Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Распространенность и межгенные взаимодействия полиморфизмов, ассоциированных с нарушениями гемостаза и фолатного обмена, при повторных ранних самопроизвольных выкидышах
Распространенность и межгенные взаимодействия полиморфизмов, ассоциированных с нарушениями гемостаза и фолатного обмена, при повторных ранних самопроизвольных выкидышах
Фролова Н.И., Белокриницкая Т.Е., Страмбовская Н.Н., Белозерцева Е.П. Распространенность и межгенные взаимодействия полиморфизмов, ассоциированных с нарушениями гемостаза и фолатного обмена, при повторных ранних самопроизвольных выкидышах. Гинекология. 2019; 21 (2): 18–22.
DOI: 10.26442/20795696.2019.2.190345
DOI: 10.26442/20795696.2019.2.190345
DOI: 10.26442/20795696.2019.2.190345
________________________________________________
DOI: 10.26442/20795696.2019.2.190345
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Цель. Проанализировать частоту встречаемости полиморфизмов и комбинаций генов FVL-1691G>A, FII-20210G>A, MTHFR-677C>T, MTHFR-1298А>C, РАІ-1-675-5G>4G и оценить их ассоциацию с повторными ранними самопроизвольными выкидышами.
Материалы и методы. В исследование были включены некурящие небеременные женщины раннего фертильного возраста (20–35 лет) без экстрагенитальной патологии и семейного анамнеза тромбозов. Основную группу составили 50 пациенток, имевших в анамнезе от 2 до 5 спонтанных выкидышей в ранние сроки гестации с исключенными известными причинами невынашивания беременности; контрольную группу – 50 женщин, имевших нормальные роды, завершившиеся рождением здорового ребенка, без анамнеза спонтанных выкидышей, преждевременных родов, потери плода, преэклампсии и других акушерских осложнений. Генотипирование проведено методом полимеразной цепной реакции. Анализ результатов включал соответствие закону Харди–Вайнберга, χ2-тест, показатель V-Крамера, отношение шансов (ОШ) и его 95% доверительный интервал (ДИ). Для оценки распределения и межгенных взаимодействий заявленных полиморфизмов генов и их аллелей использовали общую (χ2-тест, df=2) и мультипликативную (χ2-тест, df=1) модели наследования.
Результаты. Выявлен риск повторных выкидышей у носителей гетерозиготных генотипов PAI-1-5G4G (72% vs 32%, p=0,000; ОШ 5,46, 95% ДИ 2,32–12,87). Гетерозиготный генотип FII-20210GA идентифицирован только у пациенток с невынашиванием беременности (4% vs 0%). Комбинации изучаемых полиморфизмов у женщин с невынашиванием регистрировались в 2,4 раза чаще (48% vs 20%; χ2=29,20, р=0,000; сильная связь V-Крамера), что существенно увеличивало риск развития заболевания (ОШ 3,69, 95% ДИ 1,52–8,97). Максимальный риск развития осложнения (ОШ 4,64, 95% ДИ 1,55–3,84) выявлен для сочетания 2 гетерозиготных вариантов минорных аллелей, которые встречались в 3,4 раза чаще у женщин основной группы (34% vs 10%; χ2=8,73, р=0,004; средняя связь V-Крамера). Важным с позиций патогенеза заболевания является факт, что комбинация генотипов PAI-1-5G4G и FV-1691GA идентифицирована только у пациенток с невынашиванием беременности (2% vs 0%). Нами не выявлено ассоциации сочетания 3 гетерозиготных вариантов минорных аллелей с повторными ранними потерями беременности (14% vs 10%; χ2=0,09, р=0,758; ОШ 1,47, 95% ДИ 0,43–4,97).
Заключение. Установлено синергическое взаимодействие между полиморфными локусами при повторных ранних выкидышах: комбинации 2 гетерозиготных вариантов минорных аллелей повышают риск развития осложнения беременности. Сочетание генотипов FV-1691GA и PAI-1-5G4G может претендовать на роль молекулярно-генетического предиктора рецидивирующих ранних потерь беременности.
Ключевые слова: полиморфизм генов, межгенные взаимодействия, повторные ранние спонтанные выкидыши.
Materials and methods. This study included two groups of women (age range 20–35 years): 50 currently non-pregnant women with a history of 2–5 unexplained recurrent early spontaneous abortion and unknown causes of miscarriages (RPL group), and 50 currently non-pregnant women with a history of having given birth to at least one live baby and without a history of spontaneous abortion, preterm labor, stillbirth, preeclampsia and other pregnancy complications (control group). Gene polymorphisms were detected by the technique of polymerase chain reaction-real time. We have analyzed the frequencies, Hardy-Weinberg equilibrium, V-Kramer test, χ2 test, odds ratio (OR) and its 95% confidence interval (95% CI). General (χ2 test, df=2) and multiplicative (χ2 test, df=1) models of inheritance have been used to assess the presence of gene polymorphisms.
Results. Significant association between heterozygotes genotype PAI-1-5G4G (72% vs 32%, p=0.000; OR 5.46; 95% CI 2.32–12.87) and RPL was found. Heterozygous genotype FII-20210GA was detected only in RPL group (4% vs 0%). Combinations of genetic polymorphisms of FVL-1691G>A, FII-20210G>A, MTHFR-677C>T, MTHFR-1298А>C, РАІ-1-6755G>4G increase the risk of RPL by 2.4 times (56% vs 20%; χ2=29.20, р=0.000; OR 3.69, 95% CI 1.52–8.97; strong V-Kramer association). The combination of two heterozygotes variants of minor alleles was found to be a risk factor for RPL (34% vs 10%; χ2=8.73, р=0.004; OR 4.64, 95% CI 1.55–3.84). Combined PAI-1-5G4G + FVL-1691GA genotypes was detected only in RPL group of women (2% vs 0%). No significant association between the combination of three heterozygotes variants of minor alleles and RPL.
Conclusion. Our data suggest significant gene-gene interaction of the heterozygotes variants of minor alleles of FVL-1691G>A, FII-20210G>A, MTHFR-677C>T, MTHFR-1298А>C, РАІ-1-6755G>4G polymorphisms in patients with recurrent miscarriage. Combined genotypes FVL-1691GA/PAI-1-5G4G can be considered as a genetic molecular predictor of recurrent early pregnancy losses.
Key words: gene polymorphism, gene-gene interactions, recurrent early pregnancy losses.
Материалы и методы. В исследование были включены некурящие небеременные женщины раннего фертильного возраста (20–35 лет) без экстрагенитальной патологии и семейного анамнеза тромбозов. Основную группу составили 50 пациенток, имевших в анамнезе от 2 до 5 спонтанных выкидышей в ранние сроки гестации с исключенными известными причинами невынашивания беременности; контрольную группу – 50 женщин, имевших нормальные роды, завершившиеся рождением здорового ребенка, без анамнеза спонтанных выкидышей, преждевременных родов, потери плода, преэклампсии и других акушерских осложнений. Генотипирование проведено методом полимеразной цепной реакции. Анализ результатов включал соответствие закону Харди–Вайнберга, χ2-тест, показатель V-Крамера, отношение шансов (ОШ) и его 95% доверительный интервал (ДИ). Для оценки распределения и межгенных взаимодействий заявленных полиморфизмов генов и их аллелей использовали общую (χ2-тест, df=2) и мультипликативную (χ2-тест, df=1) модели наследования.
Результаты. Выявлен риск повторных выкидышей у носителей гетерозиготных генотипов PAI-1-5G4G (72% vs 32%, p=0,000; ОШ 5,46, 95% ДИ 2,32–12,87). Гетерозиготный генотип FII-20210GA идентифицирован только у пациенток с невынашиванием беременности (4% vs 0%). Комбинации изучаемых полиморфизмов у женщин с невынашиванием регистрировались в 2,4 раза чаще (48% vs 20%; χ2=29,20, р=0,000; сильная связь V-Крамера), что существенно увеличивало риск развития заболевания (ОШ 3,69, 95% ДИ 1,52–8,97). Максимальный риск развития осложнения (ОШ 4,64, 95% ДИ 1,55–3,84) выявлен для сочетания 2 гетерозиготных вариантов минорных аллелей, которые встречались в 3,4 раза чаще у женщин основной группы (34% vs 10%; χ2=8,73, р=0,004; средняя связь V-Крамера). Важным с позиций патогенеза заболевания является факт, что комбинация генотипов PAI-1-5G4G и FV-1691GA идентифицирована только у пациенток с невынашиванием беременности (2% vs 0%). Нами не выявлено ассоциации сочетания 3 гетерозиготных вариантов минорных аллелей с повторными ранними потерями беременности (14% vs 10%; χ2=0,09, р=0,758; ОШ 1,47, 95% ДИ 0,43–4,97).
Заключение. Установлено синергическое взаимодействие между полиморфными локусами при повторных ранних выкидышах: комбинации 2 гетерозиготных вариантов минорных аллелей повышают риск развития осложнения беременности. Сочетание генотипов FV-1691GA и PAI-1-5G4G может претендовать на роль молекулярно-генетического предиктора рецидивирующих ранних потерь беременности.
Ключевые слова: полиморфизм генов, межгенные взаимодействия, повторные ранние спонтанные выкидыши.
________________________________________________
Materials and methods. This study included two groups of women (age range 20–35 years): 50 currently non-pregnant women with a history of 2–5 unexplained recurrent early spontaneous abortion and unknown causes of miscarriages (RPL group), and 50 currently non-pregnant women with a history of having given birth to at least one live baby and without a history of spontaneous abortion, preterm labor, stillbirth, preeclampsia and other pregnancy complications (control group). Gene polymorphisms were detected by the technique of polymerase chain reaction-real time. We have analyzed the frequencies, Hardy-Weinberg equilibrium, V-Kramer test, χ2 test, odds ratio (OR) and its 95% confidence interval (95% CI). General (χ2 test, df=2) and multiplicative (χ2 test, df=1) models of inheritance have been used to assess the presence of gene polymorphisms.
Results. Significant association between heterozygotes genotype PAI-1-5G4G (72% vs 32%, p=0.000; OR 5.46; 95% CI 2.32–12.87) and RPL was found. Heterozygous genotype FII-20210GA was detected only in RPL group (4% vs 0%). Combinations of genetic polymorphisms of FVL-1691G>A, FII-20210G>A, MTHFR-677C>T, MTHFR-1298А>C, РАІ-1-6755G>4G increase the risk of RPL by 2.4 times (56% vs 20%; χ2=29.20, р=0.000; OR 3.69, 95% CI 1.52–8.97; strong V-Kramer association). The combination of two heterozygotes variants of minor alleles was found to be a risk factor for RPL (34% vs 10%; χ2=8.73, р=0.004; OR 4.64, 95% CI 1.55–3.84). Combined PAI-1-5G4G + FVL-1691GA genotypes was detected only in RPL group of women (2% vs 0%). No significant association between the combination of three heterozygotes variants of minor alleles and RPL.
Conclusion. Our data suggest significant gene-gene interaction of the heterozygotes variants of minor alleles of FVL-1691G>A, FII-20210G>A, MTHFR-677C>T, MTHFR-1298А>C, РАІ-1-6755G>4G polymorphisms in patients with recurrent miscarriage. Combined genotypes FVL-1691GA/PAI-1-5G4G can be considered as a genetic molecular predictor of recurrent early pregnancy losses.
Key words: gene polymorphism, gene-gene interactions, recurrent early pregnancy losses.
Полный текст
Список литературы
1. Адамян Л.В., Артымук Н.В., Белокриницкая Т.Е. и др. Выкидыш в ранние сроки беременности: диагностика и тактика ведения. Клинические рекомендации (протокол) утв. Минздравом России 07.06.2016 №15-4/10/2-2482. М., 2016.
[Adamian L.V., Artymuk N.V., Belokrinitskaia T.E. et al. Vykidysh v rannie sroki beremennosti: diagnostika i taktika vedeniia. Klinicheskie rekomendatsii (protokol) utv. Minzdravom Rossii 07.06.2016 №15-4/10/2-2482. Moscow, 2016 (in Russian).]
2. Recurrent Pregnancy loss. ESHRE Guidline, November 2017.
3. Kaiser J, Branch DW. Recurrent Pregnancy Loss: Generally Accepted Causes and Their Management. Clin Obstet Gynecol 2016; 59 (3): 464–73. DOI: 10.1097/GRF.0000000000000214
4. Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J 2015; 91 (1073): 51–62. DOI: 10.1136/postgradmedj-2014-132672
5. Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet 2015; 291 (3): 671–9. DOI: 10.1007/s00404-014-3443-x
6. Farahmand K, Totonchi M, Hashemi M et al. Thrombophilic genes alterations as risk factor for recurrent pregnancy loss. J Matern Fetal Neonatal Med 2016; 29 (8): 1269–73. DOI: 10.3109/14767058.2015.1044431
7. Kamali M, Hantoushzadeh S, Borna S et al. Association between Thrombophilic Genes Polymorphisms and Recurrent Pregnancy Loss Susceptibility in the Iranian Population: a Systematic Review and Meta-Analysis. Iran Biomed J 2018; 22 (2): 78–89.
8. Al-Achkar W, Wafa A, Ammar S et al. Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women. Reprod Sci 2017; 24 (9): 1275–9. DOI: 10.1177/1933719116682874
9. Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet 2016; 293 (2): 283–90. DOI: 10.1007/s00404-015-3894-8
10. Yang Y, Luo Y, Yuan J et al. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. Arch Gynecol Obstet 2016; 293 (6): 1197–211. DOI: 10.1007/s00404-015-3944-2
11. Jeon YJ, Kim YR, Lee BE et al. Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women. Thromb Haemost 2013; 110 (4): 742–50.
12. Chen H, Nie S, Lu M. Association between plasminogen activator inhibitor-1 gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis. Am J Reprod Immunol 2015; 73 (4): 292–300. DOI: 10.1111/aji.12321
13. Salazar Garcia MD, Sung N, Mullenix TM et al. Plasminogen Activator Inhibitor-1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles. Am J Reprod Immunol 2016; 76 (1): 70–81. DOI: 10.1111/aji.12516
14. Guan LX, Du XY, Wang JX et al. Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5,10-methylenetetrahydrofolate reductase gene with recurrent early spontaneous abortion. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005; 22 (3): 330–3.
15. Parveen F, Tuteja M, Agrawal S. Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Arch Gynecol Obstet 2013; 288 (5): 1171–7.
16. Li X, Liu Y, Zhang R et al. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Med Sci Monit 2015; 1051–6. DOI: 10.12659/MSM.892898
17. Moore JH, Gilbert JC, Tsai CT et al. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theoretic Biol 2006; 241: 252–61.
18. Баранов В.С. Генетический паспорт – основа индивидуальной и предикативной медицины. СПб.: Н-Л, 2009.
[Baranov V.S. Geneticheskii pasport – osnova individual'noi i predikativnoi meditsiny. Saint Petersburg: N-L, 2009 (in Russian).]
19. Фролова Н.И., Белокриницкая Т.Е., Страмбовская Н.Н. Молекулярно-генетические предикторы осложнений беременности у молодых здоровых женщин. Дальневосточный мед. журн. 2015; 3: 29–30.
[Frolova N.I., Belokrinitskaia T.E., Strambovskaia N.N. Molekuliarno-geneticheskie prediktory oslozhnenii beremennosti u molodykh zdorovykh zhenshchin. Dal'nevostochnyi med. zhurn. 2015; 3: 29–30 (in Russian).]
20. Djurovic J, Stojkovic O, Todorovic J et al. Genetics of suspected thrombophilia in Serbian females with infertility, including three cases, homozygous for FII 20210A or FV 1691A mutations. Hum Fertil (Camb) 2017; 20 (2): 132–9. DOI: 10.1080/14647273.2016.1255785
21. Gonçalves RO, Fraga LR, Santos WV et al. Association between the thrombophilic polymorphisms MTHFR C677T, Factor V Leiden, and prothrombin G20210A and recurrent miscarriage in Brazilian women. Genet Mol Res 2016; 15 (3). DOI: 10.4238/gmr.15038156
22. Cao Y, Xu J, Zhang Z et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene 2013; 514 (2): 105–11. DOI: 10.1016/j.gene.2012.10.091
23. Nowak I, Bylińska A, Wilczyńska K et al. The methylenetetrahydrofolate reductase c.c.677 C>T and c.c.1298 A>C polymorphisms in reproductive failures: Experience from an RSA and RIF study on a Polish population. PLoS One 2017; 12 (10): e0186022. DOI: 10.1371/journal.pone.0186022. eCollection 2017
24. Момот А.П. Проблема тромбофилии в клинической практике. Рос. журн. детской гематологии и онкологии. 2015; 1: 36–48.
[Momot A.P. Problema trombofilii v klinicheskoi praktike. Ros. zhurn. detskoi gematologii i onkologii. 2015; 1: 36–48 (in Russian).]
2. Recurrent Pregnancy loss. ESHRE Guidline, November 2017.
3. Kaiser J, Branch DW. Recurrent Pregnancy Loss: Generally Accepted Causes and Their Management. Clin Obstet Gynecol 2016; 59 (3): 464–73. DOI: 10.1097/GRF.0000000000000214
4. Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J 2015; 91 (1073): 51–62. DOI: 10.1136/postgradmedj-2014-132672
5. Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet 2015; 291 (3): 671–9. DOI: 10.1007/s00404-014-3443-x
6. Farahmand K, Totonchi M, Hashemi M et al. Thrombophilic genes alterations as risk factor for recurrent pregnancy loss. J Matern Fetal Neonatal Med 2016; 29 (8): 1269–73. DOI: 10.3109/14767058.2015.1044431
7. Kamali M, Hantoushzadeh S, Borna S et al. Association between Thrombophilic Genes Polymorphisms and Recurrent Pregnancy Loss Susceptibility in the Iranian Population: a Systematic Review and Meta-Analysis. Iran Biomed J 2018; 22 (2): 78–89.
8. Al-Achkar W, Wafa A, Ammar S et al. Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women. Reprod Sci 2017; 24 (9): 1275–9. DOI: 10.1177/1933719116682874
9. Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet 2016; 293 (2): 283–90. DOI: 10.1007/s00404-015-3894-8
10. Yang Y, Luo Y, Yuan J et al. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. Arch Gynecol Obstet 2016; 293 (6): 1197–211. DOI: 10.1007/s00404-015-3944-2
11. Jeon YJ, Kim YR, Lee BE et al. Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women. Thromb Haemost 2013; 110 (4): 742–50.
12. Chen H, Nie S, Lu M. Association between plasminogen activator inhibitor-1 gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis. Am J Reprod Immunol 2015; 73 (4): 292–300. DOI: 10.1111/aji.12321
13. Salazar Garcia MD, Sung N, Mullenix TM et al. Plasminogen Activator Inhibitor-1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles. Am J Reprod Immunol 2016; 76 (1): 70–81. DOI: 10.1111/aji.12516
14. Guan LX, Du XY, Wang JX et al. Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5,10-methylenetetrahydrofolate reductase gene with recurrent early spontaneous abortion. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005; 22 (3): 330–3.
15. Parveen F, Tuteja M, Agrawal S. Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Arch Gynecol Obstet 2013; 288 (5): 1171–7.
16. Li X, Liu Y, Zhang R et al. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Med Sci Monit 2015; 1051–6. DOI: 10.12659/MSM.892898
17. Moore JH, Gilbert JC, Tsai CT et al. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theoretic Biol 2006; 241: 252–61.
18. Baranov V.S. Geneticheskii pasport – osnova individual'noi i predikativnoi meditsiny. Saint Petersburg: N-L, 2009 (in Russian).
19. Frolova N.I., Belokrinitskaia T.E., Strambovskaia N.N. Molekuliarno-geneticheskie prediktory oslozhnenii beremennosti u molodykh zdorovykh zhenshchin. Dal'nevostochnyi med. zhurn. 2015; 3: 29–30 (in Russian).
20. Djurovic J, Stojkovic O, Todorovic J et al. Genetics of suspected thrombophilia in Serbian females with infertility, including three cases, homozygous for FII 20210A or FV 1691A mutations. Hum Fertil (Camb) 2017; 20 (2): 132–9. DOI: 10.1080/14647273.2016.1255785
21. Gonçalves RO, Fraga LR, Santos WV et al. Association between the thrombophilic polymorphisms MTHFR C677T, Factor V Leiden, and prothrombin G20210A and recurrent miscarriage in Brazilian women. Genet Mol Res 2016; 15 (3). DOI: 10.4238/gmr.15038156
22. Cao Y, Xu J, Zhang Z et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene 2013; 514 (2): 105–11. DOI: 10.1016/j.gene.2012.10.091
23. Nowak I, Bylińska A, Wilczyńska K et al. The methylenetetrahydrofolate reductase c.c.677 C>T and c.c.1298 A>C polymorphisms in reproductive failures: Experience from an RSA and RIF study on a Polish population. PLoS One 2017; 12 (10): e0186022. DOI: 10.1371/journal.pone.0186022. eCollection 2017
24. Momot A.P. Problema trombofilii v klinicheskoi praktike. Ros. zhurn. detskoi gematologii i onkologii. 2015; 1: 36–48 (in Russian).
[Adamian L.V., Artymuk N.V., Belokrinitskaia T.E. et al. Vykidysh v rannie sroki beremennosti: diagnostika i taktika vedeniia. Klinicheskie rekomendatsii (protokol) utv. Minzdravom Rossii 07.06.2016 №15-4/10/2-2482. Moscow, 2016 (in Russian).]
2. Recurrent Pregnancy loss. ESHRE Guidline, November 2017.
3. Kaiser J, Branch DW. Recurrent Pregnancy Loss: Generally Accepted Causes and Their Management. Clin Obstet Gynecol 2016; 59 (3): 464–73. DOI: 10.1097/GRF.0000000000000214
4. Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J 2015; 91 (1073): 51–62. DOI: 10.1136/postgradmedj-2014-132672
5. Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet 2015; 291 (3): 671–9. DOI: 10.1007/s00404-014-3443-x
6. Farahmand K, Totonchi M, Hashemi M et al. Thrombophilic genes alterations as risk factor for recurrent pregnancy loss. J Matern Fetal Neonatal Med 2016; 29 (8): 1269–73. DOI: 10.3109/14767058.2015.1044431
7. Kamali M, Hantoushzadeh S, Borna S et al. Association between Thrombophilic Genes Polymorphisms and Recurrent Pregnancy Loss Susceptibility in the Iranian Population: a Systematic Review and Meta-Analysis. Iran Biomed J 2018; 22 (2): 78–89.
8. Al-Achkar W, Wafa A, Ammar S et al. Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women. Reprod Sci 2017; 24 (9): 1275–9. DOI: 10.1177/1933719116682874
9. Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet 2016; 293 (2): 283–90. DOI: 10.1007/s00404-015-3894-8
10. Yang Y, Luo Y, Yuan J et al. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. Arch Gynecol Obstet 2016; 293 (6): 1197–211. DOI: 10.1007/s00404-015-3944-2
11. Jeon YJ, Kim YR, Lee BE et al. Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women. Thromb Haemost 2013; 110 (4): 742–50.
12. Chen H, Nie S, Lu M. Association between plasminogen activator inhibitor-1 gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis. Am J Reprod Immunol 2015; 73 (4): 292–300. DOI: 10.1111/aji.12321
13. Salazar Garcia MD, Sung N, Mullenix TM et al. Plasminogen Activator Inhibitor-1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles. Am J Reprod Immunol 2016; 76 (1): 70–81. DOI: 10.1111/aji.12516
14. Guan LX, Du XY, Wang JX et al. Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5,10-methylenetetrahydrofolate reductase gene with recurrent early spontaneous abortion. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005; 22 (3): 330–3.
15. Parveen F, Tuteja M, Agrawal S. Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Arch Gynecol Obstet 2013; 288 (5): 1171–7.
16. Li X, Liu Y, Zhang R et al. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Med Sci Monit 2015; 1051–6. DOI: 10.12659/MSM.892898
17. Moore JH, Gilbert JC, Tsai CT et al. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theoretic Biol 2006; 241: 252–61.
18. Баранов В.С. Генетический паспорт – основа индивидуальной и предикативной медицины. СПб.: Н-Л, 2009.
[Baranov V.S. Geneticheskii pasport – osnova individual'noi i predikativnoi meditsiny. Saint Petersburg: N-L, 2009 (in Russian).]
19. Фролова Н.И., Белокриницкая Т.Е., Страмбовская Н.Н. Молекулярно-генетические предикторы осложнений беременности у молодых здоровых женщин. Дальневосточный мед. журн. 2015; 3: 29–30.
[Frolova N.I., Belokrinitskaia T.E., Strambovskaia N.N. Molekuliarno-geneticheskie prediktory oslozhnenii beremennosti u molodykh zdorovykh zhenshchin. Dal'nevostochnyi med. zhurn. 2015; 3: 29–30 (in Russian).]
20. Djurovic J, Stojkovic O, Todorovic J et al. Genetics of suspected thrombophilia in Serbian females with infertility, including three cases, homozygous for FII 20210A or FV 1691A mutations. Hum Fertil (Camb) 2017; 20 (2): 132–9. DOI: 10.1080/14647273.2016.1255785
21. Gonçalves RO, Fraga LR, Santos WV et al. Association between the thrombophilic polymorphisms MTHFR C677T, Factor V Leiden, and prothrombin G20210A and recurrent miscarriage in Brazilian women. Genet Mol Res 2016; 15 (3). DOI: 10.4238/gmr.15038156
22. Cao Y, Xu J, Zhang Z et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene 2013; 514 (2): 105–11. DOI: 10.1016/j.gene.2012.10.091
23. Nowak I, Bylińska A, Wilczyńska K et al. The methylenetetrahydrofolate reductase c.c.677 C>T and c.c.1298 A>C polymorphisms in reproductive failures: Experience from an RSA and RIF study on a Polish population. PLoS One 2017; 12 (10): e0186022. DOI: 10.1371/journal.pone.0186022. eCollection 2017
24. Момот А.П. Проблема тромбофилии в клинической практике. Рос. журн. детской гематологии и онкологии. 2015; 1: 36–48.
[Momot A.P. Problema trombofilii v klinicheskoi praktike. Ros. zhurn. detskoi gematologii i onkologii. 2015; 1: 36–48 (in Russian).]
________________________________________________
2. Recurrent Pregnancy loss. ESHRE Guidline, November 2017.
3. Kaiser J, Branch DW. Recurrent Pregnancy Loss: Generally Accepted Causes and Their Management. Clin Obstet Gynecol 2016; 59 (3): 464–73. DOI: 10.1097/GRF.0000000000000214
4. Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J 2015; 91 (1073): 51–62. DOI: 10.1136/postgradmedj-2014-132672
5. Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet 2015; 291 (3): 671–9. DOI: 10.1007/s00404-014-3443-x
6. Farahmand K, Totonchi M, Hashemi M et al. Thrombophilic genes alterations as risk factor for recurrent pregnancy loss. J Matern Fetal Neonatal Med 2016; 29 (8): 1269–73. DOI: 10.3109/14767058.2015.1044431
7. Kamali M, Hantoushzadeh S, Borna S et al. Association between Thrombophilic Genes Polymorphisms and Recurrent Pregnancy Loss Susceptibility in the Iranian Population: a Systematic Review and Meta-Analysis. Iran Biomed J 2018; 22 (2): 78–89.
8. Al-Achkar W, Wafa A, Ammar S et al. Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women. Reprod Sci 2017; 24 (9): 1275–9. DOI: 10.1177/1933719116682874
9. Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet 2016; 293 (2): 283–90. DOI: 10.1007/s00404-015-3894-8
10. Yang Y, Luo Y, Yuan J et al. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. Arch Gynecol Obstet 2016; 293 (6): 1197–211. DOI: 10.1007/s00404-015-3944-2
11. Jeon YJ, Kim YR, Lee BE et al. Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women. Thromb Haemost 2013; 110 (4): 742–50.
12. Chen H, Nie S, Lu M. Association between plasminogen activator inhibitor-1 gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis. Am J Reprod Immunol 2015; 73 (4): 292–300. DOI: 10.1111/aji.12321
13. Salazar Garcia MD, Sung N, Mullenix TM et al. Plasminogen Activator Inhibitor-1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles. Am J Reprod Immunol 2016; 76 (1): 70–81. DOI: 10.1111/aji.12516
14. Guan LX, Du XY, Wang JX et al. Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5,10-methylenetetrahydrofolate reductase gene with recurrent early spontaneous abortion. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005; 22 (3): 330–3.
15. Parveen F, Tuteja M, Agrawal S. Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Arch Gynecol Obstet 2013; 288 (5): 1171–7.
16. Li X, Liu Y, Zhang R et al. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Med Sci Monit 2015; 1051–6. DOI: 10.12659/MSM.892898
17. Moore JH, Gilbert JC, Tsai CT et al. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theoretic Biol 2006; 241: 252–61.
18. Baranov V.S. Geneticheskii pasport – osnova individual'noi i predikativnoi meditsiny. Saint Petersburg: N-L, 2009 (in Russian).
19. Frolova N.I., Belokrinitskaia T.E., Strambovskaia N.N. Molekuliarno-geneticheskie prediktory oslozhnenii beremennosti u molodykh zdorovykh zhenshchin. Dal'nevostochnyi med. zhurn. 2015; 3: 29–30 (in Russian).
20. Djurovic J, Stojkovic O, Todorovic J et al. Genetics of suspected thrombophilia in Serbian females with infertility, including three cases, homozygous for FII 20210A or FV 1691A mutations. Hum Fertil (Camb) 2017; 20 (2): 132–9. DOI: 10.1080/14647273.2016.1255785
21. Gonçalves RO, Fraga LR, Santos WV et al. Association between the thrombophilic polymorphisms MTHFR C677T, Factor V Leiden, and prothrombin G20210A and recurrent miscarriage in Brazilian women. Genet Mol Res 2016; 15 (3). DOI: 10.4238/gmr.15038156
22. Cao Y, Xu J, Zhang Z et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene 2013; 514 (2): 105–11. DOI: 10.1016/j.gene.2012.10.091
23. Nowak I, Bylińska A, Wilczyńska K et al. The methylenetetrahydrofolate reductase c.c.677 C>T and c.c.1298 A>C polymorphisms in reproductive failures: Experience from an RSA and RIF study on a Polish population. PLoS One 2017; 12 (10): e0186022. DOI: 10.1371/journal.pone.0186022. eCollection 2017
24. Momot A.P. Problema trombofilii v klinicheskoi praktike. Ros. zhurn. detskoi gematologii i onkologii. 2015; 1: 36–48 (in Russian).
Авторы
Н.И. Фролова*, Т.Е. Белокриницкая, Н.Н. Страмбовская, Е.П. Белозерцева
ФГБОУ ВО «Читинская государственная медицинская академия» Минздрава России, Чита, Россия
*taasyaa@mail.ru
ФГБОУ ВО «Читинская государственная медицинская академия» Минздрава России, Чита, Россия
*taasyaa@mail.ru
________________________________________________
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.