RUDN Journal of Medicine

Вестник Российского университета дружбы народов. Серия: Медицина

2313-02452313-0261

Peoples’ Friendship University of Russia named after Patrice Lumumba (RUDN University)

22798

10.22363/2313-0245-2019-23-4-381-389

BIOLOGY. EXPERIMENTAL PHYSIOLOGY

БИОЛОГИЯ. ЭКСПЕРИМЕНТАЛЬНАЯ ФИЗИОЛОГИЯ

Research Article

Prevalence of Some Gene Polymorphisms Related to Early Pregnancy Loss among Russian Women

Встречаемость у женщин русской национальности некоторых генных полиморфизмов, ассоциированных с ранними репродуктивными потерями

Ahmed

A. A. M.

Ахмед

А. А. М.

azova-mm@rudn.ru

Muradian

A. A.

Мурадян

А. А.

azova-mm@rudn.ru

Azova

M. M.

Азова

М. М.

azova-mm@rudn.ru

Peoples’ Friendship University of Russia (RUDN University)Российский университет дружбы народов

15122019

234

VOL 23, NO4 (2019)

ТОМ 23, №4 (2019)

38138903022020

2019

Ahmed A.A., Muradian A.A., Azova M.M.

Ахмед А.А., Мурадян А.А., Азова М.М.

http://creativecommons.org/licenses/by/4.0

https://journals.rudn.ru/medicine/article/view/22798

Background. A variety of biological processes regulated by differential gene expression are required to maintain a normal gestation and accordingly, the mutations and polymorphisms in such genes may cause miscellaneous biological disorders that eventually result in early pregnancy loss. Many studies reported that aberrant fetal DNA methylation as well as embryonic chromosome abnormalities may lead to impairment of fetal early growth and development. Therefore, we have aimed to genotype several gene polymorphisms might be involved in the above-mentioned biological disorders to screen their prevalence in Russian population. Materials and methods. 81 Russian women without previous history of normal pregnancy or early abortion were recruited into this population study to determine the genotype and allele frequencies through genotyping using RFLP-PCR method for DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, and DNMT3L rs2070565, allele-specific PCR for SYCP3 T657C, and real-time PCR for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, and MTRR rs1801394. Results. Minor homozygous genotypes and minor alleles of the polymorphisms DNMT3B rs2424913 (TT: 11.1%, T: 37.05%), DNMT1 rs2228611 (GG: 18.5%, G: 40.75%), and DNMT1 rs8101626 (GG: 16.0%, G: 40.1%) were quite prevalent in Russian women and as frequent as those of the well-studied polymorphisms: MTRR rs1801394 (GG: 27.2%, G: 50.65%), MTHFR rs1801131 (CC: 17.3%, C: 40.15%), and MTHFR rs1801133 (TT: 11.1%, T: 29.0%).The heterozygous genotype of SYCP3 T657C (CT: 12.3%, T: 6.15%) was also quite frequent. Conclusion. Based on our study and literature data, we suggest that DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 T657C polymorphisms along with the common folate cycle gene polymorphisms can be potential genetic predictors for early pregnancy loss in Russian women.

Актуальность. Разнообразные биологические процессы, регулируемые дифференциальной экспрессией генов, необходимы для нормального протекания беременности, и, соответственно, мутации и полиморфизмы в таких генах могут вызывать различные нарушения, приводящие, в конечном итоге, к преждевременной потере беременности. Во многих исследованиях сообщалось, что изменения в метилировании ДНК и хромосомные мутации могут привести к аномалиям развития плода. В этой связи представленное исследование было направлено на изучение распространенности в русской популяции ряда генных полиморфизмов, которые могут быть вовлечены в развитие указанных нарушений. Материал и методы. В исследовании принимали участие женщины русской национальности без беременности в анамнезе ( n = 81). Генотипирование выполнялось методами ПЦР с последующей рестрикцией ДНК (DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, DNMT3L rs2070565), аллель-специфичной ПЦР (SYCP3 T657C) и ПЦР в режиме реального времени (MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, MTRR rs1801394). Результаты. Минорные гомозиготные генотипы и минорные аллели по полиморфизмам DNMT3B rs2424913 (TT 11,1%, T 37,05%), DNMT1 rs2228611 (GG 18,5%, G 40,75%) и DNMT1 rs8101626 (GG 16,0%, G 40,1%) встречаются у женщин русской национальности достаточно широко, и их частота сравнима с таковой по хорошо изученным полиморфизмам MTRR rs1801394 (GG 27,2%, G 50,65%), MTHFR rs1801131 (CC 17,3%, C 40,15%) и MTHFR rs1801133 (TT11,1%, T 29,0%). Распространен также и гетерозиготный генотип по полиморфизму SYCP3 T657C (CT 12,3%, T 6,15%). Заключение. Результаты проведенных нами исследований и анализ литературных данных позволяют полагать, что генные полиморфизмы DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626 и SYCP3 T657C, наряду с хорошо изученными полиморфизмами генов фолатного цикла, могут быть использованы в качестве генетических предикторов ранних репродуктивных потерь у женщин русской национальности.

gene polymorphismsearly pregnancy lossDNA methylationfolate cyclechromosome nondisjunction

генные полиморфизмыпотеря беременности на ранних срокахметилирование ДНКфолатный циклнерасхождение хромосом

Simpson J, Carson S. Genetic and Nongenetic Causes of Pregnancy Loss. Glob libr women's med. 2013; Available from: https://www.glowm.com/section_view/ heading/GeneticandNongeneticCausesofPregnancyLoss /item/318

Early pregnancy loss. ACOG Practice Bulletin No. 200. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2018;132(5): 197—207.

Early pregnancy loss. ACOG Practice Bulletin No. 200. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2018;132(5): 197-207.

Chaithra PT, Malini SS, Kumar CS. An Overview of Genetic and Molecular Factors Responsible for Recurrent Pregnancy Loss. Inter J Hum Genet. 2011;11(4): 217—25.

Chaithra PT, Malini SS, Kumar CS. An Overview of Genetic and Molecular Factors Responsible for Recurrent Pregnancy Loss. Inter J Hum Genet. 2011;11(4): 217-25.

Baek KH. Aberrant gene expression associated with recurrent pregnancy loss. Mol Hum Reprod. 2004;10(5): 291—7.

Baek KH. Aberrant gene expression associated with recurrent pregnancy loss. Mol Hum Reprod. 2004;10(5): 291-7.

Li E. Zhang Y. DNA methylation in mammals. Cold Spring Harb perspect biol. 2014;6(5): a019133.

Suetake I, Shinozaki F, Miyagawa J, Takeshima H, Tajima S. DNMT3L Stimulates the DNA Methylation Activity of Dnmt3a and Dnmt3b through a Direct Interaction. J Biol Chem. 2004;279(26): 27816—23.

Suetake I, Shinozaki F, Miyagawa J, Takeshima H, Tajima S. DNMT3L Stimulates the DNA Methylation Activity of Dnmt3a and Dnmt3b through a Direct Interaction. J Biol Chem. 2004;279(26): 27816-23.

Silva C, Keating E, Pinto E. The impact of folic acid supplementation on gestational and long term health: Critical temporal windows, benefits and risks. Porto Biomed J. 2017;2(6): 315—32.

Silva C, Keating E, Pinto E. The impact of folic acid supplementation on gestational and long term health: Critical temporal windows, benefits and risks. Porto Biomed J. 2017;2(6): 315-32.

Mahmood L. The metabolic processes of folic acid and Vitamin B12 deficiency. J Health Research Rev. 2014;1(1): 5—9.

Mahmood L. The metabolic processes of folic acid and Vitamin B12 deficiency. J Health Research Rev. 2014;1(1): 5-9.

Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1): 75—81.

Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1): 75-81.

10.

Yousefian E, Kardi MT, Allahveisi A. Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism in Iranian Women With Idiopathic Recurrent Pregnancy Losses. Iran Red Crescent Med J. 2014;16(7): 163—67.

11.

Hassold T, Hall H, Hunt P. The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet. 2007;16(2): 203—8.

Hassold T, Hall H, Hunt P. The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet. 2007;16(2): 203-8.

12.

Chaithra PT, Malini S, Sharath KC. An Overview of Genetic and Molecular Factors Responsible for Recurrent Pregnancy Loss. Int J Hum Genet. 2011;11(4): 217—25.

Chaithra PT, Malini S, Sharath KC. An Overview of Genetic and Molecular Factors Responsible for Recurrent Pregnancy Loss. Int J Hum Genet. 2011;11(4): 217-25.

13.

Hyde KJ, Schust DJ. Genetic considerations in recurrent pregnancy loss. Cold Spring HarbPerspect Med. 2015;5(3): 231—9.

Hyde KJ, Schust DJ. Genetic considerations in recurrent pregnancy loss. Cold Spring HarbPerspect Med. 2015;5(3): 231-9.

14.

Yuan L, Pelttari J, Brundell E, Björkroth B, Zhao J, Liu JG, Brismar H, Daneholt B, Höög C. The Synaptonemal Complex Protein SCP3 Can Form Multistranded, Cross-striated Fibers In Vivo. J Cell Biol. 1998;142(2): 331—9.

15.

Sazegari A, Kalantar S M, Pashaiefar H, Mohtaram S, Honarvar N, Feizollahi Z, Ghasemi N. The T657C polymorphism on the SYCP3 gene is associated with recurrent pregnancy loss. J Assist Reprod Genet. 2014;31(10): 1377—81.

16.

Bolor H, Mori T, Nishiyama S, Ito Y, Hosoba E, Inagaki H, et al. Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am J Hum Genet. 2009;84(1): 14—20.

Bolor H, Mori T, Nishiyama S, Ito Y, Hosoba E, Inagaki H, et al. Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am J Hum Genet. 2009;84(1): 14-20.

17.

Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q. A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res. 2002;62(17): 4992—5.

18.

Mostowska A, Sajdak S, Pawlik P. Lianeri M, Jagodzinski PP DNMT1, DNMT3A and DNMT3B gene variants in relation to ovarian cancer risk in the Polish population. Mol Biol Rep. 2013;40(8): 4893—9.

Mostowska A, Sajdak S, Pawlik P. Lianeri M, Jagodzinski PP DNMT1, DNMT3A and DNMT3B gene variants in relation to ovarian cancer risk in the Polish population. Mol Biol Rep. 2013;40(8): 4893-9.

19.

Huang JX, Scott MB, Pu XY, Zhou-Cun A. Association between single-nucleotide polymorphisms of DNMT3L and infertility with azoospermia in Chinese men. Reprod Biomed Onlin. 2012;24(1): 66—71.

Huang JX, Scott MB, Pu XY, Zhou-Cun A. Association between single-nucleotide polymorphisms of DNMT3L and infertility with azoospermia in Chinese men. Reprod Biomed Onlin. 2012;24(1): 66-71.

20.

Barišić A, Pereza N, Hodžić A, Ostojić S, Peterlin B. A Single Nucleotide Polymorphism of DNA methyltransferase 3B gene is a risk factor for recurrent spontaneous abortion. Am J ReprodImmunol. 2017;78(6): 1—7.

21.

Voronin KV, Davidenko NV, Loskutova TO. Multigenic forms of thrombophilia in habitual miscarige. Medicni perspektivi (Medical perspectives). 2015;20(1): 69—75.

Voronin KV, Davidenko NV, Loskutova TO. Multigenic forms of thrombophilia in habitual miscarige. Medicni perspektivi (Medical perspectives). 2015;20(1): 69-75.

22.

Mtiraoui N, Zammiti W, Ghazouani L, Braham NJ, Saidi S, Finan RR, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction. 2006;131(2): 395—401.

23.

Cao Y, Zhang Z, Zheng Y, Yuan W, Wang J, Liang H, Shen Y. The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes. Genes Nutr. 2014;9(3): 402—8.

24.

Nair RR, Khanna A, Singh R. Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis. Fertil Steril. 2013;99(5): 1311—8.

25.

Bae J, Shin SJ, Cha SH, Choi DH, Lee S, Kim NK. Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) in spontaneously aborted embryos. Fertil Steril. 2007;87(2): 351—355.

26.

Kim JH, Joo Jeon Y, Lee BE Kang H, Shin JE, Choi DH, Lee W, Kim NK. Association of methionine synthase and thymidylate synthase genetic polymorphisms with idiopathic recurrent pregnancy loss. Fertil Steril. 2013;99(6): 1674—80.

27.

Tatarkova EA, Tuguz AR, Tsikunib AA, Rudenko KA, Muzhenya DV, Smolkov IV, Shumilov DS. Influence of polymorphic folate gene variants on process of early pregnancy interruption at inhabitants of Adyghea Republic. ASU Bulletin. Bio. Sci. 2016;176(1): 33—41. (in Russ.)

Татаркова Е.А., Тугуз А.Р., Цикуниб А.А., Руденко К.А, Муженя Д.В., Смольков И.В., Шумилов Д.С. Влияние полиморфных вариантов генов фолатного цикла на процесс раннего прерывания беременности у жительниц Республики Адыгея // Вестник АГУ. 2016. Т. 176. № 1. С. 33-41

28.

Azova MM, Ahmed AA, Ait Aissa A, Blagonravov ML. Association of DNMT3B and DNMN3L Gene Polymorphisms with Early Pregnancy Loss. Bull ExpBiol Med. 2019;167(4): 475—7.

Азова М.М., Ахмед А.А., Аит Аисса А., Благонравов М.Л. Ассоциация полиморфизмов генов DNMT3B и DNMN3L с потерей беременности на раннем сроке // Бюллетень экспериментальной биологии и медицины. 2019. Т. 167. № 4. С. 459-462

29.

Muradian AA, Ahmed AA, Azova M.M. et al. Association of DNMT1 rs8101626 polymorphism with the early miscarriage in Russian women. FEBS Open Bio. 2019;9 (Suppl. 1): 97.

30.

Naghibalhossaini F, Mokarram P, Khalili E Naghibalhossaini S. DNMT3b-149C/T promoter variants and methylation of colorectal cancer-associated genes. Cancer Biomark. 2015;15(3): 227—33.

Naghibalhossaini F, Mokarram P, Khalili E Naghibalhossaini S. DNMT3b-149C/T promoter variants and methylation of colorectal cancer-associated genes. Cancer Biomark. 2015;15(3): 227-33.

31.

de Vogel S, Wouters KA, Gottschalk RW, van Schooten FJ, de Goeij AF, de Bruïne AP, et al. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylationin colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2009;18 (11): 3086—96.

32.

Borghese B, Santulli P, Hequet D, Pierre G, Ziegler DD, Vaiman D, Chapron C. Genetic Polymorphisms of DNMT3L Involved in Hypermethylation of Chromosomal Ends Are Associated with Greater Risk of Developing Ovarian Endometriosis. Am J Pathol. 2012;180(5): 1781—6.

33.

Bao Q, He B, Pan Y, Tang Z, Zhang Y, Qu L, Xu Y, Zhu C, Tian., Wang S. Genetic variation in the promoter of DNMT3B is associated with the risk of colorectal cancer. Int J Colorectal Dis. 2011;26(9): 1107—12.

34.

Fan H, Zhang F, Hu J, Liu D, Zhao Z. Promoter polymorphisms of DNMT3B and the risk of colorectal cancer in Chinese: a case-control study. J Exp Clin Cancer Res. 2008;27(1): 24—9.

Fan H, Zhang F, Hu J, Liu D, Zhao Z. Promoter polymorphisms of DNMT3B and the risk of colorectal cancer in Chinese: a case-control study. J Exp Clin Cancer Res. 2008;27(1): 24-9.

35.

Tretyakova TB, Demchenko NS Association between Polymorphic Genes of Folate Metabolism and Early Pregnancy Losses. Obstetrics, Gynecology and Reproduction. 2018;12(1): 42—52. (In Russ.)

Третьякова Т.Б., Демченко Н.С. Ассоциация полиморфных маркеров генов метаболизма фолатов с ранними потерями беременности // Акушерство, гинекология и репродукция. 2018. Т. 12. № 1. С. 42-52. https://doi.org/10.17749/2313-7347.2018.12.1.042-052