Skip to main content
Top

Open Access 04-05-2024 | COVID-19 | Research

FURIN, IFNL4, and TLR2 gene polymorphisms in relation to COVID-19 severity: a case–control study in Egyptian patients

Authors: Gamalat A. Elgedawy, Naglaa S. Elabd, Radwa H. Salem, Samah M. Awad, Amany A. Amer, Mohammad M. Torayah, Amal A. El-Koa, Mai Abozeid, Belal A. Montaser, Hind S. Aboshabaan, Mervat Abdelkreem, Marwa L. Helal

Published in: Infection

Login to get access

Abstract

Background and Aim

A wide range of clinical manifestations and outcomes, including liver injury, have been reported in COVID-19 patients. We investigated the association of three substantial gene polymorphisms (FURIN, IFNL4, and TLR2) with COVID-19 disease susceptibility and severity to help predict prognosis.

Methods

150 adult COVID-19-assured cases were categorized as follows: 78 patients with a non-severe presentation, 39 patients with severe disease, and 33 critically ill patients. In addition, 74 healthy controls were included. Clinical and laboratory evaluations were carried out, including complete and differential blood counts, D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin, ferritin, interleukin-6 (Il-6), and liver and kidney functions. FURIN (rs6226), IFNL4 (rs12979860), and TLR2 (rs3804099) genotyping allelic discrimination assays were conducted using real-time PCR.

Results

The FURIN, IFNL4, and TLR2 genotypes and their alleles differed significantly between COVID-19 patients and controls, as well as between patients with severe or critical illness and those with a non-severe presentation. According to a multivariable regression analysis, FURIN (C/T + T/T) and TLR2 (T/C + C/C) mutants were associated with COVID-19 susceptibility, with odds ratios of 3.293 and 2.839, respectively. FURIN C/C and IFNL4 T/T mutants were significantly linked to severe and critical illnesses. Multivariate regression analysis showed that FURIN (G/C + C/C) genotypes and IFNL4 T/T homozygosity were independent risk factors associated with increased mortality.

Conclusion

FURIN, IFNL4, and TLR2 gene variants are associated with the risk of COVID-19 occurrence as well as increased severity and poor outcomes in Egyptian patients.
Appendix
Available only for authorised users
Literature
2.
go back to reference Rahman S, Montero MTV, Rowe K, Kirton R, Kunik F Jr. Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence. Expert Rev Clin Pharmacol. 2021;14:601–21.CrossRefPubMed Rahman S, Montero MTV, Rowe K, Kirton R, Kunik F Jr. Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence. Expert Rev Clin Pharmacol. 2021;14:601–21.CrossRefPubMed
4.
go back to reference Vakil MK, Mansoori Y, Al-Awsi GRL, Hosseinipour A, Ahsant S, Ahmadi S, et al. Individual genetic variability mainly of Proinflammatory cytokines, cytokine receptors, and toll-like receptors dictates pathophysiology of COVID-19 disease. J Med Virol. 2022;94:4088–96.CrossRefPubMedPubMedCentral Vakil MK, Mansoori Y, Al-Awsi GRL, Hosseinipour A, Ahsant S, Ahmadi S, et al. Individual genetic variability mainly of Proinflammatory cytokines, cytokine receptors, and toll-like receptors dictates pathophysiology of COVID-19 disease. J Med Virol. 2022;94:4088–96.CrossRefPubMedPubMedCentral
5.
go back to reference 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 Med. 2022;14:96.CrossRefPubMedPubMedCentral 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 Med. 2022;14:96.CrossRefPubMedPubMedCentral
6.
go back to reference Braun E, Sauter D. Furin-mediated protein processing in infectious diseases and cancer. Clin Transl Immunol. 2019;8: e1073.CrossRef Braun E, Sauter D. Furin-mediated protein processing in infectious diseases and cancer. Clin Transl Immunol. 2019;8: e1073.CrossRef
7.
go back to reference Al-Mulla F, Mohammad A, Al Madhoun A, Haddad D, Ali H, Eaaswarkhanth M, et al. ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: a time to implement precision medicine against COVID-19. Heliyon. 2021;7: e06133.CrossRefPubMedPubMedCentral Al-Mulla F, Mohammad A, Al Madhoun A, Haddad D, Ali H, Eaaswarkhanth M, et al. ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: a time to implement precision medicine against COVID-19. Heliyon. 2021;7: e06133.CrossRefPubMedPubMedCentral
8.
go back to reference Andreakos E, Tsiodras S. COVID-19: lambda interferon against viral load and hyperinflammation. EMBO Mol Med. 2020;8(12): e12465.CrossRef Andreakos E, Tsiodras S. COVID-19: lambda interferon against viral load and hyperinflammation. EMBO Mol Med. 2020;8(12): e12465.CrossRef
9.
go back to reference O’Brien TR, Pfeiffer RM, Paquin A, Lang Kuhs KA, Chen S, Bonkovsky HL, et al. Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. J Hepatol. 2015;63:1103–10.CrossRefPubMedPubMedCentral O’Brien TR, Pfeiffer RM, Paquin A, Lang Kuhs KA, Chen S, Bonkovsky HL, et al. Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. J Hepatol. 2015;63:1103–10.CrossRefPubMedPubMedCentral
10.
go back to reference Saponi-Cortes JMR, Rivas MD, Calle-Alonso F, Sanchez JF, Costo A, Martin C, et al. IFNL4 genetic variant can predispose to COVID-19. Sci Rep. 2021;11:21185.CrossRefPubMedPubMedCentral Saponi-Cortes JMR, Rivas MD, Calle-Alonso F, Sanchez JF, Costo A, Martin C, et al. IFNL4 genetic variant can predispose to COVID-19. Sci Rep. 2021;11:21185.CrossRefPubMedPubMedCentral
11.
go back to reference Rahimi P, Tarharoudi R, Rahimpour A, Mosayebi Amroabadi J, Ahmadi I, Anvari E, et al. The association between interferon lambda 3 and 4 gene single-nucleotide polymorphisms and the recovery of COVID-19 patients. Virol J. 2021;18:221.CrossRefPubMedPubMedCentral Rahimi P, Tarharoudi R, Rahimpour A, Mosayebi Amroabadi J, Ahmadi I, Anvari E, et al. The association between interferon lambda 3 and 4 gene single-nucleotide polymorphisms and the recovery of COVID-19 patients. Virol J. 2021;18:221.CrossRefPubMedPubMedCentral
12.
go back to reference Elbrolosy AM, Elabd NS, ElGedawy GA, Abozeid M, Abdelkreem M, Montaser B, et al. Toll- like receptor 2 polymorphism and IL-6 profile in relation to disease progression in chronic HBV infection: a case control study in Egyptian patients. Clin Exp Med. 2023;23:117–29.PubMed Elbrolosy AM, Elabd NS, ElGedawy GA, Abozeid M, Abdelkreem M, Montaser B, et al. Toll- like receptor 2 polymorphism and IL-6 profile in relation to disease progression in chronic HBV infection: a case control study in Egyptian patients. Clin Exp Med. 2023;23:117–29.PubMed
13.
go back to reference Zheng M, Karki R, Williams EP, Yang D, Fitzpatrick E, Vogel P, et al. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat Immunol. 2021;22:829–38.CrossRefPubMedPubMedCentral Zheng M, Karki R, Williams EP, Yang D, Fitzpatrick E, Vogel P, et al. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat Immunol. 2021;22:829–38.CrossRefPubMedPubMedCentral
14.
go back to reference Varshney D, Singh S, Sinha E, Mohanty KK, Kumar S, Kumar Barik S, et al. Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection. Cytokine. 2022;152: 155791.CrossRefPubMed Varshney D, Singh S, Sinha E, Mohanty KK, Kumar S, Kumar Barik S, et al. Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection. Cytokine. 2022;152: 155791.CrossRefPubMed
15.
go back to reference Prokop M, van Everdingen W, van Rees Vellinga T, Quarles van Ufford H, Stöger L, Beenen L, et al. CO-RADS: a categorical CT assessment scheme for patients suspected of having COVID-19-definition and evaluation. Radiology. 2020;296(2):E97–104. Prokop M, van Everdingen W, van Rees Vellinga T, Quarles van Ufford H, Stöger L, Beenen L, et al. CO-RADS: a categorical CT assessment scheme for patients suspected of having COVID-19-definition and evaluation. Radiology. 2020;296(2):E97–104.
16.
go back to reference Update to living WHO guideline on drugs for covid-19. BMJ. 2023;380:57. Update to living WHO guideline on drugs for covid-19. BMJ. 2023;380:57.
17.
go back to reference Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–9.CrossRefPubMedPubMedCentral Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–9.CrossRefPubMedPubMedCentral
18.
19.
go back to reference Schmidt A, Groh AM, Frick JS, Vehreschild MJGT, Ludwig KU. Genetic predisposition and the variable course of infectious diseases. Dtsch Arztebl Int. 2022;119:117–23.PubMedPubMedCentral Schmidt A, Groh AM, Frick JS, Vehreschild MJGT, Ludwig KU. Genetic predisposition and the variable course of infectious diseases. Dtsch Arztebl Int. 2022;119:117–23.PubMedPubMedCentral
21.
go back to reference Eid RA, Attia AM, Hassan M, Shaker MA, Kamal MA. Demographic, clinical, and laboratory characteristics of patients with COVID-19 during the second and third waves of the pandemic in Egypt. J Infect Public Health. 2021;14:1358–66.CrossRefPubMedPubMedCentral Eid RA, Attia AM, Hassan M, Shaker MA, Kamal MA. Demographic, clinical, and laboratory characteristics of patients with COVID-19 during the second and third waves of the pandemic in Egypt. J Infect Public Health. 2021;14:1358–66.CrossRefPubMedPubMedCentral
22.
go back to reference Liu K, Chen Y, Lin R, Han K. Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients. J Infect. 2020;80:e14–8.CrossRefPubMedPubMedCentral Liu K, Chen Y, Lin R, Han K. Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients. J Infect. 2020;80:e14–8.CrossRefPubMedPubMedCentral
23.
go back to reference Singh AK, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations. Diabetes Metab Syndr. 2020;14:303–10.CrossRefPubMedPubMedCentral Singh AK, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations. Diabetes Metab Syndr. 2020;14:303–10.CrossRefPubMedPubMedCentral
24.
25.
go back to reference Mohammed SA, Eid KM, Anyiam FE, Wadaaallah H, Muhamed MAM, Morsi MH, et al. Liver injury with COVID-19: laboratory and histopathological outcome—systematic review and meta-analysis. Egypt Liver J. 2022;12:9.CrossRefPubMedPubMedCentral Mohammed SA, Eid KM, Anyiam FE, Wadaaallah H, Muhamed MAM, Morsi MH, et al. Liver injury with COVID-19: laboratory and histopathological outcome—systematic review and meta-analysis. Egypt Liver J. 2022;12:9.CrossRefPubMedPubMedCentral
26.
go back to reference Vitiello A, La Porta R, D’Aiuto V, Ferrara F. The risks of liver injury in COVID-19 patients and pharmacological management to reduce or prevent the damage induced. Egypt Liver J. 2021;11:11.CrossRefPubMedPubMedCentral Vitiello A, La Porta R, D’Aiuto V, Ferrara F. The risks of liver injury in COVID-19 patients and pharmacological management to reduce or prevent the damage induced. Egypt Liver J. 2021;11:11.CrossRefPubMedPubMedCentral
27.
go back to reference Elabd N, Saleh A, Elbrolosy A, Ibrahem R, Aboelkhair N, Enar M, et al. Cytokines profile and their related genotypes in COVID-19: Correlation with disease severity and outcome in Egyptian patients. Microb Infect Dis. 2024;5:53–65. Elabd N, Saleh A, Elbrolosy A, Ibrahem R, Aboelkhair N, Enar M, et al. Cytokines profile and their related genotypes in COVID-19: Correlation with disease severity and outcome in Egyptian patients. Microb Infect Dis. 2024;5:53–65.
28.
go back to reference Torre-Fuentes L, Matías-Guiu J, Hernández-Lorenzo L, Montero-Escribano P, Pytel V, Porta-Etessam J, et al. ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain. J Med Virol. 2021;93:863–9.CrossRefPubMed Torre-Fuentes L, Matías-Guiu J, Hernández-Lorenzo L, Montero-Escribano P, Pytel V, Porta-Etessam J, et al. ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain. J Med Virol. 2021;93:863–9.CrossRefPubMed
29.
go back to reference Coto E, Albaiceta GM, Amado-Rodríguez L, García-Clemente M, Cuesta-Llavona E, Vázquez-Coto D, et al. FURIN gene variants (rs6224/rs4702) as potential markers of death and cardiovascular traits in severe COVID-19. J Med Virol. 2022;94:3589–95.CrossRefPubMedPubMedCentral Coto E, Albaiceta GM, Amado-Rodríguez L, García-Clemente M, Cuesta-Llavona E, Vázquez-Coto D, et al. FURIN gene variants (rs6224/rs4702) as potential markers of death and cardiovascular traits in severe COVID-19. J Med Virol. 2022;94:3589–95.CrossRefPubMedPubMedCentral
30.
go back to reference Amodio E, Pipitone RM, Grimaudo S, Immordino P, Maida CM, Prestileo T, et al. SARS-CoV-2 viral load, IFNλ polymorphisms and the course of COVID-19: an observational study. J Clin Med. 2020;9:3315.CrossRefPubMedPubMedCentral Amodio E, Pipitone RM, Grimaudo S, Immordino P, Maida CM, Prestileo T, et al. SARS-CoV-2 viral load, IFNλ polymorphisms and the course of COVID-19: an observational study. J Clin Med. 2020;9:3315.CrossRefPubMedPubMedCentral
31.
go back to reference Agwa SHA, Kamel MM, Elghazaly H, Abd Elsamee AM, Hafez H, Girgis SA, et al. Association between interferon-lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 variant polymorphisms with the course and outcome of SARS-CoV-2 patients. Genes (Basel). 2021;12:830.CrossRefPubMedPubMedCentral Agwa SHA, Kamel MM, Elghazaly H, Abd Elsamee AM, Hafez H, Girgis SA, et al. Association between interferon-lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 variant polymorphisms with the course and outcome of SARS-CoV-2 patients. Genes (Basel). 2021;12:830.CrossRefPubMedPubMedCentral
32.
go back to reference Matic S, Milovanovic D, Mijailovic Z, Djurdjevic P, Sazdanovic P, Stefanovic S, et al. Its all about IFN-λ4: Protective role of IFNL4 polymorphism against COVID-19-related pneumonia in females. J Med Virol. 2023;95: e29152.CrossRefPubMed Matic S, Milovanovic D, Mijailovic Z, Djurdjevic P, Sazdanovic P, Stefanovic S, et al. Its all about IFN-λ4: Protective role of IFNL4 polymorphism against COVID-19-related pneumonia in females. J Med Virol. 2023;95: e29152.CrossRefPubMed
33.
go back to reference Matic S, Milovanovic D, Mijailovic Z, Djurdjevic P, Sazdanovic P, Stefanovic S, et al. IFNL3/4 polymorphisms as a two-edged sword: an association with COVID-19 outcome. J Med Virol. 2023;95: e28506.CrossRefPubMed Matic S, Milovanovic D, Mijailovic Z, Djurdjevic P, Sazdanovic P, Stefanovic S, et al. IFNL3/4 polymorphisms as a two-edged sword: an association with COVID-19 outcome. J Med Virol. 2023;95: e28506.CrossRefPubMed
34.
go back to reference Alhabibi AM, Hassan AS, Abd Elbaky NM, Eid HA, Khalifa MAAA, Wahab MA, et al. Impact of toll-like receptor 2 and 9 gene polymorphisms on COVID-19: susceptibility, severity, and thrombosis. J Inflamm Res. 2023;16:665–75.CrossRefPubMedPubMedCentral Alhabibi AM, Hassan AS, Abd Elbaky NM, Eid HA, Khalifa MAAA, Wahab MA, et al. Impact of toll-like receptor 2 and 9 gene polymorphisms on COVID-19: susceptibility, severity, and thrombosis. J Inflamm Res. 2023;16:665–75.CrossRefPubMedPubMedCentral
35.
go back to reference Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34:327–31.PubMed Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34:327–31.PubMed
36.
go back to reference Chen KH, Gu W, Zeng L, Jiang DP, Zhang LY, Zhou J, et al. Identification of haplotype tag SNPs within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock. 2011;35:35–41.CrossRefPubMed Chen KH, Gu W, Zeng L, Jiang DP, Zhang LY, Zhou J, et al. Identification of haplotype tag SNPs within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock. 2011;35:35–41.CrossRefPubMed
37.
go back to reference Xu Y, Xue W, Gao H, Cui J, Zhao L, You C. Association of toll-like receptors single nucleotide polymorphisms with HBV and HCV infection: research status. PeerJ. 2022;10: e13335.CrossRefPubMedPubMedCentral Xu Y, Xue W, Gao H, Cui J, Zhao L, You C. Association of toll-like receptors single nucleotide polymorphisms with HBV and HCV infection: research status. PeerJ. 2022;10: e13335.CrossRefPubMedPubMedCentral
Metadata
Title
FURIN, IFNL4, and TLR2 gene polymorphisms in relation to COVID-19 severity: a case–control study in Egyptian patients
Authors
Gamalat A. Elgedawy
Naglaa S. Elabd
Radwa H. Salem
Samah M. Awad
Amany A. Amer
Mohammad M. Torayah
Amal A. El-Koa
Mai Abozeid
Belal A. Montaser
Hind S. Aboshabaan
Mervat Abdelkreem
Marwa L. Helal
Publication date
04-05-2024
Publisher
Springer Berlin Heidelberg
Keyword
COVID-19
Published in
Infection
Print ISSN: 0300-8126
Electronic ISSN: 1439-0973
DOI
https://doi.org/10.1007/s15010-024-02266-1
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.