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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes</title><author><name sortKey="O Eal, Wanda K" sort="O Eal, Wanda K" uniqKey="O Eal W" first="Wanda K." last="O Eal">Wanda K. O Eal</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Gallins, Paul" sort="Gallins, Paul" uniqKey="Gallins P" first="Paul" last="Gallins">Paul Gallins</name><affiliation><nlm:aff id="aff2">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Pace, Rhonda G" sort="Pace, Rhonda G" uniqKey="Pace R" first="Rhonda G." last="Pace">Rhonda G. Pace</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Dang, Hong" sort="Dang, Hong" uniqKey="Dang H" first="Hong" last="Dang">Hong Dang</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Wolf, Whitney E" sort="Wolf, Whitney E" uniqKey="Wolf W" first="Whitney E." last="Wolf">Whitney E. Wolf</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Jones, Lisa C" sort="Jones, Lisa C" uniqKey="Jones L" first="Lisa C." last="Jones">Lisa C. Jones</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Guo, Xueliang" sort="Guo, Xueliang" uniqKey="Guo X" first="Xueliang" last="Guo">Xueliang Guo</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Zhou, Yi Hui" sort="Zhou, Yi Hui" uniqKey="Zhou Y" first="Yi-Hui" last="Zhou">Yi-Hui Zhou</name><affiliation><nlm:aff id="aff3">Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA</nlm:aff></affiliation></author><author><name sortKey="Madar, Vered" sort="Madar, Vered" uniqKey="Madar V" first="Vered" last="Madar">Vered Madar</name><affiliation><nlm:aff id="aff4">Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, Jinyan" sort="Huang, Jinyan" uniqKey="Huang J" first="Jinyan" last="Huang">Jinyan Huang</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China</nlm:aff></affiliation></author><author><name sortKey="Liang, Liming" sort="Liang, Liming" uniqKey="Liang L" first="Liming" last="Liang">Liming Liang</name><affiliation><nlm:aff id="aff6">Department of Biostatistics, Harvard University, Boston, MA 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Moffatt, Miriam F" sort="Moffatt, Miriam F" uniqKey="Moffatt M" first="Miriam F." last="Moffatt">Miriam F. Moffatt</name><affiliation><nlm:aff id="aff7">National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK</nlm:aff></affiliation></author><author><name sortKey="Cutting, Garry R" sort="Cutting, Garry R" uniqKey="Cutting G" first="Garry R." last="Cutting">Garry R. Cutting</name><affiliation><nlm:aff id="aff8">McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA</nlm:aff></affiliation></author><author><name sortKey="Drumm, Mitchell L" sort="Drumm, Mitchell L" uniqKey="Drumm M" first="Mitchell L." last="Drumm">Mitchell L. Drumm</name><affiliation><nlm:aff id="aff9">Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA</nlm:aff></affiliation></author><author><name sortKey="Rommens, Johanna M" sort="Rommens, Johanna M" uniqKey="Rommens J" first="Johanna M." last="Rommens">Johanna M. Rommens</name><affiliation><nlm:aff id="aff10">Program in Genetics and Genome Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X8, Canada</nlm:aff></affiliation></author><author><name sortKey="Strug, Lisa J" sort="Strug, Lisa J" uniqKey="Strug L" first="Lisa J." last="Strug">Lisa J. Strug</name><affiliation><nlm:aff id="aff11">Program in Child Health Evaluative Sciences, The Hospital for Sick Children, and Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, ON M5G 1X8, Canada</nlm:aff></affiliation></author><author><name sortKey="Sun, Wei" sort="Sun, Wei" uniqKey="Sun W" first="Wei" last="Sun">Wei Sun</name><affiliation><nlm:aff id="aff2">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Stonebraker, Jaclyn R" sort="Stonebraker, Jaclyn R" uniqKey="Stonebraker J" first="Jaclyn R." last="Stonebraker">Jaclyn R. Stonebraker</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Wright, Fred A" sort="Wright, Fred A" uniqKey="Wright F" first="Fred A." last="Wright">Fred A. Wright</name><affiliation><nlm:aff id="aff3">Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA</nlm:aff></affiliation></author><author><name sortKey="Knowles, Michael R" sort="Knowles, Michael R" uniqKey="Knowles M" first="Michael R." last="Knowles">Michael R. Knowles</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25640674</idno><idno type="pmc">4320265</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320265</idno><idno type="RBID">PMC:4320265</idno><idno type="doi">10.1016/j.ajhg.2014.12.022</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000354</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000354</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes</title><author><name sortKey="O Eal, Wanda K" sort="O Eal, Wanda K" uniqKey="O Eal W" first="Wanda K." last="O Eal">Wanda K. O Eal</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Gallins, Paul" sort="Gallins, Paul" uniqKey="Gallins P" first="Paul" last="Gallins">Paul Gallins</name><affiliation><nlm:aff id="aff2">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Pace, Rhonda G" sort="Pace, Rhonda G" uniqKey="Pace R" first="Rhonda G." last="Pace">Rhonda G. Pace</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Dang, Hong" sort="Dang, Hong" uniqKey="Dang H" first="Hong" last="Dang">Hong Dang</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Wolf, Whitney E" sort="Wolf, Whitney E" uniqKey="Wolf W" first="Whitney E." last="Wolf">Whitney E. Wolf</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Jones, Lisa C" sort="Jones, Lisa C" uniqKey="Jones L" first="Lisa C." last="Jones">Lisa C. Jones</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Guo, Xueliang" sort="Guo, Xueliang" uniqKey="Guo X" first="Xueliang" last="Guo">Xueliang Guo</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Zhou, Yi Hui" sort="Zhou, Yi Hui" uniqKey="Zhou Y" first="Yi-Hui" last="Zhou">Yi-Hui Zhou</name><affiliation><nlm:aff id="aff3">Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA</nlm:aff></affiliation></author><author><name sortKey="Madar, Vered" sort="Madar, Vered" uniqKey="Madar V" first="Vered" last="Madar">Vered Madar</name><affiliation><nlm:aff id="aff4">Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, Jinyan" sort="Huang, Jinyan" uniqKey="Huang J" first="Jinyan" last="Huang">Jinyan Huang</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China</nlm:aff></affiliation></author><author><name sortKey="Liang, Liming" sort="Liang, Liming" uniqKey="Liang L" first="Liming" last="Liang">Liming Liang</name><affiliation><nlm:aff id="aff6">Department of Biostatistics, Harvard University, Boston, MA 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Moffatt, Miriam F" sort="Moffatt, Miriam F" uniqKey="Moffatt M" first="Miriam F." last="Moffatt">Miriam F. Moffatt</name><affiliation><nlm:aff id="aff7">National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK</nlm:aff></affiliation></author><author><name sortKey="Cutting, Garry R" sort="Cutting, Garry R" uniqKey="Cutting G" first="Garry R." last="Cutting">Garry R. Cutting</name><affiliation><nlm:aff id="aff8">McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA</nlm:aff></affiliation></author><author><name sortKey="Drumm, Mitchell L" sort="Drumm, Mitchell L" uniqKey="Drumm M" first="Mitchell L." last="Drumm">Mitchell L. Drumm</name><affiliation><nlm:aff id="aff9">Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA</nlm:aff></affiliation></author><author><name sortKey="Rommens, Johanna M" sort="Rommens, Johanna M" uniqKey="Rommens J" first="Johanna M." last="Rommens">Johanna M. Rommens</name><affiliation><nlm:aff id="aff10">Program in Genetics and Genome Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X8, Canada</nlm:aff></affiliation></author><author><name sortKey="Strug, Lisa J" sort="Strug, Lisa J" uniqKey="Strug L" first="Lisa J." last="Strug">Lisa J. Strug</name><affiliation><nlm:aff id="aff11">Program in Child Health Evaluative Sciences, The Hospital for Sick Children, and Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, ON M5G 1X8, Canada</nlm:aff></affiliation></author><author><name sortKey="Sun, Wei" sort="Sun, Wei" uniqKey="Sun W" first="Wei" last="Sun">Wei Sun</name><affiliation><nlm:aff id="aff2">Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Stonebraker, Jaclyn R" sort="Stonebraker, Jaclyn R" uniqKey="Stonebraker J" first="Jaclyn R." last="Stonebraker">Jaclyn R. Stonebraker</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author><author><name sortKey="Wright, Fred A" sort="Wright, Fred A" uniqKey="Wright F" first="Fred A." last="Wright">Fred A. Wright</name><affiliation><nlm:aff id="aff3">Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA</nlm:aff></affiliation></author><author><name sortKey="Knowles, Michael R" sort="Knowles, Michael R" uniqKey="Knowles M" first="Michael R." last="Knowles">Michael R. Knowles</name><affiliation><nlm:aff id="aff1">Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent <italic>Pseudomonas aeruginosa</italic> (<italic>P</italic>. <italic>aeruginosa</italic>) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. <italic>LPAR6</italic>, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent <italic>P</italic>. <italic>aeruginosa</italic> infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease.</p></div></front></TEI><pmc article-type="brief-report"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25640674</article-id><article-id pub-id-type="pmc">4320265</article-id><article-id pub-id-type="publisher-id">S0002-9297(14)00528-X</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2014.12.022</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>O’Neal</surname><given-names>Wanda K.</given-names></name><email>wanda_o'neal@med.unc.edu</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Gallins</surname><given-names>Paul</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Pace</surname><given-names>Rhonda G.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Dang</surname><given-names>Hong</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Wolf</surname><given-names>Whitney E.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Jones</surname><given-names>Lisa C.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>XueLiang</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Yi-Hui</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Madar</surname><given-names>Vered</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Jinyan</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Liang</surname><given-names>Liming</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Moffatt</surname><given-names>Miriam F.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Cutting</surname><given-names>Garry R.</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Drumm</surname><given-names>Mitchell L.</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Rommens</surname><given-names>Johanna M.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Strug</surname><given-names>Lisa J.</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Wei</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Stonebraker</surname><given-names>Jaclyn R.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Wright</surname><given-names>Fred A.</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff12" ref-type="aff">12</xref><xref rid="fn1" ref-type="fn">13</xref></contrib><contrib contrib-type="author"><name><surname>Knowles</surname><given-names>Michael R.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">13</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</aff><aff id="aff2"><label>2</label>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</aff><aff id="aff3"><label>3</label>Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA</aff><aff id="aff4"><label>4</label>Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA</aff><aff id="aff5"><label>5</label>State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China</aff><aff id="aff6"><label>6</label>Department of Biostatistics, Harvard University, Boston, MA 02115, USA</aff><aff id="aff7"><label>7</label>National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK</aff><aff id="aff8"><label>8</label>McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA</aff><aff id="aff9"><label>9</label>Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA</aff><aff id="aff10"><label>10</label>Program in Genetics and Genome Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X8, Canada</aff><aff id="aff11"><label>11</label>Program in Child Health Evaluative Sciences, The Hospital for Sick Children, and Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, ON M5G 1X8, Canada</aff><aff id="aff12"><label>12</label>Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>wanda_o'neal@med.unc.edu</email></corresp><fn id="fn1"><label>13</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>05</day><month>2</month><year>2015</year></pub-date><volume>96</volume><issue>2</issue><fpage>318</fpage><lpage>328</lpage><history><date date-type="received"><day>26</day><month>9</month><year>2014</year></date><date date-type="accepted"><day>23</day><month>12</month><year>2014</year></date></history><permissions><copyright-statement>© 2015 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent <italic>Pseudomonas aeruginosa</italic> (<italic>P</italic>. <italic>aeruginosa</italic>) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. <italic>LPAR6</italic>, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent <italic>P</italic>. <italic>aeruginosa</italic> infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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