A novel prognostic signature for idiopathic pulmonary fibrosis based on five-immune-related genes

Lingxiao Qiu^{1

2

3}, Gencheng Gong⁴, Wenjuan Wu⁵, Nana Li¹, Zhaonan Li⁶, Shanshan Chen^{1

3}, Ping Li^{1

3

7}, Tengfei Chen¹, Huasi Zhao¹, Chunling Hu⁸, Zeming Fang⁹, Yan Wang¹, Hongping Liu¹, Panpan Cui¹⁰, Guojun Zhang^{1

3

7}

Affiliations

¹ Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
³ Henan Provincial Medical Key Laboratory for Interstitial Lung Disease and Lung Transplantation, Zhengzhou, China.
⁴ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁵ Department of Geriatric Medicine, Henan Provincial People's Hospital, Zhengzhou, China.
⁶ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁷ Zhengzhou Key Laboratory for Chronic Respiratory Disease, Zhengzhou, China.
⁸ Department of Respiratory Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁹ Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹⁰ School of Nursing and Heath, Zhengzhou University, Zhengzhou, China.

PMID: 34790776
PMCID: PMC8576669
DOI: 10.21037/atm-21-4545

A novel prognostic signature for idiopathic pulmonary fibrosis based on five-immune-related genes

Lingxiao Qiu et al. Ann Transl Med. 2021 Oct.

. 2021 Oct;9(20):1570.

doi: 10.21037/atm-21-4545.

Authors

Affiliations

¹ Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
³ Henan Provincial Medical Key Laboratory for Interstitial Lung Disease and Lung Transplantation, Zhengzhou, China.
⁴ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁵ Department of Geriatric Medicine, Henan Provincial People's Hospital, Zhengzhou, China.
⁶ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁷ Zhengzhou Key Laboratory for Chronic Respiratory Disease, Zhengzhou, China.
⁸ Department of Respiratory Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁹ Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹⁰ School of Nursing and Heath, Zhengzhou University, Zhengzhou, China.

PMID: 34790776
PMCID: PMC8576669
DOI: 10.21037/atm-21-4545

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a highly fatal lung disease of unknown etiology with a median survival after diagnosis of only 2-3 years. Its poor prognosis is due to the limited therapy options available as well as the lack of effective prognostic indicators. This study aimed to construct a novel prognostic signature for IPF to assist in the personalized management of IPF patients during treatment.

Methods: Differentially-expressed genes (DEGs) in IPF patients versus healthy individuals were analyzed using the "limma" package of R software. Immune-related genes (IRGs) were obtained from the ImmPort database. Univariate Cox regression analysis was adopted to screen significantly prognostic IRGs for IPF patients. Multiple Cox regression analysis was used to identify optimal prognostic IRGs and construct a prognostic signature.

Results: Compared with healthy individuals, there were a total of 52 prognosis-related DEGs in the bronchoalveolar lavage (BAL) samples of IPF patients, of which 37 genes were identified as IRGs. Of these, five genes (CXCL14, SLC40A1, RNASE3, CCR3, and RORA) were significantly associated with overall survival (OS) in IPF patients, and were utilized for establishment of the prognostic signature. IPF patients were divided into high- and low-risk groups based on the prognostic signature. Marked differences in the OS probability were observed between high- and low-risk IPF patients. The area under curves (AUCs) of the receiver operating characteristic (ROC) curve for the prognostic signature in the training and validation cohorts were 0.858 and 0.837, respectively. The expression levels between RNASE3 and SLC40A1 (P<0.01, r=0.394), between RORA and CXCL14 (P<0.01, r=-0.355), between CCR3 and CXCL14 (P<0.01, r=0.258), as well as between RNASE3 and CCR3 (P<0.01, r=0.293) were significantly correlated.

Conclusions: We developed a validated and reproducible IRG-based prognostic signature that should be helpful in the personalized management of patients with IPF, providing new insights into the relationship between the immune system and IPF.

Keywords: GEO; Idiopathic pulmonary fibrosis (IPF); bronchoalveolar lavage (BAL); immune-related genes (IRGs); prognostic signature.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-4545). The authors have no conflicts of interest to declare.

Figures

**Figure 1**
Comparison of the gene expression profile between the IPF group and the healthy individuals group. (A) Heatmap of significantly DEGs. (B) Volcano map of DEGs; red dots represent upregulated DEGs, grey dots represent non-differentially expressed genes, and green dots represent downregulated DEGs. IPF, idiopathic pulmonary fibrosis; DEGs, differentially-expressed genes.

**Figure 2**
Comparison of the IRG expression profile between the IPF group and the healthy individuals group. (A) Heatmap of significantly differentially-expressed IRGs. (B) Volcano map of IRGs; red dots represent upregulated differentially expressed IRGs, grey dots represent non-differentially expressed IRGs, and green dots represent downregulated differentially expressed IRGs. IRG, immune-related gene; IPF, idiopathic pulmonary fibrosis.

**Figure 3**
Forest plot of the differentially-expressed IRGs related to prognosis. IRGs, immune-related genes.

**Figure 4**
OS of patients with IPF stratified by the genes included in our novel signature, including (A) *CXCL14*, (B) *SLC40A1*, (C) *RNASE3*, (D) *CCR3*, and (E) *RORA*. OS, overall survival; IPF, idiopathic pulmonary fibrosis.

**Figure 5**
The risk score could effectively predict IPF patient prognosis. (A) Scatter plot of the risk score distribution of the samples. One point refers to a sample, red points are samples with higher risk scores, green points are samples with lower risk scores, and the intersecting point represents the median risk score. (B) Scatter plot of the survival outcome distribution of the samples. One point refers to a sample, red points represent live samples, green points represent dead samples with lower risk scores, and the intersecting point represents the median risk score. (C) Heatmap of signature-based genes (*CXCL14, SLC40A1, RNASE3, CCR3*, and *RORA*) between the high- and low-risk groups. IPF, idiopathic pulmonary fibrosis.

**Figure 6**
Signature of predicting survival probability for IPF patients. (A) Survival curve of the risk score distribution of the training cohort, which also shows the 1-, 2-, 3-, 4-, 5-, and 6-year survival rates of IPF patients. (B) Survival curve of the risk score distribution of the validation cohort, which also shows the 1-, 2-, 3-, 4-, 5-, and 6-year survival rates of IPF patients. (C) ROC curve of the signature in the training cohort. (D) ROC curve of the signature in the validation cohort. IPF, idiopathic pulmonary fibrosis; ROC, receiver operating characteristic.

**Figure 7**
Gene co-expression network of 5 genes: *CXCL14, SLC40A1, RNASE3, CCR3,* and *RORA*.

See this image and copyright information in PMC

References

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A novel prognostic signature for idiopathic pulmonary fibrosis based on five-immune-related genes

Affiliations

A novel prognostic signature for idiopathic pulmonary fibrosis based on five-immune-related genes

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Other Literature Sources