The role of MTHFR, MTRR, MTR1 intergenic interaction in the development of folate metabolism disturbance in patients with reproductive disorders

July 3, 2018

Purpose. Role determination of MTHFR, MTRR, MTR1 intergenic interaction in the development of folate metabolism disturbance in patients with reproductive disorders. Object and methods. Molecular genetic studies of genes: MTHFR (C677T, rs1801133, A1298C, rs1801131), MTRR (A66G, rs1801394), MTR1 (A2756G, rs1805087) and biochemical indicators of folate metabolism in 185 patients with reproductive disorders were performed. Results. Hyperhomocysteinemia (autosomal recessive hereditary metabolic disease) associated with mutations in folate metabolism genes were found in 20% of women with reproductive disorders. The level of homocysteine was significantly increased in patients with the 677TT genotype in the MTHFR gene and its combinations with 1298AA, 66AA, 66GG and 2756GG genotypes of the MTHFR, MTRR and MTR1 genes, while the levels of folic acid and vitamin B12 were decreased. A significant model risk of hyperhomocysteinemia was four-locus, involving the MTHFR, MTRR, MTR1 genes. The risk of hyperhomocysteinemia development was increased significantly with genotypes combinations: 677TT/1298AA/66GG, 1298AC/2756AG/66AG, and decreased with combination 677CC/1298AC/2756AA. The differences in folate metabolism indices are required further analysis of gene — factor interactions, taking into account vitamin and nutrient consumption.

Z.I. Rossokha, S.P. Kiryachenko, N.G. Gorovenko

Key words: genetic polymorphism, hyperhomocysteinemia, reproductive disorders.

Published: 05.07.2018


  • Ventskivska I.B., Proshchenko O.M., Zahorodnia O.S. (2015) Prohnozuvannia nevynoshuvannia vahitnosti pry poiednanni henetychno determinovanoi trombofilii y antyfosfolipidnoho syndromu. Zdorove zhenshchynы, 1(97): 83–86.
  • Veropotvelyan P.N., Veropotvelyan N.P., Pogulyay Yu.S. (2011) Gipergomotsisteinemiya i beremennost. Zdorove zhenschinyi, 9(65): 87–90.
  • Horovenko N.H., Olkhovych N.V., Rossokha Z.I. ta in. (2010) Vplyv polimorfizmu S677T henu MTHFR na folatnyi status ta riven homotsysteinu v syrovattsi krovi u ditei z kohnityvnymy rozladamy. Aktualni problemy akusherstva i hinekolohii, klinichnoi imunolohii ta medychnoi henetyky, 19: 61–70.
  • Hrechanina O.Ia., Hrechanina Yu.B., Husar V.A. (2010) Sposib profilaktyky reproduktyvnykh vtrat pry hiperhomotsysteinemii. Patent na korysnu model UA 53270, MPK (2009) GO1N33148. Kharkivskyi med. universytet, u201005921, Biul. 18.
  • Rossoha Z.I., Kiryachenko S.P., Gorovenko N.G. (2014) Diagnostika i lechenie nasledstvennoy trombofilii v akushersko-ginekologicheskoy praktike. Obzor klinicheskih rekomendatsiy i literaturyi. Med. aspektyi zdorovya zhenschinyi, 6(81): 5–13.
  • Rossokha Z.I., Kyriachenko S.P., Horovenko N.H. (2018) Porivnialna otsinka modelei henetychnoho ryzyku reproduktyvnykh rozladiv, zumovlenykh polimorfizmom heniv MTHFR, MTRR, MTR1. Med. perspektyvy, XXIII (2): 85–91.
  • aruplab (2016) Methylenetetrahydrofolate Reductase (MTHFR) 2 Variants (
  • Bae J., Shin J.S., Cha H.S. et al. (2007) Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) in spontaneously aborted embryos. Fert. Ster., 87: 351–355.
  • Baglin T., Gray E., Greaves M. (2010) Clinical guidelines for testing for heritable thrombophilia. Br. J. Haematol., 149(2): 209–220.
  • Bates S.M., Greer I.A., Middeldorp S. et al. (2012) VTE, Thrombophilia, Antithrombotic Therapy and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. CHEST, 141(2): 691–736.
  • Dahlbаck B. (2008) Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood, 112(1): 19–27.
  • Devalia V., Hamilton M.S., Molloy A.M. (2014) Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br. J. Haematol., 166(4): 496–513.
  • Feix A., Fritsche-Polanz R., Kletzmayr J. et al. (2001) Increased prevalence of combined MTR and MTHFR genotypes among individuals with severely elevated total homocysteine plasma levels. Am. J. Kid. Dis., 38(5): 956–964.
  • Fermo I., Vigano D.S., Paroni R., Mazzola G. (1995) Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann. Intern. Med., 123(10): 747—753.
  • Fodinger M., Buchmayer H., Heinz G. et al. (2001) Association of two MTHFR polymorphisms with total homocysteine plasma levels in dialysis patients. Am. J. Kid. Dis., 38: 77–84.
  • Garakanidze S., Costa E., Bronze-Rocha E. et al. (2018) Methylenetetrahydrofolate reductase gene polymorphism (C677T) as a risk factor for arterial thrombosis in Georgian patients. Clin. Appl. Thromb. Hemost., Jan. 1 [Epub. ahead of print].
  • Hickey S.E., Curry C.J., Toriello H.V. (2013) ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet. Med., 15(2): 153–156.
  • Holmes M.V., Newcombe P., Hubacek J.A. et al. (2011) Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet, 378: 584–594.
  • Isotalo P.A., Wells G.A., Donnelly J.G. (2000) Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutations. Am. J. Hum. Genet., 67: 986–990.
  • Levin B.L., Varga E.J. (2016) MTHFR: addressing genetic counseling dilemmas using evidence-based literature. J. Genet. Counsel., 25: 901–911.
  • Liu F., Silva D., Malone M.V., Seetharaman K. (2017) MTHFR A1298C and C677T polymorphisms are associated with increased risk of venous thromboembolism: a retrospective chart review study. Acta Haematol., 138: 208–215.
  • Moll S., Varga E.A. (2015) Homocysteine and MTHFR mutations. Circulation, 132 (1): e6–e9.
  • Reilly R., McNulty H., Pentieva K. et al. (2014) MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins? Proc. Nutr. Soc., 73(1): 47–56.
  • Rossokha Z., Gorovenko N. (2017) Assessment of the individual folic acid doses requirement for patients with reproductive disorders. In: Abstracts of the XIII World Congress of Perinatal Medicine, Oct. 26–29, Serbia, р. 349.
  • Sørensen J.T., Gaustadnes M., Stabler S.P. et al. (2016) Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. Mol. Genet. Metab., 117(3): 344–350.
  • Stanger O., Herrmann W., Pietrzik K. et al. (2003) DACH-LIGA homocystein (German, Austrian and Swiss Homocysteine Society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. Clin. Chem. Lab. Med., 41(11): 1392–1403.
  • Stefano V.D. (2013) Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societes and working groups. Thrombosis and Haemostasis, 110(4): 697–705.
  • Stevens S.M., Woller S.C., Bauer K.A. et al. (2016) Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J. Thromb.Thrombolysis, 41(1): 154—164.
  • Wilcken B. (2017) Therapeutic targets in homocystinuria due to cystathionine β-synthase deficiency: new European guidelines, Expert Opinion on Orphan Drugs, 5: 1–3.
  • Zappacosta B., Graziano M., Persichilli S. et al. (2014) 5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle-southern Italian adults. Cell Biochem. Funct., 32: 1–4.
  • Zetterberg H., Regland B., Palmér M. et al. (2002) Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. J. Hum. Genet., 10(2): 113–118.