{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T11:18:38Z","timestamp":1762082318946,"version":"build-2065373602"},"reference-count":127,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Advance Queensland Industry Research Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Coronavirus disease 19 (COVID-19) has affected over 112 million people and killed more than 2.5 million worldwide. When the pandemic was declared, Spain and Italy accounted for 29% of the total COVID-19 related deaths in Europe, while most infected patients did not present severe illness. We hypothesised that shared genomic characteristics, distinct from the rest of Europe, could be a contributor factor to a poor prognosis in these two populations. To identify pathways related to COVID-19 severity, we shortlisted 437 candidate genes associated with host viral intake and immune evasion from SARS-like viruses. From these, 21 were associated specifically with clinically aggressive COVID-19. To determine the potential mechanism of viral infections, we performed signalling pathway analysis with either the full list (n = 437) or the subset group (n = 21) of genes. Four pathways were significantly associated with the full gene list (Caveolar-mediated Endocytosis and the MSP-RON Signalling) or with the aggressive gene list (Hepatic Fibrosis\/Hepatic Stellate Cell (HSC) Activation and the Communication between Innate and Adaptive Immune Cells). Single nucleotide polymorphisms (SNPs) from the \u00b11 Mb window of all genes related to these four pathways were retrieved from the dbSNP database. We then performed Principal Component analysis for these SNPs in individuals from the 1000 Genomes of European ancestry. Only the Hepatic Fibrosis\/HSC Activation pathway showed population-specific segregation. The Spanish and Italian populations clustered together and away from the rest of the European ancestries, with the first segregating further from the rest. Additional in silico analysis identified potential genetic markers and clinically actionable therapeutic targets in this pathway, that may explain the severe disease.<\/jats:p>","DOI":"10.3390\/genes14010022","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T02:09:03Z","timestamp":1671761343000},"page":"22","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Severe COVID-19 May Impact Hepatic Fibrosis \/Hepatic Stellate Cells Activation as Indicated by a Pathway and Population Genetic Study"],"prefix":"10.3390","volume":"14","author":[{"given":"Leire","family":"Moya","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"},{"name":"Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6383-4203","authenticated-orcid":false,"given":"Samaneh","family":"Farashi","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"},{"name":"Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8535-278X","authenticated-orcid":false,"given":"Prashanth","family":"Suravajhala","sequence":"additional","affiliation":[{"name":"Amrita School of Biotechnology, Amrita Vishwavidyapeetham, Clappana, Kollam 690525, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panchadsaram","family":"Janaththani","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"},{"name":"Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4646-6247","authenticated-orcid":false,"given":"Jyotsna","family":"Batra","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"},{"name":"Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia"},{"name":"Centre for Genomics and Personalised Medicine, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.prrv.2004.07.009","article-title":"The chronology of the 2002\u20132003 SARS mini pandemic","volume":"5","author":"Cherry","year":"2004","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nature12005","article-title":"Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC","volume":"495","author":"Raj","year":"2013","journal-title":"Nature"},{"key":"ref_3","unstructured":"World Health Organisation (2021). Middle East Respiratory Syndrome, World Health Organisation."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11115","DOI":"10.1128\/JVI.01571-12","article-title":"Increased Viral Loads and Exacerbated Innate Host Responses in Aged Macaques Infected with the 2009 Pandemic H1N1 Influenza A Virus","volume":"86","author":"Josset","year":"2012","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1093\/cid\/ciab168","article-title":"Understanding the long-term evolution and predictors of sequelae of Ebola virus disease survivors in Guinea: A 48-month prospective, longitudinal cohort study (PostEboGui)","volume":"73","author":"Diallo","year":"2021","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0140-6736(20)30185-9","article-title":"A novel coronavirus outbreak of global health concern","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An interactive web-based dashboard to track COVID-19 in real time","volume":"20","author":"Dong","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Brake, S.J., Barnsley, K., Lu, W., McAlinden, K.D., Eapen, M.S., and Sohal, S.S. (2020). Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19). J. Clin. Med., 9.","DOI":"10.3390\/jcm9030841"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s42003-020-1088-9","article-title":"Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer","volume":"3","author":"Chakravarty","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1093\/cid\/ciaa410","article-title":"Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: An ex vivo study with implications for the pathogenesis of COVID-19","volume":"71","author":"Chu","year":"2020","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","article-title":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing","volume":"583","author":"Gordon","year":"2020","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Guzzi, P.H., Mercatelli, D., Ceraolo, C., and Giorgi, F.M. (2020). Master Regulator Analysis of the SARS-CoV-2\/Human Interactome. J. Clin. Med., 9.","DOI":"10.1101\/2020.03.15.992925"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1038\/s41467-020-15562-9","article-title":"Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV","volume":"11","author":"Ou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Singh, K.K., Chaubey, G., Chen, J.Y., and Suravajhala, P. (2020). Decoding SARS-CoV-2 Hijacking of Host Mitochondria in Pathogenesis of COVID-19. Am. J. Physiol. Cell Physiol.","DOI":"10.1152\/ajpcell.00224.2020"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Srinivasan, S., Cui, H., Gao, Z., Liu, M., Lu, S., Mkandawire, W., Narykov, O., Sun, M., and Korkin, D. (2020). Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins. Viruses, 12.","DOI":"10.3390\/v12040360"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41591-020-0868-6","article-title":"SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes","volume":"26","author":"Sungnak","year":"2020","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, K., Chen, W., Zhou, Y.-S., Lian, J.-Q., Zhang, Z., Du, P., Gong, L., Zhang, Y., Cui, H.-Y., and Geng, J.-J. (2020). SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv.","DOI":"10.1101\/2020.03.14.988345"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.abb8925","article-title":"Cytokine release syndrome in severe COVID-19","volume":"368","author":"Moore","year":"2020","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jinf.2020.03.037","article-title":"The pathogenesis and treatment of the \u2018Cytokine Storm\u2019 in COVID-19","volume":"80","author":"Ye","year":"2020","journal-title":"J. Infect."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1161\/CIRCRESAHA.120.315893","article-title":"Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations","volume":"126","author":"Young","year":"2020","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3389\/fgene.2019.00394","article-title":"Population Levels Assessment of the Distribution of Disease-Associated Variants With Emphasis on Armenians\u2014A Machine Learning Approach","volume":"10","author":"Nikoghosyan","year":"2019","journal-title":"Front. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1001\/jama.2020.17020","article-title":"Association Between African American Race and Clinical Outcomes in Men Treated for Low-Risk Prostate Cancer With Active Surveillance","volume":"324","author":"Deka","year":"2020","journal-title":"JAMA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/ng1698","article-title":"Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection","volume":"38","author":"Chan","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_25","unstructured":"World Health Organisation (2020, December 20). Coronavirus Disease (COVID-2019) Situation Reports. Available online: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports."},{"key":"ref_26","unstructured":"Univeristy of Oxford, and Blavatnik School of Government (2020). Coronavirus Government Response Tracker, Blavatnik School of Government."},{"key":"ref_27","unstructured":"Sallute, M.D.L. (2021). FAQ\u2014COVID-19."},{"key":"ref_28","unstructured":"Publica, S. (2021). Desarrollo del Estado de Alarma en las Comunidades Aut\u00f3nomas, Ministerio de Sanidad."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1038\/s41467-021-22944-0","article-title":"Estimating COVID-19 mortality in Italy early in the COVID-19 pandemic","volume":"12","author":"Modi","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Broh\u00e9e, S., and van Helden, J. (2006). Evaluation of clustering algorithms for protein-protein interaction networks. BMC Bioinform., 7.","DOI":"10.1186\/1471-2105-7-488"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1093\/bioinformatics\/btt019","article-title":"CluePedia Cytoscape plugin: Pathway insights using integrated experimental and in silico data","volume":"29","author":"Bindea","year":"2013","journal-title":"Bioinformation"},{"key":"ref_35","unstructured":"CDC (2020, June 04). Mortality Frequency Measures, Available online: https:\/\/www.cdc.gov\/csels\/dsepd\/ss1978\/lesson3\/section3.html."},{"key":"ref_36","unstructured":"World Health Organisation (2020). International Guidelines for Certification and Classification (Coding) Of COVID-19 as Cause of Death, WHO."},{"key":"ref_37","unstructured":"(2020, June 20). Population 1st January 2020. In Eurostat Data Browser. Available online: https:\/\/ec.europa.eu\/eurostat\/databrowser\/view\/tps00001\/default\/table?lang=en."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2000547","DOI":"10.1183\/13993003.00547-2020","article-title":"Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis","volume":"55","author":"Guan","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Caramelo, F., Ferreira, N., and Oliveiros, B. (2020). Estimation of risk factors for COVID-19 mortality\u2014Preliminary results. MedRxiv, MedRxiv: 2020.02.24.20027268.","DOI":"10.1101\/2020.02.24.20027268"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1111\/jgs.16472","article-title":"COVID-19 And Older Adults: What We Know","volume":"68","author":"Shahid","year":"2020","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_41","unstructured":"(2020, April 20). Worldometer Age, Sex, Existing Conditions of COVID-19 Cases and Deaths. Available online: https:\/\/www.worldometers.info\/coronavirus\/coronavirus-age-sex-demographics\/."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1056\/NEJMoa2002032","article-title":"Clinical Characteristics of Coronavirus Disease 2019 in China","volume":"382","author":"Guan","year":"2020","journal-title":"New Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1002\/humu.23791","article-title":"Predicting functional variants in enhancer and promoter elements using RegulomeDB","volume":"40","author":"Dong","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7809","DOI":"10.1073\/pnas.0711241105","article-title":"Modulation of TNF-\u03b1-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-\u03b1 production and facilitates viral entry","volume":"105","author":"Haga","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1128\/JVI.02202-13","article-title":"TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein","volume":"88","author":"Heurich","year":"2014","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nrmicro1890","article-title":"Modification of intracellular membrane structures for virus replication","volume":"6","author":"Miller","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6150","DOI":"10.1128\/JVI.03372-12","article-title":"TMPRSS2 Activates the Human Coronavirus 229E for Cathepsin-Independent Host Cell Entry and Is Expressed in Viral Target Cells in the Respiratory Epithelium","volume":"87","author":"Bertram","year":"2013","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.bbrc.2020.03.044","article-title":"Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses","volume":"526","author":"Qi","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1093\/jb\/mvv127","article-title":"Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners","volume":"159","author":"Muramatsu","year":"2016","journal-title":"J Biochem"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"15748","DOI":"10.1073\/pnas.0403812101","article-title":"CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus","volume":"101","author":"Jeffers","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-1-59745-393-6_4","article-title":"The C type lectins DC-SIGN and L-SIGN: Receptors for viral glycoproteins","volume":"379","author":"Lozach","year":"2007","journal-title":"Methods Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6841","DOI":"10.1128\/JVI.76.13.6841-6844.2002","article-title":"C-Type Lectins DC-SIGN and L-SIGN Mediate Cellular Entry by Ebola Virus in cis and in trans","volume":"76","author":"Alvarez","year":"2002","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/357420a0","article-title":"Human aminopeptidase N is a receptor for human coronavirus 229E","volume":"357","author":"Yeager","year":"1992","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1038\/nsmb.1680","article-title":"A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein","volume":"16","author":"Kamitani","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"11128","DOI":"10.1128\/JVI.01700-12","article-title":"Severe Acute Respiratory Syndrome Coronavirus nsp1 Facilitates Efficient Propagation in Cells through a Specific Translational Shutoff of Host mRNA","volume":"86","author":"Tanaka","year":"2012","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1128\/JVI.02336-05","article-title":"Role for Nonstructural Protein 1 of Severe Acute Respiratory Syndrome Coronavirus in Chemokine Dysregulation","volume":"81","author":"Law","year":"2007","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Sun, L., Xing, Y., Chen, X., Zheng, Y., Yang, Y., Nichols, D.B., Clementz, M.A., Banach, B.S., Li, K., and Baker, S.C. (2012). Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030802"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s13238-014-0026-3","article-title":"SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex","volume":"5","author":"Chen","year":"2014","journal-title":"Protein Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.str.2005.07.022","article-title":"Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1\u2019\u2019-phosphate dephosphorylation by a conserved domain of nsP3","volume":"13","author":"Saikatendu","year":"2005","journal-title":"Structure"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.1128\/JVI.02988-15","article-title":"Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses","volume":"90","author":"Forni","year":"2016","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"E10457","DOI":"10.1073\/pnas.1812130115","article-title":"ADP-ribosyl\u2013binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication","volume":"115","author":"Abraham","year":"2018","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1161\/CIRCULATIONAHA.120.047549","article-title":"The Science Underlying COVID-19: Implications for the Cardiovascular System","volume":"142","author":"Liu","year":"2020","journal-title":"Circulation"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s42256-020-0180-7","article-title":"An interpretable mortality prediction model for COVID-19 patients","volume":"2","author":"Yan","year":"2020","journal-title":"Nat. Mach. Intell."},{"key":"ref_66","unstructured":"Ingenuity Pathway Analysis (2020). Caveolar-mediated Endocytosis Signaling, Ingenuity Target Explorer."},{"key":"ref_67","unstructured":"Ingenuity Pathway Analysis (2020). MSP-RON Signaling Pathway, Ingenuity Target Explorer."},{"key":"ref_68","unstructured":"Ingenuity Pathway Analysis (2020). The Communication between Innate and Adaptive Immune Cells, Ingenuity Target Explorer."},{"key":"ref_69","unstructured":"European Union (2020, June 20). Available online: Europa.eu."},{"key":"ref_70","unstructured":"Population Reference Bureau, P. (2020, June 20). Countries With the Oldest Populations in the World. Available online: https:\/\/www.prb.org\/countries-with-the-oldest-populations\/."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3232","DOI":"10.1093\/eurheartj\/ehw334","article-title":"Cardiovascular disease in Europe: Epidemiological update 2016","volume":"37","author":"Townsend","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1007\/s00125-018-4763-3","article-title":"Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989\u20132013: A multicentre prospective registration study","volume":"62","author":"Patterson","year":"2019","journal-title":"Diabetologia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2991\/jegh.k.191028.001","article-title":"Epidemiology of Type 2 Diabetes\u2014Global Burden of Disease and Forecasted Trends","volume":"10","author":"Khan","year":"2020","journal-title":"J. Epidemiol. Glob. Health"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"145","DOI":"10.2188\/jea.JE20190344","article-title":"Who smokes in Europe? Data from 12 European countries in the TackSHS survey (2017\u20132018)","volume":"31","author":"Gallus","year":"2020","journal-title":"J. Epidemiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/ejhg.2016.205","article-title":"Whole-genome view of the consequences of a population bottleneck using 2926 genome sequences from Finland and United Kingdom","volume":"25","author":"Chheda","year":"2017","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41586-019-1457-z","article-title":"Exome sequencing of Finnish isolates enhances rare-variant association power","volume":"572","author":"Locke","year":"2019","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"104742","DOI":"10.1016\/j.antiviral.2020.104742","article-title":"The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade","volume":"176","author":"Coutard","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1080\/22221751.2020.1739565","article-title":"Emerging COVID-19 coronavirus: Glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26","volume":"9","author":"Vankadari","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1080\/22221751.2020.1713705","article-title":"Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus","volume":"9","author":"Schroeder","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.jinf.2020.02.026","article-title":"COVID-19 spike-host cell receptor GRP78 binding site prediction","volume":"80","author":"Ibrahim","year":"2020","journal-title":"J. Infect."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e1073","DOI":"10.1002\/cti2.1073","article-title":"Furin-mediated protein processing in infectious diseases and cancer","volume":"8","author":"Braun","year":"2019","journal-title":"Clin. Transl. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"7602","DOI":"10.4049\/jimmunol.173.12.7602","article-title":"Induction of IL-8 release in lung cells via activator protein-1 by recombinant baculovirus displaying severe acute respiratory syndrome-coronavirus spike proteins: Identification of two functional regions","volume":"173","author":"Chang","year":"2004","journal-title":"J. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.virol.2015.08.010","article-title":"Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome","volume":"485","author":"Torres","year":"2015","journal-title":"Virology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"11620","DOI":"10.1128\/JVI.00702-07","article-title":"Severe Acute Respiratory Syndrome Coronavirus Evades Antiviral Signaling: Role of nsp1 and Rational Design of an Attenuated Strain","volume":"81","author":"Wathelet","year":"2007","journal-title":"J. Virol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6689","DOI":"10.1128\/JVI.02220-08","article-title":"Severe Acute Respiratory Syndrome Coronavirus Papain-Like Protease Ubiquitin-Like Domain and Catalytic Domain Regulate Antagonism of IRF3 and NF-\u03baB Signaling","volume":"83","author":"Frieman","year":"2009","journal-title":"J. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"8865","DOI":"10.1096\/fj.201802418R","article-title":"Severe acute respiratory syndrome Coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC","volume":"33","author":"Siu","year":"2019","journal-title":"FASEB J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.virol.2017.07.019","article-title":"Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication","volume":"510","author":"Sakai","year":"2017","journal-title":"Virology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41392-020-0148-4","article-title":"Lymphopenia predicts disease severity of COVID-19: A descriptive and predictive study","volume":"5","author":"Tan","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1172\/JCI137244","article-title":"Clinical and immunological features of severe and moderate coronavirus disease 2019","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ijid.2020.04.086","article-title":"Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis","volume":"96","author":"Zhao","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1615\/CritRevOncog.2014010805","article-title":"Positive and negative regulation by NK cells in cancer","volume":"19","author":"Sungur","year":"2014","journal-title":"Crit Rev Oncog"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Radujkovic, A., Hippchen, T., Tiwari-Heckler, S., Dreher, S., Boxberger, M., and Merle, U. (2020). Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients, 12.","DOI":"10.3390\/nu12092757"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1186\/s40425-019-0749-z","article-title":"Immunotherapy in hepatocellular carcinoma: The complex interface between inflammation, fibrosis, and the immune response","volume":"7","author":"Keenan","year":"2019","journal-title":"J. ImmunoTherapy Cancer"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.30662","article-title":"Cholangiocyte-Derived Exosomal Long Noncoding RNA H19 Promotes Hepatic Stellate Cell Activation and Cholestatic Liver Fibrosis","volume":"70","author":"Liu","year":"2019","journal-title":"Hepatology"},{"key":"ref_96","first-page":"344","article-title":"Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology","volume":"3","author":"Weiskirchen","year":"2014","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/jgh.12023","article-title":"Hepatic stellate cells, liver innate immunity, and hepatitis C virus","volume":"28","author":"Wang","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1080\/17474124.2018.1530984","article-title":"Renal complications of liver diseases","volume":"12","author":"Noble","year":"2018","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/S2468-1253(20)30057-1","article-title":"Liver injury in COVID-19: Management and challenges","volume":"5","author":"Zhang","year":"2020","journal-title":"Lancet. Gastroenterol. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.jhep.2020.09.024","article-title":"Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study","volume":"74","author":"Marjot","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_101","first-page":"472","article-title":"COVID-19 and liver disease: An update","volume":"43","year":"2020","journal-title":"Gastroenterol. Y Hepatol. (Engl. Ed. )"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Oyelade, T., Alqahtani, J., and Canciani, G. (2020). Prognosis of COVID-19 in Patients with Liver and Kidney Diseases: An Early Systematic Review and Meta-Analysis. Trop. Med. Infect. Dis., 5.","DOI":"10.20944\/preprints202004.0464.v1"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"100688","DOI":"10.1016\/j.eclinm.2020.100688","article-title":"COVID-19 risk, disparities and outcomes in patients with chronic liver disease in the United States","volume":"31","author":"Wang","year":"2021","journal-title":"EClinicalMedicine"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s10735-020-09915-3","article-title":"COVID-19 and multiorgan failure: A narrative review on potential mechanisms","volume":"51","author":"Mokhtari","year":"2020","journal-title":"J. Mol. Histol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1097\/MEG.0000000000001809","article-title":"Covid-19 infection, liver injury and prognosis: A suggestion","volume":"33","author":"Testino","year":"2021","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_106","unstructured":"Pimpin, L., Cortez-Pinto, H., Negro, F., Corbould, E., Lazarus, J.V., Webber, L., and Sheron, N. (2018). Hepahealth Project Report; EASL, EU."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e042398","DOI":"10.1136\/bmjopen-2020-042398","article-title":"Characteristics, complications and outcomes among 1549 patients hospitalised with COVID-19 in a secondary hospital in Madrid, Spain: A retrospective case series study","volume":"10","author":"Valencia","year":"2020","journal-title":"BMJ Open"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.medin.2020.06.020","article-title":"Characteristics of critical patients with COVID-19 in a Spanish second-level hospital","volume":"45","author":"Delgado","year":"2021","journal-title":"Med. Intensiv."},{"key":"ref_109","unstructured":"Plus, M. (2020, June 20). Lactate Dehydrogenase (LDH) Isoenzymes Test, Available online: https:\/\/medlineplus.gov\/lab-tests\/lactate-dehydrogenase-ldh-isoenzymes-test\/."},{"key":"ref_110","unstructured":"University of Rochester (2020, September 01). Lactate Dehydrogenase Isoenzymes. Available online: https:\/\/www.urmc.rochester.edu\/encyclopedia\/content.aspx?contenttypeid=167&contentid=lactate_dehydrogenase_isoenzymes."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"20731","DOI":"10.1038\/s41598-020-77698-4","article-title":"Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients","volume":"10","author":"Bellan","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1001\/jamainternmed.2020.3539","article-title":"Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy","volume":"180","author":"Grasselli","year":"2020","journal-title":"JAMA Intern. Med."},{"key":"ref_113","first-page":"101744","article-title":"SARS-CoV-2 Targets by the pscRNA Profiling of ACE2, TMPRSS2 and Furin Proteases","volume":"23","author":"Zhou","year":"2020","journal-title":"CellPress"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S2468-1253(21)00008-X","article-title":"SARS-CoV-2 vaccination in patients with liver disease: Responding to the next big question","volume":"6","author":"Marjot","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/s41431-020-0636-6","article-title":"The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic","volume":"28","author":"The","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"110053","DOI":"10.1016\/j.mehy.2020.110053","article-title":"Rethinking interleukin-6 blockade for treatment of COVID-19","volume":"144","author":"Scherger","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_117","first-page":"CD013881","article-title":"Interleukin-6 blocking agents for treating COVID-19: A living systematic review","volume":"2021","author":"Ghosn","year":"2021","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e253","DOI":"10.1016\/S2665-9913(21)00012-6","article-title":"Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: A cohort study","volume":"3","author":"Cavalli","year":"2021","journal-title":"Lancet Rheumatol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.medj.2020.11.005","article-title":"The Potential for Repurposing Anti-TNF as a Therapy for the Treatment of COVID-19","volume":"1","author":"Robinson","year":"2020","journal-title":"Med"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s00296-021-04803-9","article-title":"Risk and clinical outcomes of COVID-19 in patients with rheumatic diseases compared with the general population: A systematic review and meta-analysis","volume":"41","author":"Wang","year":"2021","journal-title":"Rheumatol Int."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-020-03065-y","article-title":"Genetic mechanisms of critical illness in COVID-19","volume":"591","author":"Clohisey","year":"2021","journal-title":"Nature"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"eabd4570","DOI":"10.1126\/science.abd4570","article-title":"Inborn errors of type I IFN immunity in patients with life-threatening COVID-19","volume":"370","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"(2020). Repurposed Antiviral Drugs for Covid-19\u2014Interim WHO Solidarity Trial Results. New Engl. J. Med., 384, 497\u2013511.","DOI":"10.1056\/NEJMoa2023184"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Wang, B., Li, D., Liu, T., Wang, H., Luo, F., and Liu, Y. (2020). Subcutaneous injection of IFN alpha-2b for COVID-19: An observational study. BMC Infect. Dis., 20.","DOI":"10.1186\/s12879-020-05425-5"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1089\/jir.2020.0188","article-title":"Therapeutic Effectiveness of Interferon Alpha 2b Treatment for COVID-19 Patient Recovery","volume":"40","author":"Rivero","year":"2020","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ijid.2021.03.015","article-title":"Efficacy and safety of pegylated interferon alfa-2b in moderate COVID-19: A phase II, randomized, controlled, open-label study","volume":"105","author":"Pandit","year":"2021","journal-title":"Int. J. Infect. Dis."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1056\/NEJMoa2020283","article-title":"Genomewide Association Study of Severe Covid-19 with Respiratory Failure","volume":"383","author":"Group","year":"2020","journal-title":"New Engl. J. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/22\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:47:58Z","timestamp":1760147278000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/22"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,22]]},"references-count":127,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["genes14010022"],"URL":"https:\/\/doi.org\/10.3390\/genes14010022","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2022,12,22]]}}}