A Genome-wide Association Study of Myasthenia Gravis
Identifieur interne : 000773 ( Pmc/Corpus ); précédent : 000772; suivant : 000774A Genome-wide Association Study of Myasthenia Gravis
Auteurs : Alan E. Renton ; Hannah A. Pliner ; Carlo Provenzano ; Amelia Evoli ; Roberta Ricciardi ; Michael A. Nalls ; Giuseppe Marangi ; Yevgeniya Abramzon ; Sampath Arepalli ; Sean Chong ; Dena G. Hernandez ; Janel O. Johnson ; Emanuela Bartoccioni ; Flavia Scuderi ; Michelangelo Maestri ; J. Raphael Gibbs ; Edoardo Errichiello ; Adriano Chi ; Gabriella Restagno ; Mario Sabatelli ; Mark Macek ; Sonja W. Scholz ; Andrea Corse ; Vinay Chaudhry ; Michael Benatar ; Richard J. Barohn ; April Mcvey ; Mamatha Pasnoor ; Mazen M. Dimachkie ; Julie Rowin ; John Kissel ; Miriam Freimer ; Henry J. Kaminski ; Donald B. Sanders ; Bernadette Lipscomb ; Janice M. Massey ; Manisha Chopra ; James F. Howard ; Wilma J. Koopman ; Michael W. Nicolle ; Robert M. Pascuzzi ; Alan Pestronk ; Charlie Wulf ; Julaine Florence ; Derrick Blackmore ; Aimee Soloway ; Zaeem Siddiqi ; Srikanth Muppidi ; Gil Wolfe ; David Richman ; Michelle M. Mezei ; Theresa Jiwa ; Joel Oger ; Daniel B. Drachman ; Bryan J. TraynorSource :
- JAMA neurology [ 2168-6149 ] ; 2015.
Abstract
Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.
To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.
DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.
We calculated
In the over all case-control cohort, we identified association signals at
Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.
Url:
DOI: 10.1001/jamaneurol.2014.4103
PubMed: 25643325
PubMed Central: 4856525
Links to Exploration step
PMC:4856525Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Genome-wide Association Study of Myasthenia Gravis</title>
<author><name sortKey="Renton, Alan E" sort="Renton, Alan E" uniqKey="Renton A" first="Alan E." last="Renton">Alan E. Renton</name>
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<author><name sortKey="Pliner, Hannah A" sort="Pliner, Hannah A" uniqKey="Pliner H" first="Hannah A." last="Pliner">Hannah A. Pliner</name>
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<author><name sortKey="Provenzano, Carlo" sort="Provenzano, Carlo" uniqKey="Provenzano C" first="Carlo" last="Provenzano">Carlo Provenzano</name>
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<author><name sortKey="Evoli, Amelia" sort="Evoli, Amelia" uniqKey="Evoli A" first="Amelia" last="Evoli">Amelia Evoli</name>
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<author><name sortKey="Ricciardi, Roberta" sort="Ricciardi, Roberta" uniqKey="Ricciardi R" first="Roberta" last="Ricciardi">Roberta Ricciardi</name>
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<author><name sortKey="Nalls, Michael A" sort="Nalls, Michael A" uniqKey="Nalls M" first="Michael A." last="Nalls">Michael A. Nalls</name>
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<author><name sortKey="Marangi, Giuseppe" sort="Marangi, Giuseppe" uniqKey="Marangi G" first="Giuseppe" last="Marangi">Giuseppe Marangi</name>
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<author><name sortKey="Abramzon, Yevgeniya" sort="Abramzon, Yevgeniya" uniqKey="Abramzon Y" first="Yevgeniya" last="Abramzon">Yevgeniya Abramzon</name>
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<author><name sortKey="Arepalli, Sampath" sort="Arepalli, Sampath" uniqKey="Arepalli S" first="Sampath" last="Arepalli">Sampath Arepalli</name>
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<author><name sortKey="Chong, Sean" sort="Chong, Sean" uniqKey="Chong S" first="Sean" last="Chong">Sean Chong</name>
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<author><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G." last="Hernandez">Dena G. Hernandez</name>
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<author><name sortKey="Johnson, Janel O" sort="Johnson, Janel O" uniqKey="Johnson J" first="Janel O." last="Johnson">Janel O. Johnson</name>
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<author><name sortKey="Bartoccioni, Emanuela" sort="Bartoccioni, Emanuela" uniqKey="Bartoccioni E" first="Emanuela" last="Bartoccioni">Emanuela Bartoccioni</name>
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<author><name sortKey="Scuderi, Flavia" sort="Scuderi, Flavia" uniqKey="Scuderi F" first="Flavia" last="Scuderi">Flavia Scuderi</name>
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<author><name sortKey="Maestri, Michelangelo" sort="Maestri, Michelangelo" uniqKey="Maestri M" first="Michelangelo" last="Maestri">Michelangelo Maestri</name>
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<author><name sortKey="Raphael Gibbs, J" sort="Raphael Gibbs, J" uniqKey="Raphael Gibbs J" first="J." last="Raphael Gibbs">J. Raphael Gibbs</name>
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<author><name sortKey="Errichiello, Edoardo" sort="Errichiello, Edoardo" uniqKey="Errichiello E" first="Edoardo" last="Errichiello">Edoardo Errichiello</name>
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<author><name sortKey="Chi, Adriano" sort="Chi, Adriano" uniqKey="Chi A" first="Adriano" last="Chi">Adriano Chi</name>
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<author><name sortKey="Restagno, Gabriella" sort="Restagno, Gabriella" uniqKey="Restagno G" first="Gabriella" last="Restagno">Gabriella Restagno</name>
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<author><name sortKey="Sabatelli, Mario" sort="Sabatelli, Mario" uniqKey="Sabatelli M" first="Mario" last="Sabatelli">Mario Sabatelli</name>
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<author><name sortKey="Macek, Mark" sort="Macek, Mark" uniqKey="Macek M" first="Mark" last="Macek">Mark Macek</name>
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<author><name sortKey="Scholz, Sonja W" sort="Scholz, Sonja W" uniqKey="Scholz S" first="Sonja W." last="Scholz">Sonja W. Scholz</name>
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<author><name sortKey="Corse, Andrea" sort="Corse, Andrea" uniqKey="Corse A" first="Andrea" last="Corse">Andrea Corse</name>
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<author><name sortKey="Chaudhry, Vinay" sort="Chaudhry, Vinay" uniqKey="Chaudhry V" first="Vinay" last="Chaudhry">Vinay Chaudhry</name>
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<author><name sortKey="Benatar, Michael" sort="Benatar, Michael" uniqKey="Benatar M" first="Michael" last="Benatar">Michael Benatar</name>
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<author><name sortKey="Barohn, Richard J" sort="Barohn, Richard J" uniqKey="Barohn R" first="Richard J." last="Barohn">Richard J. Barohn</name>
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<author><name sortKey="Mcvey, April" sort="Mcvey, April" uniqKey="Mcvey A" first="April" last="Mcvey">April Mcvey</name>
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<author><name sortKey="Pasnoor, Mamatha" sort="Pasnoor, Mamatha" uniqKey="Pasnoor M" first="Mamatha" last="Pasnoor">Mamatha Pasnoor</name>
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<author><name sortKey="Dimachkie, Mazen M" sort="Dimachkie, Mazen M" uniqKey="Dimachkie M" first="Mazen M." last="Dimachkie">Mazen M. Dimachkie</name>
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<author><name sortKey="Rowin, Julie" sort="Rowin, Julie" uniqKey="Rowin J" first="Julie" last="Rowin">Julie Rowin</name>
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<author><name sortKey="Kissel, John" sort="Kissel, John" uniqKey="Kissel J" first="John" last="Kissel">John Kissel</name>
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<author><name sortKey="Freimer, Miriam" sort="Freimer, Miriam" uniqKey="Freimer M" first="Miriam" last="Freimer">Miriam Freimer</name>
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<author><name sortKey="Lipscomb, Bernadette" sort="Lipscomb, Bernadette" uniqKey="Lipscomb B" first="Bernadette" last="Lipscomb">Bernadette Lipscomb</name>
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<author><name sortKey="Massey, Janice M" sort="Massey, Janice M" uniqKey="Massey J" first="Janice M." last="Massey">Janice M. Massey</name>
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<author><name sortKey="Chopra, Manisha" sort="Chopra, Manisha" uniqKey="Chopra M" first="Manisha" last="Chopra">Manisha Chopra</name>
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<author><name sortKey="Howard, James F" sort="Howard, James F" uniqKey="Howard J" first="James F." last="Howard">James F. Howard</name>
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<author><name sortKey="Koopman, Wilma J" sort="Koopman, Wilma J" uniqKey="Koopman W" first="Wilma J." last="Koopman">Wilma J. Koopman</name>
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<author><name sortKey="Nicolle, Michael W" sort="Nicolle, Michael W" uniqKey="Nicolle M" first="Michael W." last="Nicolle">Michael W. Nicolle</name>
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<author><name sortKey="Siddiqi, Zaeem" sort="Siddiqi, Zaeem" uniqKey="Siddiqi Z" first="Zaeem" last="Siddiqi">Zaeem Siddiqi</name>
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<author><name sortKey="Muppidi, Srikanth" sort="Muppidi, Srikanth" uniqKey="Muppidi S" first="Srikanth" last="Muppidi">Srikanth Muppidi</name>
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<author><name sortKey="Wolfe, Gil" sort="Wolfe, Gil" uniqKey="Wolfe G" first="Gil" last="Wolfe">Gil Wolfe</name>
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<author><name sortKey="Drachman, Daniel B" sort="Drachman, Daniel B" uniqKey="Drachman D" first="Daniel B." last="Drachman">Daniel B. Drachman</name>
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<author><name sortKey="Traynor, Bryan J" sort="Traynor, Bryan J" uniqKey="Traynor B" first="Bryan J." last="Traynor">Bryan J. Traynor</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Genome-wide Association Study of Myasthenia Gravis</title>
<author><name sortKey="Renton, Alan E" sort="Renton, Alan E" uniqKey="Renton A" first="Alan E." last="Renton">Alan E. Renton</name>
</author>
<author><name sortKey="Pliner, Hannah A" sort="Pliner, Hannah A" uniqKey="Pliner H" first="Hannah A." last="Pliner">Hannah A. Pliner</name>
</author>
<author><name sortKey="Provenzano, Carlo" sort="Provenzano, Carlo" uniqKey="Provenzano C" first="Carlo" last="Provenzano">Carlo Provenzano</name>
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<author><name sortKey="Evoli, Amelia" sort="Evoli, Amelia" uniqKey="Evoli A" first="Amelia" last="Evoli">Amelia Evoli</name>
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<author><name sortKey="Ricciardi, Roberta" sort="Ricciardi, Roberta" uniqKey="Ricciardi R" first="Roberta" last="Ricciardi">Roberta Ricciardi</name>
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<author><name sortKey="Nalls, Michael A" sort="Nalls, Michael A" uniqKey="Nalls M" first="Michael A." last="Nalls">Michael A. Nalls</name>
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<author><name sortKey="Marangi, Giuseppe" sort="Marangi, Giuseppe" uniqKey="Marangi G" first="Giuseppe" last="Marangi">Giuseppe Marangi</name>
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<author><name sortKey="Abramzon, Yevgeniya" sort="Abramzon, Yevgeniya" uniqKey="Abramzon Y" first="Yevgeniya" last="Abramzon">Yevgeniya Abramzon</name>
</author>
<author><name sortKey="Arepalli, Sampath" sort="Arepalli, Sampath" uniqKey="Arepalli S" first="Sampath" last="Arepalli">Sampath Arepalli</name>
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<author><name sortKey="Chong, Sean" sort="Chong, Sean" uniqKey="Chong S" first="Sean" last="Chong">Sean Chong</name>
</author>
<author><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G." last="Hernandez">Dena G. Hernandez</name>
</author>
<author><name sortKey="Johnson, Janel O" sort="Johnson, Janel O" uniqKey="Johnson J" first="Janel O." last="Johnson">Janel O. Johnson</name>
</author>
<author><name sortKey="Bartoccioni, Emanuela" sort="Bartoccioni, Emanuela" uniqKey="Bartoccioni E" first="Emanuela" last="Bartoccioni">Emanuela Bartoccioni</name>
</author>
<author><name sortKey="Scuderi, Flavia" sort="Scuderi, Flavia" uniqKey="Scuderi F" first="Flavia" last="Scuderi">Flavia Scuderi</name>
</author>
<author><name sortKey="Maestri, Michelangelo" sort="Maestri, Michelangelo" uniqKey="Maestri M" first="Michelangelo" last="Maestri">Michelangelo Maestri</name>
</author>
<author><name sortKey="Raphael Gibbs, J" sort="Raphael Gibbs, J" uniqKey="Raphael Gibbs J" first="J." last="Raphael Gibbs">J. Raphael Gibbs</name>
</author>
<author><name sortKey="Errichiello, Edoardo" sort="Errichiello, Edoardo" uniqKey="Errichiello E" first="Edoardo" last="Errichiello">Edoardo Errichiello</name>
</author>
<author><name sortKey="Chi, Adriano" sort="Chi, Adriano" uniqKey="Chi A" first="Adriano" last="Chi">Adriano Chi</name>
</author>
<author><name sortKey="Restagno, Gabriella" sort="Restagno, Gabriella" uniqKey="Restagno G" first="Gabriella" last="Restagno">Gabriella Restagno</name>
</author>
<author><name sortKey="Sabatelli, Mario" sort="Sabatelli, Mario" uniqKey="Sabatelli M" first="Mario" last="Sabatelli">Mario Sabatelli</name>
</author>
<author><name sortKey="Macek, Mark" sort="Macek, Mark" uniqKey="Macek M" first="Mark" last="Macek">Mark Macek</name>
</author>
<author><name sortKey="Scholz, Sonja W" sort="Scholz, Sonja W" uniqKey="Scholz S" first="Sonja W." last="Scholz">Sonja W. Scholz</name>
</author>
<author><name sortKey="Corse, Andrea" sort="Corse, Andrea" uniqKey="Corse A" first="Andrea" last="Corse">Andrea Corse</name>
</author>
<author><name sortKey="Chaudhry, Vinay" sort="Chaudhry, Vinay" uniqKey="Chaudhry V" first="Vinay" last="Chaudhry">Vinay Chaudhry</name>
</author>
<author><name sortKey="Benatar, Michael" sort="Benatar, Michael" uniqKey="Benatar M" first="Michael" last="Benatar">Michael Benatar</name>
</author>
<author><name sortKey="Barohn, Richard J" sort="Barohn, Richard J" uniqKey="Barohn R" first="Richard J." last="Barohn">Richard J. Barohn</name>
</author>
<author><name sortKey="Mcvey, April" sort="Mcvey, April" uniqKey="Mcvey A" first="April" last="Mcvey">April Mcvey</name>
</author>
<author><name sortKey="Pasnoor, Mamatha" sort="Pasnoor, Mamatha" uniqKey="Pasnoor M" first="Mamatha" last="Pasnoor">Mamatha Pasnoor</name>
</author>
<author><name sortKey="Dimachkie, Mazen M" sort="Dimachkie, Mazen M" uniqKey="Dimachkie M" first="Mazen M." last="Dimachkie">Mazen M. Dimachkie</name>
</author>
<author><name sortKey="Rowin, Julie" sort="Rowin, Julie" uniqKey="Rowin J" first="Julie" last="Rowin">Julie Rowin</name>
</author>
<author><name sortKey="Kissel, John" sort="Kissel, John" uniqKey="Kissel J" first="John" last="Kissel">John Kissel</name>
</author>
<author><name sortKey="Freimer, Miriam" sort="Freimer, Miriam" uniqKey="Freimer M" first="Miriam" last="Freimer">Miriam Freimer</name>
</author>
<author><name sortKey="Kaminski, Henry J" sort="Kaminski, Henry J" uniqKey="Kaminski H" first="Henry J." last="Kaminski">Henry J. Kaminski</name>
</author>
<author><name sortKey="Sanders, Donald B" sort="Sanders, Donald B" uniqKey="Sanders D" first="Donald B." last="Sanders">Donald B. Sanders</name>
</author>
<author><name sortKey="Lipscomb, Bernadette" sort="Lipscomb, Bernadette" uniqKey="Lipscomb B" first="Bernadette" last="Lipscomb">Bernadette Lipscomb</name>
</author>
<author><name sortKey="Massey, Janice M" sort="Massey, Janice M" uniqKey="Massey J" first="Janice M." last="Massey">Janice M. Massey</name>
</author>
<author><name sortKey="Chopra, Manisha" sort="Chopra, Manisha" uniqKey="Chopra M" first="Manisha" last="Chopra">Manisha Chopra</name>
</author>
<author><name sortKey="Howard, James F" sort="Howard, James F" uniqKey="Howard J" first="James F." last="Howard">James F. Howard</name>
</author>
<author><name sortKey="Koopman, Wilma J" sort="Koopman, Wilma J" uniqKey="Koopman W" first="Wilma J." last="Koopman">Wilma J. Koopman</name>
</author>
<author><name sortKey="Nicolle, Michael W" sort="Nicolle, Michael W" uniqKey="Nicolle M" first="Michael W." last="Nicolle">Michael W. Nicolle</name>
</author>
<author><name sortKey="Pascuzzi, Robert M" sort="Pascuzzi, Robert M" uniqKey="Pascuzzi R" first="Robert M." last="Pascuzzi">Robert M. Pascuzzi</name>
</author>
<author><name sortKey="Pestronk, Alan" sort="Pestronk, Alan" uniqKey="Pestronk A" first="Alan" last="Pestronk">Alan Pestronk</name>
</author>
<author><name sortKey="Wulf, Charlie" sort="Wulf, Charlie" uniqKey="Wulf C" first="Charlie" last="Wulf">Charlie Wulf</name>
</author>
<author><name sortKey="Florence, Julaine" sort="Florence, Julaine" uniqKey="Florence J" first="Julaine" last="Florence">Julaine Florence</name>
</author>
<author><name sortKey="Blackmore, Derrick" sort="Blackmore, Derrick" uniqKey="Blackmore D" first="Derrick" last="Blackmore">Derrick Blackmore</name>
</author>
<author><name sortKey="Soloway, Aimee" sort="Soloway, Aimee" uniqKey="Soloway A" first="Aimee" last="Soloway">Aimee Soloway</name>
</author>
<author><name sortKey="Siddiqi, Zaeem" sort="Siddiqi, Zaeem" uniqKey="Siddiqi Z" first="Zaeem" last="Siddiqi">Zaeem Siddiqi</name>
</author>
<author><name sortKey="Muppidi, Srikanth" sort="Muppidi, Srikanth" uniqKey="Muppidi S" first="Srikanth" last="Muppidi">Srikanth Muppidi</name>
</author>
<author><name sortKey="Wolfe, Gil" sort="Wolfe, Gil" uniqKey="Wolfe G" first="Gil" last="Wolfe">Gil Wolfe</name>
</author>
<author><name sortKey="Richman, David" sort="Richman, David" uniqKey="Richman D" first="David" last="Richman">David Richman</name>
</author>
<author><name sortKey="Mezei, Michelle M" sort="Mezei, Michelle M" uniqKey="Mezei M" first="Michelle M." last="Mezei">Michelle M. Mezei</name>
</author>
<author><name sortKey="Jiwa, Theresa" sort="Jiwa, Theresa" uniqKey="Jiwa T" first="Theresa" last="Jiwa">Theresa Jiwa</name>
</author>
<author><name sortKey="Oger, Joel" sort="Oger, Joel" uniqKey="Oger J" first="Joel" last="Oger">Joel Oger</name>
</author>
<author><name sortKey="Drachman, Daniel B" sort="Drachman, Daniel B" uniqKey="Drachman D" first="Daniel B." last="Drachman">Daniel B. Drachman</name>
</author>
<author><name sortKey="Traynor, Bryan J" sort="Traynor, Bryan J" uniqKey="Traynor B" first="Bryan J." last="Traynor">Bryan J. Traynor</name>
</author>
</analytic>
<series><title level="j">JAMA neurology</title>
<idno type="ISSN">2168-6149</idno>
<idno type="eISSN">2168-6157</idno>
<imprint><date when="2015">2015</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>IMPORTANCE</title>
<p id="P1">Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.</p>
</sec>
<sec id="S2"><title>OBJECTIVE</title>
<p id="P2">To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.</p>
</sec>
<sec id="S3"><title>DESIGN, SETTING, AND PARTICIPANTS</title>
<p id="P3">DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.</p>
</sec>
<sec id="S4"><title>MAIN OUTCOMES AND MEASURES</title>
<p id="P4">We calculated <italic>P</italic>
values for association between 8114394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold <italic>P</italic>
value of 5.0 × 10<sup>−8</sup>
was set for genome-wide significance after Bonferroni correction for multiple testing.</p>
</sec>
<sec id="S5"><title>RESULTS</title>
<p id="P5">In the over all case-control cohort, we identified association signals at <italic>CTLA4</italic>
(rs231770; <italic>P</italic>
= 3.98 × 10<sup>−8</sup>
; odds ratio, 1.37; 95% CI, 1.25–1.49), <italic>HLA-DQA1</italic>
(rs9271871; <italic>P</italic>
= 1.08 × 10<sup>−8</sup>
; odds ratio, 2.31; 95% CI, 2.02 – 2.60), and <italic>TNFRSF11A</italic>
(rs4263037; <italic>P</italic>
= 1.60 × 10<sup>−9</sup>
; odds ratio, 1.41; 95% CI, 1.29–1.53). These findings replicated for <italic>CTLA4</italic>
and <italic>HLA-DQA1</italic>
in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in <italic>TNFRSF11A</italic>
(rs4263037; <italic>P</italic>
= 1.32 × 10<sup>−12</sup>
; odds ratio, 1.56; 95% CI, 1.44–1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (<italic>HLA-DQA1</italic>
; rs9271871; <italic>P</italic>
= 7.02 × 10<sup>−18</sup>
; odds ratio, 4.27; 95% CI, 3.92–4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (<italic>HLA-DQA1</italic>
; rs601006; <italic>P</italic>
= 2.52 × 10<sup>−11</sup>
; odds ratio, 4.0; 95% CI, 3.57–4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases.</p>
</sec>
<sec id="S6"><title>CONCLUSIONS AND RELEVANCE</title>
<p id="P6">Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.</p>
</sec>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101589536</journal-id>
<journal-id journal-id-type="pubmed-jr-id">40865</journal-id>
<journal-id journal-id-type="nlm-ta">JAMA Neurol</journal-id>
<journal-id journal-id-type="iso-abbrev">JAMA Neurol</journal-id>
<journal-title-group><journal-title>JAMA neurology</journal-title>
</journal-title-group>
<issn pub-type="ppub">2168-6149</issn>
<issn pub-type="epub">2168-6157</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25643325</article-id>
<article-id pub-id-type="pmc">4856525</article-id>
<article-id pub-id-type="doi">10.1001/jamaneurol.2014.4103</article-id>
<article-id pub-id-type="manuscript">NIHMS783211</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>A Genome-wide Association Study of Myasthenia Gravis</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Renton</surname>
<given-names>Alan E.</given-names>
</name>
<degrees>PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Pliner</surname>
<given-names>Hannah A.</given-names>
</name>
<degrees>BS</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Provenzano</surname>
<given-names>Carlo</given-names>
</name>
<degrees>MD, PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Evoli</surname>
<given-names>Amelia</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Ricciardi</surname>
<given-names>Roberta</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Nalls</surname>
<given-names>Michael A.</given-names>
</name>
<degrees>PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Marangi</surname>
<given-names>Giuseppe</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Abramzon</surname>
<given-names>Yevgeniya</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Arepalli</surname>
<given-names>Sampath</given-names>
</name>
<degrees>MS</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Chong</surname>
<given-names>Sean</given-names>
</name>
<degrees>BS</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Hernandez</surname>
<given-names>Dena G.</given-names>
</name>
<degrees>MS</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Johnson</surname>
<given-names>Janel O.</given-names>
</name>
<degrees>PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Bartoccioni</surname>
<given-names>Emanuela</given-names>
</name>
<degrees>PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Scuderi</surname>
<given-names>Flavia</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Maestri</surname>
<given-names>Michelangelo</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Raphael Gibbs</surname>
<given-names>J.</given-names>
</name>
<degrees>MS</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Errichiello</surname>
<given-names>Edoardo</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Chiò</surname>
<given-names>Adriano</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Restagno</surname>
<given-names>Gabriella</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Sabatelli</surname>
<given-names>Mario</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Macek</surname>
<given-names>Mark</given-names>
</name>
<degrees>MS</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Scholz</surname>
<given-names>Sonja W.</given-names>
</name>
<degrees>MD, PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Corse</surname>
<given-names>Andrea</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Chaudhry</surname>
<given-names>Vinay</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Benatar</surname>
<given-names>Michael</given-names>
</name>
<degrees>MD, PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Barohn</surname>
<given-names>Richard J.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>McVey</surname>
<given-names>April</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Pasnoor</surname>
<given-names>Mamatha</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Dimachkie</surname>
<given-names>Mazen M.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Rowin</surname>
<given-names>Julie</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Kissel</surname>
<given-names>John</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Freimer</surname>
<given-names>Miriam</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Kaminski</surname>
<given-names>Henry J.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Sanders</surname>
<given-names>Donald B.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Lipscomb</surname>
<given-names>Bernadette</given-names>
</name>
<degrees>RN</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Massey</surname>
<given-names>Janice M.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Chopra</surname>
<given-names>Manisha</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Howard</surname>
<given-names>James F.</given-names>
<suffix>Jr</suffix>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Koopman</surname>
<given-names>Wilma J.</given-names>
</name>
<degrees>RN</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Nicolle</surname>
<given-names>Michael W.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Pascuzzi</surname>
<given-names>Robert M.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Pestronk</surname>
<given-names>Alan</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Wulf</surname>
<given-names>Charlie</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Florence</surname>
<given-names>Julaine</given-names>
</name>
<degrees>PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Blackmore</surname>
<given-names>Derrick</given-names>
</name>
<degrees>BSc</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Soloway</surname>
<given-names>Aimee</given-names>
</name>
<degrees>RN</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Siddiqi</surname>
<given-names>Zaeem</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Muppidi</surname>
<given-names>Srikanth</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Wolfe</surname>
<given-names>Gil</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Richman</surname>
<given-names>David</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Mezei</surname>
<given-names>Michelle M.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Jiwa</surname>
<given-names>Theresa</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Oger</surname>
<given-names>Joel</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Drachman</surname>
<given-names>Daniel B.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Traynor</surname>
<given-names>Bryan J.</given-names>
</name>
<degrees>MD, PhD</degrees>
</contrib>
<aff id="A1">Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland (Renton, Pliner, Marangi, Abramzon, Johnson, Errichiello, Traynor); Institute of General Pathology, Catholic University, Rome, Italy (Provenzano, Bartoccioni, Scuderi); Institute of Neurology, Catholic University, Rome, Italy (Evoli, Sabatelli); Department of Neuroscience, Cisanello Hospital, University of Pisa, Pisa, Italy (Ricciardi, Maestri); Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland (Nalls); Institute of Medical Genetics, Catholic University, Rome, Italy (Marangi); Genomics Technology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland (Arepalli, Chong, Hernandez); Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland (Gibbs); Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy (Errichiello, Chiò); Molecular Genetics Unit, Department of Clinical Pathology, ASO OIRM-S Anna, Turin, Italy (Restagno); Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (Macek, Scholz, Corse, Chaudhry, Drachman, Traynor); Department of Neurology, University of Miami, Miami, Florida (Benatar); Department of Neurology, University of Kansas Medical Center, Kansas City (Barohn, McVey, Pasnoor, Dimachkie); Department of Neurology, University of Illinois College of Medicine, Chicago (Rowin); Department of Neurology, Ohio State University Medical Center, Columbus (Kissel, Freimer); Department of Neurology, George Washington University, Washington, DC (Kaminski); Department of Neurology, Duke University Medical Center, Durham, North Carolina (Sanders, Lipscomb, Massey); Department of Neurology, University of North Carolina, Chapel Hill (Chopra, Howard); Department of Clinical Neurosciences, London Health Sciences Centre, London, Ontario, Canada (Koopman, Nicolle); Department of Neurology, Indiana University–Purdue University, Indianapolis (Pascuzzi); Department of Neurology, Washington University School of Medicine, St Louis, Missouri (Pestronk, Wulf, Florence); Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada (Blackmore, Soloway, Siddiqi); Department of Neurology, University at Buffalo SMBS, State University of New York, Buffalo (Muppidi, Wolfe); Department of Neurology, University of California, Davis Medical Center (Richman); Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada (Mezei, Jiwa, Oger)</aff>
</contrib-group>
<author-notes><corresp id="FN1"><bold>Corresponding Author:</bold>
Bryan J. Traynor, MD, PhD, Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, Porter Neuroscience Research Center, 35 Convent Dr, Bethesda, MD 20892 (<email>traynorb@mail.nih.gov</email>
)</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>2</day>
<month>5</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><month>4</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>04</day>
<month>5</month>
<year>2016</year>
</pub-date>
<volume>72</volume>
<issue>4</issue>
<fpage>396</fpage>
<lpage>404</lpage>
<pmc-comment>elocation-id from pubmed: 10.1001/jamaneurol.2014.4103</pmc-comment>
<abstract><sec id="S1"><title>IMPORTANCE</title>
<p id="P1">Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.</p>
</sec>
<sec id="S2"><title>OBJECTIVE</title>
<p id="P2">To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.</p>
</sec>
<sec id="S3"><title>DESIGN, SETTING, AND PARTICIPANTS</title>
<p id="P3">DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.</p>
</sec>
<sec id="S4"><title>MAIN OUTCOMES AND MEASURES</title>
<p id="P4">We calculated <italic>P</italic>
values for association between 8114394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold <italic>P</italic>
value of 5.0 × 10<sup>−8</sup>
was set for genome-wide significance after Bonferroni correction for multiple testing.</p>
</sec>
<sec id="S5"><title>RESULTS</title>
<p id="P5">In the over all case-control cohort, we identified association signals at <italic>CTLA4</italic>
(rs231770; <italic>P</italic>
= 3.98 × 10<sup>−8</sup>
; odds ratio, 1.37; 95% CI, 1.25–1.49), <italic>HLA-DQA1</italic>
(rs9271871; <italic>P</italic>
= 1.08 × 10<sup>−8</sup>
; odds ratio, 2.31; 95% CI, 2.02 – 2.60), and <italic>TNFRSF11A</italic>
(rs4263037; <italic>P</italic>
= 1.60 × 10<sup>−9</sup>
; odds ratio, 1.41; 95% CI, 1.29–1.53). These findings replicated for <italic>CTLA4</italic>
and <italic>HLA-DQA1</italic>
in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in <italic>TNFRSF11A</italic>
(rs4263037; <italic>P</italic>
= 1.32 × 10<sup>−12</sup>
; odds ratio, 1.56; 95% CI, 1.44–1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (<italic>HLA-DQA1</italic>
; rs9271871; <italic>P</italic>
= 7.02 × 10<sup>−18</sup>
; odds ratio, 4.27; 95% CI, 3.92–4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (<italic>HLA-DQA1</italic>
; rs601006; <italic>P</italic>
= 2.52 × 10<sup>−11</sup>
; odds ratio, 4.0; 95% CI, 3.57–4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases.</p>
</sec>
<sec id="S6"><title>CONCLUSIONS AND RELEVANCE</title>
<p id="P6">Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.</p>
</sec>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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