MTHFR , polymorphisms

The MTHFR gene is a 19-kb gene located on chromosome 1 (lp36.3). Of the several MTHFR polymorphisms that have been identified (23), two polymorphisms, the C677T and A1298C polymorphisms, have been well studied for their influence on MTX s clinical effects. The C677T polymorphism leads to an alanine-to-valine... 

TS, DPD, MTHFR Polymorphisms Associated with Outcome and Toxicity... 

Two studies have reported a positive association between MTHFR polymorphisms and pediatric ALL relapse risk (Table 1). The first study by Krajinovic et al. evaluated 201 children with ALL treated with methotrexate as per Dana Farber Cancer Institute (DFCl) protocols 87-01, 91-01, or 95-01. Thus, the study demonstrated that the MHFR T677A1298 haplotype was associated with a decreased disease-free survival in multivariate analysis. When children with either the MTHFR T677A1298 haplotype or the MTHFDl A195 8 variant also had a triple-repeat thymidylate synthase polymorphism, the correlation with decreased EFS was also significant (5). However, neither of the MTHFR polymorphisms alone was significantly associated with altered survival. These analyses did not include toxicity risks. 

Kurzawski M, Pawlik A, Safranow K, Herczynska M, Drozdzik M (2007) 677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics 8 1551-1559... 

Kim SK, Jun JB, El-Sohemy A, Bae SC (2006) Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 33 1266-1274... 

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

Lopez-Lopez E, Martin-Guerrero I, Ballesteros J et al (2013) A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric lymphoblastic leukemia. Pharmacogenomics J 13(6) 498-506... 

Chen J, Giovannucci EL, Hunter DJ. MTHFR polymorphism, methyl-replete diets, and the risk of colorectal carcinoma and adenoma among U.S. men and women an example of gene-environment interactions in colorectal tumorigenesis. J Nutr 1999 129(Suppl 2) 560S-564S. 

Guieterrez Revilla, J. I. et al, C677T and A1298C MTHFR polymorphisms in the etiology of nenral tube defects in Spanish population, Med. Clin. (Bare.), 120,441 445, 2003. 

The risk of foetal malformation is increased in women with epilepsy compared with the general population. Minor dysmorphic features are most frequent, but more severe forms such as facial clefts and neural tube defects are not uncommon. The two major forms of neural tube defects are (i) anence-phaly, a lethal malformation, and (ii) spina bifida—a closure defect in the spinal eolumn that may lead to paralysis of the lower limbs. The rates of malformations are about 3% with CBZ and lamotrigine (LTG), 7% with VPA, and 15% with combinations of two or more AEDs. It is probable that AEDs have several different teratogenic mechanisms. Low folate levels appear to be associated with increased risks of foetal malformations in women on AEDs. Furthermore, it has been suggested that maternal C677T MTHFR polymorphism or some abnormality related to methionine synthetase increase the risk of foetal malformation in patients on AEDs (Mills et al. 1995). 

Large meta-analyses have demonstrated that the homozygous C677T MTHFR polymorphism is associated with a higher risk of ischemic heart disease, stroke and deep vein thrombosis, which probably is mediated through raised homocysteine. 

Leclerc, D., Rozen, R., 2007. Molecular genetics of MTHFR polymorphisms are not all benign [in French]. Medical Science Paris. 23 297-302. 

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