Abstract
Background The molecular basis of airway remodelling in chronic obstructive pulmonary disease (COPD) remains poorly understood. We identified gene expression signatures associated with chest computed tomography (CT) scan airway measures to understand molecular pathways associated with airway disease.
Methods In 2396 subjects in the COPDGene Study, we examined the relationship between quantitative CT airway phenotypes and blood transcriptomes to identify airway disease-specific genes and to define an airway wall thickness (AWT) gene set score. Multivariable regression analyses were performed to identify associations of the AWT score with clinical phenotypes, bronchial gene expression and genetic variants.
Results Type 1 interferon (IFN)-induced genes were consistently associated with AWT, square root wall area of a hypothetical airway with 10 mm internal perimeter (Pi10) and wall area percentage, with the strongest enrichment in AWT. A score derived from 18 genes whose expression was associated with AWT was associated with COPD-related phenotypes including reduced lung function (forced expiratory volume in 1 s percentage predicted β= −3.4; p<0.05) and increased exacerbations (incidence rate ratio 1.7; p<0.05). The AWT score was reproducibly associated with AWT in bronchial samples from 23 subjects (β=3.22; p<0.05). The blood AWT score was associated with genetic variant rs876039, an expression quantitative trait locus for IKZF1, a gene that regulates IFN signalling and is associated with inflammatory diseases.
Conclusions A gene expression signature with IFN-stimulated genes from peripheral blood and bronchial brushings is associated with CT AWT, lung function and exacerbations. Shared genes and genetic associations suggest viral responses and/or autoimmune dysregulation as potential underlying mechanisms of airway disease in COPD.
Abstract
Airway wall thickness in chronic obstructive pulmonary disease (COPD) is associated with type 1 interferon signalling from peripheral blood gene expression https://bit.ly/2WEjvFH
Footnotes
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COPDGene Investigators – Core Units: Administrative Center: James D. Crapo (PI), Edwin K. Silverman (PI), Barry J. Make and Elizabeth A. Regan. Genetic Analysis Center: Terri Beaty, Ferdouse Begum, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Elizabeth A. Regan, Phuwanat Sakornsakolpat, Edwin K. Silverman, Emily S. Wan and Sungho Won. Imaging Center: Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell Jr, Aleena Notary, Andrea Oh, Elizabeth A. Regan, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko and Carla G. Wilson. PFT QA Center, Salt Lake City, UT: Robert Jensen. Data Coordinating Center and Biostatistics, National Jewish Health, Denver, CO: Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand and Carla G. Wilson. Epidemiology Core, University of Colorado Anschutz Medical Campus, Aurora, CO: John E. Hokanson, Gregory Kinney, Sharon M. Lutz and Kendra A. Young. Mortality Adjudication Core: Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, MeiLan K. Han, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler and Carla G. Wilson. Biomarker Core: Russell P. Bowler, Katerina Kechris and Farnoush Banaei-Kashani.
COPDGene Investigators – Clinical Centers: Ann Arbor VA: Jeffrey L. Curtis and Perry G. Pernicano. Baylor College of Medicine, Houston, TX: Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy and Amit Parulekar. Brigham and Women's Hospital, Boston, MA: Dawn L. DeMeo, Alejandro A. Diaz, Lystra P. Hayden, Brian D. Hobbs, Craig Hersh, Francine L. Jacobson and George Washko. Columbia University, New York, NY: R. Graham Barr, John Austin, Belinda D'Souza and Byron Thomashow. Duke University Medical Center, Durham, NC: Neil MacIntyre Jr, H. Page McAdams and Lacey Washington. Grady Memorial Hospital, Atlanta, GA: Eric Flenaugh and Silanth Terpenning. HealthPartners Research Institute, Minneapolis, MN: Charlene McEvoy and Joseph Tashjian. Johns Hopkins University, Baltimore, MD: Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert and Nirupama Putcha. Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center, Torrance, CA: Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter and William Stringer. Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh and Charlie Lan. Minneapolis VA: Christine Wendt, Brian Bell and Ken M. Kunisaki. National Jewish Health, Denver, CO: Russell Bowler and David A. Lynch. Reliant Medical Group, Worcester, MA: Richard Rosiello and David Pace. Temple University, Philadelphia, PA: Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D'Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift and Maria Elena Vega-Sanchez. University of Alabama, Birmingham, AL: Mark Dransfield, William Bailey, Surya P. Bhatt, Anand Iyer, Hrudaya Nath and J. Michael Wells. University of California, San Diego, CA: Douglas Conrad, Xavier Soler and Andrew Yen. University of Iowa, Iowa City, IA: Alejandro P. Comellas, Karin F. Hoth, John Newell Jr and Brad Thompson. University of Michigan, Ann Arbor, MI: MeiLan K. Han, Ella Kazerooni, Wassim Labaki, Craig Galban and Dharshan Vummidi. University of Minnesota, Minneapolis, MN: Joanne Billings, Abbie Begnaud and Tadashi Allen. University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, Jessica Bon, Divay Chandra, Carl Fuhrman and Joel Weissfeld. University of Texas Health, San Antonio, San Antonio, TX: Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz and Harjinder Singh.
Conflict of interest: J.H. Yun reports grants from the National Institutes of Health, during the conduct of the study; personal fees from Bridge Biotherapeutics, outside the submitted work.
Conflict of interest: J. Morrow reports grants from the National Institutes of Health, during the conduct of the study.
Conflict of interest: M. Cho reports personal fees from Genetech, AstraZeneca and Illumina, grants from Bayer and GlaxoSmithKline, outside the submitted work.
Conflict of interest: P. Castaldi reports personal fees from GlaxoSmithKline and Novartis, grants from GlaxoSmithKline, outside the submitted work.
Conflict of interest: C.P. Hersh reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants from Bayer, Boehringer Ingelheim, Novartis and Vertex, and personal fees from Takeda, outside the submitted work. The remaining authors have nothing to disclose.
Support statement: Supported by National Institutes of Health (NIH) grants K08HL146972, R01HL130512, R01HL125583, U01HL089856 and U01HL089897. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the NIH. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens and Sunovion. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received February 23, 2021.
- Accepted September 24, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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