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Полиморфизм гена EGF материнского организма, связанный с развитием задержки роста плода
Полиморфизм гена EGF материнского организма, связанный с развитием задержки роста плода
Головченко О.В., Пономаренко И.В., Чурносов М.И. Полиморфизм гена EGF материнского организма, связанный с развитием задержки роста плода. Гинекология. 2021;23(6):554–558.
DOI: 10.26442/20795696.2021.6.201232
DOI: 10.26442/20795696.2021.6.201232
DOI: 10.26442/20795696.2021.6.201232
________________________________________________
DOI: 10.26442/20795696.2021.6.201232
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Цель. Изучить вовлеченность полиморфизма генов факторов роста и их рецепторов в формирование задержки роста плода (ЗРП).
Материалы и методы. В рамках данного проспективного сравнительного исследования у 196 беременных с ЗРП и 324 беременных контрольной группы выполнен генетический анализ 5 полиморфных локусов генов факторов роста и их рецепторов (rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs6214 IGF1, rs1800469 TGFβ1). Для генотипирования однонуклеотидного полиморфизма использовался метод полимеразной цепной реакции. Оценка медико-биологических механизмов, лежащих в основе выявленных ассоциаций, проводилась с применением современных биоинформатических ресурсов: GTExportal (влияние на транскрипцию генов) и HaploReg (регуляторный потенциал).
Результаты. Аллельный вариант G rs4444903 гена EGF определяет повышенный риск возникновения ЗРП в рамках следующих генетических моделей: аллельной (отношение шансов – ОШ 1,28, 95% доверительный интервал – ДИ 1,00–1,65; рperm=0,033), аддитивной (ОШ 1,33, 95% ДИ 1,02–1,75; рperm=0,039) и доминантной (ОШ 1,62, 95% ДИ 1,06–2,47; рperm=0,031). Полиморфизм rs4444903 гена EGF обладает существенным эпигенетическим потенциалом (в области промоторов, энхансеров, «открытого хроматина», белков – регуляторов транскрипции), детерминирует экспрессию генов EGF и GAR1 и альтернативный сплайсинг гена GAR1 в органах и тканях (плацента, головной мозг плода и взрослого организма и др.), являющихся значимыми для патофизиологии ЗРП.
Заключение. Показаны ассоциации rs4444903 гена EGF с формированием ЗРП.
Ключевые слова: задержка роста плода, однонуклеотидный полиморфизм, EGF, ассоциации
Materials and methods. In this prospective comparative study, genetic analysis of five polymorphic loci of growth factor genes and their receptors (rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs6214 IGF1, rs1800469 TGFß1) was performed in 196 pregnant women with FGR and 324 pregnant women in the control group. For genotyping single-nucleotide polymorphism, the polymerase chain reaction method was used. The biomedical mechanisms underlying the identified associations were evaluated using modern bioinformatic resources: GTExportal (effect on gene transcription) and HaploReg (regulatory potential).
Results. The allelic variant G rs4444903 of the EGF gene determines an increased risk of FGR in the following genetic models: allelic (OR 1.28, 95% CI 1.00–1.65; рperm=0.033), additive (OR 1.33, 95% CI 1.02–1.75; рperm=0.039) and dominant (OR 1.62, 95% CI 1.06–2.47; рperm=0.031). The polymorphism rs4444903 of the EGF gene has a significant epigenetic potential (in the field of promoters, enhancers, "open chromatin", transcription regulatory proteins), determines the expression of the EGF and GAR1 genes and alternative splicing of the GAR1 gene in organs and tissues (placenta, fetal and adult brain, etc.), which are significant for the pathophysiology of FGR.
Conclusion. The associations rs4444903 of the EGF gene with the FGR are shown.
Keywords: fetal growth retardation, single-nucleotide polymorphism, EGF, association
Материалы и методы. В рамках данного проспективного сравнительного исследования у 196 беременных с ЗРП и 324 беременных контрольной группы выполнен генетический анализ 5 полиморфных локусов генов факторов роста и их рецепторов (rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs6214 IGF1, rs1800469 TGFβ1). Для генотипирования однонуклеотидного полиморфизма использовался метод полимеразной цепной реакции. Оценка медико-биологических механизмов, лежащих в основе выявленных ассоциаций, проводилась с применением современных биоинформатических ресурсов: GTExportal (влияние на транскрипцию генов) и HaploReg (регуляторный потенциал).
Результаты. Аллельный вариант G rs4444903 гена EGF определяет повышенный риск возникновения ЗРП в рамках следующих генетических моделей: аллельной (отношение шансов – ОШ 1,28, 95% доверительный интервал – ДИ 1,00–1,65; рperm=0,033), аддитивной (ОШ 1,33, 95% ДИ 1,02–1,75; рperm=0,039) и доминантной (ОШ 1,62, 95% ДИ 1,06–2,47; рperm=0,031). Полиморфизм rs4444903 гена EGF обладает существенным эпигенетическим потенциалом (в области промоторов, энхансеров, «открытого хроматина», белков – регуляторов транскрипции), детерминирует экспрессию генов EGF и GAR1 и альтернативный сплайсинг гена GAR1 в органах и тканях (плацента, головной мозг плода и взрослого организма и др.), являющихся значимыми для патофизиологии ЗРП.
Заключение. Показаны ассоциации rs4444903 гена EGF с формированием ЗРП.
Ключевые слова: задержка роста плода, однонуклеотидный полиморфизм, EGF, ассоциации
________________________________________________
Materials and methods. In this prospective comparative study, genetic analysis of five polymorphic loci of growth factor genes and their receptors (rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs6214 IGF1, rs1800469 TGFß1) was performed in 196 pregnant women with FGR and 324 pregnant women in the control group. For genotyping single-nucleotide polymorphism, the polymerase chain reaction method was used. The biomedical mechanisms underlying the identified associations were evaluated using modern bioinformatic resources: GTExportal (effect on gene transcription) and HaploReg (regulatory potential).
Results. The allelic variant G rs4444903 of the EGF gene determines an increased risk of FGR in the following genetic models: allelic (OR 1.28, 95% CI 1.00–1.65; рperm=0.033), additive (OR 1.33, 95% CI 1.02–1.75; рperm=0.039) and dominant (OR 1.62, 95% CI 1.06–2.47; рperm=0.031). The polymorphism rs4444903 of the EGF gene has a significant epigenetic potential (in the field of promoters, enhancers, "open chromatin", transcription regulatory proteins), determines the expression of the EGF and GAR1 genes and alternative splicing of the GAR1 gene in organs and tissues (placenta, fetal and adult brain, etc.), which are significant for the pathophysiology of FGR.
Conclusion. The associations rs4444903 of the EGF gene with the FGR are shown.
Keywords: fetal growth retardation, single-nucleotide polymorphism, EGF, association
Полный текст
Список литературы
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8. 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
9. Litovkina O, Nekipelova E, Dvornyk V, et al. Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis. Gene. 2014;546(1):112-6. DOI:10.1016/j.gene.2014.04.020
10. 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. Obstetrics and Gynecology. 2019;2:98-104 (in Russian)]. DOI:10.18565/aig.2019.2.98-104
11. 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. Obstetrics and Gynecology. 2018;10:86-91 (in Russian)]. DOI:10.18565/aig.2018.10.86-91
12. Zeng F, Harris RC. Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol. 2014;28:2-11. DOI:10.1016/j.semcdb.2014.01.011
13. Wong RW, Kwan RW, Mak PH, et al. Overexpression of epidermal growth factor induced hypospermatogenesis in transgenic mice. J Biol Chem. 2000;275:18297-301.
14. Chan SY, Wong RW. Expression of epidermal growth factor in transgenic mice causes growth retardation. J Biol Chem. 2000;275:38693-8.
15. Shahbazi M, Pravica V, Nasreen N, et al. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet. 2002;359:397-401.
16. Wei Z, Park KW, Day BN, Prather RS. Effect of epidermal growth factor on preimplantation development and its receptor expression in porcine embryos. Mol Reprod Dev. 2001;60:457-62.
17. Dadi TD, Li MW, Lloyd KC. EGF and TGF-alpha supplementation enhances development of cloned mouse embryos. Cloning Stem Cells. 2007;9:315-26.
18. Krivoshei IV, Altuchova OB, Polonikov AV, Churnosov MI. Bioinformatic Analysis of the Liability to the Hyperplastic Processes of the Uterus. Res J Pharm Biol Chem Sci. 2015;6(5):1563-6.
19. Churnosov MI, Altuchova OB, Demakova NA, et al. Associations of cytokines genetic variants with myomatous knots sizes. Res J Pharm Biol Chem Sci. 2014;5(6):1344-7.
20. Krivoshei IV, Altuchova OB, Golovchenko OV, et al. Genetic Factors of Hysteromyoma. Res J Med Sci. 2015;9(4):182-5. DOI:10.36478/rjmsci.2015.182.185
2. 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
3. Sharma D, Shastri S, Sharma P. Intrauterine growth restriction: antenatal and postnatal aspects. Clin Med Insights Pediatr. 2016;10:67-83. DOI:10.4137/CMPed.S40070
4. Malhotra A, Allison BJ, Castillo-Melendez M, et al. Neonatal morbidities of fetal growth restriction: pathophysiology and impact. Front Endocrinol (Lausanne). 2019;10:55. DOI:10.3389/fendo.2019.00055
5. 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
6. Golovchenko O, Abramova M, Ponomarenko I, et al. Functionally significant polymorphisms of ESR1and 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
7. 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
8. 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
9. Litovkina O, Nekipelova E, Dvornyk V, et al. Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis. Gene. 2014;546(1):112-6. DOI:10.1016/j.gene.2014.04.020
10. 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. Obstetrics and Gynecology. 2019;2:98-104 (in Russian). DOI:10.18565/aig.2019.2.98-104
11. Ponomarenko IV, Polonikov AV, Churnosov MI. Polymorphic LHCGR gene loci associated with the development of uterine fibroids. Obstetrics and Gynecology. 2018;10:86-91 (in Russian). DOI:10.18565/aig.2018.10.86-91
12. Zeng F, Harris RC. Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol. 2014;28:2-11. DOI:10.1016/j.semcdb.2014.01.011
13. Wong RW, Kwan RW, Mak PH, et al. Overexpression of epidermal growth factor induced hypospermatogenesis in transgenic mice. J Biol Chem. 2000;275:18297-301.
14. Chan SY, Wong RW. Expression of epidermal growth factor in transgenic mice causes growth retardation. J Biol Chem. 2000;275:38693-8.
15. Shahbazi M, Pravica V, Nasreen N, et al. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet. 2002;359:397-401.
16. Wei Z, Park KW, Day BN, Prather RS. Effect of epidermal growth factor on preimplantation development and its receptor expression in porcine embryos. Mol Reprod Dev. 2001;60:457-62.
17. Dadi TD, Li MW, Lloyd KC. EGF and TGF-alpha supplementation enhances development of cloned mouse embryos. Cloning Stem Cells. 2007;9:315-26.
18. Krivoshei IV, Altuchova OB, Polonikov AV, Churnosov MI. Bioinformatic Analysis of the Liability to the Hyperplastic Processes of the Uterus. Res J Pharm Biol Chem Sci. 2015;6(5):1563-6.
19. Churnosov MI, Altuchova OB, Demakova NA, et al. Associations of cytokines genetic variants with myomatous knots sizes. Res J Pharm Biol Chem Sci. 2014;5(6):1344-7.
20. Krivoshei IV, Altuchova OB, Golovchenko OV, et al. Genetic Factors of Hysteromyoma. Res J Med Sci. 2015;9(4):182-5. DOI:10.36478/rjmsci.2015.182.185
2. 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
3. Sharma D, Shastri S, Sharma P. Intrauterine growth restriction: antenatal and postnatal aspects. Clin Med Insights Pediatr. 2016;10:67-83. DOI:10.4137/CMPed.S40070
4. Malhotra A, Allison BJ, Castillo-Melendez M, et al. Neonatal morbidities of fetal growth restriction: pathophysiology and impact. Front Endocrinol (Lausanne). 2019;10:55. DOI:10.3389/fendo.2019.00055
5. 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
6. Golovchenko O, Abramova M, Ponomarenko I, et al. Functionally significant polymorphisms of ESR1and 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
7. 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
8. 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
9. Litovkina O, Nekipelova E, Dvornyk V, et al. Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis. Gene. 2014;546(1):112-6. DOI:10.1016/j.gene.2014.04.020
10. 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. Obstetrics and Gynecology. 2019;2:98-104 (in Russian)]. DOI:10.18565/aig.2019.2.98-104
11. 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. Obstetrics and Gynecology. 2018;10:86-91 (in Russian)]. DOI:10.18565/aig.2018.10.86-91
12. Zeng F, Harris RC. Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol. 2014;28:2-11. DOI:10.1016/j.semcdb.2014.01.011
13. Wong RW, Kwan RW, Mak PH, et al. Overexpression of epidermal growth factor induced hypospermatogenesis in transgenic mice. J Biol Chem. 2000;275:18297-301.
14. Chan SY, Wong RW. Expression of epidermal growth factor in transgenic mice causes growth retardation. J Biol Chem. 2000;275:38693-8.
15. Shahbazi M, Pravica V, Nasreen N, et al. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet. 2002;359:397-401.
16. Wei Z, Park KW, Day BN, Prather RS. Effect of epidermal growth factor on preimplantation development and its receptor expression in porcine embryos. Mol Reprod Dev. 2001;60:457-62.
17. Dadi TD, Li MW, Lloyd KC. EGF and TGF-alpha supplementation enhances development of cloned mouse embryos. Cloning Stem Cells. 2007;9:315-26.
18. Krivoshei IV, Altuchova OB, Polonikov AV, Churnosov MI. Bioinformatic Analysis of the Liability to the Hyperplastic Processes of the Uterus. Res J Pharm Biol Chem Sci. 2015;6(5):1563-6.
19. Churnosov MI, Altuchova OB, Demakova NA, et al. Associations of cytokines genetic variants with myomatous knots sizes. Res J Pharm Biol Chem Sci. 2014;5(6):1344-7.
20. Krivoshei IV, Altuchova OB, Golovchenko OV, et al. Genetic Factors of Hysteromyoma. Res J Med Sci. 2015;9(4):182-5. DOI:10.36478/rjmsci.2015.182.185
________________________________________________
2. 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
3. Sharma D, Shastri S, Sharma P. Intrauterine growth restriction: antenatal and postnatal aspects. Clin Med Insights Pediatr. 2016;10:67-83. DOI:10.4137/CMPed.S40070
4. Malhotra A, Allison BJ, Castillo-Melendez M, et al. Neonatal morbidities of fetal growth restriction: pathophysiology and impact. Front Endocrinol (Lausanne). 2019;10:55. DOI:10.3389/fendo.2019.00055
5. 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
6. Golovchenko O, Abramova M, Ponomarenko I, et al. Functionally significant polymorphisms of ESR1and 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
7. 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
8. 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
9. Litovkina O, Nekipelova E, Dvornyk V, et al. Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis. Gene. 2014;546(1):112-6. DOI:10.1016/j.gene.2014.04.020
10. 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. Obstetrics and Gynecology. 2019;2:98-104 (in Russian). DOI:10.18565/aig.2019.2.98-104
11. Ponomarenko IV, Polonikov AV, Churnosov MI. Polymorphic LHCGR gene loci associated with the development of uterine fibroids. Obstetrics and Gynecology. 2018;10:86-91 (in Russian). DOI:10.18565/aig.2018.10.86-91
12. Zeng F, Harris RC. Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol. 2014;28:2-11. DOI:10.1016/j.semcdb.2014.01.011
13. Wong RW, Kwan RW, Mak PH, et al. Overexpression of epidermal growth factor induced hypospermatogenesis in transgenic mice. J Biol Chem. 2000;275:18297-301.
14. Chan SY, Wong RW. Expression of epidermal growth factor in transgenic mice causes growth retardation. J Biol Chem. 2000;275:38693-8.
15. Shahbazi M, Pravica V, Nasreen N, et al. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet. 2002;359:397-401.
16. Wei Z, Park KW, Day BN, Prather RS. Effect of epidermal growth factor on preimplantation development and its receptor expression in porcine embryos. Mol Reprod Dev. 2001;60:457-62.
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Авторы
О.В. Головченко, И.В. Пономаренко, М.И. Чурносов*
ФГАОУ ВО «Белгородский государственный национальный исследовательский университет», Белгород, Россия
*hurnosov@bsu.edu.ru
Belgorod State University, Belgorod, Russia
*hurnosov@bsu.edu.ru
ФГАОУ ВО «Белгородский государственный национальный исследовательский университет», Белгород, Россия
*hurnosov@bsu.edu.ru
________________________________________________
Belgorod State University, Belgorod, Russia
*hurnosov@bsu.edu.ru
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