Methylenetetrahydrofolate reductase, polymorphisms

MA J, STAMPFER M J, GIOVANNUCCI E, ARTIGAS C, HUNTER D J, FUCHS C, WILLETT W C, SELHUB J, HENNEKENS c H and ROZEN R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer . Cancer Res, 57, 1098-102. 

Cohen V, Panet-Raymond V, SabbaghianN et al. Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2003 9 1611-1615. 

Robien K, Ulrieh CM. 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk a HuGE minireview. Am J Epidemiol 2003 157 571-582. 

Aplenc R, Thompson J, Han P et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 2005 65 2482-2487. 

Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE. Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur J Clin Invest 1999 29 1003-1009. 

Ulrich, C.M., et al., "Pharmacogenetics of Methotrexate Toxicity Among Marrow Transplantation Patients Varies with the Methylenetetrahydrofolate Reductase C677T Polymorphism," Blood, 98, 231-234 (2001). 

Urano, W., Taniguchi, A., Yamanaka, H., et al. (2002) Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics. 12, 183-190. 

Kumagai, K., Hiyama, K., Oyama, T., Maeda, H., and Kohno, N. (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. International Journal of Molecular Medicine. 11, 593-600. 

Ulrich CM, Yasui Y, Storb R et al. Pharmacogenetics of methotrexate toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001 98 231-234. 

Sohn KJ, Croxford R, Yates Z et al. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J... 

Methylenetetrahydrofolate reductase is an approximately 19,301 base pair gene with 11 exons and located on chromosome lp36.3 (2). Multiple polymorphic sites have been described, with the C677T and A1298G most often studied. As expected, allele frequency data varies by ethnicity The MTHFR C677T variant allele is present in 34% of Caucasians, 20% of Italians and Hispanics, 14% of African-Americans, and <1 % of Africans (3,4). The MTHFR A1298G allele is present in n%-36% of Western Europeans (4). 

Shimasaki N, Mori T, Samejima H et al. Effects of methylenetetrahydrofolate reductase and reduced folate earrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. JPediatr Hematol Oncol 2006 28 64-68. 

Jakobsen A, Nielsen IN, Gyldenkerne N et al. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol... 

Weisberg I, et al, A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998 64(3) 169-172. 

Koch W, et al. Homocysteine status and polymorphisms of methylenetetrahydrofolate reductase are not associated with restenosis after stenting in coronary arteries. Arterioscler Thromb Vase Biol 2003 23(l 2) 2229-2234. 

Yamada K, Chen Z, Rozen R, and Matthews RG (2001a) Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proceedings of the National Academy of Sciences of the USA 98, 14853-8. 

Fisher MC, Cronstein BN (2009) Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 36 539-545... 

Pharmacogenetics may influence the response to antifolates and their toxicity. A mutation in methylenetetrahydrofolate reductase, the enzyme that generates methylenetetrahydrofolate cofactor for TS, reduces its activity and thereby increases methotrexate toxicity. The presence of this polymorphism in leukemic cells confers increased sensitivity to methotrexate, and may also modulate the toxicity and therapeutic effect of pemetrexed, a predominant TS inhibitor. Likewise, polymorphisms in the promoter region of TS affect its expression, and by altering the intracellular levels ofTS, modulate the response and toxicity of both antifolates and fluoropyrimidines. 

Etienne M C, Formento J L, Chazal M, et al. (2004). Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients. Pharmacogen. 14 785-792. 

Etienne, M. C., lie, K., Formento, J. L., et al. (2004) Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms relationships with 5-fluorouracil sensitivity. Br. J. Cancer 90, 526-534. 

Kunugj H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T, Hirose T, Ntuiko S. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatr 1998 3 435-437. 

Varoglu AO. Na VPA-induced acute ischemic stroke in an epileptic patient with methylenetetrahydrofolate reductase gene polymorphism. Epilepsy Res 2009 86(2-3) 232-6. 

Some 10-25% of the population have a genetic predisposition to hyperhomocysteinemia, which is a risk factor for atherosclerosis and coronary heart disease, as a result of polymorphisms in the gene for methylenetetrahydrofolate reductase. There is no evidence that supplements of vitamin Bg reduce fasting plasma homocysteine in these subjects, and like the tryptophan load test, the methionine load test may be an appropriate index of status in controlled depletion/repletion studies to determine vitamin Bg requirements, but not in population studies. 

The metliylenetetraliydrofolate reductase enzyme reduces 5,10-methylenetetrahydrofolate to form 5-methyltetrahy-drofolate, which provides methyl groups necessary for homocysteine remetliylation to methionine. The severity of the enzyme defect and of clinical symptoms varies considerably. Completely absent enzyme activity results in neonatal apneic episodes, myoclonus leading to coma, and death, whereas partial deficiency may result in mental retardation and seizures. Premature cardiovascular disease or peripheral neuropathy could be the only manifestation. A common polymorphism (677C>T) is associated with enzyme thermal lability and mild elevation of homocysteine in the presence of folate insufficiency, implicating a risk for both vascular disease and neural tube defects. ... 

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