Disease relevance of MTHFR

• The present study was undertaken with a larger sample size to determine whether the MTHFR 677C-->T polymorphism was associated with increased risk of having a child with Down syndrome [1].
• These data indicate that FVL is not an absolute prerequisite and probably not even a major determinant of venous thrombosis in homocystinuria, but, interestingly, thermolabile MTHFR may constitute a significant risk factor for thromboembolic complications in this inborn error of methionine metabolism [2].
• We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL) [3].
• On the contrary, thermolabile MTHFR caused by the 677C-->T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR [2].
• Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively [4].

Psychiatry related information on MTHFR

• ACE, MTHFR, factor V Leiden, and APOE polymorphisms in patients with vascular and Alzheimer's dementia [5].
• Taken together, these findings indicate a possible role of MTHFR TT genotype combined with hyperhomocyst(e)inemia in the pathogenesis of vascular dementia [6].
• None of the polymorphisms showed any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption the MTHFR 677CC type showed a significantly reduced risk (odds ratio (OR) = 0.45, 95% confidence interval (CI): 0.23-0.86) (P = 0.01) [7].
• The methylenetetrahydrofolate reductase (MTHFR) gene has been recently considered as a candidate gene for Alzheimer's disease (AD) [8].
• TS was divided into the H- (H/H, H/L) and L-groups (L/L) according to functional stratification and MTHFR C677T was divided into C- (C/C) and T-groups (C/T, T/T) [9].

High impact information on MTHFR

• Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility [10].
• BACKGROUND: Factor V and prothrombin-gene mutations are independent risk factors for venous thrombosis; it is debated whether a mutation in the gene encoding methylenetetrahydrofolate reductase, an enzyme involved in homocysteine metabolism, also increases the risk of venous thrombosis [11].
• Thirteen percent of the women whose fetuses died and 20 percent of the control women were homozygous for the mutation in the methylenetetrahydrofolate reductase gene (relative risk, 0.8; 95 percent confidence interval, 0.5 to 1.2) [11].
• 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine [12].
• This mutation in MTHFR may represent an important genetic risk factor in vascular disease [12].

Chemical compound and disease context of MTHFR

• A recent preliminary study suggested that abnormal folate metabolism and the 677C-->T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for Down syndrome [1].
• We observed no significant differences in plasma or cerebrospinal fluid homocysteine levels or in toxicity based on the MTHFR 677C/T or RFC 80G/A genotypes [13].
• MTHFR, folate metabolism, and dietary folic acid are also considered in conjunction with preeclampsia and early pregnancy loss, and the effect of the interaction of glutathione S-transferase (GST) with exposure to benzene or cigarette smoke on pregnancy maintenance is explored [14].
• The aim of the present study was to investigate the association between the MTHFR polymorphism and response to 5-FU and other fluoropyrimidines in patients with metastatic colorectal cancer [15].
• The MTHFR TT genotype does not modify severity and duration of mucositis and aplasia in patients receiving methotrexate prophylaxis [16].
• This study suggests that common genetic variation in MTHFR but not TYMS may be useful for predicting toxicity from capecitabine in patients with advanced colorectal cancer [17].

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

• Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05) [22].
• A linear multivariate regression analysis showed that red blood cell folate (P < 0.001), creatinine (P < 0.001), and the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677T allele (P = 0.013) are independent predictors of tHcy plasma level explaining 49% of the variance of tHcy plasma concentration [23].
• Association of MTRRA66G polymorphism (but not of MTHFR C677T and A1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population [24].
• The diagnosis was confirmed by demonstrating severe deficiency of MTHFR in the cultured skin fibroblast [25].
• SUBJECTS AND METHODS: Flow-mediated, endothelium-dependent vasodilation (FMD) and glyceryl trinitrate-induced, endothelium-independent vasodilation (GTN) were measured using high-resolution ultrasound of the brachial artery in 53 young, healthy men assigned to eNOS and MTHFR genotypes [26].

Associations of MTHFR with chemical compounds

• Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine [19].
• METHODS: Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation [27].
• Exploration of the relationship between MTHFR alleles and response rates revealed a statistically significant difference in the frequency of the valine allele among responders versus nonresponders (P = 0.0351) [15].
• A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B,2 levels (p = 0.023) [28].
• Thus, mutated MTHFR tumours should, in theory, be more sensitive to 5-fluorouracil (5FU) than wild-type tumours [29].
• The MTHFR 677C-->T polymorphism, folate, riboflavin, cobalamin, and vitamin B6 were independent predictors of tHcy in multivariate models (P<.001), and genotype effects were strongest when B vitamins were low (P<or=.006) [30].
• In subjects with the combination of serum folate in the lowest quartile, low vitamin B2, B6, and B12 status, and the MTHFR TT genotype, the difference in tHcy (mean, 95% confidence interval) across extreme plasma betaine quartiles was 8.8 (1.3-16.2) micromol/liter [31].
• Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear to modify the efficacy of pravastatin in reducing risk of cardiovascular events [32].

Physical interactions of MTHFR

• 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 [33].
• 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 [34].

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

• In the present report, we asked whether variation at MTHFR (677C-->T) or MTRR (66A-->G) might be associated with human trisomies other than trisomy 21 [21].
• The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL [4].
• Thus, this study suggests that polymorphisms at MTHFR and a novel CYP1A1 variant could influence susceptibility to endometrial cancer, although larger sample sizes would be required to corroborate these findings [41].
• We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low [42].
• The influence of the GNMT 1289 C-->T variant on homocysteine was dependent on the MTHFR C677T genotype [43].

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].

References