- Title
- Severity of Lung Function Impairment Drives Transcriptional Phenotypes of COPD and Relates to Immune and Metabolic Processes
- Creator
- Negewo, Netsanet A.; Gibson, Peter G.; Simpson, Jodie L.; McDonald, Vanessa M.; Baines, Katherine J.
- Relation
- International Journal of Chronic Obstructive Pulmonary Disease Vol. 2023, Issue 18, p. 273-287
- Publisher Link
- http://dx.doi.org/10.2147/copd.s388297
- Publisher
- Dove Medical Press
- Resource Type
- journal article
- Date
- 2023
- Description
- Purpose: This study sought to characterize transcriptional phenotypes of COPD through unsupervised clustering of sputum gene expression profiles, and further investigate mechanisms underlying the characteristics of these clusters. Patients and Methods: Induced sputum samples were collected from patients with stable COPD (n = 72) and healthy controls (n = 15). Induced sputum was collected for inflammatory cell counts, and RNA extracted. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by GeneSpring GX14.9.1. Unsupervised hierarchical clustering and differential gene expression analysis were performed, and gene alterations validated in the ECLIPSE dataset (GSE22148). Results: We identified 2 main clusters (Cluster 1 [n = 35] and Cluster 2 [n = 37]), which further divided into 4 sub-clusters (Sub-clusters 1.1 [n = 14], 1.2 [n = 21], 2.1 [n = 20] and 2.2 [n = 17]). Compared with Cluster 1, Cluster 2 was associated with significantly lower lung function (p = 0.014), more severe disease (p = 0.009) and breathlessness (p = 0.035), and increased sputum neutrophils (p = 0.031). Sub-cluster 1.1 had significantly higher proportion of people with comorbid cardiovascular disease compared to the other 3 sub-clusters (92.5% vs 57.1%, 50% and 52.9%, p < 0.013). Through supervised analysis we determined that degree of airflow limitation (GOLD stage) was the predominant factor driving gene expression differences in our transcriptional clusters. There were 452 genes (adjusted p < 0.05 and ≥ 2 fold) altered in GOLD stage 3 and 4 versus 1 and 2, of which 281 (62%) were also found to be significantly expressed between these GOLD stages in the ECLIPSE data set (GSE22148). Differentially expressed genes were largely downregulated in GOLD stages 3 and 4 and connected in 5 networks relating to lipoprotein and cholesterol metabolism; metabolic processes in oxidation/reduction and mitochondrial function; antigen processing and presentation; regulation of complement activation and innate immune responses; and immune and metabolic processes. Conclusion: Severity of lung function drives 2 distinct transcriptional phenotypes of COPD and relates to immune and metabolic processes.
- Subject
- COPD; gene expression; inflammation; sputum; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1491895
- Identifier
- uon:53093
- Identifier
- ISSN:1176-9106
- Rights
- x
- Language
- eng
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