350 rub
Journal Technologies of Living Systems №4 for 2023 г.
Article in number:
Polymorphism of genes predisposing to atherosclerosis, factors of angiogenesis and endothelial function and unexplained recurrent pregnancy loss
Type of article: scientific article
DOI: https://doi.org/10.18127/j20700997-202304-05
UDC: 618
Authors:

O.A. Nagaeva1, L.N. Shcherbakova2, D.B. Revina3, M.V. Alexeenkova4, N.I. Zaytseva5, K.I. Kirillova6, L.M. Samokhodskaya7, O.B. Panina8

1–5,8 Lomonosov Moscow State University (Moscow, Russia)

2,6,7 Medical scientific and educational center of Lomonosov Moscow State University (Moscow, Russia)

1 nagaeva.99@inbox.ru, 2 lll2906@gmail.com, 3 lozinskaya.daria@gmail.com, 4 m.alexeenkova@gmail.com, 5 tata-zaitseva@mail.com, 6 dkkirillova@gmail.com, 7 slm@fbm.msu.ru, 8 olgapanina@yandex.ru

Abstract:

Recurrent pregnancy loss (RPL) is one of the major challenges of modern obstetrics. The research of genetic polymorphisms involved in the pathogenesis of RPL is ongoing.

The aim of this work was to study the associations between the single nucleotide polymorphisms of genes, which are responsible for atherosclerosis, endothelial dysfunction, angiogenesis and RPL onset.

87 patients were included in the study. The main group consisted of 65 patients with a history of two or more consecutive pregnancy losses. The control group included 22 women with three or more deliveries at term and without episodes of pregnancy loss. Genotypes for 13 single-nucleotide polymorphisms (single-nucleotide polymorphism, SNP) were determined by real-time PCR: MTHFR 1298 A>C (rs1801131), MTHFR 677 C>T (rs1801133), F5 1691 G>A (rs6025), ESR1 -397 T>C (rs2234693), PGR -413 G>A (rs10895068), APOE 176 C>T (rs429358), NOS3 -786 T>C (rs2070744), NOS3 894 G>T (rs1799983), VEGFA -634 G>C (rs2010963), VEGFA 936 C>T (rs1109324), TNF -238 G>A (rs361525), IL1β -511 C>T (rs16944), IL6 -174 G>C (rs1800795).

The genotype GC -634 G>C of the VEGFA gene and the genotype GC -174 G>C of the IL6 gene are 2 times more common in patients with RPL, the differences between patients with RPL and the control group are significant. The carriage of the GC genotype -634 G>C VEGFA increases the risk of RPL by 4 times (OR 4.00 CI 95% (1.38-11.56)). The carriage of the GC genotype -174 G>C IL6 increases the risk of PNB by 3.11 times (OR 3.11  CI 95% (1.08-8.96)).

Determination of GC genotype -634 G>C VEGFA and GC genotype -174 G>C IL6 can be used to identify patients with a high risk of RPL.

Pages: 53-63
References
  1. Raffaelli F., Nanetti L., Vignini A., Mazzanti L., Giannubilo S.R., Curzi C.M., Turi A., Vitali P., Tranquilli A.L. Nitric oxide platelet production in spontaneous miscarriage in the first trimester. Fertility and sterility. 2010. V. 93. № 6. P. 1976–1982.
  2. Trifonova E.A., Ganzha O.A., Gabidulina T.V., Devyatiarova L.L., Sotnikova L.S., Stepanov V.A. Geneticheskiye faktory v razvitii privychnogo nevynashivaniya beremennosti: obzor dannykh meta-analizov. Akusherstvo i ginekologiya. 2017. № 4. S. 14–20. (in Russian).
  3. Hefler L.A., Tempfer C.B., Bashford M.T., Unfried G., Zeillinger R., Schneeberger C., Koelbl H., Nagele F., Huber J.C. Polymorphisms of the angiotensinogen gene, the endothelial nitric oxide synthase gene, and the interleukin-1β gene promoter in women with idiopathic recurrent miscarriage. Molecular human reproduction. 2002. V. 8. № 1. P. 95–100.
  4. Oliveira-Paula G.H., Lacchini R., Tanus-Santos J.E. Clinical and pharmacogenetic impact of endothelial nitric oxide synthase polymorphisms on cardiovascular diseases. Nitric Oxide. 2017. V. 63. P. 39–51.
  5. Sajjadi M.S., Ghandil P., Shahbazian N., Saberi A. Association of vascular endothelial growth factor A polymorphisms and aberrant expression of connexin 43 and VEGFA with idiopathic recurrent spontaneous miscarriage. Journal of Obstetrics and Gynaecology Research. 2020. V. 46. № 3. P. 369–375.
  6. He X., Chen Q. Reduced expressions of connexin 43 and VEGF in the first-trimester tissues from women with recurrent pregnancy loss. Reproductive Biology and Endocrinology. 2016. V. 14. P. 1–7.
  7. Subi T.M., Krishnakumar V., Kataru C.R., Panigrahi I., Kannan M. Association of VEGF and p53 polymorphisms and spiral artery remodeling in recurrent pregnancy loss: a systematic review and meta-analysis. Thrombosis and Haemostasis. 2022. V. 122. № 3. P. 363–376.
  8. Sun Y., Chen M., Mao B., Cheng X., Zhang X., Xu C. Association between vascular endothelial growth factor polymorphism and recurrent pregnancy loss: A systematic review and meta-analysis. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2017. V. 211. P. 169–176.
  9. Tretiakova T.B., Bashmakova N.V., Demchenko N.S. Rol polimorfnykh variantov gena sosudisto-endotelialnogo faktora rosta VEGF-A v formirovanii nerazvivayushcheysya beremennosti. Problemy reproduktsii. 2016. T. 22. № 6. C. 33–37. (in Russian).
  10. Zhao X., Li Q., Yu F., Lin L., Yin W., Li J., Feng X. Gene polymorphism associated with endothelial nitric oxide synthase (4VNTR, G894T, C786T) and unexplained recurrent spontaneous abortion risk: A meta-analysis. Medicine. 2019. V. 98. № 4. P. e14175.
  11. Sadekova O.N., Knyazeva I.P., Yarovaya E.B., Radzinskiy V.E., Demidova E.M., Samokhodskaya L.M., Tkachuk V.A. Rol sistemnykh narusheniy v formirovanii gestatsionnykh oslozhneniy i ikh geneticheskaya sostavlyayushchaya. Akusherstvo i ginekologiya. 2012. № 4–2. S. 21–28. (in Russian).
  12. Kovalev V.V., Potapov N.N. Molekulyarno-geneticheskiye faktory nerazvivayushcheysya beremennosti s neustanovlennoy etiologiyey. Uralskiy meditsinskiy zhurnal. 2016. № 2. S. 35–39. (in Russian).
  13. Klinicheskiye rekomendatsii “Privychnyy vykidysh”: standarty vedeniya bolnykh dlya vrachey. red. sovet: Tetruashvili N. K. i dr. M.: Rossiyskoye obshchestvo akusherov-ginekologov. 2022. (in Russian).
  14. Potapov N.N., Kudryavtseva E.V., Kovalev V.V. Matematicheskoye modelirovaniye poteri beremennosti v I trimestre pri normalnom kariotipe embriona. Akusherstvo. ginekologiya i reproduktsiya. 2021. T. 15. № 4. S. 379–389. (in Russian).
  15. Ramazanova F.U., Radzinskiy V.E., Khamoshina M.B., Azova M.M., Ismailova A. Rol polimorfnykh lokusov VDR rs10735810. MTHFR rs1801131. MTHFR rs1801133. MTR rs1805087. MTRR rs1801394. VEGFA rs3025039 v patogeneze nerazvivayushcheysya beremennosti: prospektivnoye kogortnoye issledovaniye. Kubanskiy nauchnyy meditsinskiy vestnik. 2022. T. 29. № 3. S. 46–61. (in Russian).
  16. Wang G., Lin Z., Wang X., Sun Q., Xun Z., Xing B., Li Z. The association between 5, 10–methylenetetrahydrofolate reductase and the risk of unexplained recurrent pregnancy loss in China: A Meta-analysis. Medicine. 2021. V. 100. № 17. P. e25487.
  17. Du B., Shi X., Yin C., Feng X. Polymorphisms of methalenetetrahydrofolate reductase in recurrent pregnancy loss: an overview of systematic reviews and meta-analyses. Journal of Assisted Reproduction and Genetics. 2019. V. 36. P. 1315–1328.
  18. Tretiakova T.B., Demchenko N.S., Rukosuyev N.E. Polimorfizm genov folatnogo tsikla u zhenshchin Uralskogo regiona v norme i s privychnym nevynashivaniyem beremennosti. Meditsinskaya genetika. 2017. T. 16. № 5. S. 42–47. (in Russian).
  19. Zhang M., Xu J., Bao X., Niu W., Wang L., Du L., Zhang N., Sun Y. Association between genetic polymorphisms in interleukin genes and recurrent pregnancy loss–a systematic review and meta-analysis. PloS one. 2017. V. 12. № 1. P. e0169891.
  20. Kim J.A., Bang C.H., Song G.G., Kim J-H., Choi S.J., Jung J.H. Tumour necrosis factor alpha gene polymorphisms in women with recurrent pregnancy loss: a meta-analysis. Human Fertility. 2018. V. 23. P. 159–169.
  21. Abusuyeva Z.A., Mukhtarova M.M., Khashayeva T.Kh., Stefanyan N.A., Kakvayeva S.Sh., Magomedova M.A., Mamayeva S.M., Aliyeva S.A. Komparativnaya otsenka provospalitelnykh tsitokinov u zhenshchin s diagnostirovannymi nasledstvennymi trombofiliyami razlichnogo geneza i ikh assotsiatsiya s rannimi i pozdnimi embrionalnymi poteryami. Problemy reproduktsii. 2022. T. 28. № 3. S. 10–17. (in Russian).
  22. Messier C. Diabetes, Alzheimer's disease and apolipoprotein genotype. Experimental gerontology. 2003. V. 38. № 9. P. 941–946.
  23. Cedazo‐Mínguez A. Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities. Journal of cellular and molecular medicine. 2007. V. 11. № 6. P. 1227–1238.
  24. Li J., Chen Y., Wu H., Li L. Apolipoprotein E (Apo E) gene polymorphisms and recurrent pregnancy loss: a meta-analysis. Journal of assisted reproduction and genetics. 2014. V. 31. P. 139–148.
  25. Veremeyeva V.V., Bukhvald N.A., Dashkevich E.V., Sedlyar N.G. Razrabotka kompleksnogo algoritma obsledovaniya zhenshchin s riskom nasledstvennykh trombofiliy pri planirovanii beremennosti. Gematologiya. Transfuziologiya. Vostochnaya Evropa. 2020. T. 6. № 2. S. 208–216. (in Russian).
  26. Glotov A.S., Vashukova E.S., Kanayeva M.D., Dvoyeglazova M.O., Danilova M.M., Pakin V.S., Marochkina E.Yu., Bikmullina D.R., Glebova M.A., Makhrova I.A., Obraztsova G.I., Glotov O.S., Zaynulina M.S., Ivashchenko T.E., Baranov V.S. Issledovaniye assotsiatsii polimorfizma genov APOE. LPL i NOS3 s riskom sosudistoy patologii u detey i beremennykh zhenshchin. Ekologicheskaya genetika. 2011. T. 9. № 4. S. 25–34. (in Russian).
  27. Anousha N., Hossein-Nezhad A., Biramijamal F., Rahmani A., Maghbooli Z., Aghababaei E., Nemati S. Association study of estrogen receptor alpha gene polymorphisms with spontaneous abortion: is this a possible reason for unexplained spontaneous abortion?. BioMed. Research International. 2013. V. 2013. P. 6.
  28. Clapauch R., Mourao A.F., Mecenas A.S., Maranhao P.A., Rossini A., Bouskela E. Endothelial function and insulin resistance in early postmenopausal women with cardiovascular risk factors: importance of ESR1 and NOS3 polymorphisms. PLoS One. 2014. V. 9. № 7. P. e103444.
  29. Tang L., Xiang Q., Xiang J., Li J. The haplotypes GCA and ACA in ESR1 gene are associated with the susceptibility of recurrent spontaneous abortion (RSA) in Chinese Han: A case-control study and meta-analysis. Medicine. 2022. V. 101. № 21. P. e29168.
  30. Melkozerova O.A., Bashmakova N.V., Tretiakova T.B., Shchedrina I.D. Molekulyarno-geneticheskiye i epigeneticheskiye aspekty narusheniya retseptivnosti endometriya u zhenshchin s nizkoy massoy tela pri rozhdenii. Voprosy ginekologii. akusherstva i perinatologii. 2019. T. 18. №. 4. S. 35–43. (in Russian).
  31. Abramovskikh O.S., Loginova Yu.V. Analiz polimorfnykh variantov genov ESR1 i PGR u zhenshchin s nevynashivaniyem beremennosti. Meditsinskaya genetika. 2022. T. 21. №. 7. S. 4–7. (in Russian).
Date of receipt: 30.06.2023
Approved after review: 30.06.2023
Accepted for publication: 20.10.2023