Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum
Identifieur interne : 002120 ( Pmc/Curation ); précédent : 002119; suivant : 002121Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum
Auteurs : Simon Rothwell ; Robert G. Cooper ; Ingrid E. Lundberg ; Peter K. Gregersen ; Michael G. Hanna ; Pedro M. Machado ; Megan K. Herbert ; Ger J. M. Pruijn ; James B. Lilleker ; Mark Roberts ; John Bowes ; Michael F. Seldin ; Jiri Vencovsky ; Katalin Danko ; Vidya Limaye ; Albert Selva-O'Callaghan ; Hazel Platt ; Yvind Molberg ; Olivier Benveniste ; Timothy R. D. J. Radstake ; Andrea Doria ; Jan De Bleecker ; Boel De Paepe ; Christian Gieger ; Thomas Meitinger ; Juliane Winkelmann ; Christopher I. Amos ; William E. Ollier ; Leonid Padyukov ; Annette T. Lee ; Janine A. Lamb ; Hector ChinoySource :
- Arthritis & Rheumatology (Hoboken, N.j.) [ 2326-5191 ] ; 2017.
Abstract
Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune‐related genes using the Immunochip.
A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA.
The HLA region was confirmed as the most strongly associated region in IBM (
This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide‐binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for
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DOI: 10.1002/art.40045
PubMed: 28086002
PubMed Central: 5516174
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D. J." last="Radstake">Timothy R. D. J. Radstake</name><affiliation><nlm:aff id="art40045-aff-0017"></nlm:aff></affiliation></author><author><name sortKey="Doria, Andrea" sort="Doria, Andrea" uniqKey="Doria A" first="Andrea" last="Doria">Andrea Doria</name><affiliation><nlm:aff id="art40045-aff-0018"></nlm:aff></affiliation></author><author><name sortKey="De Bleecker, Jan" sort="De Bleecker, Jan" uniqKey="De Bleecker J" first="Jan" last="De Bleecker">Jan De Bleecker</name><affiliation><nlm:aff id="art40045-aff-0019"></nlm:aff></affiliation></author><author><name sortKey="De Paepe, Boel" sort="De Paepe, Boel" uniqKey="De Paepe B" first="Boel" last="De Paepe">Boel De Paepe</name><affiliation><nlm:aff id="art40045-aff-0019"></nlm:aff></affiliation></author><author><name sortKey="Gieger, Christian" sort="Gieger, Christian" uniqKey="Gieger C" first="Christian" last="Gieger">Christian Gieger</name><affiliation><nlm:aff id="art40045-aff-0020"></nlm:aff></affiliation></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><affiliation><nlm:aff id="art40045-aff-0021"></nlm:aff></affiliation></author><author><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name><affiliation><nlm:aff id="art40045-aff-0021"></nlm:aff></affiliation></author><author><name sortKey="Amos, Christopher I" sort="Amos, Christopher I" uniqKey="Amos C" first="Christopher I." last="Amos">Christopher I. Amos</name><affiliation><nlm:aff id="art40045-aff-0022"></nlm:aff></affiliation></author><author><name sortKey="Ollier, William E" sort="Ollier, William E" uniqKey="Ollier W" first="William E." last="Ollier">William E. Ollier</name><affiliation><nlm:aff id="art40045-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Padyukov, Leonid" sort="Padyukov, Leonid" uniqKey="Padyukov L" first="Leonid" last="Padyukov">Leonid Padyukov</name><affiliation><nlm:aff id="art40045-aff-0023"></nlm:aff></affiliation></author><author><name sortKey="Lee, Annette T" sort="Lee, Annette T" uniqKey="Lee A" first="Annette T." last="Lee">Annette T. Lee</name><affiliation><nlm:aff id="art40045-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Lamb, Janine A" sort="Lamb, Janine A" uniqKey="Lamb J" first="Janine A." last="Lamb">Janine A. Lamb</name><affiliation><nlm:aff id="art40045-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Chinoy, Hector" sort="Chinoy, Hector" uniqKey="Chinoy H" first="Hector" last="Chinoy">Hector Chinoy</name><affiliation><nlm:aff id="art40045-aff-0024"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28086002</idno><idno type="pmc">5516174</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516174</idno><idno type="RBID">PMC:5516174</idno><idno type="doi">10.1002/art.40045</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002270</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002270</idno><idno type="wicri:Area/Pmc/Curation">002120</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002120</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum</title><author><name sortKey="Rothwell, Simon" sort="Rothwell, Simon" uniqKey="Rothwell S" first="Simon" last="Rothwell">Simon Rothwell</name><affiliation><nlm:aff id="art40045-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Cooper, Robert G" sort="Cooper, Robert G" uniqKey="Cooper R" first="Robert G." last="Cooper">Robert G. Cooper</name><affiliation><nlm:aff id="art40045-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Lundberg, Ingrid E" sort="Lundberg, Ingrid E" uniqKey="Lundberg I" first="Ingrid E." last="Lundberg">Ingrid E. Lundberg</name><affiliation><nlm:aff id="art40045-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Gregersen, Peter K" sort="Gregersen, Peter K" uniqKey="Gregersen P" first="Peter K." last="Gregersen">Peter K. Gregersen</name><affiliation><nlm:aff id="art40045-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Hanna, Michael G" sort="Hanna, Michael G" uniqKey="Hanna M" first="Michael G." last="Hanna">Michael G. Hanna</name><affiliation><nlm:aff id="art40045-aff-0005"></nlm:aff></affiliation></author><author><name sortKey="Machado, Pedro M" sort="Machado, Pedro M" uniqKey="Machado P" first="Pedro M." last="Machado">Pedro M. Machado</name><affiliation><nlm:aff id="art40045-aff-0005"></nlm:aff></affiliation></author><author><name sortKey="Herbert, Megan K" sort="Herbert, Megan K" uniqKey="Herbert M" first="Megan K." last="Herbert">Megan K. Herbert</name><affiliation><nlm:aff id="art40045-aff-0006"></nlm:aff></affiliation></author><author><name sortKey="Pruijn, Ger J M" sort="Pruijn, Ger J M" uniqKey="Pruijn G" first="Ger J. M." last="Pruijn">Ger J. M. Pruijn</name><affiliation><nlm:aff id="art40045-aff-0007"></nlm:aff></affiliation></author><author><name sortKey="Lilleker, James B" sort="Lilleker, James B" uniqKey="Lilleker J" first="James B." last="Lilleker">James B. Lilleker</name><affiliation><nlm:aff id="art40045-aff-0008"></nlm:aff></affiliation></author><author><name sortKey="Roberts, Mark" sort="Roberts, Mark" uniqKey="Roberts M" first="Mark" last="Roberts">Mark Roberts</name><affiliation><nlm:aff id="art40045-aff-0009"></nlm:aff></affiliation></author><author><name sortKey="Bowes, John" sort="Bowes, John" uniqKey="Bowes J" first="John" last="Bowes">John Bowes</name><affiliation><nlm:aff id="art40045-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Seldin, Michael F" sort="Seldin, Michael F" uniqKey="Seldin M" first="Michael F." last="Seldin">Michael F. Seldin</name><affiliation><nlm:aff id="art40045-aff-0010"></nlm:aff></affiliation></author><author><name sortKey="Vencovsky, Jiri" sort="Vencovsky, Jiri" uniqKey="Vencovsky J" first="Jiri" last="Vencovsky">Jiri Vencovsky</name><affiliation><nlm:aff id="art40045-aff-0011"></nlm:aff></affiliation></author><author><name sortKey="Danko, Katalin" sort="Danko, Katalin" uniqKey="Danko K" first="Katalin" last="Danko">Katalin Danko</name><affiliation><nlm:aff id="art40045-aff-0012"></nlm:aff></affiliation></author><author><name sortKey="Limaye, Vidya" sort="Limaye, Vidya" uniqKey="Limaye V" first="Vidya" last="Limaye">Vidya Limaye</name><affiliation><nlm:aff id="art40045-aff-0013"></nlm:aff></affiliation></author><author><name sortKey="Selva Callaghan, Albert" sort="Selva Callaghan, Albert" uniqKey="Selva Callaghan A" first="Albert" last="Selva-O'Callaghan">Albert Selva-O'Callaghan</name><affiliation><nlm:aff id="art40045-aff-0014"></nlm:aff></affiliation></author><author><name sortKey="Platt, Hazel" sort="Platt, Hazel" uniqKey="Platt H" first="Hazel" last="Platt">Hazel Platt</name><affiliation><nlm:aff id="art40045-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Molberg, Yvind" sort="Molberg, Yvind" uniqKey="Molberg " first=" Yvind" last="Molberg"> Yvind Molberg</name><affiliation><nlm:aff id="art40045-aff-0015"></nlm:aff></affiliation></author><author><name sortKey="Benveniste, Olivier" sort="Benveniste, Olivier" uniqKey="Benveniste O" first="Olivier" last="Benveniste">Olivier Benveniste</name><affiliation><nlm:aff id="art40045-aff-0016"></nlm:aff></affiliation></author><author><name sortKey="Radstake, Timothy R D J" sort="Radstake, Timothy R D J" uniqKey="Radstake T" first="Timothy R. D. J." last="Radstake">Timothy R. D. J. Radstake</name><affiliation><nlm:aff id="art40045-aff-0017"></nlm:aff></affiliation></author><author><name sortKey="Doria, Andrea" sort="Doria, Andrea" uniqKey="Doria A" first="Andrea" last="Doria">Andrea Doria</name><affiliation><nlm:aff id="art40045-aff-0018"></nlm:aff></affiliation></author><author><name sortKey="De Bleecker, Jan" sort="De Bleecker, Jan" uniqKey="De Bleecker J" first="Jan" last="De Bleecker">Jan De Bleecker</name><affiliation><nlm:aff id="art40045-aff-0019"></nlm:aff></affiliation></author><author><name sortKey="De Paepe, Boel" sort="De Paepe, Boel" uniqKey="De Paepe B" first="Boel" last="De Paepe">Boel De Paepe</name><affiliation><nlm:aff id="art40045-aff-0019"></nlm:aff></affiliation></author><author><name sortKey="Gieger, Christian" sort="Gieger, Christian" uniqKey="Gieger C" first="Christian" last="Gieger">Christian Gieger</name><affiliation><nlm:aff id="art40045-aff-0020"></nlm:aff></affiliation></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><affiliation><nlm:aff id="art40045-aff-0021"></nlm:aff></affiliation></author><author><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name><affiliation><nlm:aff id="art40045-aff-0021"></nlm:aff></affiliation></author><author><name sortKey="Amos, Christopher I" sort="Amos, Christopher I" uniqKey="Amos C" first="Christopher I." last="Amos">Christopher I. Amos</name><affiliation><nlm:aff id="art40045-aff-0022"></nlm:aff></affiliation></author><author><name sortKey="Ollier, William E" sort="Ollier, William E" uniqKey="Ollier W" first="William E." last="Ollier">William E. Ollier</name><affiliation><nlm:aff id="art40045-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Padyukov, Leonid" sort="Padyukov, Leonid" uniqKey="Padyukov L" first="Leonid" last="Padyukov">Leonid Padyukov</name><affiliation><nlm:aff id="art40045-aff-0023"></nlm:aff></affiliation></author><author><name sortKey="Lee, Annette T" sort="Lee, Annette T" uniqKey="Lee A" first="Annette T." last="Lee">Annette T. Lee</name><affiliation><nlm:aff id="art40045-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Lamb, Janine A" sort="Lamb, Janine A" uniqKey="Lamb J" first="Janine A." last="Lamb">Janine A. Lamb</name><affiliation><nlm:aff id="art40045-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Chinoy, Hector" sort="Chinoy, Hector" uniqKey="Chinoy H" first="Hector" last="Chinoy">Hector Chinoy</name><affiliation><nlm:aff id="art40045-aff-0024"></nlm:aff></affiliation></author></analytic><series><title level="j">Arthritis & Rheumatology (Hoboken, N.j.)</title><idno type="ISSN">2326-5191</idno><idno type="eISSN">2326-5205</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="art40045-sec-0001"><title>Objective</title><p>Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune‐related genes using the Immunochip.</p></sec><sec id="art40045-sec-0002"><title>Methods</title><p>A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA.</p></sec><sec id="art40045-sec-0003"><title>Results</title><p>The HLA region was confirmed as the most strongly associated region in IBM (<italic>P</italic> = 3.58 × 10<sup>−33</sup>). HLA imputation identified 3 independent associations (with HLA–DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA–DRB1 molecule. No association with anti–cytosolic 5′‐nucleotidase 1A–positive status was found independent of HLA–DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non‐HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in <italic>CCR5</italic> is thought to be the causal variant.</p></sec><sec id="art40045-sec-0004"><title>Conclusion</title><p>This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide‐binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for <italic>CCR5</italic>.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Arthritis Rheumatol</journal-id><journal-id journal-id-type="doi">10.1002/(ISSN)2326-5205</journal-id><journal-id journal-id-type="publisher-id">ART</journal-id><journal-title-group><journal-title>Arthritis & Rheumatology (Hoboken, N.j.)</journal-title></journal-title-group><issn pub-type="ppub">2326-5191</issn><issn pub-type="epub">2326-5205</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28086002</article-id><article-id pub-id-type="pmc">5516174</article-id><article-id pub-id-type="doi">10.1002/art.40045</article-id><article-id pub-id-type="publisher-id">ART40045</article-id><article-categories><subj-group subj-group-type="overline"><subject>Myositis</subject></subj-group><subj-group subj-group-type="heading"><subject>Myositis</subject></subj-group></article-categories><title-group><article-title>Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum</article-title><alt-title alt-title-type="right-running-head">ASSOCIATION OF HLA REGION WITH SUSCEPTIBILITY TO IBM</alt-title><alt-title alt-title-type="left-running-head">ROTHWELL ET AL</alt-title></title-group><contrib-group><contrib id="art40045-cr-0001" contrib-type="author" corresp="yes"><name><surname>Rothwell</surname><given-names>Simon</given-names></name><address><email>s.rothwell@manchester.ac.uk</email></address><xref ref-type="aff" rid="art40045-aff-0001"><sup>1</sup></xref></contrib><contrib id="art40045-cr-0002" contrib-type="author"><name><surname>Cooper</surname><given-names>Robert G.</given-names></name><xref ref-type="aff" rid="art40045-aff-0002"><sup>2</sup></xref></contrib><contrib id="art40045-cr-0003" contrib-type="author"><name><surname>Lundberg</surname><given-names>Ingrid E.</given-names></name><xref ref-type="aff" rid="art40045-aff-0003"><sup>3</sup></xref></contrib><contrib id="art40045-cr-0004" contrib-type="author"><name><surname>Gregersen</surname><given-names>Peter K.</given-names></name><xref ref-type="aff" rid="art40045-aff-0004"><sup>4</sup></xref></contrib><contrib id="art40045-cr-0005" contrib-type="author"><name><surname>Hanna</surname><given-names>Michael G.</given-names></name><xref ref-type="aff" rid="art40045-aff-0005"><sup>5</sup></xref></contrib><contrib id="art40045-cr-0006" contrib-type="author"><name><surname>Machado</surname><given-names>Pedro M.</given-names></name><xref ref-type="aff" rid="art40045-aff-0005"><sup>5</sup></xref></contrib><contrib id="art40045-cr-0007" contrib-type="author"><name><surname>Herbert</surname><given-names>Megan K.</given-names></name><xref ref-type="aff" rid="art40045-aff-0006"><sup>6</sup></xref></contrib><contrib id="art40045-cr-0008" contrib-type="author"><name><surname>Pruijn</surname><given-names>Ger J. M.</given-names></name><xref ref-type="aff" rid="art40045-aff-0007"><sup>7</sup></xref></contrib><contrib id="art40045-cr-0009" contrib-type="author"><name><surname>Lilleker</surname><given-names>James B.</given-names></name><xref ref-type="aff" rid="art40045-aff-0008"><sup>8</sup></xref></contrib><contrib id="art40045-cr-0010" contrib-type="author"><name><surname>Roberts</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="art40045-aff-0009"><sup>9</sup></xref></contrib><contrib id="art40045-cr-0011" contrib-type="author"><name><surname>Bowes</surname><given-names>John</given-names></name><xref ref-type="aff" rid="art40045-aff-0001"><sup>1</sup></xref></contrib><contrib id="art40045-cr-0012" contrib-type="author"><name><surname>Seldin</surname><given-names>Michael F.</given-names></name><xref ref-type="aff" rid="art40045-aff-0010"><sup>10</sup></xref></contrib><contrib id="art40045-cr-0013" contrib-type="author"><name><surname>Vencovsky</surname><given-names>Jiri</given-names></name><xref ref-type="aff" rid="art40045-aff-0011"><sup>11</sup></xref></contrib><contrib id="art40045-cr-0014" contrib-type="author"><name><surname>Danko</surname><given-names>Katalin</given-names></name><xref ref-type="aff" rid="art40045-aff-0012"><sup>12</sup></xref></contrib><contrib id="art40045-cr-0015" contrib-type="author"><name><surname>Limaye</surname><given-names>Vidya</given-names></name><xref ref-type="aff" rid="art40045-aff-0013"><sup>13</sup></xref></contrib><contrib id="art40045-cr-0016" contrib-type="author"><name><surname>Selva‐O'Callaghan</surname><given-names>Albert</given-names></name><xref ref-type="aff" rid="art40045-aff-0014"><sup>14</sup></xref></contrib><contrib id="art40045-cr-0017" contrib-type="author"><name><surname>Platt</surname><given-names>Hazel</given-names></name><xref ref-type="aff" rid="art40045-aff-0001"><sup>1</sup></xref></contrib><contrib id="art40045-cr-0018" contrib-type="author"><name><surname>Molberg</surname><given-names>Øyvind</given-names></name><xref ref-type="aff" rid="art40045-aff-0015"><sup>15</sup></xref></contrib><contrib id="art40045-cr-0019" contrib-type="author"><name><surname>Benveniste</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="art40045-aff-0016"><sup>16</sup></xref></contrib><contrib id="art40045-cr-0020" contrib-type="author"><name><surname>Radstake</surname><given-names>Timothy R. D. J.</given-names></name><xref ref-type="aff" rid="art40045-aff-0017"><sup>17</sup></xref></contrib><contrib id="art40045-cr-0021" contrib-type="author"><name><surname>Doria</surname><given-names>Andrea</given-names></name><xref ref-type="aff" rid="art40045-aff-0018"><sup>18</sup></xref></contrib><contrib id="art40045-cr-0022" contrib-type="author"><name><surname>De Bleecker</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="art40045-aff-0019"><sup>19</sup></xref></contrib><contrib id="art40045-cr-0023" contrib-type="author"><name><surname>De Paepe</surname><given-names>Boel</given-names></name><xref ref-type="aff" rid="art40045-aff-0019"><sup>19</sup></xref></contrib><contrib id="art40045-cr-0024" contrib-type="author"><name><surname>Gieger</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="art40045-aff-0020"><sup>20</sup></xref></contrib><contrib id="art40045-cr-0025" contrib-type="author"><name><surname>Meitinger</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="art40045-aff-0021"><sup>21</sup></xref></contrib><contrib id="art40045-cr-0026" contrib-type="author"><name><surname>Winkelmann</surname><given-names>Juliane</given-names></name><xref ref-type="aff" rid="art40045-aff-0021"><sup>21</sup></xref></contrib><contrib id="art40045-cr-0027" contrib-type="author"><name><surname>Amos</surname><given-names>Christopher I.</given-names></name><xref ref-type="aff" rid="art40045-aff-0022"><sup>22</sup></xref></contrib><contrib id="art40045-cr-0028" contrib-type="author"><name><surname>Ollier</surname><given-names>William E.</given-names></name><xref ref-type="aff" rid="art40045-aff-0001"><sup>1</sup></xref></contrib><contrib id="art40045-cr-0029" contrib-type="author"><name><surname>Padyukov</surname><given-names>Leonid</given-names></name><xref ref-type="aff" rid="art40045-aff-0023"><sup>23</sup></xref></contrib><contrib id="art40045-cr-0030" contrib-type="author"><name><surname>Lee</surname><given-names>Annette T.</given-names></name><xref ref-type="aff" rid="art40045-aff-0004"><sup>4</sup></xref></contrib><contrib id="art40045-cr-0031" contrib-type="author"><name><surname>Lamb</surname><given-names>Janine A.</given-names></name><xref ref-type="aff" rid="art40045-aff-0001"><sup>1</sup></xref></contrib><contrib id="art40045-cr-0032" contrib-type="author"><name><surname>Chinoy</surname><given-names>Hector</given-names></name><xref ref-type="aff" rid="art40045-aff-0024"><sup>24</sup></xref></contrib><contrib id="art40045-cr-0033" contrib-type="author"><collab collab-type="authors">for the Myositis Genetics Consortium</collab></contrib></contrib-group><contrib-group><contrib id="art40045-cr-1001" contrib-type="author"><name><surname>Denton</surname><given-names>Christopher</given-names></name><xref ref-type="contrib" rid="art40045-cr-0033"></xref></contrib><contrib id="art40045-cr-1002" contrib-type="author"><name><surname>Gheorghe</surname><given-names>Karina</given-names></name><xref ref-type="contrib" rid="art40045-cr-0033"></xref></contrib><contrib id="art40045-cr-1003" contrib-type="author"><name><surname>Hilton‐Jones</surname><given-names>David</given-names></name><xref ref-type="contrib" rid="art40045-cr-0033"></xref></contrib><contrib id="art40045-cr-1004" contrib-type="author"><name><surname>Kiely</surname><given-names>Patrick</given-names></name><xref ref-type="contrib" rid="art40045-cr-0033"></xref></contrib><contrib id="art40045-cr-1005" contrib-type="author"><name><surname>Mann</surname><given-names>Herman</given-names></name><xref ref-type="contrib" rid="art40045-cr-0033"></xref></contrib></contrib-group><aff id="art40045-aff-0001"><label><sup>1</sup></label><institution>University of Manchester</institution><named-content content-type="city">Manchester</named-content><country country="GB">UK</country></aff><aff id="art40045-aff-0002"><label><sup>2</sup></label><institution>University of Liverpool</institution><named-content content-type="city">Liverpool</named-content><country country="GB">UK</country></aff><aff id="art40045-aff-0003"><label><sup>3</sup></label><institution>Karolinska University Hospital, Karolinska Institutet</institution><named-content content-type="city">Stockholm</named-content><country country="SE">Sweden</country></aff><aff id="art40045-aff-0004"><label><sup>4</sup></label><institution>Feinstein Institute for Medical Research</institution><named-content content-type="city">Manhasset</named-content><named-content content-type="country-part">New York</named-content></aff><aff id="art40045-aff-0005"><label><sup>5</sup></label><institution>University College London</institution><named-content content-type="city">London</named-content><country country="GB">UK</country></aff><aff id="art40045-aff-0006"><label><sup>6</sup></label><institution>Beth Israel Deaconess Medical Center, Boston, Massachusetts, and Radboud University Nijmegen</institution><named-content content-type="city">Nijmegen</named-content><country country="NL">The Netherlands</country></aff><aff id="art40045-aff-0007"><label><sup>7</sup></label><institution>Radboud University Nijmegen</institution><named-content content-type="city">Nijmegen</named-content><country country="NL">The Netherlands</country></aff><aff id="art40045-aff-0008"><label><sup>8</sup></label><institution>University of Manchester, Manchester, UK, and Salford Royal NHS Foundation Trust</institution><named-content content-type="city">Salford</named-content><country country="GB">UK</country></aff><aff id="art40045-aff-0009"><label><sup>9</sup></label><institution>Salford Royal NHS Foundation Trust</institution><named-content content-type="city">Salford</named-content><country country="GB">UK</country></aff><aff id="art40045-aff-0010"><label><sup>10</sup></label><institution>University of California</institution><named-content content-type="city">Davis</named-content></aff><aff id="art40045-aff-0011"><label><sup>11</sup></label><institution>Charles University</institution><named-content content-type="city">Prague</named-content><country country="CZ">Czech Republic</country></aff><aff id="art40045-aff-0012"><label><sup>12</sup></label><institution>University of Debrecen</institution><named-content content-type="city">Debrecen</named-content><country country="HU">Hungary</country></aff><aff id="art40045-aff-0013"><label><sup>13</sup></label><institution>Royal Adelaide Hospital, Adelaide</institution><named-content content-type="city">South Australia</named-content><country country="AU">Australia</country></aff><aff id="art40045-aff-0014"><label><sup>14</sup></label><institution>Vall d'Hebron General Hospital</institution><named-content content-type="city">Barcelona</named-content><country country="ES">Spain</country></aff><aff id="art40045-aff-0015"><label><sup>15</sup></label><institution>University of Oslo</institution><named-content content-type="city">Oslo</named-content><country country="NO">Norway</country></aff><aff id="art40045-aff-0016"><label><sup>16</sup></label><institution>Hôpital Pitié‐Salpêtrière, UPMC</institution><named-content content-type="city">Paris</named-content><country country="FR">France</country></aff><aff id="art40045-aff-0017"><label><sup>17</sup></label><institution>University Medical Center Utrecht</institution><named-content content-type="city">Utrecht</named-content><country country="NL">The Netherlands</country></aff><aff id="art40045-aff-0018"><label><sup>18</sup></label><institution>University of Padova</institution><named-content content-type="city">Padua</named-content><country country="IT">Italy</country></aff><aff id="art40045-aff-0019"><label><sup>19</sup></label><institution>Ghent University Hospital</institution><named-content content-type="city">Ghent</named-content><country country="BE">Belgium</country></aff><aff id="art40045-aff-0020"><label><sup>20</sup></label><institution>Helmholtz Zentrum München</institution><named-content content-type="city">Neuherberg</named-content><country country="DE">Germany</country></aff><aff id="art40045-aff-0021"><label><sup>21</sup></label><institution>Technische Universität München, Munich, Germany, and Helmholtz Zentrum München</institution><named-content content-type="city">Neuherberg</named-content><country country="DE">Germany</country></aff><aff id="art40045-aff-0022"><label><sup>22</sup></label><institution>Dartmouth College</institution><named-content content-type="city">Hanover</named-content><named-content content-type="country-part">New Hampshire</named-content></aff><aff id="art40045-aff-0023"><label><sup>23</sup></label><institution>Karolinska Institutet</institution><named-content content-type="city">Stockholm</named-content><country country="SE">Sweden</country></aff><aff id="art40045-aff-0024"><label><sup>24</sup></label><institution>Central Manchester University Hospitals NHS Foundation Trust, University of Manchester</institution><named-content content-type="city">Manchester</named-content><country>UK</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label>Address correspondence to Simon Rothwell, PhD, Centre for Musculoskeletal Research, University of Manchester, 2.808 Stopford Building, Oxford Road, Manchester M13 9PT, UK. E‐mail: <email>s.rothwell@manchester.ac.uk</email>.</corresp></author-notes><pub-date pub-type="epub"><day>04</day><month>4</month><year>2017</year></pub-date><pub-date pub-type="ppub"><month>5</month><year>2017</year></pub-date><volume>69</volume><issue>5</issue><issue-id pub-id-type="doi">10.1002/art.v69.5</issue-id><fpage>1090</fpage><lpage>1099</lpage><history><date date-type="received"><day>12</day><month>9</month><year>2016</year></date><date date-type="accepted"><day>10</day><month>1</month><year>2017</year></date></history><permissions><pmc-comment> © 2017, American College of Rheumatology </pmc-comment>
<copyright-statement content-type="article-copyright">© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc.on behalf of American College of Rheumatology.</copyright-statement><license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="file:ART-69-1090.pdf"></self-uri><abstract><sec id="art40045-sec-0001"><title>Objective</title><p>Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune‐related genes using the Immunochip.</p></sec><sec id="art40045-sec-0002"><title>Methods</title><p>A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA.</p></sec><sec id="art40045-sec-0003"><title>Results</title><p>The HLA region was confirmed as the most strongly associated region in IBM (<italic>P</italic> = 3.58 × 10<sup>−33</sup>). HLA imputation identified 3 independent associations (with HLA–DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA–DRB1 molecule. No association with anti–cytosolic 5′‐nucleotidase 1A–positive status was found independent of HLA–DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non‐HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in <italic>CCR5</italic> is thought to be the causal variant.</p></sec><sec id="art40045-sec-0004"><title>Conclusion</title><p>This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide‐binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for <italic>CCR5</italic>.</p></sec></abstract><counts><fig-count count="3"></fig-count><table-count count="3"></table-count><page-count count="10"></page-count><word-count count="7481"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>component-id</meta-name><meta-value>art40045</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>May 2017</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:19.07.2017</meta-value></custom-meta></custom-meta-group></article-meta><notes><fn-group><fn id="art40045-note-0001"><p>The views expressed herein are those of the authors and not necessarily those of the (UK) National Health Service (NHS), the NIHR, or the (UK) Department of Health.</p></fn><fn id="art40045-note-0002"><p>Supported by the NIHR (Biomedical Research Unit Funding Scheme) and the University College London Hospitals Biomedical Research Centre. Supported in part by the Association Francaise Contre Les Myopathies, the European Science Foundation (Research Networking Programme European Myositis Network), the Swedish Research Council, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet, the Swedish Research Council, Myositis UK, Arthritis Research UK (grant 18474), and Prinses Beatrix Spierfonds (project W.OR12‐15). Dr. Rothwell's work was supported by the Wellcome Trust (grant 105610/Z/14/Z). Dr. Machado's work was supported by the NIHR (Rare Diseases Translational Research Collaboration Post‐Doctoral Fellowship). The Czech cohort was supported by the Ministry of Health, Czech Republic (Project for Conceptual Development of Research Organization grant 00023728).</p></fn><fn id="art40045-note-0003"><p>Drs. Lamb and Chinoy contributed equally to this work.</p></fn></fn-group></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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