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. 2022 May 19;59(5):2100569.
doi: 10.1183/13993003.00569-2021. Print 2022 May.

An interferon-inducible signature of airway disease from blood gene expression profiling

Jeong H Yun  1   2   3 , Sool Lee  1 , Pooja Srinivasa  1 , Jarrett Morrow  1   3 , Robert Chase  1 , Aadbida Saferali  1   3 , Zhonghui Xu  1   3 , Michael Cho  1   2   3 , Peter Castaldi  1   3 , Craig P Hersh  4   2   3
Affiliations

An interferon-inducible signature of airway disease from blood gene expression profiling

Jeong H Yun et al. Eur Respir J. .

Abstract

Background: The molecular basis of airway remodelling in chronic obstructive pulmonary disease (COPD) remains poorly understood. We identified gene expression signatures associated with chest computed tomography (CT) scan airway measures to understand molecular pathways associated with airway disease.

Methods: In 2396 subjects in the COPDGene Study, we examined the relationship between quantitative CT airway phenotypes and blood transcriptomes to identify airway disease-specific genes and to define an airway wall thickness (AWT) gene set score. Multivariable regression analyses were performed to identify associations of the AWT score with clinical phenotypes, bronchial gene expression and genetic variants.

Results: Type 1 interferon (IFN)-induced genes were consistently associated with AWT, square root wall area of a hypothetical airway with 10 mm internal perimeter (Pi10) and wall area percentage, with the strongest enrichment in AWT. A score derived from 18 genes whose expression was associated with AWT was associated with COPD-related phenotypes including reduced lung function (forced expiratory volume in 1 s percentage predicted β= -3.4; p<0.05) and increased exacerbations (incidence rate ratio 1.7; p<0.05). The AWT score was reproducibly associated with AWT in bronchial samples from 23 subjects (β=3.22; p<0.05). The blood AWT score was associated with genetic variant rs876039, an expression quantitative trait locus for IKZF1, a gene that regulates IFN signalling and is associated with inflammatory diseases.

Conclusions: A gene expression signature with IFN-stimulated genes from peripheral blood and bronchial brushings is associated with CT AWT, lung function and exacerbations. Shared genes and genetic associations suggest viral responses and/or autoimmune dysregulation as potential underlying mechanisms of airway disease in COPD.

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Conflict of interest statement

Conflict of interest: J.H. Yun reports grants from the National Institutes of Health, during the conduct of the study; personal fees from Bridge Biotherapeutics, outside the submitted work. Conflict of interest: J. Morrow reports grants from the National Institutes of Health, during the conduct of the study. Conflict of interest: M. Cho reports personal fees from Genetech, AstraZeneca and Illumina, grants from Bayer and GlaxoSmithKline, outside the submitted work. Conflict of interest: P. Castaldi reports personal fees from GlaxoSmithKline and Novartis, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: C.P. Hersh reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants from Bayer, Boehringer Ingelheim, Novartis and Vertex, and personal fees from Takeda, outside the submitted work. The remaining authors have nothing to disclose.

Figures

Fig 1.
Fig 1.
Airway gene signature and Type 1 IFN signature gene set scores are highly correlated. Gene set enrichment scores are derived from Gene Set Variation Analysis. Airway gene signature score was derived from 18 genes associated with CT airway wall thickness. Type 1 IFN score was derived from upregulated genes after treatment of peripheral blood with IFN-α and β.
Fig 2.
Fig 2.
GWAS of airway gene signature score. Manhattan plot showing the association of variants with airway gene signature score in 1,788 non-Hispanic White individuals. The dashed red line marks the threshold for genome-wide significance (p = 5 × 10−8).
See this image and copyright information in PMC

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