Genetic Variants Regulating the Immune Response Improve the Prediction of COVID-19 Severity Provided by Clinical Variables

The characteristics of the host are crucial in the final outcome of COVID-19. Herein, the influence of genetic and clinical variants in COVID-19 severity was investigated in a total of 1350 patients. Twenty-one single nucleotide polymorphisms of genes involved in SARS-CoV-2 sensing as Toll-like-Receptor 7, antiviral immunity as the type I interferon signalling pathway (TYK2, STAT1, STAT4, OAS1, SOCS) and the vasoactive intestinal peptide and its receptors (VIP/VIPR1,2) were studied. To analyse the association between polymorphisms and severity, a model adjusted by age, sex and different comorbidities was generated by ordinal logistic regression. The genotypes rs8108236-AA (OR 0.12 [95% CI 0.02-0.53]; p = 0.007) and rs280519-AG (OR 0.74 [95% CI 0.56-0.99]; p = 0.03) in TYK2, and rs688136-CC (OR 0.7 [95% CI 0.5-0.99]; p = 0.046) in VIP, were associated with lower severity; in contrast, rs3853839-GG in TLR7 (OR 1.44 [95% CI 1.07-1.94]; p = 0.016), rs280500-AG (OR 1.33 [95% CI 0.97-1.82]; p = 0.078) in TYK2 and rs1131454-AA in OAS1 (OR 1.29 [95% CI 0.95-1.75]; p = 0.110) were associated with higher severity. Therefore, these variants could influence the risk of severe COVID-19.

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References

Wu Z, McGoogan J . Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323(13):1239-1242. DOI: 10.1001/jama.2020.2648. View

Kousathanas A, Pairo-Castineira E, Rawlik K, Stuckey A, Odhams C, Walker S . Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature. 2022; 607(7917):97-103. PMC: 9259496. DOI: 10.1038/s41586-022-04576-6. View

Naushad S, Mandadapu G, Ramaiah M, Almajhdi F, Hussain T . The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants. Sci Rep. 2023; 13(1):13078. PMC: 10421879. DOI: 10.1038/s41598-023-40114-8. View

Rouf Banday A, Stanifer M, Florez-Vargas O, Onabajo O, Papenberg B, Zahoor M . Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries. Nat Genet. 2022; 54(8):1103-1116. PMC: 9355882. DOI: 10.1038/s41588-022-01113-z. View

Diebold S, Kaisho T, Hemmi H, Akira S, Reis e Sousa C . Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004; 303(5663):1529-31. DOI: 10.1126/science.1093616. View

Temerozo J, Sacramento C, Fintelman-Rodrigues N, Pao C, de Freitas C, Dias S . VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells. J Leukoc Biol. 2022; 111(5):1107-1121. PMC: 9088587. DOI: 10.1002/JLB.5COVA1121-626R. View

Siddiqi H, Mehra M . COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020; 39(5):405-407. PMC: 7118652. DOI: 10.1016/j.healun.2020.03.012. View

Hellquist A, Jarvinen T, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L . Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. J Rheumatol. 2009; 36(8):1631-8. DOI: 10.3899/jrheum.081160. View

Lamana A, Castro-Vazquez D, de la Fuente H, Triguero-Martinez A, Martinez-Hernandez R, Revenga M . VIP/VPAC Axis Expression in Immune-Mediated Inflammatory Disorders: Associated miRNA Signatures. Int J Mol Sci. 2022; 23(15). PMC: 9369218. DOI: 10.3390/ijms23158578. View

10.

Zhang Q, Matuozzo D, Le Pen J, Lee D, Moens L, Asano T . Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia. J Exp Med. 2022; 219(8). PMC: 9206114. DOI: 10.1084/jem.20220131. View

11.

Bertagnolio S, Thwin S, Silva R, Nagarajan S, Jassat W, Fowler R . Clinical features of, and risk factors for, severe or fatal COVID-19 among people living with HIV admitted to hospital: analysis of data from the WHO Global Clinical Platform of COVID-19. Lancet HIV. 2022; 9(7):e486-e495. PMC: 9090268. DOI: 10.1016/S2352-3018(22)00097-2. View

12.

Muromoto R, Shimoda K, Oritani K, Matsuda T . Therapeutic Advantage of Tyk2 Inhibition for Treating Autoimmune and Chronic Inflammatory Diseases. Biol Pharm Bull. 2021; 44(11):1585-1592. DOI: 10.1248/bpb.b21-00609. View

13.

Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P . High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012; 44(12):1336-40. PMC: 3605761. DOI: 10.1038/ng.2462. View

14.

Kreins A, Ciancanelli M, Okada S, Kong X, Ramirez-Alejo N, Kilic S . Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015; 212(10):1641-62. PMC: 4577846. DOI: 10.1084/jem.20140280. View

15.

Mukherjee T, Behl T, Sharma S, Sehgal A, Singh S, Sharma N . Anticipated pharmacological role of Aviptadil on COVID-19. Environ Sci Pollut Res Int. 2021; 29(6):8109-8125. PMC: 8630992. DOI: 10.1007/s11356-021-17824-5. View

16.

Martinez C, Juarranz Y, Gutierrez-Canas I, Carrion M, Perez-Garcia S, Villanueva-Romero R . A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases. Int J Mol Sci. 2019; 21(1). PMC: 6982157. DOI: 10.3390/ijms21010065. View

17.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z . Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229):1054-1062. PMC: 7270627. DOI: 10.1016/S0140-6736(20)30566-3. View

18.

Tian W, Jiang W, Yao J, Nicholson C, Li R, Sigurslid H . Predictors of mortality in hospitalized COVID-19 patients: A systematic review and meta-analysis. J Med Virol. 2020; 92(10):1875-1883. PMC: 7280666. DOI: 10.1002/jmv.26050. View

19.

Bautista-Becerril B, Nava-Quiroz K, Munoz-Soria E, Camarena A, Fricke-Galindo I, Buendia-Roldan I . High Expression Levels of miR-21-5p in Younger Hospitalized COVID-19 Patients Are Associated with Mortality and Critical Disease. Int J Mol Sci. 2023; 24(12). PMC: 10298718. DOI: 10.3390/ijms241210112. View

20.

Roy-Vallejo E, Fernandez de Cordoba-Onate S, Delgado-Wicke P, Triguero-Martinez A, Montes N, Carracedo-Rodriguez R . Occurrence of SARS-CoV-2 viremia is associated with genetic variants of genes related to COVID-19 pathogenesis. Front Med (Lausanne). 2023; 10:1215246. PMC: 10557488. DOI: 10.3389/fmed.2023.1215246. View