Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Periconceptional folate supplementation reduces the recurrence and occurrence risk of neural tube defects (NTD) by as much as 70%, yet the protective mechanism remains unknown. Inborn errors of folate and homocysteine metabolism may be involved in the aetiology of NTDs. Previous studies have demonstrated that both homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, and combined heterozygosity for the C677T and for another mutation in the same gene, the A1298C polymorphism, represent genetic risk factors for NTDs. In an attempt to identify additional folate related genes that contribute to NTD pathogenesis, we performed molecular genetic analysis of folate receptors (FRs). We identified 4 unrelated patients out of 50 with de novo insertions of pseudogene (PS)-specific mutations in exon 7 and 3'UTR of the FRalpha gene, arising by microconversion events. All of the substitutions affect the carboxy-terminal amino acid membrane tail, or the GPI anchor region of the nascent protein. Furthermore, among 150 control individuals, we also identified one infant with a gene conversion event within the FRalpha coding region. This study, though preliminary, provides the first genetic association between molecular variations of the FRalpha gene and NTDs and suggests that this gene can act as a risk factor for human NTD.
...
PMID:Folate pathway gene alterations in patients with neural tube defects. 1110 26

Thymidylate synthetase (TS) and methylenetetrahydrofolate reductase (MTHFR) are major enzymes in the metabolism of folates, involved in DNA 'breaks', instability and hypomethylation. To investigate the possible relations between the TS 3'-UTR and MTHFR C677T polymorphisms and environmental factors impacting on risk of esophageal and stomach cancers, we conducted a case-control study in a high incidence region of China for these cancers. We recruited 138 esophageal and 155 stomach cancer cases, and 223 controls. The TS 3' -UTR and MTHFR C677T genotypes were detected by RFLP assay, using PCR products. The frequency of the -6 bp homozygous TS 3' -UTR genotype was 37.7 % in controls, higher than in Caucasians, although the present distribution was not in Hardy-Weinberg equilibrium. Ever-smoking with the -6 bp/-6 bp TS genotype elevated the ORs (2.61, 1.24-5.49; 3.54, 1.60-7.82) for cases of esophageal and stomach cancers, respectively, when compared with never-smoking with the +6 bp/+6 bp and +6 bp/-6 bp genotypes. No combination between the TS and MTHFR genotypes gave increased ORs. The present results suggest that TS polymorphism may modify the risk of esophageal and stomach cancer with smoking, pointing to the necessity for further investigations with information on folate and methionine intake with a larger population.
...
PMID:Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking. 1524 14

The C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and the G20210A mutation at the 3' untranslated region (3'UTR) of the prothrombin gene may be considered to be genetic risk factors that contribute to the clinical heterogeneity in sickle cell disease. The current study investigated a group of sickle cell (SS) patients from Salvador-Bahia, Northeast Brazil in order to determine the prevalence of these polymorphisms, using the polymerase chain reaction (PCR) and restriction fragment length polymorphim (RFLP) techniques. Out of 69 SS patients diagnosed with the C677T MTHFR gene polymorphism, 13 (18.6%) were heterozygous and four (5.7%) homozygous. The G20210A mutation was not found in 50 SS patients investigated. These results became important once the C677T MTHFR gene polymorphism was found to be an independent risk factor for vascular disease, a common clinical event in sickle cell disease.
...
PMID:A C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism and G20210A mutation in the prothrombin gene of sickle cell anemia patients from Northeast Brazil. 1548 92

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.
...
PMID:Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. 1754 67

The aldo-keto reductase 1C3 (AKR1C3) gene located on chromosome 10p15-p14, a regulator of myeloid cell proliferation and differentiation, represents an important candidate gene for studying human carcinogenesis. In a prospectively enrolled population-based case-control study of Han Chinese conducted in Kaohsiung in southern Taiwan, a total of 114 leukemia cases and 221 controls <20 years old were recruited between November 1997 and December 2005. The present study set out to evaluate the association between childhood leukemia and both maternal and offspring's genotypes. To do so, we conducted a systematic assessment of common single-nucleotide polymorphisms (SNPs) at the 5' flanking 10 kb to 3' UTR of AKR1C3 gene. Gln5His and three tagSNPs (rs2245191, rs10508293 and rs3209896) and one multimarker (rs2245191, rs10508293 and rs3209896) were selected with average 90% coverage of untagged SNPs by using the HapMap II data set. Odds ratios and 95% confidence intervals were adjusted for age and gender. After correcting for multiple comparisons, we observed that risk of developing childhood leukemia is significantly associated with rs10508293 polymorphism on intron 4 of the AKR1C3 gene in both offspring alone and in the combined maternal and offspring genotypes (nominal P < 0.0001, permutation P < 0.005). The maternal methylenetetrahydrofolate reductase A1298C polymorphism was found to be an effect modifier of the maternal intron 4 polymorphism of the AKR1C3 gene (rs10508293) and the childhood leukemia risk. In conclusion, this study suggests that AKR1C3 polymorphisms may be important predictive markers for childhood leukemia susceptibility.
...
PMID:Maternal and offspring genetic variants of AKR1C3 and the risk of childhood leukemia. 1833 82

Fluoropyrimidine such as 5-fluorouracil(5-FU)exerts its antitumor activities via anabolism by several enzymes. Genetic polymorphisms of these enzymes related to sensitivity and toxicity of fluoropyrimidines are reviewed. Expression of thymidylate synthase(TS), a target enzyme of 5-FU, is regulated by variable number of a 28 bp tandem repeat in the enhancer region. The double tandem repeat is associated with low TS expression, and consequently, patients with double tandem repeat demonstrated higher sensitivity to 5-FU than those with triple tandem repeat. Single nucleotide polymorphism within the second tandem repeat and loss of heterozygosity are also reported to be related to fluoropyrimidine sensitivity. In addition, patients having a 6 bp deletion in 3'-UTR region showed remarkably high antitumor activity by 5-FU based chemotherapy. Genetic variations in 5-FU catabolic enzymes can also have a profound effect on 5-FU toxicity. So far 39 mutations/ polymorphisms have been identified in dihydropyrimidine dehydrogenase(DPD)gene, a major catabolic enzyme of 5- FU. Among them, IVS14+1G>A is reported to be highly associated with severe toxicity caused by chemotherapy with fluoropyrimidine. A polymorphism that may influence the efficacy of 5-FU by influencing folate pools is that of the methylenetetrahydrofolate reductase(MTHFR)gene. C677T mutation was associated with a higher response rate on 5-FU/folinic acid chemotherapy. Prospective clinical trials to confirm the predictability of genetic polymorphism for sensitivity and toxicity of 5-FU should be performed.
...
PMID:[Genetic polymorphisms related to fluoropyrimidine sensitivity and toxicity]. 1863 50

In this study, single nucleotide polymorphisms (SNPs) involved in homocysteine metabolism such as CT replacement in the 677th nucleotide in 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme; 68-bp insertion in the 844th nucleotide of cystathionine beta-synthase (CBS) enzyme; 6-bp insertion/deletion in the region of 3'UTR in thymidylate synthase (TYMS) enzyme and 19-bp deletion in dihydrofolate reductase (DHFR) enzyme were investigated. The effects of these mutations on homocysteine levels were studied. As a result; we found that TT genotype of MTHFR 677 CT is an influencing factor on homocysteine levels in Turkish population. Furthermore, there seems to be another MTHFR 677 TT haplotype, which does not have an effect on homocysteine levels. Our data revealed that other SNPs did not have any influence on homocysteine levels.
...
PMID:Single nucleotide polymorphisms that affect homocysteine levels in Turkish population. 1879 60

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5'UTR and 3'UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3-4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.
...
PMID:Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer. 1938 96

To identify the major factors predicting the response to Methotrexate (MTX) therapy in rheumatoid arthritis (RA) patients, we evaluated the relationship between the response to MTX and factors such as the concentration of MTX-polyglutamates (MTX-PGs) in erythrocytes (RBCs), genotypes of thymidylate synthase (TYMS) 5'-UTR (2R/3R) and 3'-UTR (-6/+6), 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, and other patient-related factors. Thirty-six Japanese RA patients were enrolled in this cohort study. The concentrations of MTX-PGs in RBCs were measured, and polymorphisms were determined using PCR-RFLP method. As an indicator of the accumulated capacity of MTX-PGs in the RBCs of each patient, the MTX dose/MTX-PGs (AC-MPG, l/week) was calculated. The response to MTX therapy was assessed using the MTX dose for a>or=50% decrease in CRP level (MTX dose for 50%CRP, mg/week), and the relationships between MTX dose for 50%CRP and various other factors were evaluated using multiple linear regression analysis. The MTX dose was 6.9+/-0.3 mg/week and the MTX-PGs concentration in RBCs was 97.3+/-8.1 nmol/l (n=36, blood samples=95, mean+/-S.D.). The range of MTX dose for 50%CRP was 2.0-13.0 mg/week. Most individual AC-MPG levels showed no change during the evaluation period (coefficient of variation=5.9%). Based on the results of multiple linear regression analysis, AC-MPG, TYMS 3'-UTR (-6/+6), and ESR at the start of MTX therapy were associated with the MTX dose for 50%CRP. AC-MPG, TYMS 3'-UTR (-6/+6), and ESR might be the major predictive factors for the response to MTX therapy in Japanese RA patients.
...
PMID:Preliminary study to identify the predictive factors for the response to methotrexate therapy in patients with rheumatoid arthritis. 1957 19

In view of growing body of evidence substantiating the role of aberrations in one-carbon metabolism in the pathophysiology of breast cancer and lack of studies on gene-gene interactions, we investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating the breast cancer risk in 244 case-control pairs of Indian women and explored possible gene-gene interactions using Multifactor dimensionality reduction analysis (MDR). Dietary micronutrient status was assessed using the validated Food Frequency Questionnaire. Genotyping was done for glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier (RFC)1 G80A, cytosolic serine hydroxymethyltransferase (cSHMT) C1420T, thymidylate synthase (TYMS) 5'-UTR tandem repeat, TYMS 3'-UTR ins6/del6, methylenetetrahydrofolate reductase (MTHFR) C677T, methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G, methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) A66G polymorphisms by using the PCR-RFLP/AFLP methods. Low dietary folate intake (P < 0.001), RFC1 G80A (OR: 1.38, 95% CI 1.06-1.81) and MTHFR C677T (OR: 1.74 (1.11-2.73) were independently associated with the breast cancer risk whereas cSHMT C1420T conferred protection (OR: 0.72, 95% CI 0.55-0.94). MDR analysis demonstrated a significant tri-variate interaction among RFC1 80, MTHFR 677 and TYMS 5'-UTR loci (P (trend) < 0.02) with high-risk genotype combination showing inflated risk for breast cancer (OR 4.65, 95% CI 1.77-12.24). To conclude, dietary as well as genetic factors were found to influence susceptibility to breast cancer. Further, the current study highlighted the importance of multi-loci analyses over the single-locus analysis towards establishing the epistatic interactions between loci of one-carbon metabolism modulate susceptibility to the breast cancer.
...
PMID:Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer. 2116 4


1 2 Next >>

---