Role of polymorphism of MTHFR, MTR, MTRR, FUT2 genes in the risk of developing polycystic ovary syndrome

Objective: To determine the MTHFR rs1801133, MTR rs1805087, MTRR rs1801394, and FUT2 rs602662 genes frequency and an influence of their polymorphism on the level of homocysteine, folic acid, and vitamin B₁₂ and to establish their link to the risk of polycystic ovary syndrome (PCOS) development. Materials and methods: 136 PCOS patients and 117 healthy women were provided health check-ups. The content of homocysteine, folic acid, and vitamin B₁₂ in blood serum was examined using the immunochemiluminescent assay (DxI800 analyzer, Beckman Coulter). The polymorphism of MTHFR rs1801133, MTR rs1805087, MTRR rs1801394, and FUT2 rs602662 genes was determined in buccal epithelial scrapes by polymerase chain reaction on the Bio-Rad CFX96 DNA amplifier (Novosibirsk, Russia, LLC "Basis Genotech"). Statistical analysis was carried out using the StatTech program v. 4.7.0. Results: The indicators of homocysteine, folic acid, and vitamin B₁₂ in the PCOS group and control group were significantly different (p < 0.05). A direct correlation relationship (r = 0.196, ρ < 0.022) between body mass index and homocysteine level with PCOS was revealed. The T/T MTHFR rs1801133 genotype was more common in PCOS patients compared to healthy women (OR = 3.77). Homocysteine levels differed between MTHFR genotypes (p = 0.007); the carriage of T/T in PCOS was accompanied by elevated homocysteine levels compared to C/T and C/C. The A/A MTRR rs1801394 genotype was more common in healthy women; the OR of 0.57 may serve as a protective factor. The G/G genotype is more common in PCOS compared to healthy women (OR = 1.94). Differences were found between PCOS patients and the control group for the carriage of A/G MTR rs1805087 (OR = 2.23; CI = 1.31–3.77). Conclusion: The risk of developing PCOS is linked to the T/T MTHFR rs1801133, A/G MTR rs1805087, and G/G MTRR rs1801394 genotypes. A direct correlation was found between body mass index and homocysteine levels in PCOS patients. The A/A MTRR rs1801394 genotype may serve as a protective factor.

1. Adamyan LV, Andreeva EN, Absatarova YuS, Grigoryan OR, Dedov II, Melnichenko GA, Suturina LV, Filippov OS, Sheremetyeva EV, Chernukha GE, Yarmolinskaya MI. Clinical guidelines “Polycystic Ovary Syndrome”. Problems of Endocrinology. 2022;68(2):112–27 (In Russ.). doi: 10.14341/probl12874

2. Krasnopol’skaya KV, Garina AO, Burumkulova FF, Isakova KM, Kalseidova KSh. The role of myoinositol and calcium L-methylfolate in complex therapy of polycystic ovary syndrome. Russian Journal of Human Reproduction. 2022;28(6):147–54 (In Russ.). doi: 10.17116/repro202228061147

3. Feng W, Zhang Y, Pan Y, Zhang Y, Liu M, Huang Y, Xiao Y, Mo W, Jiao J, Wang X, Tian D, Yang L, Ma Y. Association of three missense mutations in the homocysteine-related MTHFR and MTRR gene with risk of polycystic ovary syndrome in Southern Chinese women. Reprod Biol Endocrinol. 2021;19(1):5. doi: 10.1186/s12958-020-00688-8

4. Santos TBD, Paula HK, Balarin MAS, Silva-Grecco RL, Lima MFP, Resende EAMR, Gomes MKO, Cintra MTR. Can the genetic polymorphisms of the folate metabolism have an influence in the polycystic ovary syndrome? Arch Endocrinol Metab. 2019;63(5):501–8. doi: 10.20945/2359-3997000000167

5. Zhao J, Li X, Chen Q. Effects of MTHFR C677T polymorphism on homocysteine and vitamin D in women with polycystic ovary syndrome. Gene. 2024;919:148504. doi: 10.1016/j.gene.2024.148504

6. Ibragimov BF, Ibragimova NS. The role of gomocysteine in the pathogenesis of polycystic ovary syndrome in women. International Scientific Review. 2020;LXVL:111–3 (In Russ.).

7. Qi X, Zhang B, Zhao Y, Li R, Chang HM, Pang Y, Qiao J. Hyperhomocysteinemia Promotes Insulin Resistance and Adipose Tissue Inflammation in PCOS Mice Through Modulating M2 Macrophage Polarization via Estrogen Suppression. Endocrinology. 2017;158(5):1181–93. doi: 10.1210/en.2017-00039

8. Li WX, Cheng F, Zhang AJ, Dai SX, Li GH, Lv WW, Zhou T, Zhang Q, Zhang H, Zhang T, Liu F, Liu D, Huang JF. Folate Deficiency and Gene Polymorphisms of MTHFR, MTR and MTRR Elevate the Hyperhomocysteinemia Risk. Clin Lab. 2017;63(3):523–33. doi: 10.7754/Clin.Lab.2016.160917

9. Diwaker A, Kishore D. Evaluation of Plasma Homocysteine Levels in Patients of PCOS. J Assoc Physicians India. 2018;66(10):17–20.

10. de Luis D, Izaola O, Primo D. Effect of the variant rs602662 of FUT2 gene on anthropometric and metabolic parameters in a Caucasian obese population. Eur Rev Med Pharmacol Sci. 2022;26(19):7169–75. doi: 10.26355/eurrev_202210_29904

11. Chaudhary S, Kulkarni A. Metformin: Past, Present, and Future. Curr Diab Rep. 2024;24(6):119–30. doi: 10.1007/s11892-024-01539-1

12. Kamrul-Hasan A, Aalpona FTZ. Comparison of Serum Vitamin B12 Levels Among Drug-Naïve and Metformin-Treated Patients With Polycystic Ovary Syndrome. Cureus. 2022;14(10):e30447. doi: 10.7759/cureus.30447

13. Wang X, Wang K, Yan J, Wu M. A meta-analysis on associations of FTO, MTHFR and TCF7L2 polymorphisms with polycystic ovary syndrome. Genomics. 2020;112(2):1516–21. doi: 10.1016/j.ygeno.2019.08.023

14. Xiong Y, Bian C, Lin X, Wang X, Xu K, Zhao X. Methylenetetrahydrofolate reductase gene polymorphisms in the risk of polycystic ovary syndrome and ovarian cancer. Biosci Rep. 2020;40(7):BSR20200995. doi: 10.1042/BSR20200995