un" sort="Liu, Jian Un" uniqKey="Liu J" first="Jian-Jun" last="Liu">Jian-Jun Liu</name><name sortKey="Prakash, Kumar M" sort="Prakash, Kumar M" uniqKey="Prakash K" first="Kumar M" last="Prakash">Kumar M. Prakash</name><name sortKey="Tan, Eng Ing" sort="Tan, Eng Ing" uniqKey="Tan E" first="Eng-King" last="Tan">Eng-King Tan</name><name sortKey="Tan, Eng Ing" sort="Tan, Eng Ing" uniqKey="Tan E" first="Eng-King" last="Tan">Eng-King Tan</name><name sortKey="Tan, Eng Ing" sort="Tan, Eng Ing" uniqKey="Tan E" first="Eng-King" last="Tan">Eng-King Tan</name><name sortKey="Teo, Yik Ing" sort="Teo, Yik Ing" uniqKey="Teo Y" first="Yik-Ying" last="Teo">Yik-Ying Teo</name><name sortKey="Teo, Yik Ing" sort="Teo, Yik Ing" uniqKey="Teo Y" first="Yik-Ying" last="Teo">Yik-Ying Teo</name><name sortKey="Zhao, Yi" sort="Zhao, Yi" uniqKey="Zhao Y" first="Yi" last="Zhao">Yi Zhao</name></country><country name="Taïwan"><noRegion><name sortKey="Tan, Eng Ing" sort="Tan, Eng Ing" uniqKey="Tan E" first="Eng-King" last="Tan">Eng-King Tan</name></noRegion><name sortKey="Chen, Meng Ing" sort="Chen, Meng Ing" uniqKey="Chen M" first="Meng-Ling" last="Chen">Meng-Ling Chen</name><name sortKey="Lin, Chin Sien" sort="Lin, Chin Sien" uniqKey="Lin C" first="Chin-Hsien" last="Lin">Chin-Hsien Lin</name><name sortKey="Wu, Ruey Eei" sort="Wu, Ruey Eei" uniqKey="Wu R" first="Ruey-Meei" last="Wu">Ruey-Meei Wu</name><name sortKey="Wu, Ruey Eei" sort="Wu, Ruey Eei" uniqKey="Wu R" first="Ruey-Meei" last="Wu">Ruey-Meei Wu</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Peng, Rong" sort="Peng, Rong" uniqKey="Peng R" first="Rong" last="Peng">Rong Peng</name></noRegion><name sortKey="Burgunder, Jean Arc" sort="Burgunder, Jean Arc" uniqKey="Burgunder J" first="Jean-Marc" last="Burgunder">Jean-Marc Burgunder</name><name sortKey="Chang, Xue I" sort="Chang, Xue I" uniqKey="Chang X" first="Xue-Li" last="Chang">Xue-Li Chang</name><name sortKey="Mao, Xue E" sort="Mao, Xue E" uniqKey="Mao X" first="Xue-Ye" last="Mao">Xue-Ye Mao</name></country><country name="États-Unis"><region name="Texas"><name sortKey="Le, Wei Ong" sort="Le, Wei Ong" uniqKey="Le W" first="Wei-Dong" last="Le">Wei-Dong Le</name></region><name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name></country><country name="Suisse"><region name="Canton de Berne"><name sortKey="Burgunder, Jean Arc" sort="Burgunder, Jean Arc" uniqKey="Burgunder J" first="Jean-Marc" last="Burgunder">Jean-Marc Burgunder</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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