Allergy Asthma Immunol Res. 2020;12(4):626-640.

Genetic Signatures of Acute Asthma Exacerbation Related With Ineffective Response to Corticosteroid.

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제1저자 강민규 · 교신저자 박흥우

PMID 32400129 PMC7224997 DOI 10.4168/aair.2020.12.4.626 IF 4.3 알레르기내과

소속 (5)

Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.
Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.
The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. guinea71@snu.ac.kr.

Abstract

PURPOSE Acute exacerbation (AE) is an important domain of asthma management and may be related with ineffective response to corticosteroid. This study aimed to find mechanisms of AE using genome-wide gene expression profiles of blood cells from asthmatics and its perturbation by in vitro dexamethasone (Dex)-treatment.

METHODS We utilized lymphoblastoid B cells from 107 childhood asthmatics and peripheral blood mononuclear cells from 29 adult asthmatics who were treated with inhaled corticosteroids. We searched for a preserved co-expression gene module significantly associated with the AE rate in both cohorts and measured expression changes of genes belong to this module after Dex-treatment.

RESULTS We identified a preserved module composed of 77 genes. Among them, expressions of 2 genes (EIF2AK2 and NOL11) decreased significantly after Dex-treatment in both cohorts. EIF2AK2, a key gene acting antiviral defense mechanism, showed significantly higher expressions in asthmatics with AE. The protein repair pathway was enriched significantly in 64 genes which belong to the preserved module but showed no expression differences after Dex-treatment in both cohorts. Among them, MSRA and MSRB2 may play key roles by controlling oxidative stress.

CONCLUSIONS Many genes belong to the AE rate-associated and preserved module identified in blood cells from childhood and adults asthmatics showed no expression changes after in vitro Dex-treatment. These findings suggest that we may need alternative treatment options to corticosteroids to prevent AE. EIF2AK2, MSRA and MSRB2 expressions on blood cells may help us select AE-susceptible asthmatics and adjust treatments to prevent AE.

Keywords

Asthmabloodgene expressionsteroidssymptom flare up

Figures

**Fig. 1** Overall study design. LCL, lymphoblastoid B cell line; PBMC, peripheral blood mononuclear cell; Dex, dexamethasone.

**Fig. 2** Correlations between the eigengene value of the preserved gene module (black module) and the AE rate. (A) Childhood asthmatics. (B) Adult asthmatics. Both P values were adjusted ones. AE, acute exacerbation.

**Fig. 3** Preservation of gene modules identified in LCLs from childhood asthmatics in PBMCs from adult asthmatics. The first (top) panel shows a heatmap of pair-wise correlations among the genes comprising the turquoise, magenta, and purple modules. The second panel shows a heatmap of the edge weights (connections) among the genes comprising the 3 modules. The third panel shows the distribution of scaled weight degrees (relative connectedness) among the genes comprising the 3 modules. The fourth panel shows the distribution of node contributions (correlation to module eigengene) among the genes comprising the 3 modules. Genes are ordered from left to right based on their weighted degree in the discovery cohort so as to highlight the consistency of the network properties in the replication cohort. LCL, lymphoblastoid B cell line; PBMC, peripheral blood mononuclear cell.

**Fig. 4** Eukaryotic translation initiation factor 2-alpha kinase (*EIF2AK2*) expressions in lymphoblastoid cell lines form childhood asthmatics and peripheral blood mononuclear cells from adult asthmatics. Dex, dexamethasone.

**Fig. 5** Methionine sulfoxide reductase A (*MSRA*) and methionine sulfoxide reductase B2 (*MSRB2*) expressions in lymphoblastoid cell lines form childhood asthmatics and peripheral blood mononuclear cells from adult asthmatics. (A) *MSRA* gene expression. (B) *MSRB2* gene expression. Dex, dexamethasone.

그림 출처: PubMed Central 공개 논문 (PMC7224997)

Conflict of interest statement

There are no financial or other issues that might lead to conflict of interest.

그 밖의 정보

출판 형태: Journal Article
저널: Allergy, asthma & immunology research · ISSN 2092-7355
연구비: NIH HHS R01 HL092197 · NIH HHS R01 NR13391 · Seoul National University Hospital 0320140400 (2014-1194) · NIH HHS U01 HL065899 · NHLBI NIH HHS U01 HL065899 · NHLBI NIH HHS R01 HL092197 · NINR NIH HHS R01 NR013391
참고문헌: 49편