Abstract
BACKGROUND: Inadequate DNA repair is implicated in the pathogenesis of COPD. However, the mechanisms that underlie inadequate DNA repair in COPD are poorly understood.
OBJECTIVES: We applied an integrative genomic approach to identify DNA repair genes and pathways associated with COPD severity.
METHODS: We measured the transcriptomic changes of 419 genes involved in DNA repair and DNA damage tolerance that occur with severe COPD in three independent cohorts (n=1129). Differentially expressed genes were confirmed with RNA sequencing and used for patient clustering. Clinical and genome-wide transcriptomic differences were assessed following cluster identification. We complemented this analysis by performing GSEA, Z-score, and WGCNA methods to identify transcriptomic patterns of DNA repair pathways associated with clinical measurements of COPD severity.
RESULTS: Fifteen genes involved in DNA repair and DNA damage tolerance were differentially expressed in severe COPD. K-means clustering of COPD cases based on this 15-gene signature identified three patient clusters with significant differences in clinical characteristics and global transcriptomic profiles. Increasing COPD severity was associated with downregulation of the nucleotide excision repair pathway.
CONCLUSION: Systematic analysis of the lung tissue transcriptome of individuals with severe COPD identifies DNA repair responses associated with disease severity that may underlie COPD pathogenesis.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Sauler has nothing to disclose.
Conflict of interest: Dr. Lamontagne has nothing to disclose.
Conflict of interest: Eric Finnemore has nothing to disclose.
Conflict of interest: Dr. Tedrow has nothing to disclose.
Conflict of interest: Xuchen Zhang has nothing to disclose.
Conflict of interest: Julia Morneau has nothing to disclose.
Conflict of interest: Dr. Sciurba has nothing to disclose.
Conflict of interest: Dr. Timens reports grants from Merck, during the conduct of the study; personal fees from Pfizer, personal fees from GSK, personal fees from Chiesi, personal fees from Roche Diagnostics / Ventana, grants from Dutch Asthma Fund, personal fees from Biotest, personal fees from Merck Sharp Dohme, personal fees from Novartis, personal fees from Lilly Oncology, personal fees from Boehringer Ingelheim, personal fees from Astra-Zeneca, outside the submitted work; .
Conflict of interest: Dr. Lee has nothing to disclose.
Conflict of interest: Dr. Kaminski reports grants and personal fees from Biogen Idec, personal fees from Boehringer Ingelheim, personal fees from Third Rock, personal fees from MMI, non-financial support from Actelion, non-financial support from Miragen , personal fees from Pliant, from Samumed, personal fees from Numedii, outside the submitted work; In addition, Dr. Kaminski has a patent New Threapies in Pulmonary Fibrosis licensed, and a patent Peripheral Blood Gene Expression issued and Member of the Scientific Advisory Committee, the Research Advisory Forum and the Board of the Pulmonary Fibrosis Foundation. Also serves as Deputy Editor of Thorax, BMJ. None of the above relate to COPD
Conflict of interest: Dr. Bossé has nothing to disclose.
Conflict of interest: Dr. Gomez has nothing to disclose.
Conflict of interest: Dr. Herazo-Mayo has nothing to disclose.
Conflict of interest: Dr. Pare has nothing to disclose.
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