MTHFR and MTRR polymorphisms associations with unexplained female infertility

  • Received 19.08.2025
  • Revised 27.11.2025
  • Accepted 30.12.2025
  • Published 06.01.2026
  • 333 Views
  • Retrieved from Vol. 11, No. 2, 2025
  • Pages 74-80

Polymorphic alleles in genes of folate metabolism are associated with such failures of female infertility like impaired ovulation or fertilisation; however, the data about the single gene polymorphisms in genes which code the enzymes of folate metabolism are controversial. This study aimed to analyse the correlation of polymorphic variants C677T (Ala222Val), A1298C (Glu429Ala) of MTHFR gene and A66G (Ile22Met) of MTRR gene with the oocytes’ maturation and early embryo development in women with unexplained infertility. DNA extraction was performed with extraction kits, real-time polymerase chain reaction was applied for single nucleotide polymorphisms determinations, gonadotropinreleasing hormone antagonists were used for controlled ovarian stimulation, obtained oocytes were fertilised by the method of intracytoplasmic sperm injection, early embryo development in vitro was analysed according to the Istanbul Consensus, statistical hypotheses were tested at significance levels of 0.05 and 0.01. The part of good-quality cleavage stage embryos was statistically lower for infertile patients-carriers with mutant allele A1298C of MTHFR gene in genotype (χ2crit.=18.0361, P=0.000022). A presence of mutant allele A66G of MTRR gene led to decrease in the number of mature MII oocytes in women with unexplained infertility (χ2crit.=11.1469, P=0.000842). No correlations of studied polymorphisms of MTHFR and MTRR genes with total number of received oocytes, fertilisation rate and blastocysts formation rate were found out in studied group. Examination of polymorphic variants in genes of folate metabolism C677T (Ala222Val), A1298C (Glu429Ala) of MTHFR gene and A66G (Ile22Met) of MTRR gene could be included to the tests necessary for women with unexplained infertility

single nucleotide polymorphism; folate cycle; oocytes; embryo development; in vitro fertilisation

https://doi.org/10.63341/ijmmr/2.2025.74
  1. Adebisi OY, Singh M, Tobler KJ. Female infertility. In: StatPearls. Treasure Island: StatPearls Publishing; 2025.
  2. Ishitani H, Ikeda S, Egashira K, Sugimoto M, Kume S, Minami N, et al. Embryonic MTHFR contributes to blastocyst development. J Assist Reprod Genet. 2020;37(8):1807–14. DOI: 10.1007/s10815-020-01898-0
  3. Ko YR, Kim TH, Jin Hee E, Lee WS, Kim SJ. Associations between maternal MTHFR polymorphisms and embryological outcomes in Korean patients with infertility undergoing IVF/ICSI cycles. Gynecol Endocrinol. 2024;40(1):2431224. DOI: 10.1080/09513590.2024.2431224
  4. Zeng H, Liu Z, Zhang L, Liu N. MTHFR 677TT is associated with decreased number of embryos and cumulative live birth rate in patients undergoing GnRHa short protocol: A retrospective study. BMC Pregnancy Childbirth. 2022;22(1):170. DOI: 10.1186/s12884-022-04506-4
  5. Trokhуmovych OV, Borysyuk OYu, Chubeі GV, Zinchenko MV. Pre-pregnancy training of women with early pregnancy loss and adenomyosis, taking into account folate cycle gene polymorphisms. Reprod Health Woman. 2024;1(72):73–7. DOI: 10.30841/2708-8731.1.2024.301602
  6. Jose S. Maternal methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism: Implications in preventing recurrent pregnancy loss. J Prev Med Hyg. 2024;65(1):E1–3. DOI: 10.15167/2421-4248/jpmh2024.65.1.3079
  7. Zhang Y, Zhan W, Du Q, Wu L, Ding H, Liu F, et al. Variants c.677 C>T, c.1298 A>C in MTHFR, and c.66 A>G in MTRR affect the occurrence of recurrent pregnancy loss in Chinese women. Genet Test Mol Biomarkers. 2020;24(11):717–22. DOI: 10.1089/gtmb.2020.0106
  8. Arkhypkina TL, Bondarenko VO, Liubymova L, Misiura KV. The role of gene polymorphisms in the information of folate cycle disorders and their consequences in women with polycystic ovary syndrome. Probl Endocr Pathol. 2023;80(2);66–74. DOI: 10.21856/j-PEP.2023.2.08
  9. The World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects [Internet]. [cited 2024 December 13]. Available from: https://www.wma.net/what-we-do/medical-ethics/declaration-of-helsinki/
  10. Chung E, Atmoko W, Saleh R, Shah R, Agarwal A. Sixth edition of the World Health Organization laboratory manual of semen analysis: Updates and essential take away for busy clinicians. Arab J Urol. 2024;22(2);71–4. DOI: 10.1080/20905998.2023.2298048
  11. Gupta N. DNA extraction and polymerase chain reaction. J Cytol. 2019;36(2):116–7. DOI: 10.4103/JOC.JOC_110_18
  12. Gruber I, Klein M. Embryo culture media for human IVF: Which possibilities exist? J Turk Ger Gynecol Assoc. 2011;12(2):110–7. DOI: 10.5152/jtgga.2011.25
  13. Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: Proceedings of an expert meeting. Hum Reprod. 2011;26(6):1270–83. DOI: 10.1093/humrep/der037
  14. Petrie A, Sabin C. Medical statistics at a glance. Oxford: Blackwell Publishing; 2000. 157 P.
  15. Sukhareva VA, Garbuzova VYu, Ataman AV. The frequency of methylentetrahydrofolatereductase gene C677T single nucleotide polymorphisms in individuals of different sex. J Clin Exp Med Res. 2013;1(4):385–9.
  16. Fesai AO, Strelko GV, Zaychenko GV, Ulanova VV. Analysis of frequencies of polymorphisms of folate-cycle genes in women from different regions of Ukraine: Our study and review. Health Woman. 2018;5(131):111–5. DOI: 10.15574/HW.2018.131.111
  17. Berker B, Kaya C, Aytac R, Satıroglu H. Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction. Hum Reprod. 2009;24(9):2293–302. DOI: 10.1093/humrep/dep069
  18. Asami M, Lam BYH, Ma MK, Rainbow K, Braun S, VerMilyea MD, et al. Human embryonic genome activation initiates at the one-cell stage. Cell Stem Cell. 2022;29(2):209–16.e4. DOI: 10.1016/j.stem.2021.11.012
  19. Albertini DF. The oocyte’s role in embryo development. In: Manual of embryo selection in human assisted reproduction. Cambridge: Cambridge University Press; 2023. P. 43–52. DOI: 10.1017/9781009025218.006
  20. Palomares AR, Ruiz-Galdon M, Liu K, Reyes-Engel A, Rodriguez-Wallberg KA. Profiling the influence of gene variants related to folate-mediated one-carbon metabolism on the outcome of in vitro fertilisation (IVF) with donor oocytes in recipients receiving folic acid fortification. Int J Mol Sci. 2022;23(19):11298. DOI: 10.3390/ijms231911298
  21. Zhou J, Zhu Y, Liu Y, Zhan H, Niu P, Chen H, et al. The association between methionine synthase reductase c.66A>G variant and the risk of recurrent pregnancy loss: A systematic review and meta-analysis. J Gynecol Obstet Hum Reprod. 2024;53(10):102849. DOI: 10.1016/j.jogoh.2024.102849
  22. Sharhorodska YB, Makukh HV, Chorna LB, Yefimenko OK, Akopyan HR. Polymorphisms in genes involved in folate metabolism as maternal risk factors for congenital heart diseases of the fеtus. Acta Med Leopoliensia. 2019;25(2–3):31–9. DOI: 10.25040/aml2019.02.031