Methylenetetrahydrofolate Reductase C677T Genetic Polymorphisms Research Articles

The Association of Plasma Homocysteine Concentrations with a 10-Year Risk of All-Cause and Cardiovascular Mortality in a Community-Based Chinese Population.

This study is aimed to examine the association of plasma homocysteine (Hcy) concentrations with a 10-year risk of all-cause and cardiovascular (CV) mortality and to explore the modification effect of methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphism. This study included 5200 participants from a community-based Chinese population. Cox proportional hazard regression models were used to analyze the associations of Hcy and MTHFR C677T genotype with all-cause and CV mortality. The possible modification effect of the MTHFR C677T genotype on the Hcy-mortality relationship was assessed. The individuals with Hcy concentrations ≥ 10 μmol/L had a significantly higher risk of all-cause mortality compared to those with Hcy < 10 μmol/L (hazard ratio [HR]: 1.72, 95% confidence interval [CI]: 1.11-2.68, p = 0.015). The risk of CV mortality increased by 2% per 1 μmol/L Hcy increment (HR: 1.02, 95% CI: 1.00-1.03, p = 0.036). Despite the MTHFR genotype alone not being correlated with the mortality, the relationship between Hcy and all-cause mortality was significant in the CC genotype compared with CT/TT genotype (p for interaction = 0.036). Elevated plasma Hcy concentrations were associated with an increased 10-year risk of all-cause and CV mortality among the Chinese population. MTHFR C677T genetic polymorphism could modify the association between Hcy and all-cause mortality.

MTHFR C677T (rs1801133) genetic polymorphism is associated with development risk of essential hypertension in the Turkish population

BackgroundHypertension is a serious condition that is spread worldwide and may lead to severe complications such as heart attack, stroke, hypertensive retinopathy, and renal failure. Although some genetic and environmental risk factors are known to play a role in the etiology of hypertension, like most of the other multi-factorial diseases, its etiology is yet to be fully elucidated. Our study aimed to investigate the effects of methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) and A1298C (rs1801131), factor V Leiden (FVL) G1691A (rs6025), and prothrombin (PT) G20210A (rs1799963) genetic polymorphisms on the development risk of essential hypertension and level of blood pressure in hypertensive patients.ResultsThe frequency of the homozygous polymorphic TT genotype for the MTHFR C677T polymorphism was significantly higher in male hypertensive patients than in the male control group (27% vs 6.3%, p = 0.028). The rate of the variant T allele for the MTHFR C677T polymorphism was also significantly higher in male hypertensive patients compared to male healthy controls (51.4% vs 21.9%, p = 0.0004). There was no difference among hypertensive patients and healthy controls regarding the frequencies of MTHFR A1298C, FVL G1691A and PT G20210A polymorphisms. In addition, we found no difference between genotype groups regarding systolic and diastolic blood pressure levels in hypertensive patients.ConclusionsHomozygous polymorphic TT genotype and variant T allele for the MTHFR C677T polymorphism may be considered as a risk factor for the development of essential hypertension in the Turkish male population.

Association Analysis of Methylenetetrahydrofolate Reductase Common Gene Polymorphisms with Breast Cancer Risk in an Iranian Population: A Case-Control Study and a Stratified Analysis.

Genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may alter the risk of breast cancer. This study aimed to investigate the association of MTHFR C677T and A1298C genetic polymorphisms with breast cancer risk in case-control studies which was followed by stratified analysis. In the case-control study, 300 subjects including 150 women with breast cancer and 150 healthy women were enrolled. After blood sample collection, the C677T and A1298C polymorphisms genotyping were done by the PCR-RFLP method. Our data revealed a significant association between MTHFR C677T and A1298C polymorphisms and breast cancer risk. But, as a preliminary study, stratified analysis revealed no significant association between C677T and A1298C polymorphisms and tumor size and also lymph node metastasis in breast cancer. According to the mentioned findings, the C677T and A1298C polymorphisms in the MTHFR gene could be molecular risk factors for breast cancer in our studied population. However, further studies with larger sample sizes are required to obtain a more accurate conclusion in stratified analysis.

Relationship of methylenetetrahydrofolate reductase C677T genetic polymorphism and oxidative changes in Egyptian patients with β-thalassemia major

Objectives To evaluate the genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T among patients with beta-thalassemia major and its related oxidative changes. Background Accelerated oxidative damage is one of the hallmarks in beta-thalassemia major. Genetic polymorphism of MTHFR C677T has been shown to cause hyperhomocysteinemia, which acts as a prooxidant. Material and methods Genotyping for MTHFR C677T was evaluated by PCR-restriction fragment length polymorphism technique. Complete blood picture, hemoglobin electrophoresis, serum ferritin, and total antioxidant capacity (TAC) were determined in 60 patients with beta-thalassemia major and 20 controls of matched age and sex. Results MTHFR 677TT genotype was significantly higher among patients with beta-thalassemia major (23.3%) compared with controls (5%). There was significant decrease in TAC in thalassemic patients as compared with controls. TAC was significantly lower in TT group than both of CC and CT groups. Ferritin level was significantly higher in thalassemic group than controls. Conclusion Detection of MTHFR (C6777T) genetic polymorphism among thalassemic patients could be helpful in assessment of oxidative stress among these patients.

Effects of Folic Acid-Fortified Milk Consumption on Serum Folate Levels in Japanese Female Students: a Randomized Controlled Trial Stratified by Methylenetetrahydrofolate Reductase C677T Genetic Polymorphism

Objective: We studied effects of fermented milk fortified with 200 μg of folic acid (FF milk) on serum folate levels in Japanese women university students. Methods: Adopting FF milk as intervention factor, a randomized controlled trial stratified by MTHFR genetic polymorphism C677T was conducted in 143 university women students. Experimental group subjects were requested to consume FF milk for 4 weeks; control group subjects to consume usual meals. Dietary surveys were conducted using an FFQ, and serum folate concentrations were analyzed utilizing chemiluminescence immunoassay. Using oral mucous membranes, MTHFR genotypes were determined employing PCR-RFLP. Paired ttest, one-way ANOVA, Pearson correlation coefficient, Chi-square test, or Fisher’s exact probability test was adequately applied. Results: MTHFR genotype frequencies were CC type 36 (25%), CT type 75 (52.4%) and TT type 32 (22.4%) as a whole. The subjects were randomly stratified into 73 experimental group (CC type 16, CT type 41, TT type 16) and, 70 control group (CC type 20, CT type 34, TT type 16). Average of folate consumption was 246 μg/day. Average serum folate level was 9.8 ng/mL with statistically significant difference by MTHFR genotype (CC type>CT type>TT type). Serum folate concentrations in the experimental group increased by 1.5 on average after intervention. At baseline, there were 19 subjects having serum folate levels lower than the reference value of NTDs (7 ng/mL): CC type 1/36, CT type 10/75 and TT type 8/32 with statistical difference by MTHFR genotype. In the experimental group those subjects decreased from 10 to 2 (CT type 1 and TT type 1) after intervention. Conclusions: Serum folate levels increased in the experimental group subjects after intervention, suggesting consumption of the FF milk sufficiently elevated serum folate concentrations for prevention of NTDs, irrespectively of MTHFR genotypes.

Aberrant DNA methylation of the P16, MGMT, and hMLH1 genes in combination with the methylenetetrahydrofolate reductase C677T genetic polymorphism and folate intake in gastric cancer.

Epidemiological studies have indicated that folate metabolism is correlated with increased risk of gastric cancer. Since methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, in this study, we examined whether polymorphisms and haplotypes of MTHFR are correlated with the risk of gastric cancer. The polymorphisms MTHFR C677T and MTHFR A1298C were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis in 285 patients and 570 healthy controls. Association analyses based on binary logistic regression were conducted to determine the odds ratio (OR) and its 95% confidence interval (95%CI) for each genotype. The MTHFR 677TT genotype was significantly related with a reduced risk of gastric cancer (OR = 0.60, 95%CI = 0.39-0.92) compared to the CC genotype. Similarly, the MTHFR 1298CC genotype was significantly associated with a decreased risk of cancer (OR = 0.52, 95%CI = 0.32- 0.81). Haplotype analysis showed that the TC haplotype was associated with a reduced risk of gastric cancer compared to the most common haplotype, CA (OR = 0.28, 95%CI = 0.12-0.60). Our results suggest that the MTHFR C677T and MTHFR A1298C polymorphisms are related to gastric cancer susceptibility in the Chinese population.

Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in gastric cancer

We aimed to explore the association of P16, MGMT and HMLH1 with gastric cancer and their relation with Methylenetetrahydrofolate reductase (MTHFR). 322 gastric patients who were confirmed with pathological diagnosis were included in our study. Aberrant DNA methylation of P16, MGMT and HMLH1 and polymorphisms of MTHFR C677T and A1298C were detected using PCR-RFLP. The proportions of DNA hypermethylation in P16, MGMT and hMLH1 genes in gastric cancer tissues were 75.2% (242/322), 27.6% (89/322) and 5.3% (17/322), respectively. In the remote normal-appearing tissues, 29.5% (95/322) and 16.1%(52/322) showed hypermethylation in P16 and MGMT genes, respectively. We found a significantly higher proportion of DNA hypermethylation of P16 in patients with N1 TNM stage in cancer tissues and remote normal-appearing tissues (P<0.05). Similarly, we found DNA hypermethylation of MGMT had significantly higher proportion in N1 and M1 TNM stage (P<0.05). Individuals with homozygotes (TT) of MTHFR C677T had significant risk of DNA hypermethylation of MGMT in cancer tissues [OR (95% CI)=4.27(1.76-7.84)], and a significant risk was also found in those carrying MTHFR 677CT/TT genotype [OR (95% CI)= 3.27(1.21-4.77)]. We found the aberrant hypermethylation of cancer-related genes, such as P16, MGMT and HMLH1, could be predictive biomarkers for detection of gastric cancer.

Abstract 3128: Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in esophageal squamous cell carcinoma

Abstract Background: To explore the role of aberrant hypermethylation of cancer related genes in the esophageal squamous cell carcinoma (ESCC) as well as its relation to dietary folate intake and MTHFR C677T polymorphism, we conducted a molecular epidemiological study in the Chinese population. Methods: This study was conducted in Yangzhong County, an island located on the middle of Yangtze River in the southeast part of Jiangsu Province, China. Totally, 125 ESCC patients having undergone esophagectomy between January 2005 and March 2006 in the Yangzhong People's Hospital were recruited and followed. Face-to-face interviews were conducted by trained investigators using a structured questionnaire. A food frequency questionnaire was used to estimate the dietary intake. For patients having undergone surgery, tissues in the center of the cancer lesion and remote normal appearing esophagus were excised. The methylation at the promoter region of P16, MGMT and hMLH1 was determined by methylation specific PCR. The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms were analyzed. Results: The aberrant CpG island hypermethylation of P16, MGMT and hMLH1 gene could be found in cancer tissues with frequency of about 88.0%, 27.2% and 3.2% respectively, and in remote normal appearing esophageal tissues with frequency of about 36.8%, 11.2% and 0.0% respectively. MGMT gene showed a higher proportion of hypermethylation in cancer tissues while P16 gene showed a higher proportion of hypermethylation in remote normal appearing esophageal tissues in patients with lymph node metastasis. A significant association was found between MTHFR C677T genetic polymorphism and CpG island methylation status of MGMT gene. After adjustment for potential confounders, individuals carrying CT or TT genotype have higher frequency of hypermethylation in MGMT gene in cancer tissues with odds ratio 3.34 (95% CI:1.07-10.39) and 3.83 (95% CI:1.13-12.94) respectively. Based on the follow-up data, our analysis showed an inverse association between diet folate intake and the risk of death after esophagectomy. The median survival time was 2.92 years for low folate consumption, 3.18 years for moderate folate consumption and over 4.59 years for high folate consumption. After adjusting for potential confounders, the hazard ratios (95% confidence interval) were 0.72(0.36-1.46) for moderate and 0.39(0.20-0.78) for high folate intake, respectively. This preventive effect was more evident in patients carrying MTHFR 677CC genotype. Conclusions: This study indicated the aberrant CpG island hypermethylation of cancer related genes were associated with ESCC and might be a promising biomarker in diagnosis. Diet folate intake may have benefits on the prognosis of ESCC after esophagectomy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3128. doi:1538-7445.AM2012-3128

Methylenetetrahydrofolate reductase C677T genetic polymorphisms and risk of leukaemia among the North Indian population

Background: Leukaemia is a heterogeneous disease in which haematopoietic progenitor cells acquire genetic lesions that lead to a block in differentiation, increased self-renewal, and unregulated proliferation. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), involved in folate metabolism, plays a crucial role in cells because folate availability is important for DNA integrity. The aim of this case–control study was to evaluate the association of the C677T MTHFR gene polymorphism with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML) and chronic lymphocytic leukaemia (CLL). Materials and methods: A total of 275 leukaemia cases – including AML (n=112), ALL (n=81), CML (n=43), CLL (n=39) – and 251 age/sex-matched healthy control individuals participated in this study. MTHFR C677T polymorphisms in the cases and controls were evaluated by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results: The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total leukaemia cases were 68.73%, 19.64%, and 11.64% in cases, and 71.71%, 24.30%, and 3.98% in healthy controls, respectively. The average frequency of the MTHFR 677T allele was 21.45% among the cases compared to 16.13% among the controls. Conclusions: In the present case–control study we have observed a higher frequency of the MTHFR 677TT genotype in cases of leukaemia (AML, ALL, CML and CLL) as compared with controls; this might be due to ethnic and geographic variation. As per our findings, although the frequency of the MTHFR 677T allele is moderately high in AML, ALL and CLL, no statistically significant association was found; on the other hand statistically significant association was found in the context of CML cases.

Diet folate, DNA methylation and genetic polymorphisms of MTHFRC677T in association with the prognosis of esophageal squamous cell carcinoma

BackgroundFolic acid may affect the development of human cancers. However, few studies have evaluated the consumption of diet folate in the prognosis of patients with esophageal squamous cell carcinoma (ESCC).MethodsOne hundred and twenty five ESCC patients underwent esophagectomy between January 2005 and March 2006 in the Yangzhong People's Hospital were recruited and followed up. The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms on the prognosis of ESCC were evaluated by using Cox proportional hazard regression models.ResultsOur analysis showed an inverse association between diet folate intake and the risk of death after esophagectomy. The median survival time was 3.06 years for low or moderate folate consumption and over 4.59 years for high folate consumption. After adjusting for potential confounders, the hazard ratios (95% confidence interval) [HRs (95% CI)] were 0.72 (0.36-1.46) for moderate and 0.39 (0.20-0.78) for high folate intake, respectively (P for trend = 0.007). This preventive effect was more evident in patients carrying MTHFR 677CC genotype. No significant relation was observed between aberrant DNA methylation of P16, MGMT and hMLH1 gene, as well as MTHFR C677T genetic polymorphisms and the prognosis of ESCC.ConclusionsOur research indicated that diet folate intake may have benefits on the prognosis of ESCC after esophagectomy. From a practical viewpoint, the findings of our study help to establish practical intervention and surveillance strategies for managements of ESCC patients and can finally decrease the disease burden.

Interaction between the MTHFR C677T Polymorphism and Alcohol—Impact on Oral Cancer Risk and Multiple DNA Methylation of Tumor-related Genes

Several studies have reported Oral Squamous Cell Carcinoma (OSCC) association with etiological factors, such as smoking and alcohol. The aim of the present study was to establish whether the methylenetetrahydrofolate reductase (MTHFR) C677T genotype and a high alcohol intake, solely or in interaction, have an impact on the oral cancer risk, DNA methylation, or multiple methylation of tumor-related genes. MTHFR C677T genetic polymorphism was determined by the PCR/RFLP method, and DNA methylation was assessed by nested methylation-specific PCR. The risk for multiple methylation was significantly increased in heavy-drinking patients with the TT genotype, compared with CC and CT patients (OR = 10.873; 95% CI, 1.134-104.24). Multiple methylation was significantly associated with tumor stage (p = 0.018), and showed a trend of association with the presence of nodal metastases (p = 0.058). A significant association was found between TT genotype and methylation status of the RASSF1A gene in OSCC patients (p = 0.012). Heavy-drinking individuals with the TT genotype showed increased oral cancer risk compared with the CC genotype (OR = 3.601; 95% CI, 1.036-12.513), and compared with the CC and CT genotypes (OR = 4.288; 95% CI, 1.325-13.877). Our study suggested gene-environment interactions between high alcohol intake and the MTHFR 677TT genotype for elevated oral cancer risk, with a significant impact on multiple methylation of cancer-related genes.

The Interaction Between eNOS and MTHFR Genetic Polymorphism Modify Effect of Cigarette Smoking on The Risk of Ischemic Stroke

P-281 Introduction: Stroke has been related to a variety of risk factors including cigarette smoking which induce oxidative stress. Nitric oxide (NO) plays a relevant role in producing ROS and T-786C polymorphism in promoter region has been studied with various diseases. Methylenetetrahydrofolate reductase (MTHFR) gene may not be associated with disease outcome directly, the combination effect with other gene has been reported. We investigated the association between the eNOS T-786C and MTHFR C-677T genetic polymorphisms and the risk for stroke, and examined potential interaction between these polymorphisms and cigarette smoking. Methods: Total 290 cases arrived in emergency room within 24 hours after stroke and 290 age-sex matched controls were included in this study. SNP-IT was used for genotyping of eNOS and MTHFR gene. For analysis of association between these genetic polymorphisms and ischemic stroke, logistic regression was used. Results: The smoking was shown to increase the risk of stroke in the analysis controlling for polymorphisms and other significant variables, but the significant interaction between each polymorphism and smoking was not observed. When stratified by the eNOS and MTHFR genetic polymorphisms, the risky effect of smoking increased clearly. In the subjects with eNOS -786TT and MTHFR -677CC together, smokers had significantly increased OR compared to nonsmokers (OR, 3.83; 95% CI, 1.42, 10.27), and the interaction was observed (p=0.004). The increased risk of smoking also was shown in the subjects with eNOS -786 TC or CC and MTHFR -677 CT or TT, but it did not reach significance. Discussion and Conclusion: In conclusion, we found that smoking is a risk factor for ischemic stroke and the risk was modified when considering the combination effect of eNOS T-786C and MTHFR C-677T polymorphisms. Our findings suggest that there is gene-gene and gene-environment interaction between eNOS and MTHFR polymorphisms and smoking for the risk of stroke.