Methylenetetrahydrofolate Reductase G1793A Research Articles

Analysis of a G1793A polymorphism of methylenetetrahydrofolate reductase gene in children with acute leukemia

Objective To investigate the distribution of methylenetetrahydrofolate reductase (MTHFR) gene G1793A genotype and allele frequency in children with acute leukemia (AL), and to analyze the association between MTHFR gene polymorphism and the risk of AL. Methods Bone marrow samples from 109 childhood patients with AL and peripheral blood samples from 120 control children were obtained to prepare complementary DNAs (cDNAs). The cDNAs were analyzed for MTHFR G1793A polymorphism by reverse transcriptase-polymerase chain reaction-denaturing gradient gel electrophoresis and sequencing. Results The frequencies of 1793 GG, GA and AA genotypes in MTHFR of the AL patients, acute lymphoblastic leukaemia(ALL) patients, acute myeloid leukaemia(AML) patients and the control children were 83.5%, 15.6%, 0.9%; 82.8%, 16.1%, 1.1%; 86.4%, 13.6%, 0% and 89.2%, 7.5%, 3.3%, respectively. While the A allele frequency of MTHFR G1793A in those group were 8.7%, 9.2%, 6.8% and 7.1%, respectively. However, no significant difference was observed in MTHFR G1793A genotypes or A allele frequency between the patients and controls (all P>0.05). The MTHFR 1793 GA+ AA genotype was linked with an increased risk of AL, ALL and AML (AL: OR=1.71, 95%CI: 0.77-3.80, P=0.19; ALL: OR=2.00, 95%CI: 0.85-4.49, P=0.12; AML: OR=1.36, 95%CI: 0.33-5.62, P=0.67), but no significant difference in our population(all P>0.05). The A allele frequency of MTHFR G1793A in the study was 7.9%, significantly different from those reported in Ashkenazi Jewish, African-American, Brazilian, Austrian, Iran and Harbin populations (all P<0.05). Conclusion MTHFR G1793A may be not a genetic susceptibility factor for pediatric AL, but may exhibit an ethnic difference. Key words: Methylenetetrahydrofolate reductase; Single nucleotide polymorphism; Acute leukemia; Child

Frequency of MTHFR G1793A polymorphism in individuals with early coronary artery disease: cross-sectional study.

Atherosclerotic disease is the leading cause of death in Brazil. It is a complex disease and its prevention involves identification and control of risk factors. Moderately increased plasma homocysteine concentration (hyperhomocysteinemia) has been considered to be a risk factor for several vascular diseases. Mutations in the methylenetetrahydrofolate reductase (MTHFR) enzyme, which is involved in homocysteine metabolism, have been investigated as potential vascular disease risk factors. G1793A polymorphism was described in 2002 and there are few studies analyzing its involvement in diseases. The objective of this study was to investigate the prevalence of G1793A polymorphism in subjects with early coronary artery disease (CAD). Cross-sectional study with control group conducted at a private cardiology clinic and a molecular biology laboratory (Universidade do Vale do Itajaí). We studied 74 early-onset CAD+ patients and 40 CAD- individuals with normal angiography results. DNA was extracted from blood samples. Molecular data were obtained via PCR/RFLP and agarose gel electrophoresis. The occurrence of G1793A heterozygotes was similar in the control (5%) and test (6.25%) groups, thus showing that in the population studied there was no correlation between the marker and occurrences of early CAD. There was also no association between the polymorphism and the risk factors for atherosclerosis. The frequency of the 1793A allele in the test group (3.4%) was similar to what was found in the control individuals (2.5%). There was no correlation between G1793A polymorphism and occurrences of early CAD in this population.

Polymorphisms in Folate-Related Enzyme Genes in Idiopathic Infertile Brazilian Men

The aim of the study was to analyze the distribution of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and methionine synthase (MTR) polymorphisms in idiopathic infertile Brazilian men and fertile men. Case-control study comprising 133 idiopathic infertile Brazilian men with nonobstructive azoospermia ([NOA] n = 55) or severe oligozoospermia ([SO] n = 78) and 173 fertile men as controls. MTHFR C677T, A1298C, and G1793A; MTRR A66G; and MTR A2756G polymorphisms were studied by quantitative polymerase chain reaction (qPCR). The results were analyzed statistically and a P value <.05 was considered significant. Single-marker analysis revealed a significant association among MTHFR C677T polymorphism and both NOA group (P = .018) and SO group (P < .001). Considering the MTHFR A1298C, MTHFR G1793A, and MTRR A66G polymorphisms, no difference was found between NOA group and SO group. Regarding the MTR A2756G polymorphism, a significant difference was found between NOA and controls, P = .017. However, statistical analysis revealed no association between SO group and controls. Combined genotypes of 3 MTHFR polymorphisms did not identify a haplotype associated with idiopathic infertility. The combinatory analysis of the 3 polymorphisms MTHFR, MTRR, and MTR did not show difference between cases and controls. The findings suggest the MTHFR C677T and MTR A2756G polymorphisms could be an important genetic factor predisposing to idiopathic infertility in Brazilian men.

Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T, A1298C and G1793A Polymorphisms: Association with Risk for Clear Cell Renal Cell Carcinoma and Tumour Behaviour in Men

AimsMethylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated whether MTHFR C677T, A1298C and G1793A polymorphisms modified clear cell renal cell carcinoma (CCRCC) risk independently as well as in combination with serum total homocysteine (Hcy) and folate levels. Materials and methodsA case–control study of 152 cases (men) and 304 age-matched healthy controls was conducted in one geographical area of Iran. Genotyping of MTHFR gene polymorphisms was carried out using a polymerase chain reaction restriction fragment length polymorphism technique. Serum levels of total Hcy, folate and vitamin B12 were also determined. ResultsThe MTHFR 677T and 1298C allele frequencies were 42.8 and 47.4% in cases, compared with 33.7 and 33.1% in controls. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31–3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21–2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75–8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72–6.54) for grade 3 CCRCC (both P=0.0001). After adjustment for selected variants, the MTHFR 1298AC genotype showed a significantly increased risk of CCRCC compared with the wild-type (odds ratio=3.71, 95% confidence interval=2.22–5.33; P=0.001), and the 1298C allele carrier showed a positive association with the risk of CCRCC compared with the wild-type (odds ratio=3.9, 95% confidence interval=2.55–6.02; P=0.001). Furthermore, subjects carrying at least one copy of the variant allele showed a 4.4 times increased risk of developing CCRCC than their control counterparts (odds ratio=4.40, 95% confidence interval=2.41–6.72; P=0.0001). There was not a significant interaction between MTHFR polymorphisms and serum levels of total Hcy and folate in increasing the risk of CCRCC. ConclusionsOur results provide evidence that the MTHFR polymorphisms might contribute to increased CCRCC risk in men.

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men

We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different ethnicity are required to confirm our findings.

Relationship between three polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T, A1298C, and G1793A) gene and risk of prostate cancer: A case–control study

We hypothesized that genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene are associated with prostate cancer risk. We genotyped three MTHFR polymorphisms (C677T, A1298C, and G1793A) and measured serum total homocysteine (tHcy), folate, and vitamin B12 levels in a case-control study of 174 cases and 348 normal healthy controls. The cancer-free controls were frequency matched to the cases by age (±2 years), educational level, occupational status, ethnicity, and smoking status. We found that the MTHFR 677TT and 1298CC genotypes were associated with an about 40% reduction in risk of prostate cancer (adjusted OR = 0.59, 95% CI = 0.41-0.94, and adjusted OR = 0.58, 95% CI = 0.32-0.91, respectively) compared to the 677CC, and 1298AA genotypes. The combined variant genotypes of 1298AC + 677CC were associated with a 30% reduction in risk of prostate cancer (OR = 0.70; 95% CI = 0.53-0.79). In contrast, the variant genotypes of 1793GA + 677CT were associated with slightly increased risk for prostate cancer (OR = 1.64; 95% CI = 0.86-2.15). Regarding prostate cancer aggressiveness, the 677TT genotype was associated with more than 50% decreased risk of high-grade prostate cancer (Gleason score >7) compared with the 677CC and 677CT genotypes (OR = 0.35, 95% CI = 0.24-0.64; P = 0.001). There was no significant difference in plasma levels of tHcy, folate, and vitamin B12 between the two groups with any genotypes. These data suggest that all three MTHFR polymorphisms may play a pivotal role in the developing prostate cancer. Larger studies in different ethnic populations and incorporating dietary folate intake are needed to replicate our findings.

Genetic polymorphism of methylenetetrahydrofolate reductase G1793A, hyperhomocysteinemia, and folate deficiency correlate with ulcerative colitis in central China

Methylenetetrahydrofolate reductase (MTHFR) encoding genes were associated with ulcerative colitis in Chinese in our previous study. We further studied association of a new polymorphism of MTHFR G1793A with ulcerative colitis and assessed relationship of this polymorphism with hyperhomocysteinemia (HHcy, > or = 15 mmol/L) and deficiency of folate (< or = 7 nmol/L) and vitamin B(12) (< or = 150 pmol/L) in a cohort of patients with ulcerative colitis in central China. A total of 252 patients and 654 healthy controls were recruited. Polymorphism of MTHFR G1793A was examined using a polymerase chain reaction-restriction fragment length polymorphism method. Plasma levels of homocysteine (Hcy), folate and vitamin B(12) were determined by enzymatic cycling assay and corpuscle immune chemiluminescence assay, respectively. Frequencies of alleles and genotypes in MTHFR G1793A gene differed significantly between ulcerative colitis patients and the healthy controls (20.83% vs 10.47%, 95% confidence interval [CI]: 1.703-2.972, P = 0.0006; 40.48% vs 19.88%, 95% CI: 1.997-3.761, P = 0.0002, respectively). Plasma Hcy levels were higher and folate and vitamin B(12) concentrations were lower in the patients than in the healthy controls (21.72 +/- 6.59 vs 12.47 +/- 5.02, 95% CI: -10.93--7.58, P < 0.0001; 11.25 +/- 6.19 vs 15.28 +/- 7.72, 95% CI: 2.03-6.04; P < 0.001; 322.81 +/- 128.47 vs 442.59 +/- 129.36, 95% CI: 62.61-136.95, P < 0.0001, respectively). HHcy and folate deficiency were more prevalent in patients with ulcerative colitis (45.32% vs 26.17%, 95% CI: 1.285-4.378, P = 0.005; 30.68% vs 13.0%, 95% CI: 1.416-6.197, P = 0.003, respectively). MTHFR G1793A gene polymorphism, HHcy, folate deficiency and low vitamin B(12) concentration were associated with ulcerative colitis in central China. Our findings demonstrate that the Hcy-related gene and metabolites are involved in pathogenesis of ulcerative colitis.

TS and MTHFR gene polymorphisms in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head or neck (SCCHN) treated with pemetrexed (P) and bevacizumab (B)

e17011 Background: P inhibits multiple enzymes in folate metabolism. We examined polymorphisms in thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) in patients with SCCHN treated in a phase II clinical trial with P and B (ASCO 2008; A6069). Methods: All pts were treated with P 500 mg/m2 and B 15 mg/kg, given IV every 21 days until progression. Primary endpoint was time to progression (TTP). DNA was isolated from whole blood samples using commercially available kits. Polymorphisms examined were MTHFR (C677T, A1298C and G1793A) and TS (TS2R3R, TSG2RG and TSmut6). The MTHFR SNPs were detected using TaqMan based SNP genotyping kits from Applied Biosystems, run on the ABI Prism 7700 Sequence Detection systems v 1.7 (Foster City, CA). The TS promoter repeat and promoter SNP polymorphisms and the 3’ untranslated region 6 bp deletion polymorphism were determined using published methods to detect PCR product size and RFLP-PCR assays respectively. Results: 22 pts were genotyped from 34 enrolled. There was no significant difference in characteristics between pts with and without genotype data. For the MTHFR polymorphism C677T, there was a trend towards decreased disease control rate (DCR) (CR/PR/SD) (p = 0.058, Jonckheere-Terpstra trend test) and worse TTP (p = 0.04) transitioning from variant CC to CT to TT; comparing TT genotype versus CT and CC combined, pts with TT had inferior DCR (p = 0.03) and TTP (p = 0.0003); homozygotes with TT had a median TTP of 2.6 months (mo) 95% CI (1.4, NA) versus 5.6 mo (4.2, 11.4) for pts with CT or CC variants. For the MTHFR A1298C SNP, there was no significant difference in DCR between variants, median TTP for homozygotes pts with AA was 4.1 mo (2.6, NA) vs. 6.7 mo (5.1, NA) in pts with AC or CC variants (p = 0.084); median overall survival for AA was 10.2 mo (7.6, NA) and for AC or CC 17.6 mo (17, NA) (p = 0.045). The MTHFR G1793A and TS polymorphisms did not impact DCR, TTP or overall survival. There was no association between any polymorphism and the incidence of grade &gt;2 toxicities. Conclusions: Polymorphisms in MTHFR are potentially associated with antitumor efficacy of P-based therapy in recurrent or metastatic SCCHN. These results warrant validation in larger studies with P in SCCHN. No significant financial relationships to disclose.

Association of Methylenetetrahydrofolate Reductase C677T, A1298C, and G1793A Polymorphism and the Risk of Colon Cancer

Purpose: Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme regulating folate level, which affects DNA synthesis and methylation. MTHFR is highly polymorphic, and its variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Generally, a low folate level is known to be associated with a gastrointestinal neoplasm. Three common single nucleotide polymorphisms (SNPs) resulting in amino-acid changes (C677T, A1298C and G1793A) have been reported in MTHFR. We studied the relationship of MTHFR C677T, A1298C and G1793A polymorphisms between from colon cancer group and control group of Korean people. Methods: We performed a case- control study to examine the relationship between MTHFR C677, A1298C, and G1793A polymorphisms and the risk of colon cancer. Two hundred seven (207) individuals with colon cancer and 288 healthy persons were analyzed. Blood sampling of each group was performed, and (PCR-RFLP) was analyzed; as a result, MTHFR polymorphism genotypes were obtained. Results: The genotype frequencies of MTHFR C677T polymorphisms were 27.1% (CC), 48.3% (CT), 24.6% (TT), and 72.9% (CT＋TT) in the patient group and 39.2% (CC), 36.8% (CT), 24.0% (TT), and 60.8% (CT＋TT) in the control group. The genotype frequencies of MTHFR A1298C polymorphisms were 58% (AA), 35.7% (AC), 6.3% (CC), and 42% (AC＋CC) in the patient group and 55.6% (AA), 40.3% (AC), 4.2% (CC), and 44.4% (AC＋CC) in control group. The genotype frequencies of MTHFR G1793A polymorphisms were 83% (GG), 15.9% (GA), 1% (AA), and 16.9% (GA＋AA) in the patient group and 85.8% (GG), 11.8% (GA), 2.4% (AA), and 14.2% (GA＋AA) in the control group. The 677CT genotype was associated with a significantly increased risk for colon cancer (adjusted OR=1.90, 95% confidence interval: 1.25∼2.90 in CT) than the 677CC genotype. The 1298CC, 1298AC, 1793AA, and 1793GA genotypes were not associated with a significantly increased risk for colon cancer. Conclusions: The MTHFR C677T polymorphism may influence colon cancer, but the MTHFR A1298C and G1793A polymorphisms need to be studied further for careful interpretation and confirmation in larger studies.