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The role of molecular genetic alterations in genes involved in folate and homocysteine metabolism in multifactorial diseases pathogenesis

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Abstract

The molecular genetic modifications in multiple genes involved in folate and homocysteine metabolism play the pivotal role in the development of hyperhomocysteinemia. Hyperhomocysteinemia is observed in 5% of patients worldwide and accompanies various multifactorial diseases, including neurodegenerative, autoimmune and vascular disorders and tumors. It should be noted that increased homocysteine level itself may point to some imbalance in the organism and represent a diagnostic marker of the development of some pathology. The present review describes the role of molecular-genetic modifications in one carbon metabolism accompanying different multifactorial diseases, including congenital birth defects, vascular disorders, diabetes, and hormone-dependent cancers such as breast and ovarian cancer. Data of the association between the SNPs in functionally significant genes involved in the one carbon metabolism and pathologies mentioned above were demonstrated. In addition, we firstly represent the data of the involvement of epigenetic factors (hypermethylation and miRNA) in regulation of these genes in multifactorial diseases. The section devoted to the role of molecular-genetic impairments in the genes involved in homocysteine metabolism associated with breast and ovarian cancer includes worldwide findings and our own results.

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References

  1. Fenech, M, Folate,DNA damage and the aging brain, Mech. Ageing Dev., 2010, vol. 131, no. 4, pp. 236–241.

    Article  CAS  PubMed  Google Scholar 

  2. Kronenberg, G., Harms, C., Sobol, R.W., et al., Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase, J. Neurosci., 2008, vol. 28, no. 28, pp. 7219–7230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Crider, K.S., Yang, T.P., Berry, R.J., and Bailey, L.B, Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role, Adv. Nutr., 2012, vol. 3, no. 1, pp. 21–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shevchenko, O.P., Olefirenko, G.A., and Chervyakova, N.V., Gomotsistein (Homocysteine), Moscow: Meditsina, 2002.

    Google Scholar 

  5. Ansari, R., Mahta, A., Mallack, E., and Luo, J.J, Hyperhomocysteinemia and neurologic disorders: a review, J. Clin. Neurol., 2014, vol. 10, no. 1, pp. 281–288.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Baranova, E.I. and Bol’shakova, O.O, Clinical significance of homocysteinemia, Biomed. Khimiya, 2004, no. 1, pp. 92–96.

    Google Scholar 

  7. Szegedi, S.S., Castro, C.C., Koutmos, M., and Garrow, T.A., Betaine-homocysteine s-methyltransferase-2 is an s-methylmethionine-homocysteine methyltransferase, J. Biol. Chem., 2008, vol. 283, pp. 8939–8945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brustolin, S., Giugliani, R., and Félix, T.M, Genetics of homocysteine metabolism and associated disorders, Braz. J. Med. Biol. Res., 2010, vol. 43, no. 1, pp. 1–7.

    Article  CAS  PubMed  Google Scholar 

  9. González-Gross, M., Benser, J., Breidenassel, C., et al., HELENA Study group: gender and age influence blood folate, vitamin B12, vitamin B6, and homocysteine levels in European adolescents: the Helena Study, Nutr. Res., 2012, vol. 32, no. 11, pp. 817–826.

    PubMed  Google Scholar 

  10. Guo, S., Pang, H., Guo, H., et al., Ethnic differences in the prevalence of high homocysteine levels among low-income rural Kazakh and Uyghur adults in far western China and its implications for preventive public health, Int. J. Environ. Res. Public Health, 2015, vol. 12, no. 5, pp. 5373–5385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nazarenko, G.I. and Kishkun, A.A., Klinicheskaya otsenka rezul’tatov laboratornykh issledovanii (Clinical Assessment of Laboratory Results), Moscow: Meditsina, 2006.

    Google Scholar 

  12. Skvortsov, Yu.I. and Korol’kova, A.S, Homocysteine as a risk factor for coronary heart disease (review), Saratov. Nauch.-Med. Zh., 2011, vol. 7, no. 3, pp. 619–624.

    CAS  Google Scholar 

  13. Salbaum, J.M. and Kappen, C, Genetic and epigenomic footprints of folate, Prog. Mol. Biol. Transl. Sci., 2012, vol. 108, pp. 129–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stone, N., Pangilinan, F., Molloy, A.M., et al., Bioinformatic and genetic association analysis of microRNA target sites in one-carbon metabolism genes, PLoS One, 2011, vol. 6, no. 7. e21851

    Article  CAS  Google Scholar 

  15. Martin, Y.N., Salavaggione, O.E., Eckloff, B.W., et al., Human methylenetetrahydrofolate reductase pharmacogenomics: gene resequencing and functional genomics, Pharmacogenet. Genomics, 2006, vol. 16, no. 4, pp. 265–277.

    Article  CAS  PubMed  Google Scholar 

  16. Izmirli, M., A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk, Mol. Biol. Rep., 2013, vol. 40, no. 1, pp. 625–637.

    Article  CAS  PubMed  Google Scholar 

  17. Stover, P.J, Polymorphisms in 1-carbon metabolism, epigenetics and folate-related pathologies, J. Nutrigenet. Nutrigenomics, 2011, vol. 4, no. 5, pp. 293–305.

    Article  CAS  PubMed  Google Scholar 

  18. Joachim, E., Goldenberg, N.A., Bernard, T.J., et al., The methylenetetrahydrofolate reductase polymorphism (MTHFR c.677C>T) and elevated plasma homocysteine levels in a U.S. pediatric population with incident thromboembolism, Thromb. Res., 2013, vol. 132, no. 2, pp. 170–174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Martin, D.N., Boersma, B.J., Howe, T.M., et al., Association of MTHFR gene polymorphisms with breast cancer survival, BMC Cancer, 2006, vol. 6. e257

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Marini, N.J., Gin, J., Ziegle, J., et al., The prevalence of folate-remedial MTHFR enzyme variants in humans, Proc. Natl. Acad. Sci. U.S.A., 2008, vol. 105, no. 23, pp. 8055–8060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhu, Y., Zhu, R.X., He, Z.Y., et al., Association of MTHFR C677T with total homocysteine plasma levels and susceptibility to Parkinson’s disease: a meta-analysis, Neurol. Sci., 2015, vol. 36, no. 6, pp. 945–951.

    Article  PubMed  Google Scholar 

  22. Pangilinan, F.1., Molloy, A.M., Mills, J.L., et al., Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects, BMC Med. Genet., 2012, vol. 13. e62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang, D., Wen, X., Wu, W., et al., Elevated homocysteine level and folate deficiency associated with increased overall risk of carcinogenesis: meta-analysis of 83 case-control studies involving 35758 individuals, PLoS One, 2015, vol. 10, no. 5. e0123423

    Google Scholar 

  24. Shiran, A., Remer, E., Asmer, I., et al., Association of vitamin B12 deficiency with homozygosity of the TTMTHFR C677T genotype, hyperhomocysteinemia, and endothelial cell dysfunction, Isr. Med. Assoc. J., 2015, vol. 17, no. 5, pp. 288–292.

    PubMed  Google Scholar 

  25. Liew, S.C. and Gupta, E.D, Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases, Eur. J. Med. Genet., 2015, vol. 58, no. 1, pp. 1–10.

    Article  PubMed  Google Scholar 

  26. Ge, J., Wang, J., Zhang, F., et al., Correlation between MTHFR gene methylation and pre-eclampsia, and its clinical significance, Genet. Mol. Res., 2015, vol. 14, no. 3, pp. 8021–8028.

    Article  CAS  PubMed  Google Scholar 

  27. Leclerc, D., Wilson, A., Dumas, R., et al., Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria, Proc. Natl. Acad. Sci. U.S.A., 1998, vol. 95, pp. 3059–3064.

    Article  CAS  PubMed  Google Scholar 

  28. Froese, D.S., Wu, X., Zhang, J., et al., Restricted role for methionine synthase reductase defined by subcellular localization, Mol. Genet. Metab., 2008, vol. 94, no. 1, pp. 68–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grechanina, E.Ya., Lesovoi, V.N., Myasoedov, V.V., et al., The relationship between the development of some epigenetic diseases and disorders of DNA methylation due to deficiency of folate cycle enzymes, Ul’trazvuk. Perinat. Diagn., 2010, vol. 29, pp. 27–59.

    Google Scholar 

  30. Rai, V., Yadav, U., Kumar, P., and Yadav, S.K, Analysis of methionine synthase reductase polymorphism (A66G) in Indian Muslim population, Indian J. Hum. Genet., 2013, vol. 19, no. 2, pp. 183–187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kumudini, N., Uma, A., Naushad, S.M., et al., Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson’s disease among South Indians, Neurosci. Lett., 2014, vol. 568, pp. 1–5.

    Article  CAS  PubMed  Google Scholar 

  32. Hozyasz, K.K., Mostowska, A., Szaflarska-Poplawska, A., et al., Polymorphic variants of genes involved in homocysteine metabolism in celiac disease, Mol. Biol. Rep., 2012, vol. 39, no. 3, pp. 3123–3130.

    Article  CAS  PubMed  Google Scholar 

  33. Jiang, Y., Xia, X., Wang, W., et al., Hyperhomocysteinemia and related genetic polymorphisms correlate with ulcerative colitis in Chinese Han population in Central China, Cell Biochem. Biophys., 2012, vol. 62, no. 1, pp. 203–210.

    Article  CAS  PubMed  Google Scholar 

  34. Hosseini, M, Role of polymorphism of methyltetrahydrofolate–homocysteine methyltransferase (MTR) A2756G and breast cancer risk, Pol. J. Pathol., 2013, vol. 64, no. 3, pp. 191–195.

    Article  CAS  PubMed  Google Scholar 

  35. Ding, W., Zhou, D.L., Jiang, X., and Lu, L.S, Methionine synthase A2756G polymorphism and risk of colorectal adenoma and cancer: evidence based on 27 studies, PLoS One, 2013, vol. 8, no. 4. e60508

    Article  CAS  Google Scholar 

  36. Chen, L., Liu, L., Hong, K., et al., Three genetic polymorphisms of homocysteine-metabolizing enzymes and risk of coronary heart disease: a meta-analysis based on 23 case-control studies, DNA Cell Biol., 2012, vol. 31, no. 2, pp. 238–249.

    Article  CAS  PubMed  Google Scholar 

  37. Naushad, S.M., Pavani, A., Rupasree, Y., et al., Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer, Mol. Carcinog., 2012, vol. 51, suppl. 1, pp. E32–E41.

    Article  CAS  PubMed  Google Scholar 

  38. Feng, Q., Kalari, K., Fridley, B.L., et al., Betaine–homocysteine methyltransferase: human liver genotype–phenotype correlation, Mol. Genet. Metab., 2011, vol. 102, no. 2, pp. 126–133.

    Article  CAS  PubMed  Google Scholar 

  39. Strakova, J., Williams, K.T., Gupta, S., et al., Dietary intake of S-(a-carboxybutyl)-DL-homocysteine induces hyperhomocysteinemia in rats, Nutr. Res., 2010, vol. 30, pp. 492–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Teng, Y.W., Mehedint, M.G., Garrow, T.A., and Zeisel, S.H, Deletion of betainehomocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas, J. Biol. Chem., 2011, vol. 286, pp. 36258–36267.

    CAS  PubMed  Google Scholar 

  41. Li, F., Feng, Q., Lee, C., et al., Human betaine–homocysteine methyltransferase (BHMT) and BHMT2: common gene sequence variation and functional characterization, Mol. Genet. Metab., 2008, vol. 94, no. 3, pp. 326–335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liang, S., Zhou, Y., Wang, H., et al., The effect of multiple single nucleotide polymorphisms in the folic acid pathway genes on homocysteine metabolism, Biomed. Res. Int., 2014. e560183

    Google Scholar 

  43. da Silva, L.M., Galbiatti, A.L., Ruiz, M.T., et al., MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms and head and neck squamous cell carcinoma risk, Mol. Biol. Rep., 2012, vol. 39, no. 2, pp. 887–893.

    CAS  Google Scholar 

  44. Zampieri, B.L., Biselli, J.M., Goloni-Bertollo, E.M., and Pavarino, E.C., BHMT G742A and MTHFD1 G1958A polymorphisms and Down syndrome risk in the Brazilian population, Genet. Test. Mol. Biomarkers, 2012, vol. 16, no. 6, pp. 628–631.

    Article  CAS  PubMed  Google Scholar 

  45. Miller, A.L, The methylation, neurotransmitter, and antioxidant connections between folate and depression, Altern. Med. Rev., 2008, vol. 13, pp. 216–226.

    Google Scholar 

  46. Relton, C.L., Wilding, C.S., Laffling, A.J., et al., Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy, Mol. Genet. Metab., 2004, vol. 81, pp. 273–281.

    Article  CAS  PubMed  Google Scholar 

  47. Mendes, C.C., Raimundo, A.M., Oliveira, L.D., et al., DHFR 19-bp deletion and SHMT C1420T polymorphisms and metabolite concentrations of the folate pathway in individuals with Down syndrome, Genet. Test. Mol. Biomarkers, 2013, vol. 17, no. 4, pp. 274–277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fu, T.F., Hunt, S., Schirch, V., et al., Properties of human and rabbit cytosolic serine hydroxymethyl-transferase are changed by single nucleotide polymorphic mutations, Arch. Biochem. Biophys., 2005, vol. 442, pp. 92–101.

    Article  CAS  PubMed  Google Scholar 

  49. Niclot, S., Pruvot, Q., Besson, C., et al., Implication of the folate–methionine metabolism pathways in susceptibility to follicular lymphomas, Blood, 2006, vol. 108, no. 1, pp. 278–285.

    Article  CAS  PubMed  Google Scholar 

  50. Vijayakrishnan, J. and Houlston, R.S, Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis, Haematologica, 2010, vol. 95, pp. 1405–1414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Komlosi, V., Hitre, E., Pap, E., et al., SHMT1 1420 and MTHFR 677 variants are associated with rectal but not colon cancer, BMC Cancer, 2010, vol. 10. e525

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Collin, S.M., Metcalfe, C., Zuccolo, L., et al., Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis, Cancer Epidemiol. Biomarkers Prev., 2009, vol. 18, pp. 2528–2539.

    Article  CAS  Google Scholar 

  53. Wu, X., Zou, T., Cao, N., et al., Plasma homocysteine levels and genetic polymorphisms in folate metabolism are associated with breast cancer risk in Chinese women, Hered. Cancer Clin. Pract., 2014, vol. 12, no. 1. e2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Dayal, S. and Lentz, S.R, Murine models of hyperhomocysteinemia and their vascular phenotypes, Arterioscler. Thromb. Vasc. Biol., 2008, vol. 28, pp. 1596–1605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rodionov, R.N. and Lentz, S.R, The homocysteine paradox, Arterioscler. Thromb. Vasc. Biol., 2008, vol. 28, pp. 1031–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Biswas, A., Ranjan, R., Meena, A., et al., Homocystine levels, polymorphisms and the risk of ischemic stroke in young Asian Indians, J. Stroke Cerebrovasc. Dis., 2009, vol. 18, pp. 103–110.

    PubMed  Google Scholar 

  57. Gallegos-Arreola, M.P., Figuera-Villanueva, L.E., Ramos-Silva, A., et al., The association between the 844ins68 polymorphism in the CBS gene and breast cancer, Arch. Med. Sci., 2014, vol. 10, no. 6, pp. 1214–1224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Johnson, W.G., Stenroos, E.S., Spychala, J.R., et al., New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy?, Am. J. Med. Genet., Part A, 2004, vol. 124A, pp. 339–345.

    Article  Google Scholar 

  59. Gemmati, D., De Mattei, M., Catozzi, L., et al., DHFR 19-bp insertion/deletion polymorphism and MTHFR C677T in adult acute lymphoblastic leukaemia: is the risk reduction due to intracellular folate unbalancing?, Am. J. Hematol., 2009, vol. 84, no. 8, pp. 526–529.

    Article  CAS  PubMed  Google Scholar 

  60. Xu, X., Gammon, M.D., Wetmur, J.G., et al., A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users, Am. J. Clin. Nutr., 2007, vol. 85, pp. 1098–1102.

    CAS  PubMed  Google Scholar 

  61. Gellekink, H., Blom, H.J., van der Linden, I.J., and Heijer, M, Molecular genetic analysis of the human dihydrofolate reductase gene: relation with plasma total homocysteine, serum and red blood cell folate levels, Eur. J. Hum. Genet., 2007, vol. 15, no. 1, pp. 103–109.

    CAS  PubMed  Google Scholar 

  62. Cario, H., Smith, D.E., Blom, H., et al., Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease, Am. J. Hum. Genet., 2011, vol. 88, pp. 226–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Banka, S., Blom, H.J., Walter, J., et al., Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency, Am. J. Hum. Genet., 2011, vol. 88, pp. 216–225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kalogris, C., Garulli, C., Pietrella, L., et al., Sanguinarine suppresses basal-like breast cancer growth through dihydrofolate reductase inhibition, Biochem. Pharmacol., 2014, vol. 90, no. 3, pp. 226–234.

    Article  CAS  PubMed  Google Scholar 

  65. Tan, B.J., Quek, K.S., Wong, M.Y., et al., Liposomal M-V-05: formulation development and activity testing of a novel dihydrofolate reductase inhibitor for breast cancer therapy, Int. J. Oncol., 2010, vol. 37, no. 1, pp. 211–218.

    CAS  PubMed  Google Scholar 

  66. Lages, E., Ipas, H., Guttin, A., et al., MicroRNAs: molecular features and role in cancer, Front. Biosci., 2012, vol. 17, pp. 2508–2540.

    Article  CAS  Google Scholar 

  67. Griffiths-Jones, S., miRBase: microRNA sequences and annotation, Curr. Protoc. Bioinf. Chapter, 2010, vol. 12, no. 19, pp. 10–11.

    Google Scholar 

  68. Abba, M.L., Patil, N., Leupold, J.H., et al., MicroRNAs as novel targets and tools in cancer therapy, Cancer Lett., 2016, vol. S0304-3835, no. 16. e30204

    Google Scholar 

  69. Marsit, C.J., Eddy, K., and Kelsey, K.T., MicroRNA responses to cellular stress, Cancer. Res., 2006, vol. 66, pp. 10843–10848.

    Article  CAS  PubMed  Google Scholar 

  70. Wu, C., Gong, Y., Sun, A., et al., The human MTHFR rs4846049 polymorphism increases coronary heart disease risk through modifying miRNA binding, Nutr. Metab. Cardiovasc. Dis., 2013, vol. 23, no. 7. e693

    Article  CAS  PubMed  Google Scholar 

  71. Mishra, P.J., Humeniuk, R., Longo-Sorbello, G.S., et al., A miR-24 microRNA bindingsite polymorphism in dihydrofolate reductase gene leads to methotrexate resistance, Proc. Natl. Acad. Sci. U.S.A., 2007, vol. 104, pp. 13513–13518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mishra, P.J., Song, B., Mishra, P.J., et al., MiR-24 tumor suppressor activity is regulated independent of p53 and through a target site polymorphism, PLoS One, 2009, vol. 4, no. 12. e8445

    Article  CAS  Google Scholar 

  73. Baffa, R., Fassan, M., Volinia, S., et al., MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets, J. Pathol., 2009, vol. 219, no. 2, pp. 214–221.

    Article  CAS  PubMed  Google Scholar 

  74. Song, B., Wang, Y., Titmus, M.A., et al., Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells, Mol. Cancer, 2010, vol. 9. e96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Song, B., Wang, Y., Kudo, K., et al., miR-192 regulates dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit, Clin. Cancer. Res., 2008, vol. 14, no. 24, pp. 8080–8086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Blount, B.C., Mack, M.M., Wehr, C.M., et al., Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage, Proc. Natl. Acad. Sci. U.S.A., 1997, vol. 94, pp. 3290–3295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee, J.E., Willett, W.C., Fuchs, C.S., et al., Folate intake and risk of colorectal cancer and adenoma: modification by time, Am. J. Clin. Nutr., 2011, vol. 93, no. 4, pp. 817–825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Molloy, A.M., Brody, L.C., Mills, J.L., et al., The search for genetic polymorphisms in the homocysteine/folate pathway that contribute to the etiology of human neural tube defects, Birth. Defects Res., Part A, 2009, vol. 85, pp. 285–294.

    Article  CAS  Google Scholar 

  79. Crott, J.W., Liu, Z., Keyes, M.K., et al., Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines, J. Nutr. Biochem., 2008, vol. 19, pp. 328–335.

    CAS  PubMed  Google Scholar 

  80. Vainer, A.S., Zhechev, D.A., and Kechin, A.A, The folate metabolism and congenital abnormal development, Mat’ Ditya Kuzbasse, 2011, vol. 2, no. 45, pp. 3–10.

    Google Scholar 

  81. Czeizel, A.E., Dudás, I., Vereczkey, A., and Bánhidy, F, Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects, Nutrients, 2013, vol. 5, no. 11, pp. 4760–4775.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Barua, S., Kuizon, S., and Junaid, M.A, Folic acid supplementation in pregnancy and implications in health and disease, J. Biomed. Sci., 2014, vol. 21. e77

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Dasarathy, J., Gruca, L.L., Bennett, C., et al., Methionine metabolism in human pregnancy, Am. J. Clin. Nutr., 2010, vol. 91, no. 2, pp. 357–365.

    Article  CAS  PubMed  Google Scholar 

  84. Ratan, S.K., Rattan, K.N., Pandev, R.M., et al., Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls, Pediatr. Surg. Int., 2008, vol. 24, no. 7, pp. 803–808.

    PubMed  Google Scholar 

  85. Godbole, K., Deshmukh, U., and Yajnik, C, Nutrigenetic determinants of neural tube defects in India, Indian Pediatr., 2009, vol. 46, no. 6, pp. 467–475.

    PubMed  Google Scholar 

  86. MacFarlane, A.J., Greene-Finestone, L.S. and Shi, Y, Vitamin B-12 and homocysteine status in a folatereplete population: results from the Canadian Health Measures Survey, Am. J. Clin. Nutr., 2011, vol. 94, no. 4, pp. 1079–1087.

    Article  CAS  PubMed  Google Scholar 

  87. Imbard, A., Benoist, J.F., and Blom, H.J, Neural tube defects, folic acid and methylation, Int. J. Environ. Res. Public Health, 2013, vol. 10, no. 9, pp. 4352–4389.

    Article  PubMed  CAS  Google Scholar 

  88. Felix, T.M., Leistner, S., and Giugliani, R, Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil, Birth. Defects Res., Part A, 2004, vol. 70, pp. 459–463.

    Article  CAS  Google Scholar 

  89. Godbole, K., Gayathri, P., Ghule, S., et al., Maternal one-carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India, Birth. Defects Res., Part A, 2011, vol. 91, pp. 848–856.

    Article  CAS  Google Scholar 

  90. Deb, R., Arora, J., Meitei, S.Y., et al., Folate supplementation, MTHFR gene polymorphism and neural tube defects: a community based case control study in North India, Metab. Brain Dis., 2011, vol. 26, pp. 241–246.

    CAS  Google Scholar 

  91. Zhang, T., Lou, J., Zhong, R., et al., Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature, PLoS One, 2013, vol. 8, no. 4. e59570

    Article  CAS  Google Scholar 

  92. Yadav, U., Kumar, P., Yadav, S.K., et al., Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis, Metab. Brain Dis., 2015, vol. 30, no. 1, pp. 7–24.

    Article  CAS  PubMed  Google Scholar 

  93. Etheredge, A.J., Finnell, R.H., Carmichael, S.L., et al., Maternal and infant gene–folate interactions and the risk of neural tube defects, Am. J. Med. Genet., Part A, 2012, vol. 158A, no. 10, pp. 2439–2446.

    Article  CAS  Google Scholar 

  94. Boyles, A.L., Billups, A.V., Deak, K.L., et al., Neural tube defects and folate pathway genes: family-based association tests of gene–gene and gene–environment interactions, Environ. Health Perspect., 2006, vol. 114, no. 10, pp. 1547–1552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ho, V., Massey, T.E., and King, W.D, Effects of methionine synthase and methylenetetrahydrofolate reductase gene polymorphisms on markers of one-carbon metabolism, Genes Nutr., 2013, vol. 8, no. 6, pp. 571–580.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Biselli, J.M., Goloni-Bertollo, E.M., Zampieri, B.L., et al., Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil, Genet. Mol. Res., 2008, vol. 7, no. 1, pp. 33–42.

    Article  CAS  PubMed  Google Scholar 

  97. Coppedè, F., Bosco, P., Lorenzoni, V., et al., The MTRR 66A>G polymorphism and maternal risk of birth of a child with Down syndrome in Caucasian women: a case-control study and a meta-analysis, Mol. Biol. Rep., 2014, vol. 41, no. 9, pp. 5571–5583.

    Article  PubMed  CAS  Google Scholar 

  98. Amorim, M.R., Moura, C.M., Gomes, A.D., et al., Betaine–homocysteine methyltransferase 742G>A polymorphism and risk of Down syndrome offspring in a Brazilian population, Mol. Biol. Rep., 2013, vol. 40, no. 8, pp. 4685–4689.

    Article  CAS  PubMed  Google Scholar 

  99. Marucci, G.H., Zampieri, B.L., Biselli, J.M., et al., Polymorphism C1420T of serine hydroxymethyltransferase gene on maternal risk for Down syndrome, Mol. Biol. Rep., 2012, vol. 39, no. 3, pp. 2561–2566.

    Article  CAS  PubMed  Google Scholar 

  100. Botto, L.D., Correa, A., and Erickson, J.D, Racial and temporal variations in the prevalence of heart defects, Pediatrics, 2001, vol. 107, no. 3. e32

    Article  Google Scholar 

  101. Hinton, R.B, Genetic and environmental factors contributing to cardiovascular malformation: a unified approach to risk, J. Am. Heart Assoc., 2013, vol. 2, no. 3. e000292

    Article  Google Scholar 

  102. Verkleij-Hagoort, A., Bliek, J., Sayed-Tabatabaei, F., et al., Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis, Am. J. Med. Genet., Part A, 2007, vol. 143, no. 9, pp. 952–960.

    Article  CAS  Google Scholar 

  103. Kuehl, K., Loffredo, C., Lammer, E.J., et al., Association of congenital cardiovascular malformations with 33 single nucleotide polymorphisms of selected cardiovascular disease-related genes, Birth. Defects Res., Part A, 2010, vol. 88, no. 2, pp. 101–110.

    CAS  Google Scholar 

  104. Christensen, K.E., Zada, Y.F., Rohlicek, C.V., et al., Risk of congenital heart defects is influenced by genetic variation in folate metabolism, Cardiol. Young, 2013, vol. 23, no. 1, pp. 89–98.

    Article  PubMed  Google Scholar 

  105. Mamasoula, C., Prentice, R.R., Pierscionek, T., et al., Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls, Circ. Cardiovasc. Genet., 2013, vol. 6, no. 4, pp. 347–353.

    Article  CAS  PubMed  Google Scholar 

  106. Nie, Y., Gu, H., Gong, J., et al., Methylenetetrahydrofolate reductase C677T polymorphism and congenital heart disease: a meta-analysis, Clin. Chem. Lab. Med., 2011, vol. 49, no. 12, pp. 2101–2108.

    Article  CAS  PubMed  Google Scholar 

  107. Zeng, W., Liu, L., Tong, Y., et al., A66G and C524T polymorphisms of the methionine synthase reductase gene are associated with congenital heart defects in the Chinese Han population, Genet. Mol. Res., 2011, vol. 10, no. 4, pp. 2597–2605.

    Article  CAS  PubMed  Google Scholar 

  108. Wang, B., Liu, M., Yan, W., et al., Association of SNPs in genes involved in folate metabolism with the risk of congenital heart disease, J. Matern. Fetal Neonatal Med., 2013, vol. 26, no. 18, pp. 1768–1777.

    Article  CAS  PubMed  Google Scholar 

  109. Shenoy, V., Mehendale, V., Prabhu, K., et al., Correlation of serum homocysteine levels with the severity of coronary artery disease, Indian J. Clin. Biochem., 2014, vol. 29, no. 3, pp. 339–344.

    Article  CAS  PubMed  Google Scholar 

  110. Trabetti, E, Homocysteine,MTHFR gene polymorphisms, and cardiocerebrovascular risk, J. Appl. Genet., 2008, vol. 49, no. 3, pp. 267–282.

    Article  Google Scholar 

  111. Hou, X., Chen, X., and Shi, J, Genetic polymorphism of MTHFR C677T and premature coronary artery disease susceptibility: a meta-analysis, Gene, 2015, vol. 565, no. 1, pp. 39–44.

    Article  CAS  PubMed  Google Scholar 

  112. Weisberg, I.S., Park, E., Ballman, K.V., et al., Investigations of a common genetic variant in betaine–homocysteine methyltransferase (BHMT) in coronary artery disease, Atherosclerosis, 2003, vol. 167, pp. 205–214.

    Article  CAS  PubMed  Google Scholar 

  113. Singh, P.R., Lele, S.S., and Mukherjee, M.S, Gene polymorphisms and low dietary intake of micronutrients in coronary artery disease, J. Nutrigenet. Nutrigenomics, 2011, vol. 4, no. 4, pp. 203–209.

    Article  PubMed  CAS  Google Scholar 

  114. de las Fuentes, L., Yang, W., Dávila-Román, V.G., and Gu, C, Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets, Eur. J. Hum. Genet., 2012, vol. 20, no. 11, pp. 1168–1173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Guthikonda, S. and Haynes, W.G, Homocysteine: role and implications in atherosclerosis, Curr. Atheroscler. Rep., 2006, vol. 8, no. 2, pp. 100–106.

    Article  CAS  PubMed  Google Scholar 

  116. Steed, M.M. and Tyagi, S.C, Mechanisms of cardiovascular remodeling in hyperhomocysteinemia, Antioxid. Redox Signal, 2011, vol. 15, no. 7, pp. 1927–1943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhou, J. and Austin, R.C, Contributions of hyperhomocysteinemia to atherosclerosis: causal relationship and potential mechanisms, Biofactors, 2009, vol. 35, no. 2, pp. 120–129.

    Article  CAS  PubMed  Google Scholar 

  118. Geçene, M., Tuncay, F., Borman, P., et al., Atherosclerosis in male patients with ankylosing spondylitis: the relation with methylenetetrahydrofolate reductase (C677T) gene polymorphism and plasma homocysteine levels, Rheumatol. Int., 2013, vol. 33, no. 6, pp. 1519–1524.

    Article  PubMed  CAS  Google Scholar 

  119. Sen, S., Reddy, P.L., Grewal, R.P., et al., Hyperhomocysteinemia is associated with aortic atheroma progression in stroke/TIA patients, Front. Neurol., 2010, vol. 1. e131

    Article  PubMed  PubMed Central  Google Scholar 

  120. Gorgone, G., Ursini, F., Altamura, C., et al., Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: a correlation study in patients with cognitive impairment, Atherosclerosis, 2009, vol. 206, no. 1, pp. 309–313.

    CAS  PubMed  Google Scholar 

  121. Antoniades, C., Shirodaria, C., Leeson, P., et al., MTHFR 677 C>T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis, Circulation, 2009, vol. 119, no. 18, pp. 2507–2515.

    CAS  Google Scholar 

  122. Klenkova, N.A., Kapustin, S.I., Saltykova, N.B., et al., Features of allele polymorphism of genes involved in homocysteine and folate metabolism in patients with atherosclerosis of the lower extremity arteries, Vestn. Khir. im. I. I. Grekova, 2009, vol. 168, no. 6, pp. 41–44.

    CAS  Google Scholar 

  123. Mello, A.L., Cunha, S.F., Foss-Freitas, M.C., and Vannucchi, H, Evaluation of plasma homocysteine level according to the C677T and A1298C polymorphism of the enzyme MTHRF in type 2 diabetic adults, Arq. Bras. Endocrinol. Metabol., 2012, vol. 56, no. 7, pp. 429–434.

    Article  PubMed  Google Scholar 

  124. Koubaa, N., Nakbi, A., Smaoui, M., et al., Hyperhomocysteinemia and elevated ox-LDL in Tunisian type 2 diabetic patients: role of genetic and dietary factors, Clin. Biochem., 2007, vol. 40, no. 13–14, pp. 1001–1007.

    Google Scholar 

  125. Wiltshire, E.J., Mohsin, F., Chan, A., and Donaghue, K.C, Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetes, Pediatr. Diabetes, 2008, vol. 9, no. 4.2, pp. 348–353.

    Article  CAS  PubMed  Google Scholar 

  126. Laborda, S.M., Garcia-Blanco, M.I.S., Rigual, M.R., and Vázquez, B.A, Valores plasmaticos de homocisteina total en ninos con diabetes mellitus tipo 1: factores condicionantes, An. Pediatr., 2008, vol. 68, no. 3, pp. 264–268.

    Article  Google Scholar 

  127. Wotherspoon, F., Laight, D.W., Turner, C., et al., The effect of oral folic acid upon plasma homocysteine, endothelial function and oxidative stress in patients with type 1 diabetes and microalbuminuria, Int. J. Clin. Pract., 2008, vol. 62, no. 4, pp. 569–574.

    CAS  Google Scholar 

  128. Wang, H., Fan, D., and Hong, T, Is the C677T polymorphism in methylenetetrahydrofolate reductase gene or plasma homocysteine a risk factor for diabetic peripheral neuropathy in Chinese individuals?, Neural. Regen. Res., 2012, vol. 7, no. 30, pp. 2384–2391.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Cho, E.H., Kim, E.H., Kim, W.G., et al., Homocysteine as a risk factor for development of microalbuminuria in type 2 diabetes, Korean Diabetes J., 2010, vol. 34, no. 3, pp. 200–206.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Wang, Z.G., Cui, W., Yang, L.F., et al., Association of dietary intake of folate and MTHFR genotype with breast cancer risk, Genet. Mol. Res., 2014, vol. 13, no. 3, pp. 5446–5451.

    Article  CAS  PubMed  Google Scholar 

  131. Weiwei, Z., Liping, C., and Dequan, L, Association between dietary intake of folate,vitamin B6,B12 & MTHFR, MTR genotype and breast cancer risk, Pak. J. Med. Sci., 2014, vol. 30, no. 1, pp. 106–110.

    Google Scholar 

  132. Weiner, A.S., Boyarskikh, U.A., Voronina, E.N., et al., Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk, Cancer Epidemiol., 2012, vol. 36, no. 2, pp. e95–e100.

    CAS  Google Scholar 

  133. Jemal, A., Siegel, R., Ward, E., et al., Cancer statistics, Ca-Cancer J. Clin., 2009, vol. 59, no. 4, pp. 225–249.

    Article  PubMed  Google Scholar 

  134. Lewis, S.J., Harbord, R.M., Harris, R., and Smith, G.D, Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk, J. Natl. Cancer Inst., 2006, vol. 98, no. 22, pp. 1607–1622.

    Article  CAS  PubMed  Google Scholar 

  135. Lissowska, J., Gaudet, M.M., Brinton, L.A., et al., Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a populationbased case-control study and meta-analyses, Int. J. Cancer, 2007, vol. 120, no. 12, pp. 2696–2703.

    Article  CAS  PubMed  Google Scholar 

  136. Bravatà, V, Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancerdisease, Int. J. Food Sci. Nutr., 2015, vol. 66, no. 1, pp. 43–49.

    Article  PubMed  CAS  Google Scholar 

  137. Babyshkina, N., Malinovskaya, E., Nazarenko, M., et al., The effect of folate-related SNPs on clinicopathological features, response to neoadjuvant treatment and survival in pre- and postmenopausal breast cancer patients, Gene, 2013, vol. 518, no. 2, pp. 397–404.

    CAS  PubMed  Google Scholar 

  138. He, J.M., Pu, Y.D., Wu, Y.J., et al., Association between dietary intake of folate and MTHFR and MTR genotype with risk ofbreast cancer, Genet. Mol. Res., 2014, vol. 13, no. 4, pp. 8925–8931.

    Article  CAS  PubMed  Google Scholar 

  139. Ding, X.P., Feng, L., and Ma, L., MTHFR C677T polymorphism and ovarian cancer risk: a meta-analysis, Asian Pac. J. Cancer Prev., 2012, vol. 13, no. 8, pp. 3937–3942.

    Article  PubMed  Google Scholar 

  140. Suzuki, T., Matsuo, K., Hirose, K., et al., One-carbon metabolism related gene polymorphisms and risk of breast cancer, Carcinogenesis, 2008, vol. 29, no. 2, pp. 356–362.

    Article  CAS  PubMed  Google Scholar 

  141. Noh, S, Kimdo, H., Jung, W.H., and Koo, J.S., Expression levels of serine/glycine metabolism-related proteins in triple negative breast cancer tissues, Tumour Biol., 2014, vol. 35, no. 5, pp. 4457–4468.

    Article  CAS  PubMed  Google Scholar 

  142. Kim, S.K., Jung, W.H., and Koo, J.S, Differential expression of enzymes associated with serine/glycine metabolism in different breast cancer subtypes, PLoS One, 2014, vol. 9, no. 6. e101004

    Article  CAS  Google Scholar 

  143. Burdennyi, A.M., Loginov, V.I., Khokonova, V.V., et al., Association of polymorphic marker 844ins68 CBS gene with the development and progression of breast cancer among Russian females in the Moscow region, Patogenez, 2014, vol. 12, no. 4, pp. 35–39.

    Google Scholar 

  144. Burdennyi, A.M., Loginov, V.I., Kazubskaya, T.P., and Braga, E.A, The role of functional MTHFR gene C677T and A1298C polymorphysms in pathogenesis of breast cancer among Russian females in the Moscow region, Patogenez, 2015, vol. 13, no. 3, pp. 50–55.

    Google Scholar 

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Authors and Affiliations

  1. Institute of General Pathology and Pathophysiology, Moscow, 125315, Russia

    A. M. Burdennyy, V. I. Loginov, E. A. Braga & A. A. Kubatiev

  2. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia

    A. M. Burdennyy & T. M. Zavarykina

  3. Research Centre of Medical Genetics, Moscow, 115478, Russia

    V. I. Loginov & E. A. Braga

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Original Russian Text © A.M. Burdennyy, V.I. Loginov, T.M. Zavarykina, E.A. Braga, A.A. Kubatiev, 2017, published in Genetika, 2017, Vol. 53, No. 5, pp. 526–540.

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Burdennyy, A.M., Loginov, V.I., Zavarykina, T.M. et al. The role of molecular genetic alterations in genes involved in folate and homocysteine metabolism in multifactorial diseases pathogenesis. Russ J Genet 53, 528–541 (2017). https://doi.org/10.1134/S1022795417040044

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