A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19
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Abstract
The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56-0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription-polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54-0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52-0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31-0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19.
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Omics data have recently been integrated in COVID-19 research.
“Recently, these omics have also been integrated for COVID-19 studies (Barh et al., 2020;Overmyer et al., 2020;Zhou et al., 2020).”
From Using machine learning approaches for multi-omics data analysis: A review (2021) · cites this paper as Zhou et al., 2020
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Zhao, J., Guo, P., Fang, J., Wang, C., Yan, C., Bai, Y., Wang, Z., Du, G., & Liu, A. (2024) · Phytotherapy Research · doi:10.1002/ptr.8064 · Cited by 9 · see citing works
- Authors
- Zhou, Y., Hou, Y., Shen, J., Mehra, R., Kallianpur, A., Culver, D. A., Gack, M. U., Farha, S., Zein, J., Comhair, S., Fiocchi, C., Stappenbeck, T., Chan, T., Eng, C., Jung, J. U., Jehi, L., Erzurum, S., & Cheng, F.
- Affiliations
- Cleveland Clinic (US)
- Corresponding author
- Cheng, Feixiong
- ORCID
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2020-11-06
- Volume
- 18
- Issue
- 11
- Pages
- e3000970
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC7350981
- OpenAlex
- W3043574076
- Cited by
- 180
- References
- 166
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 13 · 2023: 25 · 2022: 45 · 2021: 73 · 2020: 7
- FWCI
- 12.17
- Type
- journal article
- Language
- en
- Update notices
- new_version (2020-12-10)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Royal College of Surgeons in Ireland (submittedVersion, cc-by-nc-nd)
- Funders
- Foundation for the National Institutes of Health (R00HL138272, R01AG066707, 3R01AG066707-01S1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- COVID-19 pandemic, SARS-CoV-2, network medicine, drug repurposing, melatonin, ACE2, TMPRSS2, Crohn's disease, inflammatory bowel disease, asthma, IRAK3, ADRB2, angiotensin receptor blockers, ACE inhibitors, propensity score matching, SARS-CoV-2 pathogenesis
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