Methylenetetrahydrofolate Reductase C677T Polymorphism Research Articles

Low maternal folate concentrations and maternal MTHFR C677T polymorphism are associated with an increased risk for neural tube defects in offspring: a case-control study among Pakistani case and control mothers.

There is considerable evidence that periconceptional maternal folate deficiency and coding variants in maternal genes coding for critical enzymes in the folate pathway are associated with neural tube defects (NTDs) in offspring. In a case-control study we investigated C677T polymorphism in the 5,10- methylenetetrahydrofolate reductase (MTHFR) gene in case and control mothers of Pakistani origin, and compared these with the respective maternal folate concentrations measured at the time of delivery. A case-control study was conducted among 109 case and 100 control mothers identified through the Holy Family Hospital Rawalpindi, Quaid-i-Azam University, Islamabad, Pakistan. Red blood cell (RBC) and serum folate concentrations and MTHFRC677T polymorphism were compared between case and control mothers. Mean RBC folate and serum folate concentrations were significantly lower in cases compared with control mothers (p<0.0001). Maternal MTHFR 677CT and 677TT genotypes were more common among cases compared with control mothers (CC vs TT p<0.0393 and CC/CT vs TT p<0.021). T-allele frequency was higher in cases compared with control mothers (C vs T p<0.017). Case mothers with 677CT or 677TT genotypes had significantly lower serum (p<0.0001) and RBC folate concentrations (p<0.0001) compared with control mothers. The present study provides further evidence that maternal folate deficiency and MTHFRC677T polymorphism might be associated with an increased risk for NTDs in offspring. Our results are limited by the fact that maternal folate concentrations were not obtained during the periconceptional period, but at delivery. Further analyses, including maternal folate levels during the periconceptional period, are warranted.

Association Between the Polymorphism of Methylenetetrahydrofolate Reductase Gene C677T and Risks of Congenital Heart Disease: Meta-analysis of Case-control Study

This paper discussed the association between the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene C677T and congenital heart disease (CHD). Methods: We developed literature with inclusion and exclusion criteria, and searching strategy in the meta-analysis. Studies related to the association between MTHFR C677T polymorphism of parents or progeny and CHD were identified by a search through PubMed, CNKI, CBN, and Springer Link databases, and their qualities were evaluated. Heterogeneity of these results was tested through Review Manager version 5.3.3. Appropriate effect models based on the heterogeneity were selected to complete the meta-analysis. Results: A total of 27 eligible studies (2800 cases from 3720 controls in progeny, and 2238 cases from 17175 controls in maternity) were evaluated. Statistical association was found between MTHFR gene (677 points TT/CC gene variant in maternity) and CHD risk in progeny (Odds ratio (OR) = 1.41 (1.16, 1.70), 95% confidence interval (CI) = p 0.05, respectively. In addition, MTHFR gene (677 points TT/CC) in progeny was related to CHD risk, as well as CT/CC (OR = 1.57 (1.22, 2.02), and 1.20 (1.03, 1.39), respectively, 95% CI = p < 0.05). Results show that MTHFR C677T polymorphism is associated with CHD risk. Conclusions: Furthermore, mutations of homozygous and heterozygous (TT/CC and CT/CC, respectively) MTHFR C677T in progeny, and those of homozygous MTHFR C677T (TT/CC) in maternity are risk factors of CHD.

Meta-Prediction of MTHFR Gene Polymorphisms and Air Pollution on the Risk of Hypertensive Disorders in Pregnancy Worldwide.

Hypertensive disorders in pregnancy (HDP) are devastating health hazards for both women and children. Both methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and air pollution can affect health status and result in increased risk of HDP for women. The major objective of this study was to investigate the effect of MTHFR polymorphisms, air pollution, and their interaction on the risk of HDP by using meta-predictive analytics. We searched various databases comprehensively to access all available studies conducted for various ethnic populations from countries worldwide, from 1997 to 2017. Seventy-one studies with 8064 cases and 13,232 controls for MTHFR C677T and 11 studies with 1425 cases and 1859 controls for MTHFR A1298C were included. MTHFR C677T homozygous TT (risk ratio (RR) = 1.28, p < 0.0001) and CT plus TT (RR = 1.07, p = 0.0002) were the risk genotypes, while wild-type CC played a protective role (RR = 0.94, p = 0.0017) for HDP. The meta-predictive analysis found that the percentage of MTHFR C677T TT plus CT (p = 0.044) and CT (p = 0.043) genotypes in the HDP case group were significantly increased with elevated levels of air pollution worldwide. Additionally, in countries with higher air pollution levels, the pregnant women with wild-type CC MTHFR 677 had a protection effect against HDP (p = 0.014), whereas, the homozygous TT of MTHFR C677T polymorphism was a risk genotype for developing HDP. Air pollution level is an environmental factor interacting with increased MTHFR C677T polymorphisms, impacting the susceptibility of HDP for women.

Systematic review and meta-analysis of the associations between maternal methylenetetrahydrofolate reductase polymorphisms and preterm delivery.

To date, reported associations between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and preterm delivery are conflicting. The present meta-analysis summarized the existing evidence and evaluated these associations. Eligible studies were retrieved from Medline (PubMed), EMBASE, the Chinese Biomedical Literature Database and the Cochrane Library. We calculated pooled odds ratios (ORs) and 95% confidence interval (CIs) within five genetic models using either random-effects or fixed-effects models dependent on study heterogeneity. Potential publication bias was assessed using a Begg's test. Sensitivity analysis was performed to evaluate the stability of the results. Thirteen studies involving 4816 mothers who experienced preterm delivery and 34 506 normal controls were finally included. Significant associations between MTHFR C677T polymorphism and the risk of preterm delivery were detected overall (ORT/C = 1.34, 95% CI 1.12-1.61; ORTT/CC = 1.60, 95% CI 1.21-2.11; ORCT/CC = 1.33, 95% CI 1.07-1.65; ORTT/(CC + CT) = 1.41, 95% CI 1.11-1.78; OR(TT + CT)/CC = 1.36, 95% CI 1.11-1.66) and in an Asian population (ORT/C = 1.80, 95% CI 1.24-2.62; ORTT/CC = 2.13, 95% CI 1.27-3.57; ORCT/CC = 1.93, 95% CI 1.37-2.71; OR(TT + CT)/CC = 2.03, 95% CI 1.49-2.77). Negative associations of the A1298C polymorphism were only observed among Asian pregnant women (ORC/A = 0.66, 95% CI 0.50-0.88; ORCC/AA = 0.10, 95% CI 0.02-0.53; ORCC/(AA + AC) = 0.11, 95% CI 0.02-0.57; OR(CC + AC)/AA = 0.68, 95% CI 0.49-0.94). MTHFR 677 T may play a significant role in regard to the risk of preterm delivery, especially in the Asian population.

A Meta-Analysis: Methylenetetrahydrofolate Reductase C677T Polymorphism in Gastric Cancer Patients Treated with 5-Fu Based Chemotherapy Predicts Serious Hematologic Toxicity but Not Prognosis.

5-fluorouracil (5-Fu) metabolism associated enzyme, methylenetetrahydrofolate reductase (MTHFR)'s polymorphism C677T can affect enzyme activity and a series of studies have been performed to examine the association of this MTHFR polymorphism with the clinical outcomes of gastric cancer (GC) patients treated with 5-Fu based chemotherapies. However, the results are inconsistent and inconclusive. Therefore, a more comprehensive summary like meta-analysis on this topic is needed. We performed a systematic literature search of PubMed and Embase up to May 20, 2017. Researches exploring MTHFR polymorphisms C677T's relationship with the clinical outcomes (response rate, overall survival and toxicity) of GC patients treated with 5-Fu based chemotherapy were included. The association was measured by odds ratios (ORs) or hazard ratios (HRs) combined with their 95% confidence intervals (CIs) using random/fixed effects model according to the studies' heterogeneity. Subgroup, sensitivity and publication bias analyses were conducted. Thirteen studies were finally included in this meta-analysis. No significant association was found between response rate [TT/ (CC+CT) OR=1.31, 95% CI: 0.62-2.76] or overall survival [(CT+TT)/CC HR=1.05, 95% CI: 0.86-1.26; TT/(CT+CC) HR=1.48, 95% CI: 0.53-4.15] and MTHFR polymorphism C677T. However, GC patients with CC or CT genotype tended to experience less severe hematologic toxicity than those with TT genotype [(CC+CT)/TT OR=0.66, 95% CI: 0.48-0.91]. In conclusion, MTHFR C677T polymorphism predicts severe hematologic toxicity in GC patients receiving 5-Fu based chemotherapy, but not the efficiency.

Association of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with coronary artery disease (CAD) in a North Indian population

There is significant variation in reported associations of the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and coronary artery disease (CAD) in different global populations. This study aims to identify any individual or combined associations between the 1298 and 677 loci of MTHFR and CAD in a North Indian population. A total of 159 patients and 166 controls were genotyped using validated TaqMan assays. Odds ratio analysis identified associations at crude level and multiple logistic regression controlled for confounding variables. Linkage disequilibrium between the loci was assessed along with haplotype association analysis. At the C677T locus, homozygosity of the T allele identified a significantly protective association (OR = 0.38, CI: 0.24–0.60). For the A1298C locus the AC genotype had a protective effect in codominant model (OR = 0.53, CI: 0.32–0.85) and CC genotype showed a susceptible association in recessive model when controlled for age, sex and lipids (OR = 2.70, CI: 1.27–5.77). This study identified that, independently, both heterozygous genotypes show a protective association with CAD. In addition the CC genotype of A1298C in recessive model was a susceptible genotype. The combined associations of MTHFR are protective (primarily due to the effects of C677T locus) suggesting an interaction between the loci and their associations with CAD within this sample.

The relationship between of ACE I/D and the MTHFR C677T polymorphisms in the pathophysiology of type 2 diabetes mellitus in a population of Brazilian obese patients.

Objectives This study aimed to evaluate the frequencies of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms in obese patients with and without type 2 diabetes mellitus (T2DM). Subjects and methods These polymorphisms were analyzed by polymerase chain reaction in 125 patients with obesity, 47 (T2DM) and 78 (Control Group). Results No significant difference was found on comparing the T2DM and Control Groups in respect to the genotypic frequencies of the polymorphisms - (II: 13.3% vs. 12.0%; ID: 37.8% vs. 37.3; DD: 48.9% vs. 50.7%; CC: 36.2% vs. 39.0%; CT: 46.8% vs. 49.3%; TT: 17.0% vs. 11.7%), and alleles (I: 32.2% vs. 30.7%; D: 67.8% vs. 69.3%; C: 59.6% vs. 63.6%; T: 40.4% vs. 36.4%) and their synergisms in the pathophysiology of T2DM. On analyzing the T2DM Group, there were no significant differences in the presence of complications. In this population of Brazilian obese patients, no correlation was found between the ACE and MTHFR polymorphisms in the development of T2DM. Conclusion Analyzing only the group with diabetes, there was also no relationship between these polymorphisms and comorbidities.

Uticaj polimorfizma C677T gena za metilen-tetrahidrofolat reduktazu na nastanak spontanih pobačaja

Introduction: Spontaneous abortion (SA) is a frequent obstetric complication. Up to 15% of pregnancies end by spontaneous abortion in the first trimester. Five percent of women have two, and 1-2% of women have more than three abortions. The risk of spontaneous abortion is influenced by variety of genetic and environmental factors. Enzyme methylenetetrahydrofolate reductase (MTHFR) is primarily involved in homocysteine remethylation to the methionine. Gene polymorphism C677T in the MTHFR gene causes enzyme thermolability which leads to hyperhomocysteinemia, that might increase the risk of developing placental thrombosis and spontaneous abortion. Aim: The aim of our study was to determine whether the MTHFR C677T polymorphism is associated with the increased risk of SA. Material and methods: This study included 157 women who had at least two unexplained spontaneous abortions and 135 healthy women with at least one child, without previous SA. Detection of MTHFR C677T polymorphism genotypes was performed by PCR-RFLPs method. Investigation of differences between genotype and allele frequencies, in the group of women with SA and the control group, was completed using the x2 test. Results: In the group of patients with recurrent spontaneous abortions, 58 of them had CC genotype (36.94%), 74 had CT genotype (47.13%), and 25 had TT genotype (15.92%). In the control group, 59 of them had CC genotype (43.07%), 55 had CT genotype (40.74%), and 21 had TT genotype (15.56%). The frequency of C allele in the group of patients was 60.51%, and T allele 39.49%; while the frequencies in the control group were 64.07% and 35.93%, respectively. The difference in the genotype (p=0.470) and allele (p=0.393) frequency between the two groups of patients was statistically insignificant. Conclusion: Our results do not show any influence of the analyzed polymorphism on SA.

Association between Decreased Plasma Folate Levels and MTHFR C677T, and MTRR A66G Gene Polymorphisms as Determinants for Elevated Total Homocysteine Concentrations in Pregnant Women

Aims: The aims of this paper were to examine the association between gene polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G with levels of plasma folate and tHcy. Methods: Peripheral venous blood samples were obtained from 143 pregnant women, who had been fasted for more than 10 hours. Plasma tHcy and folate concentrations were measured in plasma specimens. The genotypes for polymorphisms were identified by the PCR-restriction fragment length polymorphism (RFLP). Results: Our results demonstrated that MTHFR 677T allele was the predictors of plasma folate levels in pregnant women. While MTHFR 677TT genotype and MTRR 66G allele were the predictors of plasma tHcy concentrations. Plasma folate levels were negatively correlated with tHcy concentrations (Pearson’s correlation coefficient r=-0.358, p=0.000012). With the increase of gestational weeks, the levels of plasma folate was first risen and then fall, whereas, there was a downtrend between gestational weeks and tHcy levels. Conclusion: Plasma folate status and total homocysteine level associated with MTHFR C677T and MTRR A66G gene polymorphisms in pregnant women. According to our study, the pregnant women of homozygous mutation of MTHFR 677TT and/or MTRR 66GG genes generally have lower levels of folate. Therefore, we recommend that pregnant women with 677TT and 66GG genotypes should supplement the appropriate dosage of folic acid based on their genotypes.

Correlations between plasma homocysteine and MTHFR gene polymorphism and white matter lesions.

This study aims to investigate the correlation between the plasma homocysteine (Hcy) level and methylenetetrahydro-folate reductase (MTHFR) C677T polymorphism, and white matter lesions (WML). The plasma Hcy level and MTHFR C677T gene polymorphism in 104 patients with white matter lesions and 74 controls were measured. The severity of cerebral white matter was scored on the magnetic resonance imaging (MRI) images by the modified Scheltens scale (score of 0-30). The plasma Hcy level in the WML group was remarkably higher than that in the control group (p < 0.05), and the proportion of the patients with ahigh Hcy level in the WML group was notably higher than that in the control group (p < 0.05). Moreover, the patients with TT genotype in MTHFR gene had asignificantly higher plasma Hcy level than those with CT or CC genotype. In addition, the plasma Hcy level in the patients with CT genotype was also significantly different from that in the patients with CC genotype (p < 0.05). The severity of cerebral white matter lesions among the patients with different genotypes in MTHFR gene was not significantly different (p > 0.05). The plasma Hcy level is positively correlated with WML and significantly correlated with C677T gene polymorphism in MTHFR gene. The severity of white matter lesions is not correlated with MTHFR C677T gene polymorphism.

Methylenetetrahydrofolate reductase gene-specific methylation and recurrent miscarriages: A Case- Control Study from North India

Aim:This study aimed to understand the association of gene-specific methylation of the promoter region of methylenetetrahydrofolate reductase (MTHFR) in the causation of recurrent miscarriages (RMs) both independently and also in light of MTHFR C677T polymorphism, hyperhomocysteinemia, folate, and Vitamin B12 deficiency.Settings and Design:This was a hospital-based, case–control, observational study.Methods:The proposed study included a total of 85 RM cases and 121 nonpregnant controls. Biochemical (homocysteine, folate, and Vitamin B12) investigations, MTHFR polymorphism (C677T), and MTHFR allele-specific methylation were done on all the samples.Results:Methylation-specific polymerase chain reaction of MTHFR gene revealed that methylated allele (single dose) was found to pose a significant 3.6-fold increased risk for RM. The degree of risk of methylated allele for RM was found to be aggravated from the normal genotype CC (2.8 folds) to CT (7.5 folds) individuals. Vitamin B12 deficiency and folate repletion were found to be posing an increased risk in association with methylated allele for recurrent miscarriages as compared to the respective controls.Conclusion:Recurrent miscarriage cases were found to be hypermethylated with respect to MTHFR gene-specific methylation as compared to the controls. High prevalence of folate repletion causing imbalance between folate and Vitamin 12 levels may lead to hypermethylation among recurrent miscarriage cases. The present study highlights the significance of the epigenetic mechanisms in the causation of the recurrent miscarriages.

Maternal folic acid use during pregnancy, methylenetetrahydrofolate reductase gene polymorphism, andchild's lung function and asthma.

Folic acid supplement use during pregnancy might affect childhood respiratory health, potentially mediated by methylenetetrahydrofolate reductase polymorphism C677T (MTHFR-C677T) carriership. We examined the associations of maternal folic acid supplement use and folate, vitamin B12 and homocysteine concentrations during pregnancy with childhood lung function and asthma. This study was embedded in a population-based prospective cohort study among 5653 children. Folic acid supplement use was assessed by questionnaires. Folate, vitamin B12 and homocysteine plasma concentrations were measured in early pregnancy and at birth. At age 10years, forced expiratory volume in 1second (FEV1 ), forced vital capacity (FVC), FEV1 /FVC, forced expiratory flow between 25% and 75% (FEF25-75 ), at 75% of FVC (FEF75 ), and asthma were examined. Maternal folic acid supplement use during pregnancy was associated with higher childhood FEV1 and FVC and with a lower FEV1 /FVC, compared with no folic acid supplement use. Among mothers carrying MTHFR-C677T variants, preconceptional start of folic acid supplement use was associated with lower FEV1 /FVC (-0.17 [-0.32, -0.02]) and FEF25-75 (-0.24 [-0.40, -0.07]). Among children carrying MTHFR-C677T wild-type, a higher vitamin B12 level at birth was associated with a lower FEV1 (-0.07 [-0.12, -0.01]) and FVC (-0.09 [-0.15, -0.04]). Folate and homocysteine concentrations were not consistently associated with lower childhood lung function or asthma. Preconceptional start of maternal folic acid supplement use and higher vitamin B12 concentrations at birth might adversely affect childhood lung function depending on MTHFR-C677T carriership. The clinical implications need to be evaluated.

Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis.

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer (CRC) susceptibility has been researched in numerous studies. However, the results of these studies were controversial. Therefore, the objective of this meta-analysis was to offer a more convincible conclusion about such association with more included studies. Eligible studies published till May 1, 2017 were searched from PubMed, Embase, Web of Science, and CNKI database about such association. Pooled odds ratios (ORs) together with 95% confidence intervals (CIs) were calculated to evaluate such association. And the Begg’s funnel plot and Egger’s test were applied to assess the publication bias. This meta-analysis contained 37049 cases and 52444 controls from 87 publications with 91 eligible case–control studies. Because of lack of data for a particular genotype in several studies, all the included studies were analysed barely in the dominant model. Originally, there was no association between MTHFR C677T polymorphism and CRC susceptibility (OR =0.99, 95% CI =0.94–1.05). After excluding 13 studies according to their heterogeneity and publication bias, rs1801133 polymorphism was found to reduce the risks of CRC significantly (OR =0.96, 95% CI =0.94–0.99). In the subgroup analysis of ethnicity, there was a significant association in Asians (OR =0.94, 95% CI =0.89–1.00). Furthermore, when stratified by the source of controls and genotyping methods, the positive results were observed in population-based control group (OR =0.97, 95% CI =0.93–1.00) and PCR-restriction fragment length polymorphism (PCR-RFLP) method (OR =0.95, 95% CI =0.91–0.99. The results of the meta-analysis suggested that MTHFR C677T polymorphism was associated with CRC susceptibility, especially in Asian population.

MTHFR A1298C and C677T Polymorphisms Are Associated with Increased Risk of Venous Thromboembolism: A Retrospective Chart Review Study

Background: Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme in homocysteine metabolism. This study aims to determine the impact of MTHFR polymorphisms on plasma homocysteine levels and risks of venous thromboembolism (VTE). Methods: This retrospective chart review study included a total of 188 subjects who were tested for MTHFR polymorphisms at Metrowest Coagulation Laboratory between April 2011 and April 2016. Two independent coders were trained to extract relevant clinical data for statistical analysis. Results: VTE occurred in 50% of patients with compound mutation, compared with only 28.6% of subjects from the wild-type group. Patients with heterozygous or homozygous A1298C or C677T variants had an intermediate risk of VTE. The median homocysteine level in the wild-type group was slightly lower than that of heterozygous or homozygous MTHFR variants. The difference, however, was not significant (p = 0.6193). Moreover, there was no difference in plasma homocysteine level between patients with VTE versus VTE-free (p = 0.4923). Conclusions: Heterozygous or homozygous MTHFR variants, especially a compound mutation, are associated with increased risk of VTE. Hyperhomocysteinemia does not correlate with MTHFR polymorphisms or VTE risk. Hence, MTHFR genotyping provides more consistent assessment of VTE risk. This information can be incorporated into risk stratification for early intervention and prophylaxis of VTE.

The methylenetetrahydrofolate reductase 677T-1298C haplotype is a risk factor for acute lymphoblastic leukemia in children.

The etiology of acute lymphoblastic leukemia (ALL) is complex, linked with both environmental exposures and genetic factors. Functional variants of the methylenetetrahydrofolate reductase (MTHFR) gene result in disturbance in folate metabolism and may affect susceptibility to cancer. The study was performed to evaluate whether MTHFR C677T and A1298C polymorphisms, analyzed separately and together, are associated with the development of ALL in a population under 18 years of age of Caucasian ancestry.The study included 117 pediatric patients (59% males, mean age at diagnosis 7.4 ± 5.2 years) with ALL, confirmed by conventional immunophenotyping surface-marker analysis and 404 healthy control subjects (48.5% men, mean age 37.7 ± 11.3 years). The MTHFR C677T and A1298C genotypes were analyzed using allele discrimination tests with Taq-Man fluorescent probes.The MTHFR 677TT genotype was related to a 2-fold increase in risk of ALL (P = .014). The 677T-1298C haplotype was found in ALL patients but not in controls (frequency 0.598%; P <.0001). The observed frequency of carriers of this rare haplotype was 12%, including 677CT/1298CC (1.7%), 677TT/1298AC (6.0%), and 677CT/1298AC (4.3%) genotypes.The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL in Polish population under 18 years of age. Further studies of haplotype composition in subjects with the 677CT/1298AC genotype are necessary to assess the risk of childhood ALL.

Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Variants, Folate Intake, and Susceptibility to Breast Cancer

Context: Breast cancer is the most common cancer among women, worldwide. Both genetic and environmental factors are involved in the risk of breast cancer. Folate is an essential nutrient that is involved in DNA synthesis, repair, and methylation. Single nucleotide polymorphisms (SNPs) in folate related genes, such as methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C are suitable candidates for investigation the role of these variants in susceptibility to breast cancer. Evidence Acquisition: Using the relevant English language studies from the search engines, such as MEDLINE/PubMed, EMBASE, and Scopus from 2005 to 2016, the present review looks at the role of MTHFR C677T and A1298C variants, synergism between these gene variants along with folate intake in susceptibility to breast cancer. Results: It seems the MTHFR C677T polymorphism is associated with the risk of breast cancer among Asians but not in Caucasians. However, the MTHFR A1298C polymorphism might not be a susceptibility factor for breast cancer. The MTHFR haplotypes alone or along with low dietary intake of folate were not involved in susceptibility to breast cancer. Conclusions: Association between MTHFR C677T polymorphism with the risk of breast cancer could be attributed to the lower activity of the MTHFR enzyme in the presence of 677T allele with reduced availability of folate that may result in uracil misincorporation in the DNA and cancer development. The absence of establishment of a role for MTHFR haplotypes and a synergism between low dietary intake of folate along with MTHFR polymorphisms in susceptibility to breast cancer might be due to differences in allelic frequency of MTHFR variants in various populations, stage of cancer, the familial and early onset cancer, and the influence of environmental factors. To establish the role of MTHFR haplotypes in relation to folate intake in susceptibility to breast cancer, more studies with adequate sample size that investigate the role of MTHFR gene polymorphisms along with dietary intake of folate in the risk of breast cancer are necessary.

Correlation Between Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphisms and Pemetrexed Chemotherapy Efficacy/Toxicity in Non-Squamous Non-Small Cell Lung Cancer.

BackgroundIn the present study, we aimed to retrospectively analyze the correlation between toxicity of pemetrexed (PEM) chemotherapy and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC).Material/MethodsWe used polymerase chain reaction, gene scanning, and restriction fragment length polymorphism to analyze MTHFR C677T in 51 patients with advanced non-sq NSCLC. The patients received chemotherapies with single-agent PEM (monotherapy group) or with PEM combined with cisplatin (joint group). The correlation between MTHFR C677T polymorphisms and chemotherapy efficacy/toxicity was also assessed.ResultsThere were 40 patients in the monotherapy group and 11 patients in the joint group. Among the 40 patients received single-agent PEM chemotherapy, those with the CT/TT genotype had higher incidence of leukopenia, neutropenia, nausea, and fatigue compared to patients with the with wild-type genotype CC (all P<0.05). However, polymorphisms of MTHFR C677T were not significantly associated with other adverse events and clinical outcomes.ConclusionsCompared with genotype CC (the wild type), patients with the CT/TT genotype had higher incidence of leukopenia, neutropenia, nausea, and fatigue. Therefore, the MTHFR C677T polymorphism could be a predictive factor for leukopenia, neutropenia, nausea, and fatigue toxicities in non-sq NSCLC patients treated with single-agent PEM.

Association of MTHFR C677T and A1298C gene polymorphisms with methotrexate efficiency and toxicity in Algerian rheumatoid arthritis patients

Methotrexate (MTX) is the most used drug in rheumatoid arthritis (RA) treatment. However, it shows variability in clinical response, which is explained by an association with genetic polymorphisms. This study aimed to elucidate the role of the two gene polymorphism C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) in response to MTX in Algerian RA patients. Study included 54 early RA patient treated with MTX for one year. MTX efficiency and toxicity were evaluated at 6 and 12 months respectively and the two gene polymorphisms were genotyped. No association was found between A1298C polymorphism and MTX toxicity. However, T allele of the C677T polymorphism was associated with the occurrence of MTX adverse effects (p = 0,019, OR: 3,63, 95% CI [1,12 - 12,80]). No association was found between C677T polymorphism and MTX efficiency, while A allele of the A1298C polymorphism was associated with good and moderate response (p = 0,02, OR = 3,28, 95% CI: [1,11– 9,42]). The study of RA biological markers kinetics showed that MTX did not affect antibodies rate unlike inflammatory markers. Our study suggests that MTHFR C677T and A1298C genotyping are associated to MTX toxicity and efficiency, respectively, in RA patients. This offers new perspectives in the personalization of RA treatment in Algeria.

Risk factors of neural tube defects: A reality of Batna region in Algeria

BackgroundNeural tube defects (NTDs) are severe birth defects, with genetic and/or environmental risk factors. AimThe objective of this study was to analyze data on NTDs cases at the Batna Maternity Hospital and to investigate some environmental and two genetic risk factors suspected in the etiology of NTDs. Subjects and methodsThis study was conducted on 82 healthy participants and 48 mothers with an NTD child. Peripheral blood samples were collected, in EDTA tubes and frozen at −20°C until DNA extraction by conventional method. Genetic analysis of methylene tetrahydrofolate reductase C677T polymorphism was determined by real time PCR, while cystathionine-beta-synthase 844 insertion was investigated by traditional PCR. Chi-square analyses were used to evaluate differences in the distribution of data. The odds-ratio was also calculated. A P-value less than 0.05 were significant. ResultsThe incidence of NTD in Batna region was 1.58 per 1000 births. The rate of NTD was significantly higher in females than males, highest affected NTD newborn’s was observed in mothers aged between 25 and 29 years and the consanguinity among all NTD cases was 30%. Data showed no significant association of NTDs with personal education, obesity, diabetes, but regarding folic acid consumption, about 86% of NTD’s mothers in our region didn’t take pre-conceptional supplementation with this vitamin .Genetic factors results didn't show a significant association of NTDs with specific mutations of the variant C677T MTHFR, and no gene-gene interaction of CBS insertion and C677T polymorphism was found, despite a significant difference in heterozygote frequency of CBS 844ins68 genotype between NTD’s mothers and controls, OR: 2.85(1.18–6.88). ConclusionNTD represents a real public health problem in Batna, Algeria. Various genetic and/or nutritional factors are implicated, although the mechanism is not clear. We suggest that further research should continue planning for preventive measures and effective treatment to reduce the incidence of NTDs in Algeria.

Influence of vitamin intake and MTHFR polymorphism on the levels of DNA damage in tobacco farmers.

Genetic damage may occur spontaneously under normal metabolic circumstances, inadequate intake of nutrients, and excessive exposure to environmental mutagens. To evaluate the influence of the intake of micronutrients vitamin B12, vitamin B6, and folate and of the polymorphism methylenetetrahydrofolate reductase (MTHFR) C677T on the induction of DNA damage in tobacco farmers. The study involved 66 men and 44 women engaged in tobacco cultivation in the region of Venâncio Aires (Rio Grande do Sul state, Brazil). Peripheral blood samples were collected to analyze DNA damage using the Comet assay, the micronucleus (MN) test and MTHFR C677T polymorphism. Dietary intake was evaluated based on the mean values obtained from three 24-h diet recall questionnaires, and nutrient intake data were computerized and estimated in the Food Processor SQL 10.9 program. The statistical tests used to generate the stated results were Kruskal-Wallis test, Exact Fisher's test, and multivariate linear regression analysis. DNA damage was significantly higher in individuals who had an inadequate intake of folate, vitamin B12, and vitamin B6 (P<0.01) assessed by Comet assay. In relation to MN test results, buccal cells showed MN frequency higher in individuals with inadequate intake of vitamin B6 (P<0.01). No difference was observed in MN lymphocytes frequency. No significant association was detected between MTHFR C677T polymorphism and DNA damage in tobacco farmers. Our results suggest that folate, vitamin B12, and vitamin B6 deficiency may be associated with genotoxic effect in individuals exposed to pesticides.