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Gene Review

MTHFR  -  methylenetetrahydrofolate reductase (NAD(P)H)

Homo sapiens

Synonyms: Methylenetetrahydrofolate reductase
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Disease relevance of MTHFR


Psychiatry related information on MTHFR


High impact information on MTHFR


Chemical compound and disease context of MTHFR


Biological context of MTHFR

  • CONCLUSIONS: APC-I1307K, HRAS1-VNTR, and MTHFR variants represent the strongest candidates for low penetrance susceptibility alleles identified to date [18].
  • A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype [19].
  • In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene [19].
  • Very recently, we identified a common mutation (677C-->T; A-->V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHRF activity and elevated homocysteine levels [20].
  • We observed a significant increase in the MTHFR polymorphism in mothers of trisomy 18 conceptuses but were unable to identify any other significant associations [21].

Anatomical context of MTHFR


Associations of MTHFR with chemical compounds


Physical interactions of MTHFR


Regulatory relationships of MTHFR

  • No significant difference in the frequency of MTHFR polymorphisms between patients and controls and no significant association between MTHFR677 or MTHFR1298 genotypes and methylation of MGMT promoter were observed [35].
  • Genetic variation in the MTHFR gene influences thiopurine methyltransferase activity [36].
  • However, the ORs for carriers of the FV R506Q mutation were not significantly influenced by MTHFR gene C677T homozygosity [37].
  • We tested the hypothesis of the existence of a defect in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) in ovarian tumours that could cause reduced intracellular regeneration of the 5-methyltetrahydrofolate and induce increased FBP expression [38].
  • Thus, the C677T mutation of the MTHFR gene may influence MS susceptibility [39].
  • This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC [40].

Other interactions of MTHFR


Analytical, diagnostic and therapeutic context of MTHFR

  • METHODS: Subjects were genotyped for MTHFR using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques, and for CBS using PCR [44].
  • CONCLUSIONS: Our results show a link between the MTHFR polymorphism and tumor response to fluoropyrimidine-based chemotherapy and suggest that MTHFR genotyping may be of predictive benefit in selecting treatment regimens [15].
  • Here, we performed a genetic case-control study in a Japanese population to investigate whether three polymorphisms of the MTHFR gene, C677T (Ala222Val), A1298C (Glu429Ala), and A1793G (Arg594Gln), are associated with the development of late-onset AD (LOAD) [45].
  • CONCLUSION: This study does not support the routine use of MTHFR or MTRR genotyping for prognostic evaluation or risk-stratification in kidney transplant recipients [46].
  • Effects of single-nucleotide polymorphisms in MTHFR and MTRR on mortality and allograft loss in kidney transplant recipients [46].


  1. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Hobbs, C.A., Sherman, S.L., Yi, P., Hopkins, S.E., Torfs, C.P., Hine, R.J., Pogribna, M., Rozen, R., James, S.J. Am. J. Hum. Genet. (2000) [Pubmed]
  2. Homozygous cystathionine beta-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. Kluijtmans, L.A., Boers, G.H., Verbruggen, B., Trijbels, F.J., Novakova, I.R., Blom, H.J. Blood (1998) [Pubmed]
  3. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Skibola, C.F., Smith, M.T., Hubbard, A., Shane, B., Roberts, A.C., Law, G.R., Rollinson, S., Roman, E., Cartwright, R.A., Morgan, G.J. Blood (2002) [Pubmed]
  4. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Skibola, C.F., Forrest, M.S., Coppedé, F., Agana, L., Hubbard, A., Smith, M.T., Bracci, P.M., Holly, E.A. Blood (2004) [Pubmed]
  5. ACE, MTHFR, factor V Leiden, and APOE polymorphisms in patients with vascular and Alzheimer's dementia. Chapman, J., Wang, N., Treves, T.A., Korczyn, A.D., Bornstein, N.M. Stroke (1998) [Pubmed]
  6. Pathogenicity of thermolabile methylenetetrahydrofolate reductase for vascular dementia. Yoo, J.H., Choi, G.D., Kang, S.S. Arterioscler. Thromb. Vasc. Biol. (2000) [Pubmed]
  7. One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. Matsuo, K., Ito, H., Wakai, K., Hirose, K., Saito, T., Suzuki, T., Kato, T., Hirai, T., Kanemitsu, Y., Hamajima, H., Tajima, K. Carcinogenesis (2005) [Pubmed]
  8. The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer's disease. Brunelli, T., Bagnoli, S., Giusti, B., Nacmias, B., Pepe, G., Sorbi, S., Abbate, R. Neurosci. Lett. (2001) [Pubmed]
  9. Prognostic significance of the polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase gene in lung cancer. Takehara, A., Kawakami, K., Ohta, N., Oyama, K., Ota, Y., Oda, M., Watanabe, G. Anticancer Res. (2005) [Pubmed]
  10. Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. Bezold, G., Lange, M., Peter, R.U. N. Engl. J. Med. (2001) [Pubmed]
  11. Mutations in coagulation factors in women with unexplained late fetal loss. Martinelli, I., Taioli, E., Cetin, I., Marinoni, A., Gerosa, S., Villa, M.V., Bozzo, M., Mannucci, P.M. N. Engl. J. Med. (2000) [Pubmed]
  12. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Frosst, P., Blom, H.J., Milos, R., Goyette, P., Sheppard, C.A., Matthews, R.G., Boers, G.J., den Heijer, M., Kluijtmans, L.A., van den Heuvel, L.P. Nat. Genet. (1995) [Pubmed]
  13. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. Kishi, S., Griener, J., Cheng, C., Das, S., Cook, E.H., Pei, D., Hudson, M., Rubnitz, J., Sandlund, J.T., Pui, C.H., Relling, M.V. J. Clin. Oncol. (2003) [Pubmed]
  14. Gene-environment interactions: a review of effects on reproduction and development. Cummings, A.M., Kavlock, R.J. Crit. Rev. Toxicol. (2004) [Pubmed]
  15. Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Cohen, V., Panet-Raymond, V., Sabbaghian, N., Morin, I., Batist, G., Rozen, R. Clin. Cancer Res. (2003) [Pubmed]
  16. Impact of thrombophilic gene mutations and graft-versus-host disease on thromboembolic complications after allogeneic hematopoietic stem-cell transplantation. Pihusch, M., Lohse, P., Reitberger, J., Hiller, E., Andreesen, R., Kolb, H.J., Holler, E., Pihusch, R. Transplantation (2004) [Pubmed]
  17. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients. Sharma, R., Hoskins, J.M., Rivory, L.P., Zucknick, M., London, R., Liddle, C., Clarke, S.J. Clin. Cancer Res. (2008) [Pubmed]
  18. Polymorphisms and colorectal tumor risk. Houlston, R.S., Tomlinson, I.P. Gastroenterology (2001) [Pubmed]
  19. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Friso, S., Choi, S.W., Girelli, D., Mason, J.B., Dolnikowski, G.G., Bagley, P.J., Olivieri, O., Jacques, P.F., Rosenberg, I.H., Corrocher, R., Selhub, J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  20. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Kluijtmans, L.A., van den Heuvel, L.P., Boers, G.H., Frosst, P., Stevens, E.M., van Oost, B.A., den Heijer, M., Trijbels, F.J., Rozen, R., Blom, H.J. Am. J. Hum. Genet. (1996) [Pubmed]
  21. Maternal folate polymorphisms and the etiology of human nondisjunction. Hassold, T.J., Burrage, L.C., Chan, E.R., Judis, L.M., Schwartz, S., James, S.J., Jacobs, P.A., Thomas, N.S. Am. J. Hum. Genet. (2001) [Pubmed]
  22. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Weisman, M.H., Furst, D.E., Park, G.S., Kremer, J.M., Smith, K.M., Wallace, D.J., Caldwell, J.R., Dervieux, T. Arthritis Rheum. (2006) [Pubmed]
  23. Effect of glutamate carboxypeptidase II and reduced folate carrier polymorphisms on folate and total homocysteine concentrations in dialysis patients. Födinger, M., Dierkes, J., Skoupy, S., Röhrer, C., Hagen, W., Puttinger, H., Hauser, A.C., Vychytil, A., Sunder-Plassmann, G. J. Am. Soc. Nephrol. (2003) [Pubmed]
  24. Association of MTRRA66G polymorphism (but not of MTHFR C677T and A1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population. Guéant-Rodriguez, R.M., Juilliére, Y., Candito, M., Adjalla, C.E., Gibelin, P., Herbeth, B., Van Obberghen, E., Gueánt, J.L. Thromb. Haemost. (2005) [Pubmed]
  25. Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency. Al-Essa, M.A., Al Amir, A., Rashed, M., Al Jishi, E., Abutaleb, A., Mobaireek, K., Shin, Y.S., Ozand, P.T. Brain Dev. (1999) [Pubmed]
  26. Endothelial nitric oxide synthase and methylenetetrahydrofolate reductase gene polymorphisms are associated with endothelial dysfunction in young, healthy men. Imamura, A., Okumura, K., Matsui, H., Mizuno, T., Ogawa, Y., Imai, H., Numaguchi, Y., Sakai, K., Murohara, T. The Canadian journal of cardiology. (2004) [Pubmed]
  27. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. van Ede, A.E., Laan, R.F., Blom, H.J., Huizinga, T.W., Haagsma, C.J., Giesendorf, B.A., de Boo, T.M., van de Putte, L.B. Arthritis Rheum. (2001) [Pubmed]
  28. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events. D'Angelo, A., Coppola, A., Madonna, P., Fermo, I., Pagano, A., Mazzola, G., Galli, L., Cerbone, A.M. Thromb. Haemost. (2000) [Pubmed]
  29. Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients. Etienne, M.C., Formento, J.L., Chazal, M., Francoual, M., Magné, N., Formento, P., Bourgeon, A., Seitz, J.F., Delpero, J.R., Letoublon, C., Pezet, D., Milano, G. Pharmacogenetics (2004) [Pubmed]
  30. The methylenetetrahydrofolate reductase 677C-->T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Hustad, S., Midttun, Ø., Schneede, J., Vollset, S.E., Grotmol, T., Ueland, P.M. Am. J. Hum. Genet. (2007) [Pubmed]
  31. Modulation of the homocysteine-betaine relationship by methylenetetrahydrofolate reductase 677 C->t genotypes and B-vitamin status in a large-scale epidemiological study. Holm, P.I., Hustad, S., Ueland, P.M., Vollset, S.E., Grotmol, T., Schneede, J. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  32. Interactions between the single nucleotide polymorphisms in the homocysteine pathway (MTHFR 677C>T, MTHFR 1298 A>C, and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk patients of hypertension: the GenHAT study. Maitland-van der Zee, A.H., Lynch, A., Boerwinkle, E., Arnett, D.K., Davis, B.R., Leiendecker-Foster, C., Ford, C.E., Eckfeldt, J.H. Pharmacogenet. Genomics (2008) [Pubmed]
  33. Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate. Gaspar, D.A., Matioli, S.R., de Cássia Pavanello, R., Araújo, B.C., Alonso, N., Wyszynski, D., Passos-Bueno, M.R. Eur. J. Hum. Genet. (2004) [Pubmed]
  34. Rapid combined genotyping of factor V, prothrombin and methylenetetrahydrofolate reductase single nucleotide polymorphisms using minor groove binding DNA oligonucleotides (MGB probes) and real-time polymerase chain reaction. Louis, M., Dekairelle, A.F., Gala, J.L. Clin. Chem. Lab. Med. (2004) [Pubmed]
  35. Methylenetetrahydrofolate reductase genotype in diffuse large B-cell lymphomas with and without hypermethylation of the DNA repair gene O6-methylguanine DNA methyltransferase. Toffoli, G., Rossi, D., Gaidano, G., Cecchin, E., Boiocchi, M., Carbone, A. Int. J. Biol. Markers (2003) [Pubmed]
  36. Genetic variation in the MTHFR gene influences thiopurine methyltransferase activity. Arenas, M., Simpson, G., Lewis, C.M., Shobowale-Bakre, e.l.-.M., Escuredo, E., Fairbanks, L.D., Duley, J.A., Ansari, A., Sanderson, J.D., Marinaki, A.M. Clin. Chem. (2005) [Pubmed]
  37. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Alhenc-Gelas, M., Arnaud, E., Nicaud, V., Aubry, M.L., Fiessinger, J.N., Aiach, M., Emmerich, J. Thromb. Haemost. (1999) [Pubmed]
  38. Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas. Viel, A., Dall'Agnese, L., Simone, F., Canzonieri, V., Capozzi, E., Visentin, M.C., Valle, R., Boiocchi, M. Br. J. Cancer (1997) [Pubmed]
  39. Genetic investigation of methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) in multiple sclerosis. Tajouri, L., Martin, V., Gasparini, C., Ovcaric, M., Curtain, R., Lea, R.A., Haupt, L.M., Csurhes, P., Pender, M.P., Griffiths, L.R. Brain Res. Bull. (2006) [Pubmed]
  40. Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma. Yuan, J.M., Lu, S.C., Van Den Berg, D., Govindarajan, S., Zhang, Z.Q., Mato, J.M., Yu, M.C. Hepatology (2007) [Pubmed]
  41. Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility. Esteller, M., Garcia, A., Martinez-Palones, J.M., Xercavins, J., Reventos, J. Carcinogenesis (1997) [Pubmed]
  42. The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine. Brown, K.S., Kluijtmans, L.A., Young, I.S., Murray, L., McMaster, D., Woodside, J.V., Yarnell, J.W., Boreham, C.A., McNulty, H., Strain, J.J., McPartlin, J., Scott, J.M., Mitchell, L.E., Whitehead, A.S. Atherosclerosis (2004) [Pubmed]
  43. The glycine N-methyltransferase (GNMT) 1289 C->T variant influences plasma total homocysteine concentrations in young women after restricting folate intake. Beagle, B., Yang, T.L., Hung, J., Cogger, E.A., Moriarty, D.J., Caudill, M.A. J. Nutr. (2005) [Pubmed]
  44. A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability. Shannon, B., Gnanasampanthan, S., Beilby, J., Iacopetta, B. Gut (2002) [Pubmed]
  45. A haplotype of the methylenetetrahydrofolate reductase gene is protective against late-onset Alzheimer's disease. Wakutani, Y., Kowa, H., Kusumi, M., Nakaso, K., Yasui, K., Isoe-Wada, K., Yano, H., Urakami, K., Takeshima, T., Nakashima, K. Neurobiol. Aging (2004) [Pubmed]
  46. Effects of single-nucleotide polymorphisms in MTHFR and MTRR on mortality and allograft loss in kidney transplant recipients. Winkelmayer, W.C., Kramar, R., Sunder-Plassmann, G., Födinger, M. Kidney Int. (2005) [Pubmed]
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