Polymorphisms of folate cycle enzyme genes: prevalence, relationships to the plasma level of homocysteine, folic acid, and vitamin B12
Objective: To study the distribution of genotypes of the main genes that control the functions of folate cycle enzymes, such as MTHFR-677C>T, MTHFR-1298A>C, MTR-2756A>G, MTRR-66A>G in the Russian population and to analyze their relationship to the plasma level of folates, homocysteine, vitamin B12.Shikh E.V., Putintseva A.V.
Materials and methods: An observational study was conducted in an outpatient setting, which enrolled 194 women aged 20 to 38 years, who had sought advice for pregravid preparation. The polymorphic loci of MTHFR-677C>T, MTHFR-1298A>C, MTR-2756A>G, MTRR-66A>G were genotyped by polymerase chain reaction and melting curve analysis. The levels of folate, homocysteine, and vitamin B12 were quantitatively analyzed by chemiluminescence immunoassay. The oftware package of IBM SPSS Statistics 26 and computing environment R 4.0.5 were used for statistical processing.
Results: The prevalence of genotypes in the examined women was as follows: MTHFR-677CT (48.5%), MTHFR- 1298AC (27.3%), MTR-2756AG (32.5%), MTRR-66AG (68.6%), MTHFR-677TT (7.7 %), MTHFR-1298CC (12.9%), MTR 2756GG (15%), and MTRR-66GG (4.1%). It was statistically significantly established that the genotypes MTHFR-677TT and MTR 2756GG were associated with the low mean levels of folates (3.6±0.3 and 4.3±0.3 ng/ml, respectively), vitamin B12 (124.3 ±4.0 and 136.8±1.0 pg/ml, respectively) and with the high mean level of homocysteine (15.1±0.2 and 15.2±0.3 pmol/l, respectively); the genotypes MTHFR-1298CC, MTHFR-1298AC, MTR-2756AG, and MTRR-66GG were related to the low level offolates (3.5±0.2, 5.6±0.4, 5.8±0.3, and 4.5±0.6 ng/ml, respectively) and to the elevated level of homocysteine (15.3±0.2, 14.3±0.3, 13.5±0.3, and 14.4±0.6 pmol/l, respectively).
Conclusion: The findings indicating the prevalence ofpolymorphisms in the genes of the folate cycle enzymes in the study participants are similar to the global general population indicators. The genotypes MTHFR-677TT and MTR-2756GG are associated with the elevated level of homocysteine and the reduced levels offolates and vitamin B12; the genotypes MTHFR-1298CC, MTHFR-1298AC, MTR-2756AG, and MTRR-66GG are related to the low level offolates and to the elevated level of homocysteine. The presented data can be taken into account when predicting the risks of obstetric complications and designing a personalized micronutrient support regimen.
Keywords
genetic polymorphism
folate cycle enzyme genes
folates
homocysteine
vitamin B12
pregravid preparation
SNP
References
1. Федеральная служба государственной статистики. Рождаемость, смертность и естественный прирост (дата обращения 09.02.2022). [Federal State Statistics Service. Birth rate, mortality and natural growth (accessed 09.02.2022) (in Russian)].
2. Федеральная служба государственной статистики. Состояние здоровья беременных, рожениц, родильниц и новорожденных (дата обращения 09.02.2022). [Federal state statistics service. Health status of pregnant women, women in labor, women in labor and newborns (accessed 09.02.2022) (in Russian)].
3. United Nations Secretary-General Ban Ki-moon. Global Strategy for Women’s and Children’s Health. N.Y.: United Nations, 2010. URL: http://www.who. int/pmnch/topics/maternal/20100914_gswch_en.pdf (дата обращения 23.02.2023).
4. Progress Report on the EWEC Global Strategy. Protect the Progress: Rise, Refocus, 2020 (accessed 23.02.2022) URL: https://www.everywomaneverychild. org/wp-content/uploads/2017/10/EWEC_GSUpdate_Brochure_RU_2017_ web.pdf
5. Rogers L.M., Cordero A.M., Pfeiffer C.M., Hausman D.B., Tsang B.L. et al. Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues. Ann N Y Acad Sci. 2018; 1431(1): 35-57. https://doi.org/10.1111/nyas.13963.
6. Abdollahi Z., Elmadfa I., Djazayeri A., Sadeghian S., Freisling H., Mazandarani F.S., Mohamed K. Folate, Vitamin B 12 and Homocysteine Status in Women of Childbearing Age: Baseline Data of Folic Acid Wheat Flour Fortification in Iran. Ann Nutr Metab. 2008; 53(2):143-50. https://doi.org/10.1159/ 000170890.
7. WHO. Guideline: Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects. 2015.
8. Farrell C.-J.L., Kirsch S.H., Herrmann M. Red cell or serum folate: what to do in clinical practice? Clin Chem Lab Med. 2013; 51(3): 555-69. https://doi.org/ 10.1515/cclm-2012-0639.
9. Министерство здравоохранения Российской Федерации. Клинические рекомендации «Витамин В12 дефицитная анемия». 2020. [Ministry of Health of the Russian Federation. Clinical guidelines "Vitamin B12 deficiency anemia". 2020 (in Russian)].
10. Peker E., Demir N., Tuncer O., Ustyol L., Balahoroglu R., Kaba S., Karaman K. The levels of vitamin B12, folate and homocysteine in mothers and their babies with neural tube defects. J Matern Fetal Neonatal Med. 2016; 29(18): 2944-8. https://doi.org/10.3109/14767058.2015.1109620.
11. House S.H., Nichols J.A., Rae S. Folates, folic acid and preconception care - a review. JRSM Open. 2021; 12(5): 2054270420980875. https://doi.org/ 10.1177/2054270420980875.
12. Hiraoka M., Kagawa Y. Genetic polymorphisms and folate status. Congenit Anom (Kyoto). 2017; 57(5): 142-9. https://dx.doi.org/10.1111/cga.12232.
13. Sah A.K., Shrestha N., Joshi P., Lakha R., Shrestha S. et al. Association of parental methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in couples with unexplained recurrent pregnancy loss. BMC Res Notes. 2018; 11(1): 233. https://doi.org/10.1186/s13104-018-3321-x.
14. Weisberg I., Tran P., Christensen B., Sibani S., Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998; 64(3): 169-72. https://doi.org/10.1006/mgme.1998.2714.
15. Yang H.-L., Yang Y.-L., Yu C.H., Shiao S.P.K. Meta-Prediction of MTHFR Gene Polymorphism and Air Pollution on the Risks of Congenital Heart Defects Worldwide: A Transgenerational Analysis. Int J Environ Res Public Health. 2018; 15(8): 1660. https://doi.org/10.3390/ijerph15081660.
16. Clement A., Menezo Y., Cohen M., Cornet D., Clement P. 5-Methyltetrahydrofolate reduces blood homocysteine level significantly in C677T methyltetrahydrofolate reductase single-nucleotide polymorphism carriers consulting for infertility. J Gynecol Obstet Hum Reprod. 2020; 49(1): 101622. https://doi.org/10.1016/ j.jogoh.2019.08.005.
17. Zetterberg H., Regland B., Palmer M., Ricksten A., Palmqvist L. et al. Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Eur J Hum Genet. 2002; 10(2): 113-8. https://doi.org/10.1038/sj.ejhg.5200767.
18. Zhang Y., Zhan W., Du Q., Wu L., Ding H., Liu F., Yin A. 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. https://doi.org/10.1089/gtmb.2020.0106.
19. Bosco P., Gueant-Rodriguez R.M., Anello G., Barone C., Namor F. et al. Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet A. 2003; 121A(3): 219-24. https://doi.org/10.1002/ajmg.a.20234.
20. Bae J., Shin S.J., Cha S.H., Choi D.H., Lee S., Kim N.K. Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) in spontaneously aborted embryos. Fertil Steril. 2007; 87(2): 351-5. https://doi.org/10.1016/j.fertnstert.2006.06.027.
21. Balderrabano-Saucedo N.A., Sanchez-Urbina R., Sierra-Ramirez J.A., Garcia-Hernandez N., Sanchez-Boiso A. et al. Polymorphism 677C ^ T MTHFR gene in Mexican mothers of children with complex congenital heart disease. Pediatr Cardiol. 2013; 34(1): 46-51. https://doi.org/10.1007/ s00246-012-0380-y.
22. Agodi A., Barchitta M., Valenti G., Marzagalli R., Frontini V., Marchese A.E. Increase in the prevalence of the MTHFR 677 TT polymorphism in women born since 1959: potential implications for folate requirements. Eur J Clin Nutr. 2011; 65(12): 1302-8. https://doi.org/10.1038/ejcn.2011.125.
23. Cirillo M., Coccia M.E., Attanasio M., Fatini C. Homocysteine, vitamin B status and MTHFR polymorphisms in Italian infertile women. Eur J Obstet Gynecol Reprod Biol. 2021; 263: 72-8. https://doi.org/10.1016/j.ejogrb.2021.06.003.
24. Allen L.H., Miller J.W., de Groot L., Rosenberg I.H., Smith A.D., Refsum H., Raiten D.J. Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review. J Nutr. 2018; 148(suppl 4):1995S-2027S. https://doi.org/10.1093/ jn/nxy201.
25. Zara-Lopes T., Gimenez-Martins A.P.A., Nascimento-Filho C.H.V., Castanhole- Nunes M.M.U., Galbiatti-Dias A.L.S. et al. Role of MTHFR C677T and MTR A2756G polymorphisms in thyroid and breast cancer development. Genet Mol Res. 2016; 15(2). https://doi.org/10.4238/gmr.15028222.
26. Barbosa P.R., Stabler S.P., Machado A.L.K., Braga R.C., Hirata R.D.C. et al. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women. Eur J Clin Nutr. 2008; 62(8): 1010-21. https://doi.org/10.1038/sj.ejcn.1602810.
27. Li W.-X., Lv W.-W., Dai S.-X., Pan M.-L., Huang J.-F. Joint associations of folate, homocysteine and MTHFR, MTR and MTRR gene polymorphisms with dyslipidemia in a Chinese hypertensive population: a cross-sectional study. Lipids Health Dis. 2015; 14:101. https://doi.org/10.1186/s12944-015-0099-x.
28. Brandalize A.P.C., Bandinelli E., Borba J.B., Felix T.M., Roisenberg I., Schuler- Faccini L. Polymorphisms in genes MTHFR, MTR and MTRR are not risk factors for cleft lip/palate in South Brazil. Braz J Med Biol Res. 2007; 40(6): 787-91. https://doi.org/10.1590/s0100-879x2006005000112.
29. Фролова Н.И., Белокриницкая Т.Е. Потребление фолатов и полиморфизм генов фолатного цикла у здоровых студенток с позиций прогноза репро-дуктивных нарушений. Репродуктивное здоровье детей и подростков. 2015; 5: 86-92. [Frolova N.I., Belokrinitskaya T.E. Intake of folate and genes polymorphisms of the folate cycle among healthy female students from the viewpoint of prognosis of the reproductive disorders. Reproductive health of children and adolescents. 2015; 5: 86-92. (in Russian)].
Received 11.03.2022
Accepted 21.03.2022
About the Authors
Evgenia V. Shikh, Dr. Med. Sci., Professor, Head of the Department of Clinical Pharmacology and Propaedeutics of Internal Medicine, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First MSMU Ministry of Health of Russia (Sechenov University), shikh_e_v@staff.sechenov.ru, 119991, Russia, Moscow, Trubetskaya str., 8-2.Anna V. Putintseva, PhD student of the Department of Clinical Pharmacology and Propaedeutics of Internal Medicine, N.V. Sklifosovsky Institute of Clinical Medicine,
I.M. Sechenov First MSMU Ministry of Health of Russia (Sechenov University), +7(985)506-51-59, putintseva@list.ru, 119991, Russia, Moscow, Trubetskaya str., 8-2.
Authors' contributions: Shikh E.V. - setting up a problem, development of the concept of the article, critical analysis of literature; Putintseva A.V. - collection of statistical data, tabular and graphical representation of the results, description of the results, formation of conclusions.
Conflicts of interest: The authors declare that there are no possible conflicts of interest.
Funding: The investigation has not been sponsored.
Ethical Approval: The investigation has been approved by the local Ethics Committee, Minutes dated 26 December, 2018, under No. 07/01 of the Meeting of the Ethics Commission on Biomedical Research, OOO “Medical Technologies”, Saint Petersburg. Patient Consent for Publication: All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Shikh E.V., Putintseva A.V. Polymorphisms of folate cycle enzyme genes: prevalence, relationships to the plasma level of homocysteine, folic acid, and vitamin B12.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 3: 104-111 (in Russian)
https://dx.doi.org/10.18565/aig.2022.3.104-111
Similar Articles
