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. 2025 Apr 26;203(1):58.
doi: 10.1007/s00408-025-00814-6.

Genome-Wide Differential Airway Gene Expression Analysis Identifies Genes Associated with COPD Comorbidities

Alen Faiz  1 , Else A M D Ter Haar  2   3 , Jorine E Hartman  2   3 , Corry-Anke Brandsma  3   4 , Wim Timens  3   4 , Janette K Burgess  3   4 , David F Choy  5 , Michele A Grimbaldeston  5 , Lowie E G W Vanfleteren  6 , Dirk-Jan Slebos  2   3 , Maarten van den Berge  2   3 , Simon D Pouwels  7   8   9
Affiliations

Genome-Wide Differential Airway Gene Expression Analysis Identifies Genes Associated with COPD Comorbidities

Alen Faiz et al. Lung. .

Abstract

Chronic obstructive pulmonary disease (COPD) is often associated with the co-occurrence of extra-pulmonary diseases, yet the underlying pathophysiology of comorbidities is poorly understood. In COPD patients, the bronchial epithelium often displays cellular damage and is chronically inflamed. The current study aimed to identify differentially expressed genes in bronchial epithelium of COPD patients with and without comorbidities. To this end, a genome-wide differential gene expression analysis was performed on bronchial epithelial samples of 123 severe COPD patients with and without the following comorbidities: anxiety, atherosclerosis, depression, hypercholesterolemia, hypertension, muscle wasting, osteoporosis, and low BMI. COPD patients with osteoporosis displayed higher expression of COL6A3 and lower expression of PHEX. Furthermore, COPD patients with hypercholesterolemia displayed a distinct bronchial epithelial gene expression profile, with 162 differentially expressed genes. No differentially expressed genes were identified for the other comorbidities. This study identified differentially expressed bronchial epithelial genes associated with osteoporosis and hypercholesterolemia in COPD patients.

Keywords: COPD; Comorbidities; GWAS; Hypercholesterolemia; Notch; Osteoporosis.

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Conflict of interest statement

Declarations. Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Ethical Approval: This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the Medical Ethical committee of the University Medical Center Groningen (UMCG), the Netherlands (ECnumber: 2014/102). Consent to Participate: Informed consent was obtained from all individual participants included in the study. Consent for Publication: The authors affirm that all individual participants included in the study provided informed consent for publication of pseudonymized data.

Figures

Fig. 1
Fig. 1
Genes associated with the COPD comorbidity osteoporosis. A Volcano plot showing genes of which the bronchial epithelial gene expression levels associated with COPD patients having osteoporosis as comorbidity. Significant (False Discovery Rate (FDR) < 0.05) genes are depicted in the figure as a red dot. The normalized bronchial epithelial gene expression of B COL6A3 and C PHEX in COPD patients with (n = 22) and without (n = 52) osteoporosis
Fig. 2
Fig. 2
Genes associated with the COPD comorbidity hypercholesterolemia. A Volcano plot showing genes where the bronchial epithelial expression levels are associated with COPD patients having hypercholesterolemia as a comorbidity. Significant (False Discovery Rate (FDR) < 0.05) genes are depicted in the volcano plot. Red dots indicate genes with significantly higher gene expression, while blue dots indicate genes with significantly lower gene expression in COPD patients with hypercholesterolemia. B Heatmap showing genes with higher (red) and lower (blue) expression in COPD patients with hypercholesterolemia (red) compared to COPD patients without hypercholesterolemia (black). C The normalized bronchial epithelial gene expression of IGHG1, TTN, GNG4, and WIF1 in COPD patients with (n = 11) and without (n = 63) hypercholesterolemia. D Local network cluster analysis showing the interactions between the 162 identified differentially expressed genes (FDR < 0.1) in COPD patients with and without hypercholesterolemia
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