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Integrative Analyses of Bulk and Single-Cell RNA Seq Identified the Shared Genes in Acute Respiratory Distress Syndrome and Rheumatoid Arthritis

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Abstract

Acute respiratory distress syndrome (ARDS), a progressive status of acute lung injury (ALI), is primarily caused by an immune-mediated inflammatory disorder, which can be an acute pulmonary complication of rheumatoid arthritis (RA). As a chronic inflammatory disease regulated by the immune system, RA is closely associated with the occurrence and progression of respiratory diseases. However, it remains elusive whether there are shared genes between the molecular mechanisms underlying RA and ARDS. The objective of this study is to identify potential shared genes for further clinical drug discovery through integrated analysis of bulk RNA sequencing datasets obtained from the Gene Expression Omnibus database, employing differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). The hub genes were identified through the intersection of common DEGs and WGCNA-derived genes. The Random Forest (RF) and least absolute shrinkage and selection operator (LASSO) algorithms were subsequently employed to identify key shared target genes associated with two diseases. Additionally, RA immune infiltration analysis and COVID-19 single-cell transcriptome analysis revealed the correlation between these key genes and immune cells. A total of 59 shared genes were identified from the intersection of DEGs and gene clusters obtained through WGCNA, which analyzed the integrated gene matrix of ALI/ARDS and RA. The RF and LASSO algorithms were employed to screen for target genes specific to ALI/ARDS and RA, respectively. The final set of overlapping genes (FCMR, ADAM28, HK3, GRB10, UBE2J1, HPSE, DDX24, BATF, and CST7) all exhibited a strong predictive effect with an area under the curve (AUC) value greater than 0.8. Then, the immune infiltration analysis revealed a strong correlation between UBE2J1 and plasma cells in RA. Furthermore, scRNA-seq analysis demonstrated differential expression of these nine target genes primarily in T cells and NK cells, with CST7 showing a significant positive correlation specifically with NK cells. Beyond that, transcriptome sequencing was conducted on lung tissue collected from ALI mice, confirming the substantial differential expression of FCMR, HK3, UBE2J1, and BATF. This study provides unprecedented evidence linking the pathophysiological mechanisms of ALI/ARDS and RA to immune regulation, which offers novel understanding for future clinical treatment and experimental research.

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Data Availability

The datasets involved in the study were all obtained from the GEO (https://www.ncbi.nlm.nih.gov/geo/) database. The datasets generated from the study were included in the article and the core code of this study was available from the corresponding author upon reasonable request.

Abbreviations

ALI:

Acute lung injury

ARDS:

Acute respiratory distress syndrome

BALF:

Bronchoalveolar lavage fluid

COVID-19:

Coronavirus Disease-2019

DEGs:

Differentially expressed genes

ECMO:

Extracorporeal membrane oxygenation

FAIM3:

Fas apoptotic inhibitory molecule 3

GEO:

Gene Expression Omnibus

IFNs:

Type I interferons

IRF1:

Interferon regulatory factor 1

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LASSO:

Least Absolute Shrinkage and Selection Operator

RA:

Rheumatoid arthritis

RF:

Random forest

scRNA-seq:

Single-cell RNA sequencing

TOM:

Topological overlap matrix

WGCNA:

Weighted gene co-expression network analysis

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Acknowledgements

We acknowledge the GEO database for providing their platforms and contributors for uploading their meaningful datasets (GSE2322, GSE76293, GSE55235, GSE55457, GSE77298, GSE145926) and Xiantao (www.xiantao.love) for partial data processing.

Funding

This study was funded by the Natural Science Foundation of Beijing Municipality (NO.7232169).

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Author notes

  1. Jun Shi, Jiajia Tang, and Lu Liu have contributed equally to this work.

Authors and Affiliations

  1. School of Medicine, South China University of Technology, Guangzhou, 510006, China

    Jun Shi, Jiajia Tang, Lu Liu, Zhihai Han & Xuxin Chen

  2. Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China

    Jun Shi, Jiajia Tang, Lu Liu, Chunyang Zhang, Wei Chen, Man Qi, Zhihai Han & Xuxin Chen

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  1. Jun Shi
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  2. Jiajia Tang
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  8. Xuxin Chen
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Contributions

All authors contributed to the study’s conception and design. JS, JT, and LL contributed equally to this work. Data collection and analysis: JS, JT, LL, CZ, WC, and MQ; Writing original draft preparation: JS, JT, LL, and XC; Experimental design and financial support: XC and ZH; Conception and design and final approval of the version to be published: XC and ZH; All authors have read and agreed to the published version of the manuscript.

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Correspondence to Zhihai Han or Xuxin Chen.

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Shi, J., Tang, J., Liu, L. et al. Integrative Analyses of Bulk and Single-Cell RNA Seq Identified the Shared Genes in Acute Respiratory Distress Syndrome and Rheumatoid Arthritis. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01141-6

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