Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease
Identifieur interne : 001A03 ( Ncbi/Merge ); précédent : 001A02; suivant : 001A04Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease
Auteurs : Nadia N. Hansel ; Peter D. Paré ; Nicholas Rafaels ; Don D. Sin ; Andrew Sandford ; Denise Daley ; Candelaria Vergara ; Lili Huang ; W. Mark Elliott ; Chris D. Pascoe ; Bryna A. Arsenault ; Dirkje S. Postma ; H. Marike Boezen ; Yohan Bossé ; Maarten Van Den Berge ; Pieter S. Hiemstra ; Michael H. Cho ; Augusto A. Litonjua ; David Sparrow ; Carole Ober ; Robert A. Wise ; John Connett ; Enid R. Neptune ; Terri H. Beaty ; Ingo Ruczinski ; Rasika A. Mathias ; Kathleen C. BarnesSource :
- American Journal of Respiratory Cell and Molecular Biology [ 1044-1549 ] ; 2015.
Abstract
Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (
Url:
DOI: 10.1165/rcmb.2014-0198OC
PubMed: 25514360
PubMed Central: 4566043
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<author><name sortKey="Bosse, Yohan" sort="Bosse, Yohan" uniqKey="Bosse Y" first="Yohan" last="Bossé">Yohan Bossé</name>
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<author><name sortKey="Van Den Berge, Maarten" sort="Van Den Berge, Maarten" uniqKey="Van Den Berge M" first="Maarten" last="Van Den Berge">Maarten Van Den Berge</name>
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<author><name sortKey="Hiemstra, Pieter S" sort="Hiemstra, Pieter S" uniqKey="Hiemstra P" first="Pieter S." last="Hiemstra">Pieter S. Hiemstra</name>
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<author><name sortKey="Litonjua, Augusto A" sort="Litonjua, Augusto A" uniqKey="Litonjua A" first="Augusto A." last="Litonjua">Augusto A. Litonjua</name>
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<front><div type="abstract" xml:lang="en"><p>Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (<italic>n</italic>
= 2,814) and Year 5 (<italic>n</italic>
= 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by <italic>LINGO2</italic>
met a predetermined threshold of genome-wide significance (<italic>P</italic>
< 9.57 × 10<sup>−8</sup>
). Markers on chromosomes 3q13.1 (flanked by <italic>MYH15</italic>
), 5q33 (<italic>SGCD</italic>
), and 6q21 (<italic>PDSS2</italic>
) yielded suggestive evidence of association (9.57 × 10<sup>−8</sup>
< <italic>P</italic>
≤ 4.6 × 10<sup>−6</sup>
). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for <italic>SGCD</italic>
(<italic>P</italic>
= 2.57 × 10<sup>−9</sup>
) and <italic>MYH15</italic>
(<italic>P</italic>
= 1.62 × 10<sup>−6</sup>
), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Respir Cell Mol Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">Am. J. Respir. Cell Mol. Biol</journal-id>
<journal-id journal-id-type="publisher-id">ajrcmb</journal-id>
<journal-title-group><journal-title>American Journal of Respiratory Cell and Molecular Biology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1044-1549</issn>
<issn pub-type="epub">1535-4989</issn>
<publisher><publisher-name>American Thoracic Society</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25514360</article-id>
<article-id pub-id-type="pmc">4566043</article-id>
<article-id pub-id-type="publisher-manuscript">2014-0198OC</article-id>
<article-id pub-id-type="doi">10.1165/rcmb.2014-0198OC</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Hansel</surname>
<given-names>Nadia N.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Paré</surname>
<given-names>Peter D.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rafaels</surname>
<given-names>Nicholas</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sin</surname>
<given-names>Don D.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sandford</surname>
<given-names>Andrew</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Daley</surname>
<given-names>Denise</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vergara</surname>
<given-names>Candelaria</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Lili</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Elliott</surname>
<given-names>W. Mark</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pascoe</surname>
<given-names>Chris D.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arsenault</surname>
<given-names>Bryna A.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Postma</surname>
<given-names>Dirkje S.</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff8"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boezen</surname>
<given-names>H. Marike</given-names>
</name>
<xref ref-type="aff" rid="aff8"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff7"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bossé</surname>
<given-names>Yohan</given-names>
</name>
<xref ref-type="aff" rid="aff9"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van den Berge</surname>
<given-names>Maarten</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff8"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hiemstra</surname>
<given-names>Pieter S.</given-names>
</name>
<xref ref-type="aff" rid="aff10"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cho</surname>
<given-names>Michael H.</given-names>
</name>
<xref ref-type="aff" rid="aff11"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Litonjua</surname>
<given-names>Augusto A.</given-names>
</name>
<xref ref-type="aff" rid="aff11"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sparrow</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="aff12"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ober</surname>
<given-names>Carole</given-names>
</name>
<xref ref-type="aff" rid="aff13"><sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wise</surname>
<given-names>Robert A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Connett</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="aff14"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Neptune</surname>
<given-names>Enid R.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Beaty</surname>
<given-names>Terri H.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>13</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ruczinski</surname>
<given-names>Ingo</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>14</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mathias</surname>
<given-names>Rasika A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Barnes</surname>
<given-names>Kathleen C.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>13</sup>
</xref>
<on-behalf-of>on behalf of the Lung Health Study</on-behalf-of>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<aff id="aff1"><label><sup>1</sup>
</label>
Department of Medicine, School of Medicine; and</aff>
<aff id="aff2">Departments of<label><sup>2</sup>
</label>
Environmental Health Sciences</aff>
<aff id="aff3"><label><sup>13</sup>
</label>
Epidemiology, and</aff>
<aff id="aff6"><label><sup>14</sup>
</label>
Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland</aff>
<aff id="aff11"><label><sup>9</sup>
</label>
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts</aff>
<aff id="aff12"><label><sup>10</sup>
</label>
VA Normative Aging Study and Boston University School of Medicine, Boston, Massachusetts</aff>
<aff id="aff13"><label><sup>11</sup>
</label>
Department of Human Genetics, University of Chicago, Chicago, Illinois</aff>
<aff id="aff14"><label><sup>12</sup>
</label>
Division of Biostatistics, School of Public Health, University of Minnesota, St. Paul, Minnesota</aff>
<aff id="aff5"><label><sup>3</sup>
</label>
Department of Pathology, Centre for Heart Lung Innovation, St. Paul’s Hospital, Division of Respirology, University of British Columbia, Vancouver, British Columbia</aff>
<aff id="aff9"><label><sup>7</sup>
</label>
Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec City, Québec, Canada</aff>
<aff id="aff4">Departments of<label><sup>4</sup>
</label>
Pulmonary Diseases and</aff>
<aff id="aff7"><label><sup>6</sup>
</label>
Epidemiology, and</aff>
<aff id="aff8"><label><sup>5</sup>
</label>
Groningen Research Institute for Asthma and COPD Research Institute, University Medical Center Groningen, Groningen; and</aff>
<aff id="aff10"><label><sup>8</sup>
</label>
Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands</aff>
</contrib-group>
<author-notes><corresp>Correspondence and requests for reprints should be addressed to Nadia N. Hansel, M.D., M.P.H., Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Room 4B69, Baltimore, MD 21224. E-mail: <email xlink:href="nhansel1@jhmi.edu">nhansel1@jhmi.edu</email>
</corresp>
<fn id="fn1"><label>*</label>
<p>A complete list of members may be found before the beginning of the R<sc>eferences</sc>
.</p>
</fn>
</author-notes>
<pub-date pub-type="epub-ppub"><month>8</month>
<year>2015</year>
<pmc-comment>string-date: August 2015</pmc-comment>
</pub-date>
<pmc-comment>Fake ppub date generated by PMC from publisher
pub-date/@pub-type='epub-ppub' </pmc-comment>
<pub-date pub-type="ppub"><month>8</month>
<year>2015</year>
<pmc-comment>string-date: August 2015</pmc-comment>
</pub-date>
<volume>53</volume>
<issue>2</issue>
<fpage>226</fpage>
<lpage>234</lpage>
<history><date date-type="received"><day>16</day>
<month>5</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>08</day>
<month>12</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015 by the American Thoracic Society</copyright-statement>
<copyright-year>2015</copyright-year>
</permissions>
<self-uri content-type="pdf" xlink:href="rcmb.2014-0198OC.pdf"></self-uri>
<abstract><p>Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (<italic>n</italic>
= 2,814) and Year 5 (<italic>n</italic>
= 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by <italic>LINGO2</italic>
met a predetermined threshold of genome-wide significance (<italic>P</italic>
< 9.57 × 10<sup>−8</sup>
). Markers on chromosomes 3q13.1 (flanked by <italic>MYH15</italic>
), 5q33 (<italic>SGCD</italic>
), and 6q21 (<italic>PDSS2</italic>
) yielded suggestive evidence of association (9.57 × 10<sup>−8</sup>
< <italic>P</italic>
≤ 4.6 × 10<sup>−6</sup>
). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for <italic>SGCD</italic>
(<italic>P</italic>
= 2.57 × 10<sup>−9</sup>
) and <italic>MYH15</italic>
(<italic>P</italic>
= 1.62 × 10<sup>−6</sup>
), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.</p>
</abstract>
<kwd-group><title>Keywords</title>
<kwd>COPD</kwd>
<kwd>airway reactivity</kwd>
<kwd>bronchial responsiveness</kwd>
<kwd>eQTL</kwd>
<kwd>δ-sarcoglycan</kwd>
</kwd-group>
<counts><fig-count count="4"></fig-count>
<table-count count="4"></table-count>
<page-count count="9"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Arsenault, Bryna A" sort="Arsenault, Bryna A" uniqKey="Arsenault B" first="Bryna A." last="Arsenault">Bryna A. Arsenault</name>
<name sortKey="Barnes, Kathleen C" sort="Barnes, Kathleen C" uniqKey="Barnes K" first="Kathleen C." last="Barnes">Kathleen C. Barnes</name>
<name sortKey="Beaty, Terri H" sort="Beaty, Terri H" uniqKey="Beaty T" first="Terri H." last="Beaty">Terri H. Beaty</name>
<name sortKey="Boezen, H Marike" sort="Boezen, H Marike" uniqKey="Boezen H" first="H. Marike" last="Boezen">H. Marike Boezen</name>
<name sortKey="Bosse, Yohan" sort="Bosse, Yohan" uniqKey="Bosse Y" first="Yohan" last="Bossé">Yohan Bossé</name>
<name sortKey="Cho, Michael H" sort="Cho, Michael H" uniqKey="Cho M" first="Michael H." last="Cho">Michael H. Cho</name>
<name sortKey="Connett, John" sort="Connett, John" uniqKey="Connett J" first="John" last="Connett">John Connett</name>
<name sortKey="Daley, Denise" sort="Daley, Denise" uniqKey="Daley D" first="Denise" last="Daley">Denise Daley</name>
<name sortKey="Elliott, W Mark" sort="Elliott, W Mark" uniqKey="Elliott W" first="W. Mark" last="Elliott">W. Mark Elliott</name>
<name sortKey="Hansel, Nadia N" sort="Hansel, Nadia N" uniqKey="Hansel N" first="Nadia N." last="Hansel">Nadia N. Hansel</name>
<name sortKey="Hiemstra, Pieter S" sort="Hiemstra, Pieter S" uniqKey="Hiemstra P" first="Pieter S." last="Hiemstra">Pieter S. Hiemstra</name>
<name sortKey="Huang, Lili" sort="Huang, Lili" uniqKey="Huang L" first="Lili" last="Huang">Lili Huang</name>
<name sortKey="Litonjua, Augusto A" sort="Litonjua, Augusto A" uniqKey="Litonjua A" first="Augusto A." last="Litonjua">Augusto A. Litonjua</name>
<name sortKey="Mathias, Rasika A" sort="Mathias, Rasika A" uniqKey="Mathias R" first="Rasika A." last="Mathias">Rasika A. Mathias</name>
<name sortKey="Neptune, Enid R" sort="Neptune, Enid R" uniqKey="Neptune E" first="Enid R." last="Neptune">Enid R. Neptune</name>
<name sortKey="Ober, Carole" sort="Ober, Carole" uniqKey="Ober C" first="Carole" last="Ober">Carole Ober</name>
<name sortKey="Pare, Peter D" sort="Pare, Peter D" uniqKey="Pare P" first="Peter D." last="Paré">Peter D. Paré</name>
<name sortKey="Pascoe, Chris D" sort="Pascoe, Chris D" uniqKey="Pascoe C" first="Chris D." last="Pascoe">Chris D. Pascoe</name>
<name sortKey="Postma, Dirkje S" sort="Postma, Dirkje S" uniqKey="Postma D" first="Dirkje S." last="Postma">Dirkje S. Postma</name>
<name sortKey="Rafaels, Nicholas" sort="Rafaels, Nicholas" uniqKey="Rafaels N" first="Nicholas" last="Rafaels">Nicholas Rafaels</name>
<name sortKey="Ruczinski, Ingo" sort="Ruczinski, Ingo" uniqKey="Ruczinski I" first="Ingo" last="Ruczinski">Ingo Ruczinski</name>
<name sortKey="Sandford, Andrew" sort="Sandford, Andrew" uniqKey="Sandford A" first="Andrew" last="Sandford">Andrew Sandford</name>
<name sortKey="Sin, Don D" sort="Sin, Don D" uniqKey="Sin D" first="Don D." last="Sin">Don D. Sin</name>
<name sortKey="Sparrow, David" sort="Sparrow, David" uniqKey="Sparrow D" first="David" last="Sparrow">David Sparrow</name>
<name sortKey="Van Den Berge, Maarten" sort="Van Den Berge, Maarten" uniqKey="Van Den Berge M" first="Maarten" last="Van Den Berge">Maarten Van Den Berge</name>
<name sortKey="Vergara, Candelaria" sort="Vergara, Candelaria" uniqKey="Vergara C" first="Candelaria" last="Vergara">Candelaria Vergara</name>
<name sortKey="Wise, Robert A" sort="Wise, Robert A" uniqKey="Wise R" first="Robert A." last="Wise">Robert A. Wise</name>
</noCountry>
</tree>
</affiliations>
</record>
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