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. 2021 Sep 17;14(1):226.
doi: 10.1186/s12920-021-01079-7.

Lung disease network reveals impact of comorbidity on SARS-CoV-2 infection and opportunities of drug repurposing

Affiliations

Lung disease network reveals impact of comorbidity on SARS-CoV-2 infection and opportunities of drug repurposing

Asim Bikas Das. BMC Med Genomics. .

Abstract

Background: Higher mortality of COVID-19 patients with lung disease is a formidable challenge for the health care system. Genetic association between COVID-19 and various lung disorders must be understood to comprehend the molecular basis of comorbidity and accelerate drug development.

Methods: Lungs tissue-specific neighborhood network of human targets of SARS-CoV-2 was constructed. This network was integrated with lung diseases to build a disease-gene and disease-disease association network. Network-based toolset was used to identify the overlapping disease modules and drug targets. The functional protein modules were identified using community detection algorithms and biological processes, and pathway enrichment analysis.

Results: In total, 141 lung diseases were linked to a neighborhood network of SARS-CoV-2 targets, and 59 lung diseases were found to be topologically overlapped with the COVID-19 module. Topological overlap with various lung disorders allows repurposing of drugs used for these disorders to hit the closely associated COVID-19 module. Further analysis showed that functional protein-protein interaction modules in the lungs, substantially hijacked by SARS-CoV-2, are connected to several lung disorders. FDA-approved targets in the hijacked protein modules were identified and that can be hit by exiting drugs to rescue these modules from virus possession.

Conclusion: Lung diseases are clustered with COVID-19 in the same network vicinity, indicating the potential threat for patients with respiratory diseases after SARS-CoV-2 infection. Pathobiological similarities between lung diseases and COVID-19 and clinical evidence suggest that shared molecular features are the probable reason for comorbidity. Network-based drug repurposing approaches can be applied to improve the clinical conditions of COVID-19 patients.

Keywords: COVID-19; Comorbidity; Disease network; Lung disease; SARS-CoV-2.

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Conflict of interest statement

The author declares he has no competing interests.

Figures

Fig. 1
Fig. 1
a Neighbourhood interaction network of SARS-CoV-2 targets (STN) in the lung. The size of the node is proportional to its degree. b SARS-CoV-2 targets form a LCC of size 181 in the lung interactome. The size of the LCC is significantly larger than the random expectation
Fig. 2
Fig. 2
Disease-gene association network. a Lung disease-gene network (LDGN), including COVID19 (yellow node). The network shows the SARS-CoV-2 targets (red) and neighborhood genes (green). b, c Dot plot shows the highly connected diseases (k > 20) and genes in LDGN, respectively
Fig. 3
Fig. 3
Disease-disease association network (DDAN). a DDAN, including COVID19, red nodes represent the diseases that are directly direct linked to COVID19. b Scatter plot shows the degree distribution of DDAN, which does not follow the scale-free property. c The average path length between the diseases in DDNA and distribution of average path length of 1000 random networks (green). d Transitivity of DDNA and distribution of transitivity of 1000 random networks (pink)
Fig. 4
Fig. 4
Network-based separation (Sab) and pathobiological similarities. aj shows observed Sab, z-score (red arrow) and distribution of Sabran of top 10 overlapping lung diseases with COVID-19 (here, ARMCM indicates abnormal respiratory motile cilium morphology). k Box plot represents the pairwise correlation between genes is significantly (p-value < 0.0001) higher than the random gene sets. l, m Box plots show the distribution of functional similarities (MF) and GO processes (BP) between the genes involved in lung disease and COVID-19. The GO processes and functional similarity between the genes are significantly high (p < 0.0001) compared to the random gene sets (note, in figures k, l, and m 1–10 indicates disease in a similar sequence as it is mentioned in figures a to j). n The strategy of drug repurposing to target the COVID19 module
Fig. 5
Fig. 5
Community detection in STN and functional protein module. ad show the modules 1 to 4, pathway and process enrichment analysis of each module, their disease associations, and positive correlation between genes in each module in healthy lung tissue. The pairwise correlation between genes in each module is significantly (p-value < 2.2 × e−16) higher than the random gene sets
Fig. 6
Fig. 6
Targetable protein in functional modules: The red nodes in each module indicate the FDA-approved targets

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