Front Med (Lausanne). 2021;8:652824.

Different Biological Pathways Between Good and Poor Inhaled Corticosteroid Responses in Asthma.

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제1저자 김병근 · 교신저자 박흥우

PMID 33816533 PMC8012484 DOI 10.3389/fmed.2021.652824 IF 3.6 알레르기내과

소속 (4)

Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.
Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Abstract

Gene regulatory networks address how transcription factors (TFs) and their regulatory roles in gene expression determine the responsiveness to anti-asthma therapy. The purpose of this study was to assess gene regulatory networks of adult patients with asthma who showed good or poor lung function improvements in response to inhaled corticosteroids (ICSs). A total of 47 patients with asthma were recruited and classified as good responders (GRs) and poor responders (PRs) based on their responses to ICSs. Genome-wide gene expression was measured using peripheral blood mononuclear cells obtained in a stable state. We used Passing Attributes between Networks for Data Assimilations to construct the gene regulatory networks associated with GRs and PRs to ICSs. We identified the top-10 TFs that showed large differences in high-confidence edges between the GR and PR aggregate networks. These top-10 TFs and their differentially-connected genes in the PR and GR aggregate networks were significantly enriched in distinct biological pathways, such as TGF-β signaling, cell cycle, and IL-4 and IL-13 signaling pathways. We identified multiple TFs and related biological pathways influencing ICS responses in asthma. Our results provide potential targets to overcome insensitivity to corticosteroids in patients with asthma.

Keywords

asthmabloodgene expressiongene regulatory networksinhaled corticosteroidpharmacogenomicstranscription factor

Figures

**Figure 1** Overall study design. Poor responders (PRs) or good responder (GRs) to inhaled corticosteroids was defined as patients who had less or more than 12% improvement in FEV1 compared to baseline values at 4 weeks after initiation of treatment, respectively, and genome-wide gene expression profiles were obtained from peripheral blood mononuclear cells of participants. Due to the small sample size, two-thirds of the participants were chosen from each GR and PR group at random (without replacement) to form subsamples. We constructed 50 gene regulatory networks in GRs and PRs using PANDA with these 50 subsamples. We then generated a single, aggregate gene regulatory network by averaging Z-scores of edges across the 50 networks identified from subsamples. Finally, we illustrated subnetworks using the top-10 transcription factors (TFs) identified and their differentially-connected genes in each aggregate GR and PR network.

**Figure 2** Good (GR) and poor responder (PR) subnetwork made by the top-10 transcription factors and their differentially-connected genes. **(A)** GR and **(B)** PR. Based on edge enrichment score, we selected the top-10 TFs from aggregate networks (5 of the highest ones and 5 of the lowest ones). We then identified genes connected to these 10 TFs differentially in the aggregate GR and PR networks and illustrated subnetworks using them. The edges are directed from TFs to their targeting genes whose differences in high-confidence edge Z-scores are >0.75. This means that these genes have at least a 75% chance of existing and being different in each aggregate network.

그림 출처: PubMed Central 공개 논문 (PMC8012484)

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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