IFNL4 rs12979860 polymorphism in patients with herpetic keratitis and a history of COVID-19
DOI:
https://doi.org/10.31288/Ukr.j.ophthalmol.20261513Keywords:
herpetic keratitis, COVID-19, gene polymorphism, IFNL4, corneaAbstract
Purpose: To investigate a possible association between IFNL4 rs12979860 variants and susceptibility to herpetic keratitis (HK) in individuals with a history of COVID-19.
Material and Methods: The study group included 50 eyes in 50 patients with HK and a history of COVID-19 (16 patients with primary HK and 34 patients with recurrent HK). Patients were genotyped for IFNL4 rs12979860 using Taqman probe real-time polymerase chain reaction. Analysis of amplification curves was performed to obtain all polymorphic variants of IFNL4 SNP rs12979860. Genotyping data of the comparison group (n = 73; women with a history of COVID-19 of various severity but without manifestations of eye disease during hospitalization for COVID-19) were available from project N 0120U104508 and were used for analysis in this study. Genotyping data of the population control group (n = 100) were available from the database of the Human Genomics Laboratory, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine and were used as controls. These groups included healthy individuals from various Ukrainian regions who were not related to each other.
Results: Fisher exact test showed a significant difference (р < 0.05) in the distribution of genotypes and polymorphic variants (alleles) between the study group and the comparison group and between the study group and the control group. We compared the distribution of genotype and alleles for rs12979860 between patients with recurrent HK and the control group. The homozygous (CC) genotype of rs12979860 was significantly more common in patients with HK.
Conclusion: We found an association between the homozygous CC genotype of IFNL4 (SNP rs12979860) with recurrent HK. The C allele could be viewed as a genetic marker of inherited predisposition to HK in individuals with a history of COVID-19.
References
1. Das N, Das J, Pal D. Stromal and endothelial herpes simplex virus keratitis reactivation in the convalescent period of COVID-19. A case report. Indian J Ophthalmol. 2022 Mar 22;70(4):1410-1412. https://doi.org/10.4103/ijo.IJO_2838_21
2. Maldonado MD, Romero-Aibar J, Pérez-San-Gregorio M A. COVID-19 pandemic as a risk factor for the reactivation of herpes viruses. Epidemiol Infect. 2021 Jun 16:149:e145. https://doi.org/10.1017/S0950268821001333
3. Majtanova N, Kriskova P, Keri P. et al. Herpes Simplex Keratitis in Patients with SARS-CoV-2 Infection: A Series of Five Cases. Medicina (Kaunas). 2021 Apr 24;57(5):412. https://doi.org/10.3390/medicina57050412
4. St. Leger AJ, Rowe AM, Jeon S. et al. Herpes keratitis. Prog Retin Eye Res. 2013 Jan:32:88-101. https://doi.org/10.1016/j.preteyeres.2012.08.002
5. Olsson J, Kok E, Adolfsson R. et al. Herpes virus seroepidemiology in the adult Swedish population. Immun Ageing. 2017 May 10:14:10. eCollection 2017. https://doi.org/10.1186/s12979-017-0093-4
6. White ML, Chodosh J. Herpes Simplex Virus Keratitis: A Treatment Guideline. American Academy of Ophthalmology. Clinical Statements. 2014.
7. Remeijer L, Osterhaus A, Verjans G. Human herpes simplex virus keratitis: the pathogenesis revisited. Ocul Immunol Inflamm. 2004 Dec;12(4):255-85. https://doi.org/10.1080/092739490500363
8. Lobo AM, Agelidis AM, Shukla D. Pathogenesis of herpes simplex keratitis. Ocul Surf. 2019 Jan;17(1):40-49.https://doi.org/10.1016/j.jtos.2018.10.002
9. Sanjay S, Srinivasan P, Jayadev C. et al. Post COVID-19 Ophthalmic Manifestations. Ocul Immunol Inflamm. 2021 May 19;29(4):656-661. https://doi.org/10.1080/09273948.2020.1870147
10. Sanjay S, Singh YP, Roy D, Mahendradas P, Kawali A, Shetty R. Recurrent bilateral idiopathic anterior uveitis with vitritis post Coronavirus Disease 2019 infection. Indian J Rheumatol 2021;16:460-3.https://doi.org/10.4103/injr.injr_114_21
11. Sanjay S, Mutalik D, Gowda S, Mahendradas P, Kawali A, Shetty R. Post Coronavirus Disease (COVID-19) Reactivation of a Quiescent Unilateral Anterior Uveitis. SN Compr Clin Med. 2021;3(9):1843-1847. https://doi.org/10.1007/s42399-021-00985-2
12. Sanjay S, Gowda PB, Rao B, Mutalik D, Mahendradas P, Kawali A, et al. Old wine in a new bottle - post COVID-19 infection, central serous chorioretinopathy and the steroids. J Ophthalmic Inflamm Infect. 2021;11:14. https://doi.org/10.1186/s12348-021-00244-4
13. Mahendradas P, Hande P, Patil A, Kawali A, Sanjay S, Ahmed SA, et al. Bilateral Post Fever Retinitis With Retinal Vascular Occlusions Following Severe Acute Respiratory Syndrome Corona Virus (SARS-CoV2) Infection. Ocul Immunol Inflamm. 2022 Oct-Nov;30(7-8):1715-1720. https://doi.org/10.1080/09273948.2021.1936564
14. Wu P, Duan F, Luo C, Liu Q, Qu X, Liang L, Wu K. Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol. 2020 May 1;138(5):575-578. https://doi.org/10.1001/jamaophthalmol.2020.1291
15. Soltani S, Sadrkhanloo M, Siri G, Zakeri A M, Emadi M S, et al. HSV-1 Infection Among COVID-19 Cases with Ocular and Neurological Manifestations.Jundishapur J Microbiol. 2023; 16(1): e135251. https://doi.org/10.5812/jjm-135251
16. Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell. 2021 Apr 1;184(7):1671-1692. https://doi.org/10.1016/j.cell.2021.02.029
17. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003 Jan;4(1):69-77. https://doi.org/10.1038/ni875
18. Chronopoulou S, Tsochantaridis I. Interferon Lambda: The Next Frontier in Antiviral Therapy? Pharmaceuticals (Basel). 2025 May 24;18(6):785. https://doi.org/10.3390/ph18060785
19. Rugwizangoga B, Andersson ME, Kabayiza JC, Nilsson MS, Ármannsdóttir B, Aurelius J, Nilsson S, Hellstrand K, Lindh M, Martner A. IFNL4 Genotypes Predict Clearance of RNA Viruses in Rwandan Children With Upper Respiratory Tract Infections. Front Cell Infect Microbiol. 2019 Oct 4;9:340. https://doi.org/10.3389/fcimb.2019.00340
20. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009 Oct 8;461(7265):798-801. https://doi.org/10.1038/nature08463
21. Griffiths SJ, Koegl M, Boutell C, Zenner HL, Crump CM, Pica F, et al. A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. PLoS Pathog. 2013;9(8):e1003514. https://doi.org/10.1371/journal.ppat.1003514
22. Drozhzhyna GI, Sereda KV, Khramenko NI. Features of the course of post-COVID-19 primary and recurrent herpetic keratitis. J Ophthalmology (Ukraine). 2024: 6:3-6.https://doi.org/10.31288/oftalmolzh2024639
23. Liesegang TJ. Classification of herpes simplex virus keratitis and anterior uveitis. Cornea. 1999 Mar;18(2):127-43. https://doi.org/10.1097/00003226-199903000-00001
24. Gibson UE, Heid CA, Williams PM. A novel method for real time quantitative RT-PCR. Genome Res. 1996 Oct;6(10):995-1001. https://doi.org/10.1101/gr.6.10.995
25. Kim JYH, Ragusa M, Tortosa F, Torres A, Gresh L, Méndez-Rico JA, et al. Viral reactivations and co-infections in COVID-19 patients: a systematic review. BMC Infect Dis. 2023 Apr 26;23(1):259. https://doi.org/10.1186/s12879-023-08117-y
26. Franceschini E, Cozzi-Lepri A, Santoro A, Bacca E, Lancellotti G, et al. Herpes Simplex Virus Re-Activation in Patients with SARS-CoV-2 Pneumonia: A Prospective, Observational Study. Microorganisms. 2021 Sep 7;9(9):1896. https://doi.org/10.3390/microorganisms9091896
27. Majtanova N, Kriskova P, Keri P, Fellner Z, Majtan J, Kolar P. Herpes Simplex Keratitis in Patients with SARS-CoV-2 Infection: A Series of Five Cases. Medicina (Kaunas). 2021 Apr 24;57(5):412. https://doi.org/10.3390/medicina57050412
28. Daher ND, Syed ZA. Bilateral interstitial keratitis following COVID-19: a case report. BMC Ophthalmol. 2023 Oct 13;23:414. https://doi.org/10.1186/s12886-023-03160-4
29. Enguita-Germán M, Librero J, Leache L, Gutiérrez-Valencia M, Tamayo I, Jericó C, et al. Role of the AB0 blood group in COVID-19 infection and complications: A population-based study. Transfus Apher Sci. 2022 Jun;61(3):103357. https://doi.org/10.1016/j.transci.2022.103357
30. Sienko J, Marczak I, Kotowski M, Bogacz A, Tejchman K, Sienko M, et al. Association of ACE2 Gene Variants with the Severity of COVID-19 Disease-A Prospective Observational Study. Int J Environ Res Public Health. 2022 Oct 2;19(19):12622. https://doi.org/10.3390/ijerph191912622
31. Livshits LA, Harashchenko TA, Umanets TR, Krasnienkov DS, Gorodna OV, Podolskiy Vl, et al. Relationship between the prevalenceof ACE1 I/D polymorphism genotype II and COVID-19 morbidity, mortality in Ukraine and in some Europe countries. Cytol Genet. 2021;55(5):427-432. https://doi.org/10.3103/S0095452721050054
32. Boraey NF, Bebars MA, Wahba AA, Abd El Lateef HM, Attia MA, Elsayed AH, et al. Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents. Pediatr Res. 2024 Oct;96(5):1347-1354. https://doi.org/10.1038/s41390-023-02982-8
33. Zheng H, Cao JJ. Angiotensin-Converting Enzyme Gene Polymorphism and Severe Lung Injury in Patients with Coronavirus Disease 2019. Am J Pathol. 2020 Oct;190(10):2013-2017. https://doi.org/10.1016/j.ajpath.2020.07.009
34. Bradic M, Taleb S, Thomas B, Chidiac O, Robay A, Hassan N, et al. DNA methylation predicts the outcome of COVID-19 patients with acute respiratory distress syndrome. J Transl Med. 2022 Nov 12;20(1):526.https://doi.org/10.1186/s12967-022-03737-5
35. Bannerjee A, Ganguli U, Daha S, et al. Vitamin D andimmuno-pathologyof COVID-19: many interactions but uncertain therapeutic benefits. Expert Rev Anti Infect Ther. 2021 Apr 1:1-14. https://doi.org/10.1080/14787210.2021.1905519
36. Hutsaliuk KM. [Structure and frequency of retinal changes in patients with COVID-19]. [Dissertation for a degree of PhD in medicine]. Odesa; 2025. Ukrainian. https://filatovinstitut.org.ua
37. Harashchenko TA, Umanets TR, Kaminska TM, Gorodna OV, Krasnienkov DS, Antypkin YuG, et al. Distribution of IFNL genotypes in children with COVID-19. Cytology and Genetics. 2023; 57(6): 579-586, https://doi.org/10.3103/S0095452723060038
38. Sorrentino L, Silvestri V, Oliveto G, Scordio M, Frasca F, Fracella M, et al. Distribution of Interferon Lambda 4 Single Nucleotide Polymorphism rs11322783 Genotypes in Patients with COVID-19. Microorganisms. 2022 Feb 4;10(2):363. https://doi.org/10.3390/microorganisms10020363
39. Borivoje S, Svetlana S, Milan HM, Nela Đ, Olivera MĐ, Filip M, et al. IL28B Genetic Variations in Patients with Recurrent Herpes Simplex Keratitis. Medicina (Kaunas). 2019 Sep 26;55(10):642. https://doi.org/10.3390/medicina55100642
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Sereda K. V., Gorodna O. V., Nechyporenko M. V., Drozhzhyna G. I., Livshits L. A.
This work is licensed under a Creative Commons Attribution 4.0 International License.
This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) that allows users to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author as long as they cite the source.
COPYRIGHT NOTICE
Authors who publish in this journal agree to the following terms:
- Authors hold copyright immediately after publication of their works and retain publishing rights without any restrictions.
- The copyright commencement date complies the publication date of the issue, where the article is included in.
DEPOSIT POLICY
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) during the editorial process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work with an acknowledgement of its initial publication in this journal.
- Post-print (post-refereeing manuscript version) and publisher's PDF-version self-archiving is allowed.
- Archiving the pre-print (pre-refereeing manuscript version) not allowed.
