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Original Article
Lung tissue gene-expression signature for the ageing lung in COPD
  1. Maaike de Vries1,2,3,
  2. Alen Faiz1,3,4,
  3. Roy R Woldhuis1,3,
  4. Dirkje S Postma3,4,
  5. Tristan V de Jong3,5,
  6. Don D Sin6,7,
  7. Yohan Bossé8,9,
  8. David C Nickle10,
  9. Victor Guryev3,5,
  10. Wim Timens1,3,
  11. Maarten van den Berge3,4,
  12. Corry-Anke Brandsma1,3
  1. 1University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands
  2. 2University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
  3. 3University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
  4. 4University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands
  5. 5European Research Institute for the Biology of Ageing, Universitair Medisch Centrum Groningen, Groningen, Netherlands
  6. 6Center for Heart Lung Innovation, St Paul’s Hospital, The University of British Columbia, Vancouver, Canada
  7. 7Respiratory Division, University of British Columbia, Vancouver, Canada
  8. 8Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec, Canada
  9. 9Department of Molecular Medicine, Laval University, Quebec, Canada
  10. 10Merck Research Laboratories, Boston, Massachusetts, USA
  1. Correspondence to Dr Maaike de Vries, Department of Epidemiology, University Medical Center Groningen, Hanzeplein, 9713 GZ, The Netherlands; m.de.vries04{at}umcg.nl

Abstract

Introduction COPD is a chronic, progressive, inflammatory disease of the lungs and the third leading cause of death worldwide. The current knowledge of the pathophysiology of COPD is limited and novel insights in underlying disease mechanisms are urgently needed. Since there are clear parallels between ageing and COPD, we investigated genes underlying lung ageing in general and abnormal lung ageing in COPD.

Methods Whole genome mRNA profiling was performed on lung tissue samples (n=1197) and differential gene expression with increasing age was analysed using an adjusted linear regression model. Subsequent pathway analysis was performed using GeneNetwork and the gene-expression signature was compared with lung ageing in the Genotype-Tissue Expression (GTEx) project. In a subset of patients with COPD (n=311) and non-COPD controls (n=270), we performed an interaction analysis between age and COPD to identify genes differentially expressed with age in COPD compared with controls, followed by gene set enrichment pathway analysis.

Results We identified a strong gene-expression signature for lung ageing with 3509 differentially expressed genes, of which 33.5% were found nominal significant in the GTEx project. Interestingly, we found EDA2R as a strong candidate gene for lung ageing. The age*COPD interaction analysis revealed 69 genes significantly differentially expressed with age between COPD and controls.

Conclusions Our study indicates that processes related to lung development, cell-cell contacts, calcium signalling and immune responses are involved in lung ageing in general. Pathways related to extracellular matrix, mammalian target of rapamycin signalling, splicing of introns and exons and the ribosome complex are proposed to be involved in abnormal lung ageing in COPD.

  • Copd ÀÜ Mechanisms

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Footnotes

  • MB and C-AB contributed equally.

  • Contributors MdV, AF, DSP, DDS, YB, DN, VG, WT, MvdB and C-AB were involved in the conception, design and/or supervision of research; MdV, AF, RRW and TVdJ analysed data; MdV, AF, DSP, WT, MvdB and C-AB interpreted results of analyses; MdV prepared figures and drafted the manuscript; AF, DSP, WT, MvdB and C-AB. critically reviewed and revised the manuscript; all authors read and approved the final version of the manuscript. The authors would like to thank Wierd Kooistra for his technical assistance with the EDA2RqRT-PCR validation.

  • Funding This work was supported by an UMCG Healthy Ageing Pilot grant. CAB is an active member of COST Action BM1201.

  • Competing interests None declared.

  • Ethics approval The ethics committees of the Institut Universitaire de Cardiologie et de Pneumologie de Québec, UBC-Providence Health Care Research Ethics Board and University Medical Center Groningen conform the Dutch national ethical and professional guidelines.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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