Prevalence of innate immunity gene variants rs5743708, rs3853839, and rs8177374 in patients hospitalized in 2021 with a diagnosis of COVID-19

The host genotype is one of the key factors determining the likelihood of infection, severity and outcome of the novel coronavirus infection in humans. The aim of this work was to assess the frequencies of common variants of the innate immunity genes rs5743708 (TLR2), rs3853839 (TLR7) and rs8177374 (TIRAP) in patients hospitalized with COVID-19. Material and methods. Real-time PCR genotyping was performed on DNA samples from 1000 patients hospitalized with moderate to severe COVID-19 in 2021. Results and discussion. The frequencies of the rs5743708, rs3853839 and rs8177374 alleles in the examined patients did not differ from the population ones, their association with the likelihood of transfer to the intensive care unit and death was not revealed. In hospitalized women, an association was found between the T allele of rs8177374 of the TIRAP gene and type 2 diabetes mellitus (χ² = 5.763; p = 0.020), as well as the G allele of rs3853839 of the TLR7 gene with coronary heart disease and chronic heart failure (χ² = 4.094; p = 0.048 and χ² = 5.573; p = 0.022, respectively). It is possible that the association of the rs3853839 G allele with the severity of COVID-19 described in some studies is determined by the interaction of the genotype for this variant with the phenotype of chronic cardiovascular diseases.

1. COVID-19 Host Genetics Initiative. A second update on mapping the human genetic architecture of COVID-19. Nature. 2023;621(7977):E7–E26. doi: 10.1038/s41586-023-06355-3

2. Cao H., Baranova A., Wei X., Wang C., Zhang F. Bidirectional causal associations between type 2 diabetes and COVID-19. J. Med. Virol. 2023; 95(1):e28100. doi: 10.1002/jmv.28100

3. Bragina A.E., Tarzimanova A.I., Rodionova Y.N., Ogibenina E.S., Suvorov A.Y., Druzhinina N.A., Vasilyeva L.V., Ishina T.I., Medvedev I.D., Borlakova M.S., Komelkova A.R., Gushchina D.V., Khachaturov A.A., Podzolkov V.I. Renin-angiotensin system genes polymorphisms in patients with COVID-19 and its relation to severe cases of SARS-CoV-2 Infection. J. Clin. Med. Res. 2024;16(7-8):355–362. doi: 10.14740/jocmr5223

4. Garg E., Arguello-Pascualli P., Vishnyakova O., Halevy A.R., Yoo S., Brooks J.D., Bull S.B., Gagnon F., Greenwood C.M.T., Hung R.J., Lawless J.F., Lerner-Ellis J., Dennis J.K., Abraham R.J.S., Garant J.M., Thiruvahindrapuram B., Jones S.J.M., Initiative C.G.H., Strug L.J., Paterson A.D., Sun L., Elliott L.T. Canadian COVID-19 host genetics cohort replicates known severity associations. PLoS Genet. 2024;20(3):e1011192. doi: 10.1371/journal.pgen.1011192

5. Kovalenko E., Shaheen L., Vergasova E., Kamelin A., Rubinova V., Kharitonov D., Kim A., Plotnikov N., Elmuratov A., Borovkova N., Storozheva M., Solonin S., Gilyazova I., Mironov P., Khusnutdinova E., Petrikov S., Ilinskaya A., Ilinsky V., Rakitko A. GWAS and polygenic risk score of severe COVID-19 in Eastern Europe. Front. Med. (Lausanne). 2024;11:1409714. doi: 10.3389/fmed.2024.1409714.

6. Loktionov A., Kobzeva K., Dorofeeva A., Sergeeva V., Bushueva O. GWAS-identified loci are associated with obesity and type 2 diabetes mellitus in patients with severe COVID-19. Front. Biosci. (Schol. Ed.). 2024;16(3):14. doi: 10.31083/j.fbs1603014

7. Minnai F., Biscarini F., Esposito M., Dragani T.A., Bujanda L., Rahmouni S., Alarcón-Riquelme M.E., Bernardo D., Carnero-Montoro E., Buti M., Zeberg H., Asselta R., Romero-Gomez M., Study G.-C.M., Fernandez-Cadenas I., Fallerini C., Zguro K., Croci S., Baldassarri M., Bruttini M., Furini S., Renieri A., Colombo F. A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death. Sci. Rep. 2024;14(1):3000. doi: 10.1038/s41598-024-53310-x

8. Nakanishi T., Pigazzini S., Degenhardt F., Cordioli M., Butler-Laporte G., Maya-Miles D., Bujanda L., Bouysran Y., Niemi M.E., Palom A., Ellinghaus D., Khan A., Martinez-Bueno M., Rolker S., Amitrano S., Roade Tato L., Fava F., FinnGen, Initiative C.H.G., Spinner C.D., Prati D., Bernardo D., Garcia F., Darcis G., Fernandez-Cadenas I., Holter J.C., Banales J.M., Frithiof R., Kiryluk K., Duga S., Asselta R., Pereira A.C., Romero-Gomez M., Nafria-Jimenez B., Hov J.R., Migeotte I., Renieri A., Planas A.M., Ludwig K.U., Buti M., Rahmouni S., Alarcón-Riquelme M.E., Schulte E.C., Franke A., Karlsen T.H., Valenti L., Zeberg H., Richards J.B., Ganna A. Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality. J. Clin. Invest. 2021;131(23):e152386. doi: 10.1172/JCI152386

9. Skerenova M., Cibulka M., Dankova Z., Holubekova V., Kolkova Z., Lucansky V., Dvorska D., Kapinova A., Krivosova M., Petras M., Baranovicova E., Baranova I., Novakova E., Liptak P., Banovcin P., Bobcakova A., Rosolanka R., Janickova M., Stanclova A., Gaspar L., Caprnda M., Prosecky R., Labudova M., Gabbasov Z., Rodrigo L., Kruzliak P., Lasabova Z., Matakova T., Halasova E. Host genetic variants associated with COVID-19 reconsidered in a Slovak cohort. Adv. Med. Sci. 2024;69(1):198–207. doi: 10.1016/j.advms.2024.03.007

10. Mantovani S., Oliviero B., Varchetta S., Renieri A., Mondelli M.U. TLRs: Innate immune sentries against SARS-CoV-2 infection. Int. J. Mol. Sci. 2023;24(9):8065. doi: 10.3390/ijms24098065

11. Mabrey F.L., Morrell E.D., Wurfel M.M. TLRs in COVID-19: How they drive immunopathology and the rationale for modulation. Innate Immun. 2021;27(78):503–513. doi: 10.1177/17534259211051364

12. Campos-Bayardo T.I., Román-Rojas D., García-Sánchez A., Cardona-Muñoz E.G., Sánchez-Lozano D.I., Totsuka-Sutto S., Gómez-Hermosillo L.F., Casillas-Moreno J., Andrade-Sierra J., Pazarín-Villaseñor L., Campos-Perez W., Martinez-Lopez E., Miranda-Díaz A.G. The role of TLRs in obesity and its related metabolic disorders. Int. J. Mol. Sci. 2025;26(5):2229. doi: 10.3390/ijms26052229

13. Khan S., Shafiei M.S., Longoria C., Schoggins J.W., Savani R.C., Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of theNF-κB pathway. Elife. 2021;10:e68563. doi: 10.7554/eLife.68563

14. Zheng M., Karki R., Williams E.P., Yang D., Fitzpatrick E., Vogel P., Jonsson C.B., Kanneganti T.D. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat. Immunol. 2021;22(7):829–838. doi: 10.1038/s41590021-00937-x

15. Ben-Ali M., Corre B., Manry J., Barreiro L.B., Quach H., Boniotto M., Pellegrini S., Quintana-Murci L. Functional characterization of naturally occurring genetic variants in the human TLR1-2-6 gene family. Hum. Mutat. 2011;32(6):643–652. doi: 10.1002/humu.21486

16. Chen R., Wang X., Li Z., Dai Y., Du W., Wu L. Human Toll-like receptor 2 genetic polymorphisms with tuberculosis susceptibility: A systematic review and meta-analysis. Cytokine. 2023;172:156405. doi: 10.1016/j.cyto.2023.156405

17. Mikhailova S.V., Shcherbakova L.V., Logvinenko N.I., Logvinenko I.I., Voevoda M.I. Polymorphism of genes associated with infectious lung diseases in Northern Asian populations and in patients with community-acquired pneumonia. Vavilovskii Zhurnal Genet. Selektsii. 2021;25(3):301–309. doi: 10.18699/VJ21.51-o

18. Teräsjärvi J., Kainulainen L., Peltola V., Mertsola J., Hakanen A., He Q. Genetic polymorphisms of TLR1, TLR2, TLR3 and TLR4 in patients with recurrent or severe infections. Int. J. Immunogenet. 2024;51(4):242–251. doi: 10.1111/iji.12676

19. Bakaros E., Voulgaridi I., Paliatsa V., Gatselis N., Germanidis G., Asvestopoulou E., Alexiou S., Botsfari E., Lygoura V., Tsachouridou O., Mimtsoudis I., Tseroni M., Sarrou S., Mouchtouri V.A., Dadouli K., Kalala F., Metallidis S., Dalekos G., Hadjichristodoulou C., Speletas M. Innate immune gene polymorphisms and COVID-19 prognosis. Viruses. 2023;15(9):1784. doi: 10.3390/v15091784

20. Alhabibi A.M., Hassan A.S., Abd Elbaky N.M., Eid H.A., Khalifa M.A.A.A., Wahab M.A., Althoqapy A.A., Abdou A.E., Zakaria D.M., Nassef E.M., Kasim S.A., Saleh O.I., Elsheikh A.A., Lotfy M., Sayed A. Impact of Toll-Like Receptor 2 and 9 Gene Polymorphisms on COVID-19: Susceptibility, Severity, and Thrombosis. J. Inflamm. Res. 2023;16:665–675. doi: 10.2147/JIR.S394927

21. Belhaouane I., Hoffmann E., Chamaillard M., Brodin P., Machelart A. Paradoxical roles of the MAL/Tirap adaptor in pathologies. Front. Immunol. 2020;11:569127. doi: 10.3389/fimmu.2020.569127

22. Lannoy V., Côté-Biron A., Asselin C., Rivard N. TIRAP, TRAM, and Toll-like receptors: The untold story. Mediators Inflamm. 2023;2023:2899271. doi: 10.1155/2023/2899271

23. Traets M.J.M., Nijhuis R.H.T., Morré S.A., Ouburg S., Remijn J.A., Blok B.A., de Laat B., Jong E., Herder G.J.M., Fiolet A.T.L., Verweij S.P. Association of geneticvariations in ACE2, TIRAP and factor X with outcomes in COVID-19. PLoS ONE. 2022;17(1):e0260897. doi: 10.1371/journal.pone.0260897

24. Antolí A., Vargas-Parra G., Sierra-Fortuny A., Gomez-Vazquez J.L., Rofes P., Munté E., Viana-Errasti J., Marín-Montes R., López-Doriga A., Feliubadaló L., Del Valle J., Perez-Gonzalez A., Poveda E., Solanich X., Lázaro C. From Rare to Common: Genetic Insights into TLR7 Variants in a Multicentric Spanish Study on COVID-19 Severity. J. Clin. Immunol. 2025;45(1):100. doi: 10.1007/s10875-025-01892-0

25. Deng Y., Zhao J., Sakurai D., Kaufman K.M., Edberg J.C., Kimberly R.P., Kamen D.L., Gilkeson G.S., Jacob C.O., Scofield R.H., Langefeld C.D., Kelly J.A., Ramsey-Goldman R., Petri M.A., Reveille J.D., Vila L.M., Alarcon G.S., Vyse T.J., Pons-Estel B.A., Argentine Collaborative G., Freedman B.I., Gaffney P.M., Sivils K.M., James J.A., Gregersen P.K., Anaya J.M., Niewold T.B., Merrill J.T., Criswell L.A., Stevens A.M., Boackle S.A., Cantor R.M., Chen W., Grossman J.M., Hahn B.H., Harley J.B., Alarcomicronn-Riquelme M.E., Biolupus, networks G., Brown E.E., Tsao B.P. MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet. 2013;9(2):e1003336. doi: 10.1371/journal.pgen.1003336

26. El-Hefnawy S.M., Eid H.A., Mostafa R.G., Soliman S.S., Omar T.A., Azmy R.M. COVID-19 susceptibility, severity, clinical outcome and Toll-like receptor (7) mRNA expression driven by TLR7 gene polymorphism (rs3853839) in middle-aged individuals without previous comorbidities. Gene Rep. 2022;27:101612. doi: 10.1016/j.genrep.2022.101612

27. Delgado-Wicke P., Fernández de Córdoba-Oñate S., Roy-Vallejo E., Alegría-Carrasco E., Rodríguez-Serrano D.A., Lamana A., Montes N., Nicolao-Gómez A., Carracedo-Rodríguez R., Marcos-Jimenez A., Diaz-Fernandez P., Galvan-Roman J.M., Rabes-Rodriguez L., Sanz-Alba M., Alvarez-Rodriguez J., Villa-Marti A., Rodriguez-Franco C., Villapalos-Garcia G., Zubiaur P., Abad-Santos F., de Los Santos I., Gomariz R.P., Garcia-Vicuna R., Munoz-Calleja C., Gonzalez-Alvaro I., Fernandez-Ruiz E., Group P.-C. Genetic variants regulating the immune response improve the prediction of COVID-19 severity provided by clinical variables. Sci. Rep. 2024;14(1):20728. doi: 10.1038/s41598-024-71476-2

28. Martínez-Gómez L.E., Martinez-Armenta C., Medina-Luna D., Ordoñez-Sánchez M.L., Tusie-Luna T., Ortega-Peña S., Herrera-López B., Suarez-Ahedo C., Jimenez-Gutierrez G.E., Hidalgo-Bravo A., Vazquez-Cardenas P., Vidal-Vazquez R.P., Ramirez-Hinojosa J.P., Martinez Matsumoto P.M., Vargas-Alarcon G., Posadas-Sanchez R., Fragoso J.M., Martinez-Ruiz F.J., Zayago-Angeles D.M., Mata-Miranda M.M., Vazquez-Zapien G.J., Martinez-Cuazitl A., Andrade-Alvarado J., Granados J., Ramos-Tavera L., Camacho-Rea M.D.C., Segura-Kato Y., Rodriguez-Perez J.M., Coronado-Zarco R., Franco-Cendejas R., Lopez-Jacome L.E., Magana J.J., Vela-Amieva M., Pineda C., Martinez-Nava G.A., López-Reyes A. Implication of myddosome complex genetic variants in outcome severity of COVID-19 patients. J. Microbiol. Immunol. Infect. 2023;56(5):939–950. doi: 10.1016/j.jmii.2023.06.002

29. Denisova D.V., Zavialova L.G. Long-term trends in selected indicators of physical development of adolescent population in Novosibirsk (population-based study 1989–2009). Byulleten’ Sibirskogo otdeleniya Rossiyskoy akademii meditsinskikh nauk = Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences. 2011;31(5):84–89. [In Russian].

30. Shesternia P.A., Nikulina S.Yu., Shul’man V.A., Parfenova T.M., Maksimov V.N., Voevoda M.I. Association of the locus 9P21.3 with long-term outcomes of myocardial infarction: a prospective study. Profilakticheskaya meditsina = Preventive Medicine. 2013;16(6):79–84. [In Russian].

31. Sambrook J., Russell D.W. Purification of nucleic acids by extraction with phenol:chloroform. CSH Protoc. 2006;2006(1):pdb.prot4455. doi: 10.1101/pdb.prot4455

32. Shapkina M.Yu., Ryabikov A.N., Voronina E.V., Mazdorova E.V., Sherbakova L.V., Bobak M., Malyutina S.K. Atrial FIBRILLATION: prevalence and cross-sectional determinants in Novosibirsk population (HAPIEE cohort, 9255 participants). Ateroscleroz = Atherosclerosis. 2016;12(3):22–27. [In Russian].

33. Degirmenci I., Ozbayer C., Kebapci M.N., Kurt H., Colak E., Gunes H.V. Common variants of genes encoding TLR4 and TLR4 pathway members TIRAP and IRAK1 are effective on MCP1, IL6, IL1β, and TNFα levels in type 2 diabetes and insulin resistance. Inflamm. Res. 2019;68(9):801–814. doi: 10.1007/s00011-019-01263-7

34. Shafeghat M., Kazemian S., Aminorroaya A., Aryan Z., Rezaei N. Toll-like receptor 7 regulates cardiovascular diseases. Int. Immunopharmacol. 2022;113(Pt. A):109390. doi: 10.1016/j.intimp.2022.109390