Identification of the susceptibility genes for COVID-19 in lung adenocarcinoma with global data and biological computation methods

Abstract

Introduction: The risk of infection with COVID-19 is high in lung adenocarcinoma (LUAD) patients, and there is a dearth of studies on the molecular mechanism underlying the high susceptibility of LUAD patients to COVID-19 from the perspective of the global differential expression landscape.

Objectives: To fill the research void on the molecular mechanism underlying the high susceptibility of LUAD patients to COVID-19 from the perspective of the global differential expression landscape.

Methods: Herein, we identified genes, specifically the differentially expressed genes (DEGs), correlated with the susceptibility of LUAD patients to COVID-19. These were obtained by calculating standard mean deviation (SMD) values for 49 SARS-CoV-2-infected LUAD samples and 24 non-affected LUAD samples, as well as 3931 LUAD samples and 3027 non-cancer lung samples from 40 pooled RNA-seq and microarray datasets. Hub susceptibility genes significantly related to COVID-19 were further selected by weighted gene co-expression network analysis. Then, the hub genes were further analyzed via an examination of their clinical significance in multiple datasets, a correlation analysis of the immune cell infiltration level, and their interactions with the interactome sets of the A549 cell line.

Results: A total of 257 susceptibility genes were identified, and these genes were associated with RNA splicing, mitochondrial functions, and proteasomes. Ten genes, MEA1, MRPL24, PPIH, EBNA1BP2, MRTO4, RABEPK, TRMT112, PFDN2, PFDN6, and NDUFS3, were confirmed to be the hub susceptibility genes for COVID-19 in LUAD patients, and the hub susceptibility genes were significantly correlated with the infiltration of multiple immune cells.

Conclusion: In conclusion, the susceptibility genes for COVID-19 in LUAD patients discovered in this study may increase our understanding of the high risk of COVID-19 in LUAD patients.

Keywords: CI, confidence interval; COVID-19; COVID-19, coronavirus disease 2019; DEG; DEG, differentially expressed genes; FC, fold change; FPKM, fragments per kilobase per million; GTEx, Genotype-tissue Expression; HPA, human protein atlas; IHC, immunohistochemistry; Immune infiltration; LUAD; LUAD, lung adenocarcinoma; PPI, protein-to-protein interaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SMD, standard mean difference; SROC, summarized receiver’s operating characteristics; Susceptibility; TF, transcription factor; TPM, transcripts per million reads; WGCNA; WGCNA, weighted gene co-expression network analysis.

Graphical abstract

Fig. 1

Weighted gene co-expression network analysis results for susceptibility genes for COVID-19 in LUAD. A. Sample dendrogram and heatmap of the diagnostic information on COVID-19 based on the GSE161731 dataset. The name of each sample was labeled in the dendrogram. The red bar indicates the diagnosis of COVID-19. B. The selection of the best soft thresholding power. The red line represents the cut-off value of the evaluation parameters of the scale-free network (R² = 0.9). C. Cluster dendrogram and the merged gene modules. Bars in different colors distinguish different gene modules. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Prognostic analysis results for five hub susceptibility genes in LUAD. A. Kaplan–Meier survival curves on the impact of MEA1 expression on the overall survival of LUAD patients. B. Kaplan–Meier survival curves on the impact of MRPL24 expression on the overall survival of LUAD patients. C. Kaplan–Meier survival curves on the impact of PFDN2 expression on the overall survival of LUAD patients. D. Kaplan–Meier survival curves on the impact of PFDN6 expression on the overall survival of LUAD patients. E. Kaplan–Meier survival curves on the impact of NDUFS3 expression on the overall survival of LUAD patients. HR: hazard ratio. The black and red lines delineate the overall survival probability of LUAD patients in the low and high expression groups, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

The validation of the survival analysis for susceptibility genes in LUAD. A. Forest plots of the hazard ratio value for MEA1. B. Forest plots of the hazard ratio value for PFDN2. C. Forest plots of the hazard ratio value for PFDN6. TE: Estimate of treatment effect. SETE: Standard error of treatment estimate.

Fig. 4

K-means clustering of LUAD patients based on hub susceptibility genes and TMPRSS2 expression in different groups. A. Cluster plot. LUAD patient samples in clusters 1 or 2 are represented by blue dots and green triangles, respectively. B. Heatmap of the expression characteristics of hub susceptibility genes in two clusters of LUAD samples. C. Box plot of TMPRSS2 expression in LUAD samples of clusters 1 and 2. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

The scale-stacked bar plot of the proportions of various immune cells in 77 COVID-19 patient samples. The fractions of the infiltration levels of various immune cells are represented in bars of different colors.

Fig. 6

The correlation diagram of the relationships between the infiltration levels of various immune cells and the expression of hub susceptibility genes in COVID-19 samples. Positive and negative correlations are indicated in blue and red colors, respectively. The size of nodes indicated the absolute value size of the correlation coefficient. Significant correlation results are marked with a red box. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

Overlap between hub susceptibility genes and eight interactome sets of the A549 cell lines. A. Overlaps at the gene level, in which identical genes are linked by purple curves; B. Overlaps at the shared term level, in which genes belonging to the same ontology term are linked by blue curves. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)