Аннотация
Пандемия COVID-19 привела к огромному распространению заболеваемости во всем мире, но с весьма различными исходами. Развитие тяжёлых форм заболевания и смертность чаще наблюдаются у пожилых людей, мужчин и лиц с сопутствующими заболеваниями. Доказано, что с повышенным риском тяжёлого течения COVID-19 тесно связаны генетические мутации факторов иммунной системы. Особая роль в тяжести COVID-19 отводится про- и противовоспалительным цитокинам, избыточная секреция которых ведёт к эндотелиальной дисфункции, вызывающей повреждение жизненно важных органов, особенно легких. Выявление дефекта вариабельности генов про- и противовоспалительных цитокинов, связанных с COVID-19, имеет решающее значение для прогнозирования риска развития заболевания. Цель исследования — изучение полиморфных вариантов генов IL-1β (Т-31С), TNF-α (G-308A), IL-10 (G-1082A), IL-17(G-197A), IL-4 (С-589Т) у больных COVID-19. Обследованы 142 пациента с доказанным диагнозом COVID-19. Контрольную группу составили 72 здоровых донора. Методом полимеразной цепной реакции в реальном времени (ПЦР-РВ) исследованы полиморфизмы генов цитокинов IL-1β (Т-31С), TNF-α (G-308A), IL-10 (G-1082A), IL-17(G-197A), IL-4 (С-589Т) у больных COVID-19 по сравнению с показателями здоровых лиц. Среди изученных полиморфных вариантов генов цитокинов значимыми предикторами повышенного риска развития COVID-19 явились генотип -1082А/A гена IL-10, генотип -197A/А гена IL-17. Предикторами пониженного риска развития COVID-19 явились: генотип -589С/Т гена IL-4, генотип -31С/С гена IL-1β, генотипы -308 G/А и -308 А/А гена TNF-α. Анализ полиморфизма генов наиболее значимых цитокинов, таких как IL-4, IL-10, IL-17A, IL-1β, TNF-α даёт возможность оценить генетическую предрасположенность пациентов к повышенному риску развития COVID-19, является важным для прогноза рисков заболевания.
Annotation
The COVID-19 pandemic has resulted in a huge spread of disease worldwide, but with very different outcomes. The development of severe disease and mortality are more common in the elderly, men and those with comorbidities. Genetic mutations of immune system factors have been shown to be closely associated with an increased risk of severe COVID-19. A special role in the severity of COVID-19 is attributed to pro- and anti-inflammatory cytokines, the excessive secretion of which ultimately leads to endothelial dysfunction causing damage to vital organs, especially the lungs. Therefore, identifying a defect in COVID-19-related pro- and anti-inflammatory cytokine gene variability is crucial for predicting the risk of disease progression. The aim of the study was to investigate the polymorphic variants of IL-1β (T-31C), TNF-α (G-308A), IL-10 (G-1082A), IL-17(G-197A), and IL-4 (C-589T) genes in COVID-19 patients. We examined 142 patients with proven diagnosis of COVID-19. The control group consisted of 72 healthy donors. Realtime polymerase chain reaction method was used to study polymorphisms of cytokine genes IL-1β (T-31C), TNF-α (G-308A), IL-10 (G-1082A), IL-17(G-197A), IL-4 (C-589T) in COVID-19 patients compared to healthy individuals. Among the studied polymorphic variants of cytokine genes the most significant predictors of increased risk of COVID-19 development were: genotype -1082A/A of IL-10 gene, genotype -197A/A of IL-17 gene. On the contrary, the following were predictors of reduced risk of COVID-19 development: genotype -589C/T of IL-4 gene, genotype -31C/C of IL-1β gene, genotypes -308 G/A and -308 A/A of TNF-α gene. Thus, the analysis of gene polymorphisms of the most important cytokines such as IL-4, IL-10, IL-17A, IL-1β, TNF-α allows us to assess the genetic predisposition of patients to an increased risk of COVID-19 development, which is important for predicting the outcome of the disease.
Key words: COVID-19; cytokines; gene polymorphisms; risk of development.
Список литературы
1.Malinnikova E.Yu. A new coronavirus infection. Today’s view of a twenty-first century pandemic. Infektsionnye bolezni: novosti, mneniya, obuchenie. 2020; 9(2):18-32. DOI: 10.33029/2305-3496-2020-9-2-18-32. (in Russian)
2.Boldyreva M.N. SARS-CoV-2 virus and other epidemic coronaviruses: pathogenetic and genetic factors in the development of infections. Immunologiya. 2020; 4 (3):197-205. DOI: 10.33029/0206-4952-2020-41-3-197-205. (in Russian)
3.Gupta K., Kaur G., Pathak T., Banerjee I. Systematic review and meta-analysis of human genetic variants contributing to COVID-19 susceptibility and severity. Review Gene. 2022; 30(844):146790. DOI: 10.1016/j.gene.2022.146790.
4.Arutyunov G.P., Tarlovskaya E.I., Koziolova N.A., Boldina M.V., Batyushin M.M. Agreed position of experts of the Eurasian Association of Therapists on the tactics of management of patients with comorbid pathology infected with SARS-CoV-2. Terapevticheskiy arkhiv. 2020; 92(9):108–24. DOI: 10.26442/00403660.2020.09.000703. (in Russian)
5.Sabirov I.S., Abduvakhapov B.Z., Mamedova K.M., Sultanova M.S., Sabirova A.I. Gerontologic aspects of the clinical and pathogenetic features of novel coronavirus infection (COVID-19). The scientific heritage. 2021; 61(2):45-53. DOI: 10.24412/9215-0365-2021-61-2-45-53. (in Russian)
6.Kantemirova B.I., Vasil’kova V.V. Gene polymorphisms in patients with novel coronavirus infection. Infektsionnye bolezni: novosti, mneniya, obuchenie. 2022; 11(3): 130–7. DOI: 10.33029/2305-3496-2022-11-3-130-137. (in Russian)
7.Ahmadian E, Khatibi S.M., Soofiyani S.R., Abediazar S., Shoja M., Ardalan M., et al. COVID-19 and kidney injury: pathophysiology and molecular mechanisms. Rev. Med. Virol. 2020; 3: e2176. DOI: 10.1002/rmv.2176.
8.Sakurai A., Sasaki T., Kato S., Hayashi M. Natural history of asymptomatic SARS-CoV-2 infection. N. Engl. J. Med. 2020; 383(3): 885–6. DOI: 10.1056/NEJMc2013020.
9.Vologzhanin D.A, Golota A.S., Kamilova T.A., Shneyder O.V., Shcherbak S.G. Genetics of COVID-19. Klinicheskaya praktika. 2021; 12(1):41-52. DOI: 10.17816/clinpract64972. (in Russian)
10.Zeberg H., Paabo S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature. 2020; (587):610-2. DOI: 10.1038/s41586-020-2818-3.
11.Kaser A. Genetic risk of severe COVID-19. N. Engl. J. Med. 2020; 383(16):1590-1. DOI: 10.1056/NEJMe2025501.
12.Lu Q., Zhu Z., Tan C., Zhou H. Changes of serum IL‐10, IL‐1β, IL‐6, MCP‐1, TNF‐α, IP‐10 and IL‐4 in COVID‐19 patients. International Journal of Clinical Practice. 2021; 75(9):14462. DOI: 10.1111/ijcp.14462.
13.Kirtipal N., Bharadwaj S. Interleukin 6 polymorphisms as an indicator of COVID-19 severity in humans. J. biomol. Struct. Dyn. 2020; 39(12):4563-5. DOI: 10.1080/07391102.2020.1776640.
14.Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; (395):497–506. DOI: 10.1016/S0140-67362030183-5.
15.Schooling C.M., Li M., Yeung S.L. Interleukin-18 and COVID-19. Epidemiol. Infect. 2021; (150):e14. DOI: 10.1017/S0950268821002636.
16.Drapkina O.M., Maev I.V., Bakulin I.G., Nikonov E.L., Chulanov V.P., Belousova E.A. et al. Temporary methodological recommendations «Diseases of digestive organs in conditions of pandemic of new coronavirus1 infection (COVID-19)». Profilakticheskaya meditsina. 2020; 23(3-2):120-52. DOI: 10.17116/profmed202023032120. (in Russian)
17.Qin C., Zhou L., Hu Z., Zhang S. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis. 2020; 71(15):248. DOI: 10.1093/cid/ciaa248.
18.Manik M., Singh R.K. Role of toll-like receptors in modulation of cytokine storm signaling in SARS-CoV-2-induced COVID-19. J. Med. Virol. 2022; 94(3):869-77. DOI: 10.1002/jmv.27405.
19.Chen G., Wu D., Guo W., Cao Y., Huang D., Wang H. et al. Clinical and immunologic features in severe and moderate Coronavirus Disease 2019. J. Clin. Invest. 2020; 130(5): 2620-9. DOI: 10.1101/2020.02.16.20023903.
20.Mulla S., Molla M.A., Ali-Ahmed S.M., Saleh A.A., Anwar S. Association of interferon gamma inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, interleukin-6, and rs12252 single nucleotide polymorphism of interferon-induced transmembrane protein-3 gene with the severity of COVID-19 infection. Egypt J. Intern. Med. 2022; 34(1):53. DOI: 10.1186/s43162-022-00141-9.
21.Belyaeva S.V., Stashkevich D.S., Balandina S.E., Myakotina D.E. IL-6 gene polymorphism in COVID-19 russian patients of the Chelyabinsk region. Vestnik Сhelyabinskogo gosudarstvennogo universiteta. Obrazovanie i zdravookhranenie. 2022; 4 (20):5-11. DOI: 10.24411/2409-4102-2022-10401. (in Russian)
22.Aladawy S.A., Lamiaa A Adel L.A. Abdel Salam S.A., Raafat R.H., Khattab M.A. Polymorphism in the promoter region of the IL6 gene as a predictor of disease severity in COVID-19 patients. Egypt. J. Immunol. 2022; 29 (2):1-9. PMID: 35436049.
23.Verma S., Verma Su., Khan F. H, Siddiqi Z., Raza S.T., Abbas M., et al. Genetic polymorphisms of IL6 gene -174G > C and -597G > A are associated with the risk of COVID-19 severity. Int. J. Immunogenet. 2023; 50(1):5-11. DOI: 10.1111/iji.12605.
24.Narovlyanskiy A.N., Ershov F.I., Sanin A.V., Pronin A.V. The interferon system in COVID-19. Immunologiya. 2022; 43(3):245-54. DOI: 10.33029/0206-4952-2022-43-3-245-254. (in Russian)
25.Ruan Q, Yang K, Wang W, Jiang L., Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020; 46 (5): 846–8. DOI: .1007/s00134-020-05991-x.
26.Renu K, Subramaniam M. D., Chakraborty R., Myakala H., Iyer M., Bharathi G. , et.al. The role of Interleukin-4 in COVID-19 associated male infertility — A hypothesis. J. Reprod. Immunol. 2020; 142:103213. DOI: 10.1016/j.jri.2020.103213.
27.Balzanelli M.G., Distratis P., Lazzaro R., Pham V.H., Tran T. C., Dipalma G. Analysis of gene single nucleotide polymorphisms in COVID-19 disease highlighting the susceptibility and the severity towards the infection. Diagnostics (Basel). 2022; 12(11): 2824. DOI: 10.3390/diagnostics12112824.
28.Vabret N., Britton, G.J., Gruber C., Hegde S., Kim J., Kuksin M., et al. The Sinai Immunology Review Project, Immunology of COVID-19: current state of the science. Immunity. 2020; 52(6):910–41. DOI: 10.1016/j.immuni.2020.05.002.
29.Kindler E., Thiel V., Weber F. Interaction of SARS and MERS coronaviruses with the antiviral interferon response. Adv. Virus. Res. 2016; (96):219–43. DOI: 10.1016/bs.aivir.2016.08.006.
30.Rizvi S., Rizvi M., Raza S.T., Abbas M., Fatima K., Zaidi Z.H. Effect of single nucleotide polymorphisms in the interleukin-10 gene (rs1800896 and rs1800872) on the severity of COVID-19. Egypt J. Med. Hum. Genet. 2022; 23(1):145. DOI: 10.1186/s43042-022-00344-3.
31.El-Desoky M.M., Tharwat S., Mostafa N., Rehabilitation E., Abdelhafez M.S., El-Ashri A.H. et.al. Association of interleukin-17F polymorphisms and predictors of mortality with COVID-19 risk. International Clinical Practice. 2022; Article ID 4761631:1-8. DOI: 10.1155/2022/4761631.