SUMMARY. First identified in late 2019 in Wuhan City, Hubei Province, China, coronavirus disease 2019 (COVID-19) remains a pressing public health challenge of the twenty-first century with significant morbidity and mortality despite the implementation of a vaccine campaign. The particular interest is results of research on the role of genetic factors in the course of COVID-19. Such data indicate the probable existence of a hereditary predisposition of individuals to a severe and complicated course of the coronavirus disease. The results of a number of studies indicate the involvement of polymorphic variants I/D of the ACE1 gene in the particular course of the corona virus disease. The purpose of our work was to study the peculiarities of the distribution of genotypes according to the rs4646994 polymorphism of the ACE1 gene and to assess the association of this polymorphism with the severity of the course of the coronavirus disease, the risk of developing pathological changes in the lungs during the coronavirus disease in a cohort of children who suffered from COVID-19. For this purpose, in the examined group of 244 children with laboratory-confirmed COVID-19, genotyping was carried out according to the rs4646994 polymorphism of the ACE1 gene using melting curve analysis of PCR products, the detection of which occurs due to the fluorescence of the intercalating dye EvaGreen. According to the results of the study, an association was established between homo- and heterozygous carriers of the I allele with a severe course of the disease and, in particular, with lung injury. The obtained data can serve as a basis for the use of the I/D polymorphism of the ACE1 gene as a genetic marker for predicting the course of the disease for COVID-19 and become important information for the development of personalized therapy in children.
Keywords: children, COVID-19, lung injury, genetic marker, I/D polymorphism of the ACE1 gene

Full text and supplemented materials
Free full text: PDFReferences
Al-Eitan, L. and Alahmad, S., Allelic and genotypic analysis of the ACE I/D polymorphism for the possible prediction of COVID-19-related mortality and morbidity in Jordanian Arabs, J. Biosaf. Biosecur., 2023. https://doi.org/10.1016/j.jobb.2023.07.005
Beyerstedt, S., Casaro, E.B., and Rangel, É.B., COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection, Eur. J. Clin. Microbiol. Infect. Dis., 2021, vol. 40, no. 5, pp. 905–919. https://doi.org/10.1007/s10096-020-04138-6
Boraey, N.F., Bebars, M.A., Wahba, A.A., et al., Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents, Pediatr. Res., 2024. https://doi.org/10.1038/s41390-023-02982-8
Camporota, L., Cronin, J.N., Busana, M., et al., Gattinoni L, Formenti F. Pathophysiology of coronavirus-19 disease acute lung injury, Curr. Opin. Crit. Care., 2022, vol. 28, no. 1, pp. 9–16. https://doi.org/10.1097/MCC.0000000000000911
Chan, J.F., Yuan, S., Kok, K.H., et al., A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster, Lancet, 2020, vol. 395, no. 10223, pp. 514–523. https://doi.org/10.1016/S0140-6736(20)30154-9
Delanghe, J.R., Speeckaert, M.M., and De Buyzere, M.L., COVID-19 infections are also affected by human ACE1 D/I polymorphism, Clin. Chem. Lab. Med., 2020, vol. 58, no. 7, pp. 1125–1126. https://doi.org/10.1515/cclm-2020-0425
Hamming, I., Cooper, M.E., Haagmans, B.L., et al., The emerging role of ACE2 in physiology and disease, J. Pathol., 2007, vol. 212, no. 1, pp. 1–11. https://doi.org/10.1002/path.2162
Hoffmann, M., Kleine-Weber, H., Schroeder, S., et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell, 2020, vol. 181, no. 2, pp. 271–280.e8. https://moz.gov.ua/uploads/3/19713-standarti_med_ dopomogi_covid_19.pdfhttps://doi.org/10.1016/j.cell.2020.02.052
Hu, B., Huang, S., and Yin, L., The cytokine storm and COVID-19, J. Med. Virol., 2021, vol. 93, no. 1, pp. 250–256. https://doi.org/10.1002/jmv.26232
Huang, C., Wang, Y., Li, X., et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet, 2020, vol. 395, no. 10223, pp. 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
Hubacek, J.A., Dusek, L., Majek, O., et al., ACE I/D polymorphism in Czech first-wave SARS-CoV-2-positive survivors, Clin. Chim. Acta., 2021, vol. 519, pp. 206–209. https://doi.org/10.1016/j.cca.2021.04.024
Johnston, J., Dorrian, D., Linden, D., et al., Pulmonary sequelae of COVID-19: Focus on interstitial lung disease, Cells, 2023, vol. 12, no. 18, p. 2238. https://doi.org/10.3390/cells12182238
Livshits, L.A., Harashchenko, T.A., Umanets, T.R., Krasnienkov, D.S., Gorodna, O.V., Podolskiy, V.V., Kaminska, T.M., Lapshyn, V.F., Podolskiy, V.V., and Antipkin, Y.G., Relationship between the Prevalence of ACE1 I/D polymorphism genotype II and Covid-19 morbidity, mortality in Ukraine and in some Europe countries, Cytol. Genet., 2021, vol. 55, no. 5, pp. 427–432. https://doi.org/10.3103/S0095452721050054
Luoyi, H., Yan, P., and Qihong, F., Relationship between angiotensin-converting enzyme insertion/deletion polymorphism and the risk of COVID-19: A meta-analysis, J. Renin Angiotensin Aldosterone Syst., 2023, vol. 2023, p. 3431612. https://doi.org/10.1155/2023/3431612
Mukae, S., Aoki, S., Itoh, S., et al., Bradykinin B(2) receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitor-related cough, Hypertension, 2000, vol. 36, no. 1, pp. 127–31. https://doi.org/10.1161/01.hyp.36.1.127
Qi, F., Qian, S., Zhang, S., and Zhang, Z., Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses, Biochem. Biophys. Res. Commun., 2020, vol. 526, no. 1, pp. 135–140. https://doi.org/10.1016/j.bbrc.2020.03.044
Thakur, S., Sharma, V., Kaur, D., and Purkait, P., Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a conjoint regulator of coagulation, fibrinolytic, and RAAS pathway in infertility and associated pregnancy complications, J. Renin Angiotensin Aldosterone Syst., 2022.
Tomita, H., Ina, Y., Sugiura, Y., et al., Polymorphism in the angiotensin-converting enzyme (ACE) gene and sarcoidosis, Am. J. Respir. Crit. Care Med., 1997, vol. 156, no. 1, pp. 255–259. https://doi.org/10.1164/ajrccm.156.1.9612011
Verma, S., Abbas, M., Verma, S., et al., Impact of I/D polymorphism of angiotensin-converting enzyme 1 (ACE1) gene on the severity of COVID-19 patients, Infect. Genet. Evol., 2021, vol. 91, p. 104801. https://doi.org/10.1016/j.meegid.2021.104801
Webb Hooper, M., Nápoles, A.M., and Pérez-Stable, E.J., COVID-19 and racial/ethnic disparities, JAMA, 2020, vol. 323, no. 24, pp. 2466–2467. https://doi.org/10.1001/jama.2020.8598
World Health Organization (WHO), Coronavirus Disease (COVID-19) Situation Reports, Geneva: World Health Organization, 2020.
Zheng, H. and Cao, J.J., Angiotensin-converting enzyme gene polymorphism and severe lung injury in patients with coronavirus disease 2019, Am. J. Pathol., 2020, vol. 190, no. 10, pp. 2013–2017. https://doi.org/10.1016/j.ajpath.2020.07.009
Zobel, C.M., Kuhn, H., Schreiner, M., Wenzel, W., Wendtland, J., Goekeri, C., Scheit, L., Oltmanns, K., Rauschning, D., Grossegesse, M., Hofmann, N., Wirtz, H., and Spethmann, S., Impact of ACE I gene insertion/deletion, A-240T polymorphisms and the renin-angiotensin-aldosterone system on COVID-19 disease, Virol. J., 2024, vol. 21, no. 1, p. 15. https://doi.org/10.1186/s12985-023-02283-w
Zou, X., Chen, K., Zou, J., et al., Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection, Front. Med., 2020, vol. 14, no. 2, pp. 185–192. https://doi.org/10.1007/s11684-020-0754-0