Analysis of frequencies of polymorphism of folate-cycle genes in women from different regions of ukraine: own study and review
Keywords:pregnancy, miscarriages, polymorphism in the folate-cycle genes, hyperhomocysteinemia, folic acid, metafolin
The aim of this study were to analyze prevalence of the polymorphism of the MTHFR, MTRR, MTR genes in women with chronic miscarriages compared with the control population; to generalize Ukrainian data about MTHFR, MTRR and MTR genes polymorphism prevalence in women with chronic miscarriages and in general women population; to analyze impact of low-functional alleles of folate-cycle genes on processes related to the pregnancy course.
To study the prevalence of polymorphic variants of the folate cycle genes, 53 patients of medical centre “Family source” with a miscarriage who had one or more spontaneous miscarriages and/or frozen/regressing pregnancies in the obstetric-gynecological history were examined. The control group 1 contained of 24 conditionally healthy women with a favorable obstetrical anamnesis (absence of spontaneous abortions, complications of pregnancies and childbirths). As a control group 2 was used comparison group from the study of SI “Institute of hereditary diseases of the NAMS of Ukraine” (Lviv) – 150 women of the Western region of Ukraine without complicated genetic and obstetric history who had two or more healthy children. All groups were similar in terms of basic demographic characteristics.
Results and сonclusions. A significant percentage of women with low-functional alleles in one, several or all genes MTHFR, MTRR, MTR, was found 83% (44 of 53 studied women of main group). The genotype frequencies of these genes in patients with miscarriages were compared with population control groups from Ukraine. According to data from different regions of Ukraine, the mean frequency of low-functional polymorphic variants of gene MTHFR С677->Т exceeds 50% in the general women population. The relation/association of low-functional alleles of genes MTHFR, MTRR, MTR with disorders of various processes associated with the pregnancy course was considered.
Chorna, L.B., Makukh, G.V., Akopyan, G.R., et al. “Analysis of polymorphous variants of MTHFR, MTR, MTRR genes and FV and FII gene mutations in blood coagulation in women with miscarriage.” Bulletin of V.N. Karazin Kharkiv National University. Series: Biology. 947 Issue 13 (2001): 118–24.
Zhilkova, E.S., Sotnik, N.N., Feskov, A.M., Fedota, A.M. “Analysis of polymorphic variants of the MTHFR (C677T, A1298C) and MTRR (A66G) genes in men with reduced reproductive function.” Bulletin of biological and medicinal problems 2.125 Issue 4 (2015): 253–8.
Mashkina, E.V., Kovalenko, K.A., Gutnikova, L.V., et al. “Association of polymorphic variants of folate cycle genes and integrins with miscarriage.” Medical Genetics 1 (2013): 40–5.
Beskorovainaya, Т.S. The influence of some genetic factors on the violation of reproduction in humans. Thesis for PhD degree. Moscow (2005): 89 p.
Bespalova, O.N. “Genetics of miscarriage.” Journal of Obstetrics and Women’s Diseases LVI Issue 1 (2007): 81–95.
World Health Organization. Estimation of folate status in different groups of the population by the concentration of folate in blood serum and red blood cells. Information system of data on the content of vitamins and minerals in food. Geneva. WHO (2012). Available from: [http://www.who.int/iris/bitstream/10665/75584/4/WHO_NMH_NHD_EPG_12.1_rus.pdf].
Zaychenko, A.V. “Folates and omega-3-PUFA in obstetrics: more than the prevention of neural tube defects.” Health of Ukraine, thematic number (March 2018): 10–1.
Grechanina, E.Y., Lesovoi, V.N., Myasoedov, V.V. “The natural connection between the development of some epigenetic diseases and the violation of DNA methylation due to a deficiency of folate cycle enzymes.” Ultrasound perinatal dіagnostics 29 (2010): 27–59.
Vashukova, E.S., Glotov, A.S., Kanaeva, M.D., et al. “Investigation of the polymorphism of blood clotting and fibrinolysis genes in conditionally healthy pregnant women in Russia and Ukraine.” Ecological Genetics 1 Vol. IX (2011): 70–80.
Order of the MOH of Ukraine No. 417 from 15.07.2011. «About organization of ambulatory obstetric and gynecological care in Ukraine».
Marceniuk, O.P., Sazonova, L.Y., Mishlanova, Ch., Obolenska, M.Y. “Polymorphism of methylenetetrahydrofolate reductase genes, glutathione transfereases P1, M1 and cytochrome Z450 1A1 and glutathione transfected activity in human placenta.” Biopolymers and cell 6 Issue 22 (2006): 452–7.
Thrombohemorrhagic complications in obstetric-gynecological practice. Manual for doctors. Moscow. Medical Information Agency Ltd (2011): 1056 p.
Fetisova, I.N. “Polymorphism of genes of folate cycle and human diseases.” Bulletin of the Ivanovo Medical Academy 11.1–2 (2006): 77–82.
Friso, S., Choi, S.W., Girelli, D., et al. “A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.” Proc Natl Acad Sci USA 99.8 (2002): 5606–11.
Van der Put, N.M., Gabreels, F., Stevens, E.M., et al. “A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?” Am J Hum Genet 62 (1998): 1044–51.
Weisberg, I., Tran, P., Christensen, B., et al. “A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.” Mol Genet Metab 64 (1998): 169–72.
Branch, D.W., Gibson, M., Silver, R.M. “Clinical practice. Recurrent miscarriage.” N Engl J Med 363.18 (2010): 1740–7.
Jivraj, S., Rai, R., Underwood, J., et al. “Genetic thrombophilic mutations among couples with recurrent miscarriage.” Hum Reprod 21.5 (2006): 1161–5.
Stern, L.L., Mason, J.B., Selhub, J., et al. “Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene.” Cancer Epidemiol Biomarkers Prev 9.8 (2000): 849–53.
Franchis, R., Mangini, F., D’Angelo, A., et al. “Elevated total plasma homocysteine and 677 CﬁT mutation of 5, 10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease.” Am J Hum Genet 59 (1996): 262–4.
Jauniaux, E., Farquharson, R.G., Christiansen, O.B., Exalto, N. “Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage.” Hum Reprod 21.9 (2006): 2216–22.
Kim, Y.I., Pogribny, I.P., Basnakian, A.G., et al. “Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene.” Am J Clin Nutr 65.1 (1997): 46–52.
Duthie, S.J., Narayanan, S., Blum, S., et al. “Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells.” Nutr Cancer 37.2 (2000): 245–51.
Levi Setti, P.E., Colombo, G.V., Savasi, V., et al. “Implantation failure in assisted reproduction technology and a critical approach to treatment.” Ann N Y Acad Sci 1034 (2004): 184–99.
Keijzer, M.B.A.J., den Heijer, M., Blom, H.J., et al. “Interaction between hyperhomocysteinemia, mutated methylenetetr ahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis.” Thromb Hemost 88 (2002): 723–8.
Kimura, M., Umegaki, K., Higuchi, M., et al. “Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in cultured human lymphocytes.” J Nutr 134.1 (2004): 48–56.
Chen, Z., Karaplis, A.C., Ackerman, S.L., et al. “Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition.” Hum Mol Genet 10.5 (2001): 433–43.
Jacob, R.A., Gretz, D.M., Taylor, P.C., et al. “Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women.” J Nutr 128.7 (1998): 1204–12.
Obeid, R., Holzgreve, W., Pietrzik, K. “Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?” J Perinat Med 41.5 (2013): 469–83.
Toth, B., Vocke, F., Rogenhofer, N., et al. “Paternal thrombophilic gene mutations are not associated with recurrent miscarriage.” Am J Reprod Immunol 60.4 (2008): 325–32.
Ratanas Thien, K., Blair, J.A., Leeming, R.J., et al. “Serum folates in man.” J Clin Path 30 (1977): 438–48.
Tatarskyy, P., Kucherenko, A., Livshits, L. “Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine.” Cytology and genetics 3 (2010): 3–8.
Berry, C.W., Brambati, B., Eskes, T.K., et al. “The Euro-Team Early Pregnancy (ETEP) protocol for recurrent miscarriage.” Hum Reprod 10.6 (1995): 1516–20.
Castro, R., Rivera, I., Ravasco, P., et al. “5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C mutations are associated with DNA hypomethylation.” J Med Genet 41.6 (2004): 454–8.
Vorobey-Vykhivska, V.M. “The role of the hemostasis system in the effectiveness of programs of auxiliary reproductive technologies.” Thesis abstract for MD degree. Kyiv (2017): 20 p.
Linnikov, V.I. “Clinical significance of the detection of thrombophilia in patients with infertility and failure of in vitro fertilization.” Women’s Health 3.99 (2015): 175–81.
Copyright (c) 2018 О. А. Фесай, Г. В. Стрелко, Г. В. Зайченко, В. В. Уланова
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.