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Экспрессия генов MSX1, HOXA11 и TP53I3 в эндометрии, связанная с наступлением беременности после неоднократных неудачных попыток экстракорпорального оплодотворения у пациенток с трубно-перитонеальным фактором бесплодия
Экспрессия генов MSX1, HOXA11 и TP53I3 в эндометрии, связанная с наступлением беременности после неоднократных неудачных попыток экстракорпорального оплодотворения у пациенток с трубно-перитонеальным фактором бесплодия
Князева Е.А., Кузнецова М.В., Бурменская О.В. и др. Экспрессия генов MSX1, HOXA11 и TP53I3 в эндометрии, связанная с наступлением беременности после неоднократных неудачных попыток экстракорпорального оплодотворения у пациенток с трубно-перитонеальным фактором бесплодия. Гинекология. 2020; 22 (1): e. 23.
DOI: 10.26442/20795696.2020.1.200028
DOI: 10.26442/20795696.2020.1.200028
DOI: 10.26442/20795696.2020.1.200028
________________________________________________
DOI: 10.26442/20795696.2020.1.200028
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Актуальность. Успешность программы экстракорпорального оплодотворения (ЭКО) в числе прочих факторов зависит от готовности эндометрия принять эмбрион. Считается, что это возможно в так называемое «окно имплантации», сроки которого могут сдвигаться под влиянием разных факторов. Оценка рецептивности эндометрия и «окна имплантации» на основе анализа экспрессии генов эндометрия перед переносом эмбрионов является перспективным подходом для предсказания вероятности наступления беременности в программах ЭКО.
Цель. Построить классификатор на основе экспрессии генов эндометрия для предсказания исходов программы ЭКО у пациенток с трубно-перитонеальным фактором бесплодия и неоднократными неудачными попытками ЭКО в анамнезе.
Материалы и методы. Перед очередной программой ЭКО было проведено полногеномное транскриптомное профилирование с помощью микрочипов Affymetrix образцов эндометрия 15 женщин с трубно-периотонеальным фактором бесплодия и неоднократными неудачными попытками ЭКО в анамнезе. Были выбраны потенциальные гены, способные классифицировать исходы программы ЭКО, после чего экспрессия данных генов анализировалась методом полимеразной цепной реакции в реальном времени в эндометрии 47 женщин для построения классификаторов исходов ЭКО на основе экспрессии пар и троек генов.
Результаты. Классификатор на основе экспрессии тройки генов MSX1 (HOX7), HOXA11 и TP53I3 позволял определять наступление беременности в программе ЭКО с чувствительностью 73% и специфичностью 71% при площади под ROC-кривой (AUC) 0,738 (95% доверительный интервал 0,577–0,898). Ранее была выявлена связь экспрессии данных генов с рецептивностью эндометрия, что позволяет предполагать, что эти гены играют роль в наступлении «окна имплантации».
Выводы. Использование классификатора на основе генов MSX1 (HOX7), HOXA11 и TP53I3 может определять готовность эндометрия принять эмбрион и создавать индивидуальный прогноз исхода программы ЭКО у женщин с трубно-перитонеальным фактором бесплодия и неоднократными неудачными попытками ЭКО в анамнезе.
Ключевые слова: экстракорпоральное оплодотворение, бесплодие, рецептивность эндометрия, «окно имплантации», метилирование ДНК, НОХ-гены, НОХА11, MSX1, TP53I3.
Aim. To construct a classifier based on the expression of endometrial genes for predicting the outcome of an IVF program in patients with tubal-peritoneal infertility factor and repeated failed IVF attempts in history.
Materials and methods. Before the IVF program, a genome-wide transcriptome profiling of endometrial samples of 15 women with tubal-perioneal infertility factor and repeated unsuccessful IVF attempts in history was carried out using Affymetrix arrays. Potential genes capable of classifying IVF program outcomes were selected, after which the expression of these genes was analyzed by qPCR-RT in the endometrium of 47 women to construct IVF outcome classifiers based on the expression of pairs or triples of genes.
Results. A classifier based on the expression of the triple of genes MSX1 (HOX7), HOXA11, and TP53I3 made it possible to determine the onset of pregnancy in an IVF program with a sensitivity of 73% and a specificity of 71% with an area under the ROC-curve (AUC) of 0.738 (95% confidence interval 0.577–0.898) . Earlier, a relationship was found between the expression of these genes and receptivity of the endometrium, which suggests that these genes play a role in the onset of the "implantation window".
Conclusions. The use of a classifier based on the genes MSX1 (HOX7), HOXA11, and TP53I3 can determine the readiness of the endometrium to accept an embryo and create an individual prognosis of the outcome of an IVF program in women with tubal-peritoneal infertility factor and repeated failed IVF attempts in history.
Key words: in vitro fertilisation, infertility, endometrial receptivity, implantation window, DNA methylation, HOX genes, HOXA11, MSX1, TP53I3.
Цель. Построить классификатор на основе экспрессии генов эндометрия для предсказания исходов программы ЭКО у пациенток с трубно-перитонеальным фактором бесплодия и неоднократными неудачными попытками ЭКО в анамнезе.
Материалы и методы. Перед очередной программой ЭКО было проведено полногеномное транскриптомное профилирование с помощью микрочипов Affymetrix образцов эндометрия 15 женщин с трубно-периотонеальным фактором бесплодия и неоднократными неудачными попытками ЭКО в анамнезе. Были выбраны потенциальные гены, способные классифицировать исходы программы ЭКО, после чего экспрессия данных генов анализировалась методом полимеразной цепной реакции в реальном времени в эндометрии 47 женщин для построения классификаторов исходов ЭКО на основе экспрессии пар и троек генов.
Результаты. Классификатор на основе экспрессии тройки генов MSX1 (HOX7), HOXA11 и TP53I3 позволял определять наступление беременности в программе ЭКО с чувствительностью 73% и специфичностью 71% при площади под ROC-кривой (AUC) 0,738 (95% доверительный интервал 0,577–0,898). Ранее была выявлена связь экспрессии данных генов с рецептивностью эндометрия, что позволяет предполагать, что эти гены играют роль в наступлении «окна имплантации».
Выводы. Использование классификатора на основе генов MSX1 (HOX7), HOXA11 и TP53I3 может определять готовность эндометрия принять эмбрион и создавать индивидуальный прогноз исхода программы ЭКО у женщин с трубно-перитонеальным фактором бесплодия и неоднократными неудачными попытками ЭКО в анамнезе.
Ключевые слова: экстракорпоральное оплодотворение, бесплодие, рецептивность эндометрия, «окно имплантации», метилирование ДНК, НОХ-гены, НОХА11, MSX1, TP53I3.
________________________________________________
Aim. To construct a classifier based on the expression of endometrial genes for predicting the outcome of an IVF program in patients with tubal-peritoneal infertility factor and repeated failed IVF attempts in history.
Materials and methods. Before the IVF program, a genome-wide transcriptome profiling of endometrial samples of 15 women with tubal-perioneal infertility factor and repeated unsuccessful IVF attempts in history was carried out using Affymetrix arrays. Potential genes capable of classifying IVF program outcomes were selected, after which the expression of these genes was analyzed by qPCR-RT in the endometrium of 47 women to construct IVF outcome classifiers based on the expression of pairs or triples of genes.
Results. A classifier based on the expression of the triple of genes MSX1 (HOX7), HOXA11, and TP53I3 made it possible to determine the onset of pregnancy in an IVF program with a sensitivity of 73% and a specificity of 71% with an area under the ROC-curve (AUC) of 0.738 (95% confidence interval 0.577–0.898) . Earlier, a relationship was found between the expression of these genes and receptivity of the endometrium, which suggests that these genes play a role in the onset of the "implantation window".
Conclusions. The use of a classifier based on the genes MSX1 (HOX7), HOXA11, and TP53I3 can determine the readiness of the endometrium to accept an embryo and create an individual prognosis of the outcome of an IVF program in women with tubal-peritoneal infertility factor and repeated failed IVF attempts in history.
Key words: in vitro fertilisation, infertility, endometrial receptivity, implantation window, DNA methylation, HOX genes, HOXA11, MSX1, TP53I3.
Полный текст
Список литературы
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11. Nikulin SV, Knyazev EN, Poloznikov AA et al. Expression of SLC30A10 and SLC23A3 Transporter mRNAs in Caco-2 Cells Correlates with an Increase in the Area of the Apical Membrane. Mol Biol 2018; 52 (4): 577–82.
12. Burmenskaya OV, Bozhenko VK, Smolnikova VY et al. Transcription profile analysis of the endometrium revealed molecular markers of the personalized “window of implantation” during in vitro fertilization. Gynecol Endocrinol 2017; 33 (Suppl. 1): 22–7.
13. Bolnick AD, Bolnick JM, Kilburn BA et al. Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility. Hum Reprod 2016; 31 (9): 2042–50.
14. Salilew-Wondim D, Hölker M, Rings F et al. Bovine pretransfer endometrium and embryo transcriptome fingerprints as predictors of pregnancy success after embryo transfer. Physiol Genomics 2010; 42 (2): 201–18.
15. Qin L, Wang R, Li S et al. Differentially Gene Expression Profile Related to Inflammation in Endometrial Cells Induce by Lipopolysaccharide. J Reprod Contracept 2009; 20 (1): 27–34.
16. Knyazeva EA, Alieva KU, Kalinina EA. Ovarian pregnancy after an IVF program in a patient with reduced endometrial receptivity. Akusherstvo Ginekol (Russian Fed.) 2018; 8: 180–4.
17. Knyazeva EA, Kalinina EA, Bystritsky AA et al. Role of HOX genes associated with infertility in female reproductive system diseases. Akusherstvo Ginekol (Russian Fed.) 2017; 11: 16–22.
18. Bourdiec A, Ahmad S-F, Lachhab A et al. Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells. Reprod Biomed Online 2016; 32 (1): 85–95.
19. Du H, Taylor HS. The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility. Cold Spring Harb. Perspect Med 2016; 6 (1): a023002.
20. Nazarenko TA, Kalinina EA, Knyazeva EA et al. The role of abnormal hypermethylation of the HOXA10 and HOXA11 promoters in implantation failures in IVF programs. Gynecol Endocrinol 2019; 35 (Suppl. 1): 31–4.
2. Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions 11 Medical and Health Sciences 1114 Paediatrics and Reproductive Medicine. Reprod Biol Endocrinol 2018; 16 (1): 1–18.
3. Teh WT, McBain J, Rogers P. What is the contribution of embryo-endometrial asynchrony to implantation failure? J Assist Reprod Genet 2016; 33 (11): 1419–30.
4. Hertig AT, Rock J, Adams EC. A description of 34 human ova within the first 17 days of development. Am J Anat 1956; 98 (3): 435–93.
5. Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril 2017; 108 (1): 15–8.
6. Ruiz-Alonso M, Blesa D, Díaz-Gimeno P et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 2013; 100 (3): 818–24.
7. Mahajan N. Endometrial receptivity array: Clinical application. J Hum Reprod Sci 2015; 8 (3): 121–9.
8. Kibanov MV, Makhmudova GM, Gokhberg YA. In search for an ideal marker of endometrial receptivity: from histology to comprehensive molecular genetics-based approaches. Alm Clin Med 2019; 47 (1):
12–25.
9. Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril 2011; 95 (1): 50–60.e15.
10. Craciunas L, Gallos I, Chu J et al. Conventional and modern markers of endometrial receptivity: A systematic review and meta-analysis. Hum Reprod Update 2019; 25 (2): 202–23.
11. Nikulin SV, Knyazev EN, Poloznikov AA et al. Expression of SLC30A10 and SLC23A3 Transporter mRNAs in Caco-2 Cells Correlates with an Increase in the Area of the Apical Membrane. Mol Biol 2018; 52 (4): 577–82.
12. Burmenskaya OV, Bozhenko VK, Smolnikova VY et al. Transcription profile analysis of the endometrium revealed molecular markers of the personalized “window of implantation” during in vitro fertilization. Gynecol Endocrinol 2017; 33 (Suppl. 1): 22–7.
13. Bolnick AD, Bolnick JM, Kilburn BA et al. Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility. Hum Reprod 2016; 31 (9): 2042–50.
14. Salilew-Wondim D, Hölker M, Rings F et al. Bovine pretransfer endometrium and embryo transcriptome fingerprints as predictors of pregnancy success after embryo transfer. Physiol Genomics 2010; 42 (2): 201–18.
15. Qin L, Wang R, Li S et al. Differentially Gene Expression Profile Related to Inflammation in Endometrial Cells Induce by Lipopolysaccharide. J Reprod Contracept 2009; 20 (1): 27–34.
16. Knyazeva EA, Alieva KU, Kalinina EA. Ovarian pregnancy after an IVF program in a patient with reduced endometrial receptivity. Akusherstvo Ginekol (Russian Fed.) 2018; 8: 180–4.
17. Knyazeva EA, Kalinina EA, Bystritsky AA et al. Role of HOX genes associated with infertility in female reproductive system diseases. Akusherstvo Ginekol (Russian Fed.) 2017; 11: 16–22.
18. Bourdiec A, Ahmad S-F, Lachhab A et al. Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells. Reprod Biomed Online 2016; 32 (1): 85–95.
19. Du H, Taylor HS. The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility. Cold Spring Harb. Perspect Med 2016; 6 (1): a023002.
20. Nazarenko TA, Kalinina EA, Knyazeva EA et al. The role of abnormal hypermethylation of the HOXA10 and HOXA11 promoters in implantation failures in IVF programs. Gynecol Endocrinol 2019; 35 (Suppl. 1): 31–4.
[Khabarov S.V., Khadartseva K.A. Vozrastnye aspekty v neudachakh programm vspomogatel'nykh reproduktivnykh tekhnologii. Vestn. novykh meditsinskikh tekhnologii. 2018; 12 (2): 74–9 (in Russian).]
2. Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions 11 Medical and Health Sciences 1114 Paediatrics and Reproductive Medicine. Reprod Biol Endocrinol 2018; 16 (1): 1–18.
3. Teh WT, McBain J, Rogers P. What is the contribution of embryo-endometrial asynchrony to implantation failure? J Assist Reprod Genet 2016; 33 (11): 1419–30.
4. Hertig AT, Rock J, Adams EC. A description of 34 human ova within the first 17 days of development. Am J Anat 1956; 98 (3): 435–93.
5. Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril 2017; 108 (1): 15–8.
6. Ruiz-Alonso M, Blesa D, Díaz-Gimeno P et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 2013; 100 (3): 818–24.
7. Mahajan N. Endometrial receptivity array: Clinical application. J Hum Reprod Sci 2015; 8 (3): 121–9.
8. Kibanov MV, Makhmudova GM, Gokhberg YA. In search for an ideal marker of endometrial receptivity: from histology to comprehensive molecular genetics-based approaches. Alm Clin Med 2019; 47 (1):
12–25.
9. Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril 2011; 95 (1): 50–60.e15.
10. Craciunas L, Gallos I, Chu J et al. Conventional and modern markers of endometrial receptivity: A systematic review and meta-analysis. Hum Reprod Update 2019; 25 (2): 202–23.
11. Nikulin SV, Knyazev EN, Poloznikov AA et al. Expression of SLC30A10 and SLC23A3 Transporter mRNAs in Caco-2 Cells Correlates with an Increase in the Area of the Apical Membrane. Mol Biol 2018; 52 (4): 577–82.
12. Burmenskaya OV, Bozhenko VK, Smolnikova VY et al. Transcription profile analysis of the endometrium revealed molecular markers of the personalized “window of implantation” during in vitro fertilization. Gynecol Endocrinol 2017; 33 (Suppl. 1): 22–7.
13. Bolnick AD, Bolnick JM, Kilburn BA et al. Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility. Hum Reprod 2016; 31 (9): 2042–50.
14. Salilew-Wondim D, Hölker M, Rings F et al. Bovine pretransfer endometrium and embryo transcriptome fingerprints as predictors of pregnancy success after embryo transfer. Physiol Genomics 2010; 42 (2): 201–18.
15. Qin L, Wang R, Li S et al. Differentially Gene Expression Profile Related to Inflammation in Endometrial Cells Induce by Lipopolysaccharide. J Reprod Contracept 2009; 20 (1): 27–34.
16. Knyazeva EA, Alieva KU, Kalinina EA. Ovarian pregnancy after an IVF program in a patient with reduced endometrial receptivity. Akusherstvo Ginekol (Russian Fed.) 2018; 8: 180–4.
17. Knyazeva EA, Kalinina EA, Bystritsky AA et al. Role of HOX genes associated with infertility in female reproductive system diseases. Akusherstvo Ginekol (Russian Fed.) 2017; 11: 16–22.
18. Bourdiec A, Ahmad S-F, Lachhab A et al. Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells. Reprod Biomed Online 2016; 32 (1): 85–95.
19. Du H, Taylor HS. The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility. Cold Spring Harb. Perspect Med 2016; 6 (1): a023002.
20. Nazarenko TA, Kalinina EA, Knyazeva EA et al. The role of abnormal hypermethylation of the HOXA10 and HOXA11 promoters in implantation failures in IVF programs. Gynecol Endocrinol 2019; 35 (Suppl. 1): 31–4.
________________________________________________
2. Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions 11 Medical and Health Sciences 1114 Paediatrics and Reproductive Medicine. Reprod Biol Endocrinol 2018; 16 (1): 1–18.
3. Teh WT, McBain J, Rogers P. What is the contribution of embryo-endometrial asynchrony to implantation failure? J Assist Reprod Genet 2016; 33 (11): 1419–30.
4. Hertig AT, Rock J, Adams EC. A description of 34 human ova within the first 17 days of development. Am J Anat 1956; 98 (3): 435–93.
5. Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril 2017; 108 (1): 15–8.
6. Ruiz-Alonso M, Blesa D, Díaz-Gimeno P et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 2013; 100 (3): 818–24.
7. Mahajan N. Endometrial receptivity array: Clinical application. J Hum Reprod Sci 2015; 8 (3): 121–9.
8. Kibanov MV, Makhmudova GM, Gokhberg YA. In search for an ideal marker of endometrial receptivity: from histology to comprehensive molecular genetics-based approaches. Alm Clin Med 2019; 47 (1):
12–25.
9. Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril 2011; 95 (1): 50–60.e15.
10. Craciunas L, Gallos I, Chu J et al. Conventional and modern markers of endometrial receptivity: A systematic review and meta-analysis. Hum Reprod Update 2019; 25 (2): 202–23.
11. Nikulin SV, Knyazev EN, Poloznikov AA et al. Expression of SLC30A10 and SLC23A3 Transporter mRNAs in Caco-2 Cells Correlates with an Increase in the Area of the Apical Membrane. Mol Biol 2018; 52 (4): 577–82.
12. Burmenskaya OV, Bozhenko VK, Smolnikova VY et al. Transcription profile analysis of the endometrium revealed molecular markers of the personalized “window of implantation” during in vitro fertilization. Gynecol Endocrinol 2017; 33 (Suppl. 1): 22–7.
13. Bolnick AD, Bolnick JM, Kilburn BA et al. Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility. Hum Reprod 2016; 31 (9): 2042–50.
14. Salilew-Wondim D, Hölker M, Rings F et al. Bovine pretransfer endometrium and embryo transcriptome fingerprints as predictors of pregnancy success after embryo transfer. Physiol Genomics 2010; 42 (2): 201–18.
15. Qin L, Wang R, Li S et al. Differentially Gene Expression Profile Related to Inflammation in Endometrial Cells Induce by Lipopolysaccharide. J Reprod Contracept 2009; 20 (1): 27–34.
16. Knyazeva EA, Alieva KU, Kalinina EA. Ovarian pregnancy after an IVF program in a patient with reduced endometrial receptivity. Akusherstvo Ginekol (Russian Fed.) 2018; 8: 180–4.
17. Knyazeva EA, Kalinina EA, Bystritsky AA et al. Role of HOX genes associated with infertility in female reproductive system diseases. Akusherstvo Ginekol (Russian Fed.) 2017; 11: 16–22.
18. Bourdiec A, Ahmad S-F, Lachhab A et al. Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells. Reprod Biomed Online 2016; 32 (1): 85–95.
19. Du H, Taylor HS. The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility. Cold Spring Harb. Perspect Med 2016; 6 (1): a023002.
20. Nazarenko TA, Kalinina EA, Knyazeva EA et al. The role of abnormal hypermethylation of the HOXA10 and HOXA11 promoters in implantation failures in IVF programs. Gynecol Endocrinol 2019; 35 (Suppl. 1): 31–4.
Авторы
Е.А. Князева*, М.В. Кузнецова, О.В. Бурменская, А.Е. Донников, Е.А. Калинина
ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии
им. академика В.И. Кулакова» Минздрава России, Москва, Россия
*dr.knyazeva.ea@gmail.com
Kulakov Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
*dr.knyazeva.ea@gmail.com
ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии
им. академика В.И. Кулакова» Минздрава России, Москва, Россия
*dr.knyazeva.ea@gmail.com
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Kulakov Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
*dr.knyazeva.ea@gmail.com
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