Lung tissue shows divergent gene expression between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis
Authors: Ghosh Auyon J. , Hobbs Brian D. , Yun Jeong H. , Saferali Aabida , Moll Matthew , Xu Zhonghui , Chase Robert P. , Morrow Jarrett , Ziniti John , Sciurba Frank , Barwick Lucas , Limper Andrew H. , Flaherty Kevin , Criner Gerard , Brown Kevin K. , Wise Robert , Martinez Fernando J. , McGoldrick Daniel , Cho Michael H. , DeMeo Dawn L. , Silverman Edwin K. , Castaldi Peter J. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Crapo James D. , Silverman Edwin K. , Make Barry J. , Regan Elizabeth A. , Beaty Terri , Begum Ferdouse , Castaldi Peter J. , Cho Michael , DeMeo Dawn L. , Boueiz Adel R. , Foreman Marilyn G. , Halper-Stromberg Eitan , Hayden Lystra P. , Hersh Craig P. , Hetmanski Jacqueline , Hobbs Brian D. , Hokanson John E. , Laird Nan , Lange Christoph , Lutz Sharon M. , McDonald Merry-Lynn , Parker Margaret M. , Prokopenko Dmitry , Qiao Dandi , Sakornsakolpat Phuwanat , Wan Emily S. , Won Sungho , Centeno Juan Pablo , Charbonnier Jean-Paul , Coxson Harvey O. , Galban Craig J. , Han MeiLan K. , Hoffman Eric A. , Humphries Stephen , Jacobson Francine L. , Judy Philip F. , Kazerooni Ella A. , Kluiber Alex , Lynch David A. , Nardelli Pietro , Newell Jr John D. , Notary Aleena , Oh Andrea , Ross James C. , Estepar Raul San Jose , Schroeder Joyce , Sieren Jered , Stoel Berend C. , Tschirren Juerg , Van Beek Edwin , van Ginneken Bram , Rikxoort Eva van , Sanchez-Ferrero Gonzalo Vegas , Veitel Lucas , Washko George R. , Wilson Carla G. , Jensen Robert , Everett Douglas , Crooks Jim , Pratte Katherine , Strand Matt , Kinney Gregory , Young Kendra A. , Bhatt Surya P. , Bon Jessica , Diaz Alejandro A. , Murray Susan , Soler Xavier , Bowler Russell P. , Kechris Katerina , Banaei-Kashani Farnoush , Curtis Jeffrey L. , Pernicano Perry G. , Hanania Nicola , Atik Mustafa , Boriek Aladin , Guntupalli Kalpatha , Guy Elizabeth , Parulekar Amit , Graham Barr R. , Austin John , D’Souza Belinda , Thomashow Byron , MacIntyre Neil , Page McAdams H. , Washington Lacey , Flenaugh Eric , Terpenning Silanth , McEvoy Charlene , Tashjian Joseph , Wise Robert , Brown Robert , Hansel Nadia N. , Horton Karen , Lambert Allison , Putcha Nirupama , Casaburi Richard , Adami Alessandra , Budoff Matthew , Fischer Hans , Porszasz Janos , Rossiter Harry , Stringer William , Sharafkhaneh Amir , Lan Charlie , Wendt Christine , Bell Brian , Kunisaki Ken M. , Rosiello Richard , Pace David , Criner Gerard , Ciccolella David , Cordova Francis , Dass Chandra , D’Alonzo Gilbert , Desai Parag , Jacobs Michael , Kelsen Steven , Kim Victor , James Mamary A. , Marchetti Nathaniel , Satti Aditi , Shenoy Kartik , Steiner Robert M. , Swift Alex , Swift Irene , Vega-Sanchez Maria Elena , Dransfield Mark , Bailey William , Iyer Anand , Nath Hrudaya , Michael Wells J. , Conrad Douglas , Yen Andrew , Comellas Alejandro P. , Hoth Karin F. , Thompson Brad , Labaki Wassim , Vummidi Dharshan , Billings Joanne , Begnaud Abbie , Allen Tadashi , Sciurba Frank , Chandra Divay , Fuhrman Carl , Weissfeld Joel , Anzueto Antonio , Adams Sandra , Maselli-Caceres Diego , Ruiz Mario E. , Sing Harjinder , Hersh Craig P. 
Published: April 2022

Abstract
Background
Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF.

Methods
We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets.

Results
We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts.

Conclusions
We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF.