Russian Military Medical Academy ReportsRussian Military Medical Academy ReportsИзвестия Российской Военно-медицинской академии2713-23152713-2323Eco-Vector10903610.17816/rmmar109036ReviewsНаучные обзорыReview ArticleGenetic factors of early termination of pregnancyГенетические факторы преждевременного прерывания беременности3005939248-9806TsechoevaLeila Sh.ЦечоеваЛейла Шахмурзаевна
Russian Federation

M.D., Ph.D. (Medicine), the Head of division of gynecology

канд. мед. наук, заведующая гинекологическим отделением

doctor-leila@yandex.ruDementyevaElena I.ДементьеваЕлена Ивановна
Russian Federation

M.D., doctor obstetrician-gynecologist

врач акушер-гинеколог

02102005@bk.ruhttps://orcid.org/0000-0002-3813-299510645068158-4744LeonovaMargarita D.ЛеоноваМаргарита Дмитриевна
Russian Federation

M.D., doctor obstetrician-gynecologist, the Head of the Maternity Department

врач акушер-гинеколог, заведующая родильным отделением

_margarita_@bk.ru10890073465-2522PoloskovAnton I.ПолосковАнтон Иванович
Russian Federation

junior researcher of the department (Medical and Biological Research) of the Research Center

младший научный сотрудник НИО (медико-биологических исследований) НИЦ

a.i.poloskov@gmail.comGavrichkovaYuliya V.ГавричковаЮлия Владимировна
Russian Federation

M.D., doctor obstetrician-gynecologist

врач акушер-гинеколог

_ignatenkoiuliia@gmail.comBardinovaMariya V.БардиноваМария Владимировна
Russian Federation

doctor obstetrician-gynecologist, obstetrics and gynecology clinic

врач акушер-гинеколог клиники акушерства и гинекологии

mariabardinova@gmail.comhttps://orcid.org/0000-0001-5309-00871679243605-0413Tapil'skayaNatalya I.ТапильскаяНаталья Игоревна
Russian Federation

M.D., D.Sc. (Medicine), Professor, Professor of the Obstetrics and Gynecology Department, the Head of Reproductology Department

докт. мед. наук профессор, профессор кафедры акушерства и гинекологии; заведующая отделом репродуктологии

tapnatalia@yandex.ru10721933626-6262SlizhovPavel А.СлижовПавел Алексеевич
Russian Federation

junior researcher of the Department (experimental medicine) of the Research Center

младший научный сотрудник отдела (медико-биологических исследований) научно-исследовательского центра

maidel@bk.ruhttps://orcid.org/0000-0002-0161-59776219956860-8990GlushakovRuslan I.ГлушаковРуслан Иванович
Russian Federation

M.D., D.Sc. (Medicine), the Head of the Department (medical and biological research) of the Research Center

докт. мед. наук, начальник отдела (медико-биологических исследований) научно-исследовательского центра

glushakoffruslan@yandex.ruI.I. Dzhanelidze Saint Petersburg Research Institute of Emergency MedicineСанкт-Петербургский научно-исследовательский институт скорой помощи имени И.И. ДжанелидзеSaint Petersburg State Pediatric Medical UniversityСанкт-Петербургский государственный педиатрический медицинский университетMaternity Hospital N 13Родильный дом № 13Military Medical AcademyВоенно-медицинская академияCity Mariinsky HospitalГородская Мариинская больницаOtt Research institute of obstetrics, gynecology and reproductologyНаучно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта0405202342143532806202222022023Copyright ©; 2023, Eco-VectorCopyright ©; 2023, Эко-Вектор2023Eco-VectorЭко-Векторhttps://creativecommons.org/licenses/by-nc-nd/4.0https://journals.eco-vector.com/RMMArep/article/view/109036

Pregnancy loss and premature delivery are combined by the definition Premature Termination of Pregnancy, while these conditions affect up to 5% of women of reproductive age. In some cases, genetic components are both etiologic and pathogenetic factors of premature birth, however, This challenge is further complicated by the fact that extensive population-based genetic studies and subsequent validation of the data are required, especially in multi-ethnic populations.

Genome-wide studies will demonstrate polymorphic variants of hundreds of genes that are candidates for being associated with termination of pregnancy, including those regulating embryo implantation, pregnancy support, and immune system response. The review provides information about the genes and genetic polymorphisms that are involved in the regulation of the female reproductive system and associated with premature birth. A special role in the genetic mechanisms of miscarriage and/or preterm birth belongs to steroid hormone receptors, enzymes of the arachidonic acid metabolism, pro- and anti-inflammatory cytokines. However, the infectious factor takes the first place as a leading one, forming cause-and-effect relationships in the chain of pathogenetic links or giving modality to other factors. Most often, it is genetic polymorphisms associated with an over-activity of the immune system that underlie premature termination of pregnancy.

Subsequent Investigation of the human genome, epigenome, and transcriptome helps to identify molecular mechanisms linked with preterm delivery and premature newborn clinical appearance in early and late neonatal life and even predict developmental outcomes. These data could be used to develop targeted interventions aimed at selecting the most effective individual treatment and rehabilitation plan. The data obtained in future studies could be used to develop for preconception care, targeted therapy and the most effective individual treatment plan.

Keywords: genetic polymorphism; miscarriage; over-active immune responses; premature birth; premature termination of pregnancy; transcriptome.

Прерывание беременности и преждевременные роды объединяют термином «преждевременное прерывание беременности», при этом данные состояния затрагивают до 5 % женщин репродуктивного возраста. В некоторых случаях генетические факторы терминации беременности являются как этиологическими, так и патогенетическими, однако проверка этих данных осложняется необходимостью проведения емких популяционных генетических исследований и последующей интерпретации данных.

Полиморфные варианты сотен генов являются потенциальными кандидатами для их изучения в качестве ведущих факторов, влияющих на невынашивание беременности — особенно среди генов, регулирующих имплантацию эмбрионов, поддержание беременности и особенности ответа иммунной системы на инвазию патогена. В обзоре представлена информация об участвующих в регуляции репродуктивной функции генах, которые ассоциированы с преждевременным прерыванием беременности. Особая роль в генетически детерминированных механизмах невынашивания беременности и/или возникновении преждевременных родов принадлежит полиморфным вариантам генов, кодирующих рецепторы стероидных гормонов, про- и противовоспалительные цитокинов, а также ферменты, регулирующие метаболизм арахидоновой кислоты и ее производных. Однако ведущим, образующим в цепи патогенетических звеньев причинно-следственные связи или придающим модальность другим факторам является инфекционный фактор. Наиболее часто именно генетические полиморфизмы, ассоциированные с гиперответом иммунной системы, лежат в основе преждевременного прерывания беременности.

Последующие исследования генома, эпигенома и транскриптома человека позволят установить молекулярные механизмы, связанные с преждевременными родами и клиническими проявлениями недоношенных новорожденных в раннем и позднем неонатальном периоде, а также прогнозировать исходы беременности. Также полученные в будущих исследованиях данные можно будет использовать для предгравидарной подготовки, разработки таргетной терапии и определения эффективного индивидуального плана лечения.

genetic polymorphismmiscarriageover-active immune responsespremature birthpremature termination of pregnancytranscriptomeгенетические полиморфизмыгиперответ иммунной системыпреждевременное прерывание беременностипреждевременные родысамопроизвольный выкидыштранскриптомHobel CJ, Dolan SM, Hindoyan NA, et al. History of the establishment of the Preterm Birth international collaborative (PREBIC). Placenta. 2019;79:3–20. DOI: 10.1016/j.placenta.2019.03.008Hobel C.J., Dolan S.M., Hindoyan N.A., et al. History of the establishment of the Preterm Birth international collaborative (PREBIC) // Placenta. 2019. Vol. 79. P. 3–20. DOI: 10.1016/j.placenta.2019.03.008Kashkin VA, Fedorova OV, Bagrov AY, et al. Endogenous sodium pump inhibitors, diabetes mellitus and preeclampsia. preliminary observations and a hypothesis. Pathophysiology. 2007;14(3–4): 147–151. DOI: 10.1016/j.pathophys.2007.09.003Kashkin V.A., Fedorova O.V., Bagrov A.Y., et al. Endogenous sodium pump inhibitors, diabetes mellitus and preeclampsia. preliminary observations and a hypothesis // Pathophysiology. 2007. Vol. 14, No. 3–4. P. 147–151. DOI: 10.1016/j.pathophys.2007.09.003Wilkins-Haug L. Genetic innovations and our understanding of stillbirth. Hum Genet. 2020;139(9):1161–1172. DOI: 10.1007/s00439-020-02146-2Wilkins-Haug L. Genetic innovations and our understanding of stillbirth // Hum. Genet. 2020. Vol. 139, No. 9. P. 1161–1172. DOI: 10.1007/s00439-020-02146-2Conde-Agudelo A, Romero R, Nicolaides KH. Cervical pessary to prevent preterm birth in asymptomatic high-risk women: a systematic review and meta- analysis. Am J Obstet Gynecol. 2020;223(1): 42–65.e2. DOI: 10.1016/j.ajog.2019.12.266Conde-Agudelo A., Romero R., Nicolaides K.H. Cervical pessary to prevent preterm birth in asymptomatic high-risk women: a systematic review and meta- analysis // Am. J. Obstet. Gynecol. 2020. Vol. 223, No. 1. P. 42–65.e2. DOI: 10.1016/j.ajog.2019.12.266Quintero-Ronderos P, Laissue P. Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches. Reprod Sci. 2020;27(8):1541–1552. DOI: 10.1007/s43032-020-00187-6Quintero-Ronderos P., Laissue P. Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches // Reprod. Sci. 2020. Vol. 27, No. 8. P. 1541–1552. DOI: 10.1007/s43032-020-00187-6Zeberg H, Kelso J, Pääbo S. The Neandertal Progesterone Receptor. Mol Biol Evol. 2020:37(9):2655–2660. DOI: 10.1093/molbev/msaa119Zeberg H., Kelso J., Pääbo S. The Neandertal Progesterone Receptor // Mol. Biol. Evol. 2020. Vol. 37, No. 9. P. 2655–2660. DOI: 10.1093/molbev/msaa119Tapil’skaya NI. The role of the immune system in the pathogenesis of pregnancy loss. Preconditions for pharmacological correction. Reviews on clinical pharmacology and drug therapy. 2002;1(2):15–26. (In Russ.)Тапильская Н.И. Роль иммунной системы в патогенезе невынашивания беременности, предпосылки для фармакологической коррекции // Обзоры по клинической фармакологии и лекарственной терапии. 2002. T. 1, № 2. C. 15–26.Proshin SN, Glushakov RI, Shabanov PD, et al. The value of the expression of TLR-receptors for the selection of pharmacological correction of pathology of the cervix and endometrium. Genes and Cells. 2011;6(1):91–97. (In Russ.)Прошин С.Н., Глушаков Р.И., Шабанов П.Д., и др. Значение экспрессии TLR-рецепторов для выбора фармакологической коррекции патологии шейки матки и эндометрия // Гены и клетки. 2011. Т. 6, № 1. C. 91–97.Ehn NL, Cooper ME, Orr K, et al. Evaluation of fetal and maternal genetic variation in the progesterone receptor gene for contributions to preterm birth. Pediatr Res. 2007;62(5):630–635. DOI: 10.1203/PDR.0b013e3181567bfcEhn N.L., Cooper M.E., Orr K., et al. Evaluation of fetal and maternal genetic variation in the progesterone receptor gene for contributions to preterm birth // Pediatr Res. 2007. Vol. 62, No. 5. P. 630–635. DOI: 10.1203/PDR.0b013e3181567bfcMann PC, Cooper ME, Ryckman KK, et al. Polymorphisms in the fetal progesterone receptor and a calcium-activated potassium channel isoform are associated with preterm birth in an Argentinian population. J Perinatol. 2013;33(5):336–340. DOI: 10.1038/jp.2012.118Mann P.C., Cooper M.E., Ryckman K.K., et al. Polymorphisms in the fetal progesterone receptor and a calcium-activated potassium channel isoform are associated with preterm birth in an Argentinian population // J. Perinatol. 2013. Vol. 33, No. 5. P. 336–340. DOI: 10.1038/jp.2012.118Manuck TA, Major HD, Varner MW, et al. Progesterone receptor genotype, family history, and spontaneous preterm birth. Obstet Gynecol. 2010;115(4):765–770. DOI: 10.1097/AOG.0b013e3181d53b83Manuck T.A., Major H.D., Varner M.W., et al. Progesterone receptor genotype, family history, and spontaneous preterm birth // Obstet. Gynecol. 2010. Vol. 115, No. 4. P. 765–770. DOI: 10.1097/AOG.0b013e3181d53b83Manuck TA, Lai Y, Meis PJ, et al. Progesterone receptor polymorphisms and clinical response to 17-alpha- hydroxyprogesterone caproate. Am J Obstet Gynecol. 2011;205(2):135.e1–e9. DOI: 10.1016/j.ajog.2011.03.048Manuck T.A., Lai Y., Meis P.J., et al. Progesterone receptor polymorphisms and clinical response to 17-alpha- hydroxyprogesterone caproate // Am. J. Obstet. Gynecol. 2011. Vol. 205, No. 2. P. 135.e1–e9. DOI: 10.1016/j.ajog.2011.03.048Kim J, Stirling KJ, Cooper ME, et al. Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study. BMC Med Genet. 2013;14:77. DOI: 10.1186/1471-2350-14-77Kim J., Stirling K.J., Cooper M.E., et al. Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study // BMC Med. Genet. 2013. Vol. 14. P. 77. DOI: 10.1186/1471-2350-14-77Kuessel L. Grimm C, Knöfler M, et al. Common oxytocin receptor gene polymorphisms and the risk for preterm birth. Dis Markers. 2013;34(1):51–56. DOI: 10.3233/DMA-2012-00936Kuessel L., Grimm C., Knöfler M., et al. Common oxytocin receptor gene polymorphisms and the risk for preterm birth // Dis. Markers. 2013. Vol. 34, No. 1. P. 51–56. DOI: 10.3233/DMA-2012-00936Bryant-Greenwood GD, Kern A, Yamamoto SY, et al. Relaxin and the human fetal membranes. Reprod Sci. 2007;4(8 Suppl):42–45. DOI: 10.1177/1933719107310821Bryant-Greenwood G.D., Kern A., Yamamoto S.Y., et al. Relaxin and the human fetal membranes // Reprod. Sci. 2007. Vol. 4 (8 Suppl.). P. 42–45. DOI: 10.1177/1933719107310821Vogel I, Hollegaard MV, Hougaard DM, et al. Polymorphisms in the promoter region of relaxin-2 and preterm birth: involvement of relaxin in the etiology of preterm birth. In Vivo. 2009;23(6):1005–1009.Vogel I., Hollegaard M.V., Hougaard D.M., et al. Polymorphisms in the promoter region of relaxin-2 and preterm birth: involvement of relaxin in the etiology of preterm birth // In Vivo. 2009. Vol. 23, No. 6. P. 1005–1009.Rocha FG. Slavin TP, Li D, et al. Genetic associations of relaxin: preterm birth and premature rupture of fetal membranes. Am J Obstet Gynecol. 2013;209(3):258.e1–e8. DOI: 10.1016/j.ajog.2013.05.020Rocha F.G., Slavin T.P., Li D., et al. Genetic associations of relaxin: preterm birth and premature rupture of fetal membranes // Am. J. Obstet. Gynecol. 2013. Vol. 209, No. 3. P. 258.e1–e8. DOI: 10.1016/j.ajog.2013.05.020Ryckman KK, Morken NH, White MJ, et al. Maternal and fetal genetic associations of PTGER3 and PON1 with preterm birth. PLoS One. 2010;5(2):e9040. DOI: 10.1371/journal.pone.0009040Ryckman K.K., Morken N.H., White M.J., et al. Maternal and fetal genetic associations of PTGER3 and PON1 with preterm birth // PLoS One. 2010. Vol. 5, No. 2. Art. e9040. DOI: 10.1371/journal.pone.0009040Jeffcoat MK, Jeffcoat RL, Tanna N, Parry SH. Association of a common genetic factor, PTGER3, with outcome of periodontal therapy and preterm birth. J Periodontol. 2014;85(3):446–454. DOI: 10.1902/jop.2013.130006Jeffcoat M.K., Jeffcoat R.L., Tanna N., Parry S.H. Association of a common genetic factor, PTGER3, with outcome of periodontal therapy and preterm birth // J. Periodontol. 2014. Vol. 85, No. 3. P. 446–454. DOI: 10.1902/jop.2013.130006Grisaru-Granovsky S, Altarescu G, Finci S, et al. Prostanoid DP receptor (PTGDR) variants in mothers with post-coital associated preterm births: preliminary observations. J Perinatol. 2010;30(1): 33–37. DOI: 10.1038/jp.2009.127Grisaru-Granovsky S., Altarescu G., Finci S., et al. Prostanoid DP receptor (PTGDR) variants in mothers with post-coital associated preterm births: preliminary observations // J. Perinatol. 2010. Vol. 30, No. 1. P. 33–37. DOI: 10.1038/jp.2009.127Haataja R, Karjalainen MK, Luukkonen A, et al. Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis. PLoS Genet. 2011;7(2): e1001293. DOI: 10.1371/journal.pgen.1001293Haataja R., Karjalainen M.K., Luukkonen A., et al. Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis // PLoS Genet. 2011. Vol. 7, No. 2. Art. e1001293. DOI: 10.1371/journal.pgen.1001293Bream EN, Leppellere CR, Cooper ME, et al. Candidate gene linkage approach to identify DNA variants that predispose to preterm birth. Pediatr Res. 2013;73(2):135–141. DOI: 10.1038/pr.2012.166Bream E.N., Leppellere C.R., Cooper M.E., et al. Candidate gene linkage approach to identify DNA variants that predispose to preterm birth // Pediatr Res. 2013. Vol. 73, No. 2. P. 135–141. DOI: 10.1038/pr.2012.166Schmid M, Grimm C, Leipold H, et al. A polymorphism of the corticotropin-releasing hormone receptor 2 (CRHR2) and preterm birth. Dis Markers. 2010;28(1):37–42. DOI: 10.3233/DMA-2010-0681Schmid M., Grimm C., Leipold H., et al. A polymorphism of the corticotropin-releasing hormone receptor 2 (CRHR2) and preterm birth // Dis. Markers. 2010. Vol. 28, No. 1. P. 37–42. DOI: 10.3233/DMA-2010-0681Ledingham MA, Thomson AJ, Jordan F, et al. Cell adhesion molecule expression in the cervix and myometrium during pregnancy and parturition. Obstet Gynecol. 2001;97(2):235–242. DOI: 10.1016/s0029-7844(00)01126-1Ledingham M.A., Thomson A.J., Jordan F., et al. Cell adhesion molecule expression in the cervix and myometrium during pregnancy and parturition // Obstet. Gynecol. 2001. Vol. 97, No. 2. P. 235–242. DOI: 10.1016/s0029-7844(00)01126-1Osmers RG, Blaser J, Kuhn W, Tschesche H. Interleukin-8 synthesis and the onset of labor. Obstet Gynecol. 1995;86(2):223–229. DOI: 10.1016/0029-7844(95)93704-4Osmers R.G., Blaser J., Kuhn W., Tschesche H. Interleukin-8 synthesis and the onset of labor // Obstet. Gynecol. 1995. Vol. 86, No. 2. P. 223–229. DOI: 10.1016/0029-7844(95)93704-4Giannoulias D, Patel FA, Holloway AC, et al. Differential changes in 15-hydroxyprostaglandin dehydrogenase and prostaglandin H synthase (types I and II) in human pregnant myometrium. J Clin Endocrinol Metab. 2002;87(3):1345–1352. DOI: 10.1210/jcem.87.3.8317Giannoulias D., Patel F.A., Holloway A.C., et al. Differential changes in 15-hydroxyprostaglandin dehydrogenase and prostaglandin H synthase (types I and II) in human pregnant myometrium // J. Clin. Endocrinol. Metab. 2002. Vol. 87, No. 3. P. 1345–1352. DOI: 10.1210/jcem.87.3.8317Sparey C, Robson SC, Bailey J, et al. The differential expression of myometrial connexin-43, cyclooxygenase-1 and -2, and Gs alpha proteins in the upper and lower segments of the human uterus during pregnancy and labor. J Clin Endocrinol Metab. 1999;84(5): 1705–1710. DOI: 10.1210/jcem.84.5.5644Sparey C., Robson S.C., Bailey J., et al. The differential expression of myometrial connexin-43, cyclooxygenase-1 and -2, and Gs alpha proteins in the upper and lower segments of the human uterus during pregnancy and labor // J. Clin. Endocrinol. Metab. 1999. Vol. 84, No. 5. P. 1705–1710. DOI: 10.1210/jcem.84.5.5644Havelock JC, Keller P, Muleba N, et al. Human myometrial gene expression before and during parturition. Biol Reprod. 2005;72(3):707–719. DOI: 10.1095/biolreprod.104.032979Havelock J.C., Keller P., Muleba N., et al. Human myometrial gene expression before and during parturition // Biol. Reprod. 2005. Vol. 72, No. 3 P. 707–719. DOI: 10.1095/biolreprod.104.032979Anum EA, Springel EH, Shriver MD, Strauss JF 3rd. Genetic contributions to disparities in preterm birth. Pediatr Res. 2009;65(1):1–9. DOI: 10.1203/PDR.0b013e31818912e7Anum E.A., Springel E.H., Shriver M.D., Strauss J.F. 3rd. Genetic contributions to disparities in preterm birth // Pediatr Res. 2009. Vol. 65, No. 1. P. 1–9. DOI: 10.1203/PDR.0b013e31818912e7Magnus P, Birke C, Vejrup K, et al. Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa). Int J Epidemiol. 2016;45(2):382–388. DOI: 10.1093/ije/dyw029Magnus P., Birke C., Vejrup K., et al. Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa) // Int. J. Epidemiol. 2016. Vol. 45, No. 2. P. 382–388. DOI: 10.1093/ije/dyw029Liu X, Wang G, Hong X, et al. Associations between gene polymorphisms in fatty acid metabolism pathway and preterm delivery in a US urban black population. Hum Genet. 2012;131(3):341–351. DOI: 10.1007/s00439-011-1079-5Liu X., Wang G., Hong X., et al. Associations between gene polymorphisms in fatty acid metabolism pathway and preterm delivery in a US urban black population // Hum. Genet. 2012. Vol. 131, No. 3. P. 341–351. DOI: 10.1007/s00439-011-1079-5Sata F, Toya S, Yamada H, et al. Proinflammatory cytokine polymorphisms and the risk of preterm birth and low birthweight in a Japanese population. Mol Hum Reprod. 2009;15(2):121–130. DOI: 10.1093/molehr/gan078Sata F., Toya S., Yamada H., et al. Proinflammatory cytokine polymorphisms and the risk of preterm birth and low birthweight in a Japanese population // Mol. Hum. Reprod. 2009. Vol. 15, No. 2. P. 121–130. DOI: 10.1093/molehr/gan078Jones NM, Holzman C, Friderici KH. et al. Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery. J Reprod Immunol. 2010;87(1–2):82–89. DOI: 10.1016/j.jri.2010.06.1Jones N.M., Holzman C., Friderici K.H., et al. Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery // J. Reprod. Immunol. 2010. Vol. 87, No. 1–2. P. 82–89. DOI: 10.1016/j.jri.2010.06.158Kalish RB, Vardhana S, Gupta M, et al. Interleukin-1 receptor antagonist gene polymorphism and multifetal pregnancy outcome. Am J Obstet Gynecol. 2003;189(4):911–914. DOI: 10.1067/s0002-9378(03)00770-1Kalish R.B., Vardhana S., Gupta M., et al. Interleukin-1 receptor antagonist gene polymorphism and multifetal pregnancy outcome // Am. J. Obstet. Gynecol. 2003. Vol. 189, No. 4. P. 911–914. DOI: 10.1067/s0002-9378(03)00770-1Murtha AP, Nieves A, Hauser ER, et al. Association of maternal IL1 receptor antagonist intron 2 gene polymorphism and preterm birth. Am J Obstet Gynecol. 2006;195(5):1249–1253. DOI: 10.1016/j.ajog.2006.09.002Murtha A.P., Nieves A., Hauser E.R., et al. Association of maternal IL1 receptor antagonist intron 2 gene polymorphism and preterm birth // Am. J. Obstet. Gynecol. 2006. Vol. 195, No. 5. P. 1249–1253. DOI: 10.1016/j.ajog.2006.09.002Unfried G, Tempfer C, Schneeberger C, et al. Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage. Fertil Steril. 2001;75(4):683–687. DOI: 10.1016/s0015-0282(01)01675-2Unfried G., Tempfer C., Schneeberger C., et al. Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage // Fertil Steril. 2001. Vol. 75, No. 4. P. 683–687. DOI: 10.1016/s0015-0282(01)01675-2Chaves JH, Babayan A, de Melo Bezerra C, et al. Maternal and neonatal interleukin-1 receptor antagonist genotype and pregnancy outcome in a population with a high rate of pre-term birth. Am J Reprod Immunol. 2008;60(4):312–317. DOI: 10.1111/j.1600-0897.2008.00625.xChaves J.H., Babayan A., de Melo Bezerra C., et al. Maternal and neonatal interleukin-1 receptor antagonist genotype and pregnancy outcome in a population with a high rate of pre-term birth // Am. J. Reprod. Immunol. 2008. Vol. 60, No, 4. P. 312–317. DOI: 10.1111/j.1600-0897.2008.00625.xKalinka J, Bitner A. [Selected cytokine gene polymorphisms and the risk of preterm delivery in the population of Polish women]. Ginekol Pol. 2009;80(2):111–117. (In Polish)Kalinka J., Bitner A. [Selected cytokine gene polymorphisms and the risk of preterm delivery in the population of Polish women] // Ginekol. Pol. 2009. Vol. 80, No. 2. P. 111–117.Jones NM, Holzman C, Tian Y, et al. Innate immune system gene polymorphisms in maternal and child genotype and risk of preterm delivery. J Matern Fetal Neonatal Med. 2012;25(3):240–247. DOI: 10.3109/14767058.2011.569614Jones N.M., Holzman C., Tian Y., et al. Innate immune system gene polymorphisms in maternal and child genotype and risk of preterm delivery // J. Matern. Fetal. Neonatal. Med. 2012. Vol. 25, No. 3. P. 240–247. DOI: 10.3109/14767058.2011.569614Velez DR, Menon R, Thorsen P, et al. Ethnic differences in interleukin 6 (IL-6) and IL6 receptor genes in spontaneous preterm birth and effects on amniotic fluid protein levels. Ann Hum Genet. 2007;71(Pt 5):586–600. DOI: 10.1111/j.1469-1809.2007.00352.xVelez D.R., Menon R., Thorsen P., et al. Ethnic differences in interleukin 6 (IL-6) and IL6 receptor genes in spontaneous preterm birth and effects on amniotic fluid protein levels // Ann. Hum. Genet. 2007. Vol. 71 (Pt. 5). P. 586–600. DOI: 10.1111/j.1469-1809.2007.00352.xVelez DR, Fortunato SJ, Williams SM, Menon R. Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth. Hum Mol Genet. 2008;17(11):1619–1630. DOI: 10.1093/hmg/ddn049Velez D.R., Fortunato S.J., Williams S.M., Menon R. Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth // Hum. Mol. Genet. 2008. Vol. 17, No. 11. P. 1619–1630. DOI: 10.1093/hmg/ddn049Sugita N, Kobayashi T, Kikuchi A, et al. Immunoregulatory gene polymorphisms in Japanese women with preterm births and periodontitis. J Reprod Immunol. 2012;93(2):94–101. DOI: 10.1016/j.jri.2012.01.005Sugita N., Kobayashi T., Kikuchi A., et al. Immunoregulatory gene polymorphisms in Japanese women with preterm births and periodontitis // J. Reprod. Immunol. 2012. Vol. 93, No. 2. P. 94–101. DOI: 10.1016/j.jri.2012.01.005Bitner A, Kalinka J. IL-1β, IL-6 promoter, TNF-α promoter and IL-1RA gene polymorphisms and the risk of preterm delivery due to preterm premature rupture of membranes in a population of Polish women. Arch Med Sci. 2010;6(4):552–557. DOI: 10.5114/aoms.2010.14467Bitner A., Kalinka J. IL-1β, IL-6 promoter, TNF-α promoter and IL-1RA gene polymorphisms and the risk of preterm delivery due to preterm premature rupture of membranes in a population of Polish women // Arch Med Sci. 2010. Vol. 6, No. 4. P. 552–557.. DOI: 10.5114/aoms.2010.14467Velez DR, Fortunato S, Thorsen P, et al. Spontaneous preterm birth in African Americans is associated with infection and inflammatory response gene variants. Am J Obstet Gynecol. 2009;200(2):209.e1–e27. DOI: 10.1016/j.ajog.2008.08.051Velez D.R., Fortunato S., Thorsen P., et al. Spontaneous preterm birth in African Americans is associated with infection and inflammatory response gene variants // Am. J. Obstet. Gynecol. 2009. Vol. 200, No. 2. P. 209.e1–e27. DOI: 10.1016/j.ajog.2008.08.051Heinzmann A, Mailaparambil B, Mingirulli N, Krueger M. Association of interleukin-13/-4 and toll-like receptor 10 with preterm births. Neonatology. 2009;96(3):175–181. DOI: 10.1159/000210091Heinzmann A., Mailaparambil B., Mingirulli N., Krueger M. Association of interleukin-13/-4 and toll-like receptor 10 with preterm births // Neonatology. 2009. Vol. 96, No. 3. P. 175–181. DOI: 10.1159/000210091Gomez LM, Sammel MD, Appleby DH, et al. Evidence of a gene-environment interaction that predisposes to spontaneous preterm birth: a role for asymptomatic bacterial vaginosis and DNA variants in genes that control the inflammatory response. Am J Obstet Gynecol. 2010;202(4): 386.e1–e6. DOI: 10.1016/j.ajog.2010.01.042Gomez L.M., Sammel M.D., Appleby D.H., et al. Evidence of a gene-environment interaction that predisposes to spontaneous preterm birth: a role for asymptomatic bacterial vaginosis and DNA variants in genes that control the inflammatory response // Am. J. Obstet. Gynecol. 2010. Vol. 202, No. 4. Art. 386.e1–e6. DOI: 10.1016/j.ajog.2010.01.042Pu J, Zeng WY. [Gene polymorphism of tumor necrosis factor-alpha receptor II in 196 site and premature births in Chinese Han Population]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2010;41(1): 25–127. (In Chinese)Pu J., Zeng W.Y. [Gene polymorphism of tumor necrosis factor-alpha receptor II in 196 sites and premature births in Chinese Han Population] // Sichuan Da Xue Xue Bao Yi Xue Ban. 2010. Vol. 41, No. 1. P. 125–127.Hollegaard MV, Grove J, Thorsen P, et al. Polymorphisms in the tumor necrosis factor alpha and interleukin 1- beta promoters with possible gene regulatory functions increase the risk of preterm birth. Acta Obstet Gynecol Scand. 2008;87(12):1285–1290. DOI: 10.1080/00016340802468340Hollegaard M.V., Grove J., Thorsen P., et al. Polymorphisms in the tumor necrosis factor alpha and interleukin 1- beta promoters with possible gene regulatory functions increase the risk of preterm birth // Acta Obstet. Gynecol. Scand. 2008. Vol. 87, No. 12. P. 1285–1290. DOI: 10.1080/00016340802468340Moura E, Mattar R, de Souza E, et al. Inflammatory cytokine gene polymorphisms and spontaneous preterm birth. J Reprod Immunol. 2009;80 (1–2):115–121. DOI: 10.1016/j.jri.2008.11.007Moura E., Mattar R., de Souza E., et al. Inflammatory cytokine gene polymorphisms and spontaneous preterm birth // J. Reprod. Immunol. 2009. Vol. 80, No. 1–2. P. 115–121. DOI: 10.1016/j.jri.2008.11.007Liang M, Wang X, Li J, et al. Association of combined maternal-fetal TNF-alpha gene G308A genotypes with preterm delivery: a gene-gene interaction study. J Biomed Biotechnol. 2010;2010:396184. DOI: 10.1155/2010/396184Liang M., Wang X., Li J., et al. Association of combined maternal-fetal TNF-alpha gene G308A genotypes with preterm delivery: a gene-gene interaction study // J. Biomed. Biotechnol. 2010. Vol. 2010. Art. 396184. DOI: 10.1155/2010/396184