Association of TLR7 rs864058 Genotypic Variation and mRNA Expression with COVID-19 Severity and Clinical Outcomes: TLR7 rs864058 Genotypic Variation and mRNA Expression with COVID-19

Beenish Khalid; Saeeda Baig; Shian Angelo; Misbah Riaz; Padma Rathore; Fauzia Perveen

doi:10.54393/pjhs.v6i4.2929

Authors

Beenish Khalid Department of Biochemistry, Hamdard University, Karachi, Pakistan
Saeeda Baig Department of Biochemistry, Ziauddin University, Karachi, Pakistan
Shian Angelo Department of Biochemistry, Ziauddin University, Karachi, Pakistan
Misbah Riaz Department of Biochemistry, Bahria University Health Sciences, Karachi, Pakistan
Padma Rathore Department of Physiology, Jinnah Sindh Medical University, Karachi, Pakistan
Fauzia Perveen Department of Biochemistry, Liaquat College of Medicine and Dentistry, Karachi, Pakistan

DOI:

https://doi.org/10.54393/pjhs.v6i4.2929

Keywords:

Genetic Polymorphism, COVID-19, Toll-like Receptor 7, SARS-CoV-2

Abstract

Genetic variations in TLR7 could modulate the severity of COVID-19. Objectives: To find the association between TLR7 mRNA expression, genotypic variations, and disease severity in COVID-19 patients. Methods: A cross-sectional observational study was conducted on 59 PCR-confirmed COVID-19 patients at Ziauddin Hospital, Karachi (June 2022–May 2023). Blood samples were analyzed for TLR7 genotyping via PCR and Sanger sequencing. Disease severity was classified into three groups based on clinical guidelines. TLR7 mRNA expression was quantified using real-time PCR (qPCR), and hospitalization, ICU admission, and complications were documented. Results: Higher TLR7 mRNA expression was observed in patients with the GG genotype compared to those with the GA genotype (p=0.04). Individuals carrying the GG genotype exhibited greater hospitalization rates (75.5% vs. 40%, p=0.009), increased ICU admission (28.6% vs. 10%, p=0.041), and a higher need for mechanical ventilation (20.4% vs. 10%, p=0.049). Respiratory failure occurred more often in the GG genotype group (20.4% vs. 10%, p=0.038). Conclusions: It was concluded that the GG genotype of TLR7 was related to higher susceptibility to severe COVID-19 outcomes, with higher hospitalization rates, ICU admission, and respiratory failure.

References

Mohammad HH, Galway K, McLaughlin D, McKinney A. The Exploration of the Biopsychosocial Impact of the COVID-19 Pandemic On the Nurses Working in the Intensive Care Unit in the Middle East and North Africa: A Scoping Review Protocol. 2024 Jun. doi: 10.1371/journal.pone.0313838. DOI: https://doi.org/10.1371/journal.pone.0313838

Gandhi RT, Lynch JB, Del Rio C. Mild or Moderate Covid-19. New England Journal of Medicine. 2020 Oct; 383(18): 1757-66. doi: 10.1056/NEJMcp2009249. DOI: https://doi.org/10.1056/NEJMcp2009249

Maslove DM, Sibley S, Boyd JG, Goligher EC, Munshi L, Bogoch II et al. Complications of Critical COVID-19: Diagnostic and Therapeutic Considerations for the Mechanically Ventilated Patient. Chest. 2022 Apr; 161(4): 989-98. doi: 10.1016/j.chest.2021.10.011. DOI: https://doi.org/10.1016/j.chest.2021.10.011

Van der Made CI, Netea MG, van der Veerdonk FL, Hoischen A. Clinical Implications of Host Genetic Variation and Susceptibility to Severe or Critical COVID-19. Genome Medicine. 2022 Aug; 14(1): 96. doi: 10.1186/s13073-022-01100-3. DOI: https://doi.org/10.1186/s13073-022-01100-3

Manik M and Singh RK. Role of Toll‐Like Receptors in Modulation of Cytokine Storm Signaling in SARS‐Cov‐2‐Induced COVID‐19. Journal of Medical Virology. 2022 Mar; 94(3): 869-77. doi: 10.1002/jmv.27405. DOI: https://doi.org/10.1002/jmv.27405

Stergioti EM, Manolakou T, Boumpas DT, Banos A. Antiviral Innate Immune Responses in Autoimmunity: Receptors, Pathways, and Therapeutic Targeting. Biomedicines. 2022 Nov; 10(11): 2820. doi: 10.3390/biomedicines10112820. DOI: https://doi.org/10.3390/biomedicines10112820

Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z et al. Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients. Cell Host and Microbe. 2020 Jun; 27(6): 883-90. doi: 10.1016/j.chom.2020.04.017. DOI: https://doi.org/10.1016/j.chom.2020.04.017

Alseoudy MM, Elgamal M, Abdelghany DA, Borg AM, El-Mesery A, Elzeiny D et al. Prognostic Impact of Toll-Like Receptors Gene Polymorphism On Outcome of COVID-19 Pneumonia: A Case-Control Study. Clinical Immunology. 2022 Feb; 235: 108929. doi: 10.1016/j.clim.2022.108929. DOI: https://doi.org/10.1016/j.clim.2022.108929

El-Hefnawy SM, Eid HA, Mostafa RG, Soliman SS, Omar TA, Azmy RM. 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 Reports. 2022 Jun; 27: 101612. doi: 10.1016/j.genrep.2022.101612. DOI: https://doi.org/10.1016/j.genrep.2022.101612

Severe Covid-19 GWAS Group. Genome Wide Association Study of Severe Covid-19 with Respiratory Failure. New England Journal of Medicine. 2020 Oct; 383(16): 1522-34. doi: 10.1056/NEJMoa2020283. DOI: https://doi.org/10.1056/NEJMoa2020283

Mukherjee S, Huda S, Sinha Babu SP. Toll‐like Receptor Polymorphism in Host Immune Response to Infectious Diseases: A Review. Scandinavian Journal of Immunology. 2019 Jul; 90(1): e12771. doi: 10.1111/sji.12771. DOI: https://doi.org/10.1111/sji.12771

Van Der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S et al. Presence of Genetic Variants Among Young Men with Severe COVID-19. Journal of American and Medical Association. 2020 Aug; 324(7): 663-73. doi: 10.1001/jama.2020.13719. DOI: https://doi.org/10.1001/jama.2020.13719

Yip JQ, Oo A, Ng YL, Chin KL, Tan KK, Chu JJ et al. The Role of Inflammatory Gene Polymorphisms in Severe COVID-19: A Review. Virology Journal. 2024 Dec; 21(1): 327. doi: 10.1186/s12985-024-02597-3. DOI: https://doi.org/10.1186/s12985-024-02597-3

Fallerini C, Daga S, Mantovani S, Benetti E, Pujol A, Picchiotti N et al. Association of Toll-like Receptor 7 Variants with Life-Threatening COVID-19 Disease in Males. medRxiv. 2020 Nov: 2020-11. doi: 10.1101/2020.11.19.20234237. DOI: https://doi.org/10.1101/2020.11.19.20234237

Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y et al. Autoantibodies Against Type I IFNS in Patients with Life-Threatening COVID-19. Science. 2020 Oct; 370(6515): eabd4585. doi: 10.1126/science.abd4585. DOI: https://doi.org/10.1126/science.abd4585

Oberfeld B, Achanta A, Carpenter K, Chen P, Gilette NM, Langat P et al. Snap Shot: Covid-19. Cell. 2020 May; 181(4): 954-. doi: 10.1016/j.cell.2020.04.013. DOI: https://doi.org/10.1016/j.cell.2020.04.013

Sinatti G, Santini SJ, Tarantino G, Picchi G, Cosimini B, Ranfone F et al. PaO2/FiO 2 Ratio Forecasts COVID-19 Patients’ Outcome Regardless of Age: A Cross-Sectional, Monocentric Study. Internal and Emergency Medicine. 2022 Apr: 1-9. doi: 10.1007/s11739-021-02840-7. DOI: https://doi.org/10.1007/s11739-021-02840-7

Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J et al. Inborn Errors of Type I IFN Immunity in Patients with Life-Threatening COVID-19. Science. 2020 Oct; 370(6515): eabd4570. doi: 10.1126/science.abd4570. DOI: https://doi.org/10.1126/science.abd4570

Mukherjee S and Tripathi A. Contribution of Toll Like Receptor Polymorphisms to Dengue Susceptibility and Clinical Outcome Among Eastern Indian Patients. Immuno-biology. 2019 Nov; 224(6): 774-85. doi: 10.1016/j.imbio.2019.08.009. DOI: https://doi.org/10.1016/j.imbio.2019.08.009

Zhang T, Zhu J, Su B, Cao L, Li Z, Wei H et al. Effects of TLR7 Polymorphisms On the Susceptibility and Progression of HIV-1 Infection in Chinese MSM Population. Frontiers in Immunology. 2020 Oct; 11: 589010. doi: 10.3389/fimmu.2020.589010. DOI: https://doi.org/10.3389/fimmu.2020.589010

Dutta SK And Tripathi A. Association of Toll-Like Receptor Polymorphisms with Susceptibility to Chikungunya Virus Infection. Virology. 2017 Nov; 511: 207-13. doi: 10.1016/j.virol.2017.08.009. DOI: https://doi.org/10.1016/j.virol.2017.08.009

Nilsson D, Andiappan AK, Halldén C, De Yun W, Säll T, Tim CF, Cardell LO. Toll-like Receptor Gene Polymorphisms Are Associated with Allergic Rhinitis: A Case Control Study. BioMed Central Medical Genetics. 2012 Dec; 13: 1-9. doi: 10.1186/1471-2350-13-66. DOI: https://doi.org/10.1186/1471-2350-13-66

Hussein SA, Mohammed HQ, Mohammed HA. Exploring the Significant Role of TLR 7 Gene Polymorphism with Severity Infection of COVID-19 Patients in Wasit Province. International Journal of Health Sciences. 2022 Jul; 6(S6): 9216-25. doi: 10.53730/ijhs.v6nS6.12425. DOI: https://doi.org/10.53730/ijhs.v6nS6.12425

Dos Santos BR, Dos Santos LK, Ferreira JM, Dos Santos AC, Sortica VA, de Souza Figueiredo EV. Toll-like Receptors Polymorphisms and COVID-19: A Systematic Review. Molecular and Cellular Biochemistry. 2024 Nov: 1-2. doi: 10.1007/s11010-024-05137-3. DOI: https://doi.org/10.1007/s11010-024-05137-3

Zayed M, Kim YC, Lee CS, Jeong BH. No Association Between SARS-CoV-2 Infection and the Polymorphism of the Toll-like Receptor 7 (TLR7) Gene in Female Population. Diagnostics. 2023 Nov; 13(23): 3510. doi: 10.3390/diagnostics13233510. DOI: https://doi.org/10.3390/diagnostics13233510

Sartorius R, Trovato M, Manco R, D’Apice L, De Berardinis P. Exploiting Viral Sensing Mediated by Toll-Like Receptors to Design Innovative Vaccines. Nature Partner Journals Vaccines. 2021 Oct; 6(1): 127. doi: 10.1038/s41541-021-00391-8. DOI: https://doi.org/10.1038/s41541-021-00391-8

Khafaei M, Asghari R, Zafari F, Sadeghi M. Impact of IL-6 Rs1800795 and IL-17A Rs2275913 Gene Polymorphisms on the COVID-19 Prognosis and Susceptibility in a Sample of Iranian Patients. Cytokine. 2024 Feb; 174: 156445. doi: 10.1016/j.cyto.2023.156445. DOI: https://doi.org/10.1016/j.cyto.2023.156445

Zanza C, Romenskaya T, Manetti AC, Franceschi F, La Russa R, Bertozzi G et al. Cytokine Storm in COVID-19: Immunopathogenesis and Therapy. Medicina. 2022 Jan; 58(2): 144. doi: 10.3390/medicina58020144. DOI: https://doi.org/10.3390/medicina58020144

Camblor DG, Miranda D, Albaiceta GM, Amado-Rodríguez L, Cuesta-Llavona E, Vázquez-Coto D et al. Genetic Variants in the NF-Κb Signaling Pathway (NFKB1, NFKBIA, NFKBIZ) And Risk of Critical Outcome Among COVID-19 Patients. Human Immunology. 2022 Aug; 83(8-9): 613-7. doi: 10.1016/j.humimm.2022.06.002. DOI: https://doi.org/10.1016/j.humimm.2022.06.002

Stokes EK. Coronavirus Disease 2019 Case Surveillance—United States, January 22–May 30, 2020. Morbidity and Mortality Weekly Report. 2020; 69. doi: 10.15585/mmwr.mm6924e2. DOI: https://doi.org/10.15585/mmwr.mm6924e2

Harrison SL, Fazio-Eynullayeva E, Lane DA, Underhill P, Lip GY. Comorbidities Associated with Mortality in 31,461 Adults with COVID-19 in the United States: A Federated Electronic Medical Record Analysis. Plos Medicine. 2020 Sep; 17(9): e1003321. doi: 10.1371/journal.pmed.1003321. DOI: https://doi.org/10.1371/journal.pmed.1003321

Klok FA, Kruip MJ, Van der Meer NJ, Arbous MS, Gommers DA, Kant KM et al. Incidence of Thrombotic Complications in Critically Ill ICU Patients with COVID-19. Thrombosis Research. 2020 Jul; 191: 145-7. doi: 10.1016/j.thromres.2020.04.013. DOI: https://doi.org/10.1016/j.thromres.2020.04.013

Galloway JB, Norton S, Barker RD, Brookes A, Carey I, Clarke BD et al. A Clinical Risk Score to Identify Patients with COVID-19 at High Risk of Critical Care Admission Or Death: An Observational Cohort Study. Journal of Infection. 2020 Aug; 81(2): 282-8. doi: 10.1016/j.jinf.2020.05.064. DOI: https://doi.org/10.1016/j.jinf.2020.05.064

Khanmohammadi S and Rezaei N. Role of Toll‐like Receptors in the Pathogenesis of COVID‐19. Journal of Medical Virology. 2021 May; 93(5): 2735-9. doi: 10.1002/jmv.26826. DOI: https://doi.org/10.1002/jmv.26826

Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU. TLRs: Innate Immune Sentries Against SARS-CoV-2 Infection. International Journal of Molecular Sciences. 2023 Apr; 24(9): 8065. doi: 10.3390/ijms24098065. DOI: https://doi.org/10.3390/ijms24098065