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Полиморфизм rs5918 гена ITGB3 повышает риск развития преэклампсии у беременных с задержкой роста плода
Полиморфизм rs5918 гена ITGB3 повышает риск развития преэклампсии у беременных с задержкой роста плода
Головченко О.В., Пономаренко И.В., Чурносов М.И. Полиморфизм rs5918 гена ITGB3 повышает риск развития преэклампсии у беременных с задержкой роста плода. Гинекология. 2021; 23 (4): 330–334.
DOI: 10.26442/20795696.2021.4.200863
DOI: 10.26442/20795696.2021.4.200863
DOI: 10.26442/20795696.2021.4.200863
________________________________________________
DOI: 10.26442/20795696.2021.4.200863
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Цель. Оценить связь полиморфных локусов rs5918 ITGB3, rs1126643 ITGA2 и rs5985 F13A1 с риском развития преэклампсии (ПЭ) у беременных с задержкой роста плода (ЗРП).
Материалы и методы. Группа для исследования включала 272 беременных, из которых 76 – с сочетанием ПЭ и ЗРП и 196 – с ЗРП. В исследуемых группах проведено генетическое тестирование трех полиморфных локусов генов-кандидатов наследственных тромбофилий (rs5918 ITGB3, rs1126643 ITGA2 и rs5985 F13A1).
Результаты. Генетический вариант rs5918 гена ITGB3 связан с развитием ПЭ у беременных с ЗРП: аллель С rs5918 ITGB3 в 1,8 раза повышает риск формирования этого осложнения беременности (отношение шансов 1,76–1,77, р≤0,036, рperm≤0,038). Полиморфизм rs5918 определяет повышение аффинности мотивов ДНК к семи факторам транскрипции (BDP1, ELF1, IRF, NRSF, Pax-5, Sp1 и Zfx), является миссенс-мутацией и обусловливает аминокислотную замену Leu59Pro в β3-субъединице интегрина, разнонаправленно связан с экспрессией пяти генов (EFCAB13, TBKBP1, NPEPPS, MRPL45P2, THCAT158) и альтернативным сплайсингом двух генов (EFCAB13, MRPL45P2), расположен в области функционально значимых регионов ДНК (промоторы и энхансеры) в патогенетически значимых для формирования ПЭ и ЗРП культурах клеток и органах.
Заключение. Полиморфизм rs5918 гена ITGB3 повышает риск развития ПЭ у беременных с ЗРП.
Ключевые слова: преэклампсия, задержка роста плода, полиморфизм, ITGB3, ассоциации
Materials and methods. The study included 272 pregnant women, of which 76 had a combination of PE and FGR and 196 had FGR. In the studied groups, genetic testing was carried out for three polymorphic loci of candidate genes for hereditary thrombophilia (rs5918 ITGB3, rs1126643 ITGA2, and rs5985 F13A1).
Results. The rs5918 genetic variant in the ITGB3 gene is associated with the development of PE in pregnant women with FGR: C allele of rs5918 ITGB3 increases the risk for this complication of pregnancy by 1,8 times (OR 1.76–1.77, p≤0.036, pperm≤0.038). The rs5918 polymorphism determines an increase in the affinity of DNA motifs for seven transcription factors (BDP1, ELF1, IRF, NRSF, Pax-5, Sp1, and Zfx), is a missense mutation and causes the Leu59Pro amino acid substitution in the β3 subunit of integrin, is multidirectionally associated with the expression of five genes (EFCAB13, TBKBP1, NPEPPS, MRPL45P2, THCAT158) and alternative splicing of two genes (EFCAB13, MRPL45P2), is located in the region of functionally important DNA regions (promoters and enhancers) in cell cultures and organs which are pathogenetically important for the formation of PE and FGR.
Conclusion. The rs5918 polymorphism in the ITGB3 gene increases the risk for PE in pregnant women with FGR.
Keywords: preeclampsia, fetal growth retardation, polymorphism, ITGB3, associations
Материалы и методы. Группа для исследования включала 272 беременных, из которых 76 – с сочетанием ПЭ и ЗРП и 196 – с ЗРП. В исследуемых группах проведено генетическое тестирование трех полиморфных локусов генов-кандидатов наследственных тромбофилий (rs5918 ITGB3, rs1126643 ITGA2 и rs5985 F13A1).
Результаты. Генетический вариант rs5918 гена ITGB3 связан с развитием ПЭ у беременных с ЗРП: аллель С rs5918 ITGB3 в 1,8 раза повышает риск формирования этого осложнения беременности (отношение шансов 1,76–1,77, р≤0,036, рperm≤0,038). Полиморфизм rs5918 определяет повышение аффинности мотивов ДНК к семи факторам транскрипции (BDP1, ELF1, IRF, NRSF, Pax-5, Sp1 и Zfx), является миссенс-мутацией и обусловливает аминокислотную замену Leu59Pro в β3-субъединице интегрина, разнонаправленно связан с экспрессией пяти генов (EFCAB13, TBKBP1, NPEPPS, MRPL45P2, THCAT158) и альтернативным сплайсингом двух генов (EFCAB13, MRPL45P2), расположен в области функционально значимых регионов ДНК (промоторы и энхансеры) в патогенетически значимых для формирования ПЭ и ЗРП культурах клеток и органах.
Заключение. Полиморфизм rs5918 гена ITGB3 повышает риск развития ПЭ у беременных с ЗРП.
Ключевые слова: преэклампсия, задержка роста плода, полиморфизм, ITGB3, ассоциации
________________________________________________
Materials and methods. The study included 272 pregnant women, of which 76 had a combination of PE and FGR and 196 had FGR. In the studied groups, genetic testing was carried out for three polymorphic loci of candidate genes for hereditary thrombophilia (rs5918 ITGB3, rs1126643 ITGA2, and rs5985 F13A1).
Results. The rs5918 genetic variant in the ITGB3 gene is associated with the development of PE in pregnant women with FGR: C allele of rs5918 ITGB3 increases the risk for this complication of pregnancy by 1,8 times (OR 1.76–1.77, p≤0.036, pperm≤0.038). The rs5918 polymorphism determines an increase in the affinity of DNA motifs for seven transcription factors (BDP1, ELF1, IRF, NRSF, Pax-5, Sp1, and Zfx), is a missense mutation and causes the Leu59Pro amino acid substitution in the β3 subunit of integrin, is multidirectionally associated with the expression of five genes (EFCAB13, TBKBP1, NPEPPS, MRPL45P2, THCAT158) and alternative splicing of two genes (EFCAB13, MRPL45P2), is located in the region of functionally important DNA regions (promoters and enhancers) in cell cultures and organs which are pathogenetically important for the formation of PE and FGR.
Conclusion. The rs5918 polymorphism in the ITGB3 gene increases the risk for PE in pregnant women with FGR.
Keywords: preeclampsia, fetal growth retardation, polymorphism, ITGB3, associations
Полный текст
Список литературы
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5. Головченко О.В. Молекулярно-генетические детерминанты преэклампсии. Научные результаты биомедицинских исследований. 2019;5(4):139-49 [Golovchenko OV. Molecular genetic determinants of pre-eclampsia. Research Results in Biomedicine. 2019;5(4):139-49 (in Russian)]. DOI:10.18413/2658-6533-2019-5-4-0-11
6. Reshetnikov E, Ponomarenko I, Golovchenko O, et al. The VNTR polymorphism of the endothelial nitric oxide synthase gene and blood pressure in women at the end of pregnancy. Taiwan J Obstet Gynecol. 2019;58(3):390-5. DOI:10.1016/j.tjog.2018.11.035
7. Ефремова О.А. Изучение ассоциации полиморфных локусов генов фолатного цикла с развитием синдрома задержки роста плода 2–3 степени. Научные результаты биомедицинских исследований. 2020;6(1):37-50 [Efremova OA. The study of the association of polymorphic loci of the folate cycle genes with the development of the 2-3-degree fetal growth restriction syndrome. Research Results in Biomedicine. 2020;6(1):37-50 (in Russian)]. DOI:10.18413/2658-6533-2020-6-1-0-4
8. Golovchenko O, Abramova M, Ponomarenko I, et al. Functionally significant polymorphisms of ESR1 and PGR and risk of intrauterine growth restriction in population of Central Russia. Eur J Obstet Gynecol Reprod Biol. 2020;253:52-7. DOI:10.1016/j.ejogrb.2020.07.045
9. Dugalić S, Petronijevic M, Stefanovic A, et al. The association between IUGR and maternal inherited thrombophilias: A case-control study. Medicine (Baltimore). 2018;97(41):e12799. DOI:10.1097/MD.0000000000012799
10. Reshetnikov E, Zarudskaya O, Polonikov A, et al. Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia. J Obstet Gynaecol Res. 2017;43(7):1139-44. DOI:10.1111/jog.13329
11. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.
N Engl J Med. 2002;347(1):19-25. DOI:10.1056/NEJM200207043470105
12. Ponomarenko IV, Reshetnikov EA, Altuchova OB, et al. Association of genetic polymorphisms with age at menarche in Russian women. Gene. 2019;686:228-36. DOI:10.1016/j.gene.2018.11.042
13. Пономаренко И.В., Решетников Е.А., Полоников А.В., Чурносов М.И. Полиморфный локус rs314276 гена LIN28B ассоциирован с возрастом менархе у женщин Центрального Черноземья России. Акушерство и гинекология. 2019;2:98-104 [Ponomarenko IV, Reshetnikov EA, Polonikov AV, Churnosov MI. The polymorphic locus rs314276 of the LIN28B gene is associated with the age of menarche in women of the Central Black Earth Region of Russia. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2019;2:98-104 (in Russian)]. DOI:10.18565/aig.2019.2.98-104
14. Пономаренко И.В., Полоников А.В., Чурносов М.И. Полиморфные локусы гена LHCGR, ассоциированные с развитием миомы матки. Акушерство и гинекология. 2018;10:86-91 [Ponomarenko IV, Polonikov AV, Churnosov MI. Polymorphic LHCGR gene loci associated with the development of uterine fibroids. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2018;10:86-91 (in Russian)].
DOI:10.18565/aig.2018.10.86-91
15. Gibbs JR, van der Brug MP, Hernandez DG, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6(5):e1000952. DOI:10.1371/journal.pgen.1000952
16. Goncharova IA, Babushkina NP, Minaĭcheva LI, et al. Prevalence of alleles of polymorphic variants Leu33Pro and Leu66Arg gene ITGB3 among inhabitants of Siberia. Genetika. 2013;49(8):1008-12.
17. Karami F, Askari M, Modarressi MH. Investigating Association of rs5918 Human Platelets Antigen 1 and rs1800790 Fibrinogen β Chain as Critical Players with Recurrent Pregnancy Loss. Med Sci (Basel). 2018;6(4):98. DOI:10.3390/medsci6040098
18. Ruzzi L, Ciarafoni I, Silvestri L, et al. Association of PLA2 polymorphism of the ITGB3 gene with early fetal loss. Fertil Steril. 2005;83(2):511-2. DOI:10.1016/j.fertnstert.2004.10.024
19. Khatami M, Heidari MM, Soheilyfar S. Common rs5918 (PlA1/A2) polymorphism in the ITGB3 gene and risk of coronary artery disease. Arch Med Sci Atheroscler Dis. 2016;1(1):e9-e15. DOI:10.5114/amsad.2016.59587
20. Komsa-Penkova R, Golemanov G, Tsankov B, et al. Rs5918 ITGB3 Polymorphism, Smoking, and BMI as Risk Factors for Early Onset and Recurrence of DVT in Young Women. Clin Appl Thromb Hemost. 2017;23(6):585-95. DOI:10.1177/1076029615624778
2. Heshmat SH. Intrauterine Growth Restriction – A Review Article. Anatomy Physiol Biochem Int J. 2017;1(5):555-72. DOI:10.19080/APBIJ.2017.01.555572
3. Simcox LE, Ormesher L, Tower C, Greer IA. Thrombophilia and Pregnancy Complications. Int J Mol Sci. 2015;16(12):28418-28. DOI:10.3390/ijms161226104
4. Reshetnikov EA, Akulova LY, Dobrodomova IS, et al. The insertion-deletion polymorphism of the ACE gene is associated with increased blood pressure in women at the end of pregnancy. J Renin Angiotensin Aldosterone Syst. 2015;16(3):623-32. DOI:10.1177/1470320313501217
5. Golovchenko OV. Molecular genetic determinants of pre-eclampsia. Research Results in Biomedicine. 2019;5(4):139-49 (in Russian). DOI:10.18413/2658-6533-2019-5-4-0-11
6. Reshetnikov E, Ponomarenko I, Golovchenko O, et al. The VNTR polymorphism of the endothelial nitric oxide synthase gene and blood pressure in women at the end of pregnancy. Taiwan J Obstet Gynecol. 2019;58(3):390-5. DOI:10.1016/j.tjog.2018.11.035
7. Efremova OA. The study of the association of polymorphic loci of the folate cycle genes with the development of the 2-3-degree fetal growth restriction syndrome. Research Results in Biomedicine. 2020;6(1):37-50 (in Russian). DOI:10.18413/2658-6533-2020-6-1-0-4
8. Golovchenko O, Abramova M, Ponomarenko I, et al. Functionally significant polymorphisms of ESR1 and PGR and risk of intrauterine growth restriction in population of Central Russia. Eur J Obstet Gynecol Reprod Biol. 2020;253:52-7. DOI:10.1016/j.ejogrb.2020.07.045
9. Dugalić S, Petronijevic M, Stefanovic A, et al. The association between IUGR and maternal inherited thrombophilias: A case-control study. Medicine (Baltimore). 2018;97(41):e12799. DOI:10.1097/MD.0000000000012799
10. Reshetnikov E, Zarudskaya O, Polonikov A, et al. Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia. J Obstet Gynaecol Res. 2017;43(7):1139-44. DOI:10.1111/jog.13329
11. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.
N Engl J Med. 2002;347(1):19-25. DOI:10.1056/NEJM200207043470105
12. Ponomarenko IV, Reshetnikov EA, Altuchova OB, et al. Association of genetic polymorphisms with age at menarche in Russian women. Gene. 2019;686:228-36. DOI:10.1016/j.gene.2018.11.042
13. Ponomarenko IV, Reshetnikov EA, Polonikov AV, Churnosov MI. The polymorphic locus rs314276 of the LIN28B gene is associated with the age of menarche in women of the Central Black Earth Region of Russia. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2019;2:98-104 (in Russian). DOI:10.18565/aig.2019.2.98-104
14. Ponomarenko IV, Polonikov AV, Churnosov MI. Polymorphic LHCGR gene loci associated with the development of uterine fibroids. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2018;10:86-91 (in Russian).
DOI:10.18565/aig.2018.10.86-91
15. Gibbs JR, van der Brug MP, Hernandez DG, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6(5):e1000952. DOI:10.1371/journal.pgen.1000952
16. Goncharova IA, Babushkina NP, Minaĭcheva LI, et al. Prevalence of alleles of polymorphic variants Leu33Pro and Leu66Arg gene ITGB3 among inhabitants of Siberia. Genetika. 2013;49(8):1008-12.
17. Karami F, Askari M, Modarressi MH. Investigating Association of rs5918 Human Platelets Antigen 1 and rs1800790 Fibrinogen β Chain as Critical Players with Recurrent Pregnancy Loss. Med Sci (Basel). 2018;6(4):98. DOI:10.3390/medsci6040098
18. Ruzzi L, Ciarafoni I, Silvestri L, et al. Association of PLA2 polymorphism of the ITGB3 gene with early fetal loss. Fertil Steril. 2005;83(2):511-2. DOI:10.1016/j.fertnstert.2004.10.024
19. Khatami M, Heidari MM, Soheilyfar S. Common rs5918 (PlA1/A2) polymorphism in the ITGB3 gene and risk of coronary artery disease. Arch Med Sci Atheroscler Dis. 2016;1(1):e9-e15. DOI:10.5114/amsad.2016.59587
20. Komsa-Penkova R, Golemanov G, Tsankov B, et al. Rs5918 ITGB3 Polymorphism, Smoking, and BMI as Risk Factors for Early Onset and Recurrence of DVT in Young Women. Clin Appl Thromb Hemost. 2017;23(6):585-95. DOI:10.1177/1076029615624778
2. Heshmat SH. Intrauterine Growth Restriction – A Review Article. Anatomy Physiol Biochem Int J. 2017;1(5):555-72. DOI:10.19080/APBIJ.2017.01.555572
3. Simcox LE, Ormesher L, Tower C, Greer IA. Thrombophilia and Pregnancy Complications. Int J Mol Sci. 2015;16(12):28418-28. DOI:10.3390/ijms161226104
4. Reshetnikov EA, Akulova LY, Dobrodomova IS, et al. The insertion-deletion polymorphism of the ACE gene is associated with increased blood pressure in women at the end of pregnancy. J Renin Angiotensin Aldosterone Syst. 2015;16(3):623-32. DOI:10.1177/1470320313501217
5. Головченко О.В. Молекулярно-генетические детерминанты преэклампсии. Научные результаты биомедицинских исследований. 2019;5(4):139-49 [Golovchenko OV. Molecular genetic determinants of pre-eclampsia. Research Results in Biomedicine. 2019;5(4):139-49 (in Russian)]. DOI:10.18413/2658-6533-2019-5-4-0-11
6. Reshetnikov E, Ponomarenko I, Golovchenko O, et al. The VNTR polymorphism of the endothelial nitric oxide synthase gene and blood pressure in women at the end of pregnancy. Taiwan J Obstet Gynecol. 2019;58(3):390-5. DOI:10.1016/j.tjog.2018.11.035
7. Ефремова О.А. Изучение ассоциации полиморфных локусов генов фолатного цикла с развитием синдрома задержки роста плода 2–3 степени. Научные результаты биомедицинских исследований. 2020;6(1):37-50 [Efremova OA. The study of the association of polymorphic loci of the folate cycle genes with the development of the 2-3-degree fetal growth restriction syndrome. Research Results in Biomedicine. 2020;6(1):37-50 (in Russian)]. DOI:10.18413/2658-6533-2020-6-1-0-4
8. Golovchenko O, Abramova M, Ponomarenko I, et al. Functionally significant polymorphisms of ESR1 and PGR and risk of intrauterine growth restriction in population of Central Russia. Eur J Obstet Gynecol Reprod Biol. 2020;253:52-7. DOI:10.1016/j.ejogrb.2020.07.045
9. Dugalić S, Petronijevic M, Stefanovic A, et al. The association between IUGR and maternal inherited thrombophilias: A case-control study. Medicine (Baltimore). 2018;97(41):e12799. DOI:10.1097/MD.0000000000012799
10. Reshetnikov E, Zarudskaya O, Polonikov A, et al. Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia. J Obstet Gynaecol Res. 2017;43(7):1139-44. DOI:10.1111/jog.13329
11. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.
N Engl J Med. 2002;347(1):19-25. DOI:10.1056/NEJM200207043470105
12. Ponomarenko IV, Reshetnikov EA, Altuchova OB, et al. Association of genetic polymorphisms with age at menarche in Russian women. Gene. 2019;686:228-36. DOI:10.1016/j.gene.2018.11.042
13. Пономаренко И.В., Решетников Е.А., Полоников А.В., Чурносов М.И. Полиморфный локус rs314276 гена LIN28B ассоциирован с возрастом менархе у женщин Центрального Черноземья России. Акушерство и гинекология. 2019;2:98-104 [Ponomarenko IV, Reshetnikov EA, Polonikov AV, Churnosov MI. The polymorphic locus rs314276 of the LIN28B gene is associated with the age of menarche in women of the Central Black Earth Region of Russia. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2019;2:98-104 (in Russian)]. DOI:10.18565/aig.2019.2.98-104
14. Пономаренко И.В., Полоников А.В., Чурносов М.И. Полиморфные локусы гена LHCGR, ассоциированные с развитием миомы матки. Акушерство и гинекология. 2018;10:86-91 [Ponomarenko IV, Polonikov AV, Churnosov MI. Polymorphic LHCGR gene loci associated with the development of uterine fibroids. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2018;10:86-91 (in Russian)].
DOI:10.18565/aig.2018.10.86-91
15. Gibbs JR, van der Brug MP, Hernandez DG, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6(5):e1000952. DOI:10.1371/journal.pgen.1000952
16. Goncharova IA, Babushkina NP, Minaĭcheva LI, et al. Prevalence of alleles of polymorphic variants Leu33Pro and Leu66Arg gene ITGB3 among inhabitants of Siberia. Genetika. 2013;49(8):1008-12.
17. Karami F, Askari M, Modarressi MH. Investigating Association of rs5918 Human Platelets Antigen 1 and rs1800790 Fibrinogen β Chain as Critical Players with Recurrent Pregnancy Loss. Med Sci (Basel). 2018;6(4):98. DOI:10.3390/medsci6040098
18. Ruzzi L, Ciarafoni I, Silvestri L, et al. Association of PLA2 polymorphism of the ITGB3 gene with early fetal loss. Fertil Steril. 2005;83(2):511-2. DOI:10.1016/j.fertnstert.2004.10.024
19. Khatami M, Heidari MM, Soheilyfar S. Common rs5918 (PlA1/A2) polymorphism in the ITGB3 gene and risk of coronary artery disease. Arch Med Sci Atheroscler Dis. 2016;1(1):e9-e15. DOI:10.5114/amsad.2016.59587
20. Komsa-Penkova R, Golemanov G, Tsankov B, et al. Rs5918 ITGB3 Polymorphism, Smoking, and BMI as Risk Factors for Early Onset and Recurrence of DVT in Young Women. Clin Appl Thromb Hemost. 2017;23(6):585-95. DOI:10.1177/1076029615624778
________________________________________________
2. Heshmat SH. Intrauterine Growth Restriction – A Review Article. Anatomy Physiol Biochem Int J. 2017;1(5):555-72. DOI:10.19080/APBIJ.2017.01.555572
3. Simcox LE, Ormesher L, Tower C, Greer IA. Thrombophilia and Pregnancy Complications. Int J Mol Sci. 2015;16(12):28418-28. DOI:10.3390/ijms161226104
4. Reshetnikov EA, Akulova LY, Dobrodomova IS, et al. The insertion-deletion polymorphism of the ACE gene is associated with increased blood pressure in women at the end of pregnancy. J Renin Angiotensin Aldosterone Syst. 2015;16(3):623-32. DOI:10.1177/1470320313501217
5. Golovchenko OV. Molecular genetic determinants of pre-eclampsia. Research Results in Biomedicine. 2019;5(4):139-49 (in Russian). DOI:10.18413/2658-6533-2019-5-4-0-11
6. Reshetnikov E, Ponomarenko I, Golovchenko O, et al. The VNTR polymorphism of the endothelial nitric oxide synthase gene and blood pressure in women at the end of pregnancy. Taiwan J Obstet Gynecol. 2019;58(3):390-5. DOI:10.1016/j.tjog.2018.11.035
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Авторы
О.В. Головченко, И.В. Пономаренко, М.И. Чурносов*
ФГАОУ ВО «Белгородский государственный национальный исследовательский университет», Белгород, Россия
*churnosov@bsu.edu.ru
Belgorod State University, Belgorod, Russia
*churnosov@bsu.edu.ru
ФГАОУ ВО «Белгородский государственный национальный исследовательский университет», Белгород, Россия
*churnosov@bsu.edu.ru
________________________________________________
Belgorod State University, Belgorod, Russia
*churnosov@bsu.edu.ru
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