Effect of Smoking and Its Cessation on the Transcript Profile of Peripheral Monocytes in COPD Patients

Abstract

Rationale

Smoking is the primary cause of chronic obstructive pulmonary disease (COPD); however, only 10–20% of smokers develop the disease suggesting possible genomic association in the causation of the disease. In the present study, we aimed to explore the whole genome transcriptomics of blood monocytes from COPD smokers (COPD-S), COPD Ex-smokers (COPD-ExS), Control smokers (CS), and Control Never-smokers (CNS) to understand the differential effects of smoking, COPD and that of smoking cessation.

Methods

Exploratory analyses in form of principal component analysis (PCA) and hierarchical component analysis (uHCA) were performed to evaluate the similarity in gene expression patterns, while differential expression analyses of different supervised groups of smokers and never smokers were performed to study the differential effect of smoking, COPD and smoking cessation. Differentially expressed genes among groups were subjected to post-hoc enrichment analysis. Candidate genes were subjected to external validation by quantitative RT-PCR experiments.

Results

CNS made a cluster completely segregated from the other three subgroups (CS, COPDS and COPD-ExS). About 550, 8 and 5 genes showed differential expression, respectively, between CNS and CS, between CS and COPD-S, and between COPD-S and COPD-ExS. Apoptosis, immune response, cell adhesion, and inflammation were the top process networks identified in enrichment analysis. Two candidate genes (CASP9 and TNFRSF1A) found to be integral to several pathways in enrichment analysis were validated in an external validation experiment.

Conclusion

Control never smokers had formed a cluster distinctively separated from all smokers (COPDS, COPD-ExS, and CS), while amongst all smokers, control smokers had aggregated in a separate cluster. Smoking cessation appeared beneficial if started at an early stage as many genes altered due to smoking started reverting towards the baseline, whereas only a few COPD-related genes showed reversal after smoking cessation.

Keywords:

• chronic obstructive pulmonary disease
• apoptosis
• immune response
• cell adhesion
• smoking

Acknowledgment

We would like to acknowledge Professor Dr. Ghosh (Department of Physiology, All India Institute of Medical Sciences, New Delhi) for his immense support and contribution in bringing the concept and overall study design, data analysis, editing, proofreading, and finalizing the manuscript. The authors also wish to thank the patients and personnel of the hospital unit for their cooperation during this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest for this work.

Additional information

Funding

The study was funded by the Department of Science and Technology (DST), India.