Methylenetetrahydrofolate Reductase C677T Allele Research Articles

Genetic variants of folate metabolism and the risk of multiple sclerosis

ABSTRACT Background and aims Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of unknown cause. Alterations in one-carbon metabolism have impact in the pathophysiology by genetic susceptibility to MS and increased the risk of MS. The aim of this study was to investigate the contribution of the gene polymorphism on Methylenetetrahydrofolate Reductase (MTHFR), Methionine Synthase Reductase (MTRR), Methionine Synthase (MTR) enzymes and of the essential factors (homocysteine, Hcy; cysteine, Cys; and vitamin B12, VitB12) in folate metabolism. Methods Eligible MS patients (n = 147) and health controls (n = 127) were participated. The gene polymorphisms were analyzed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and the levels of plasma Hcy, Cys and VitB12 were measured by Enzyme Linked Immunuabsorbent Assay (ELISA). Results and conclusion Our results showed that the levels of Hcy and VitB12 were lower and the levels of Cys were higher in MS compared to controls. The observation of high Cys values in all 3 gene polymorphisms suggests that the transsulfiration pathway of Hcy is directed towards Cys formation since the methionine synthesis pathway does not work. We could not find any association with all gene polymorphisms with the risk of MS. The T allele of MTHFR C677T and G allele of MTR A2756G are risk factors for serum Cys level on MS. As for MTR A2756G, serum vitB12 was observed in MS patients with G allele.

Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension

ObjectiveTo analyse the relationship between the polymorphisms of the H-type hypertensive methylenetetrahydrofolate reductase (MTHFR) C677T gene and neutrophil gelatinase-associated lipocalin (NGAL) in early kidney injury.MethodA total of 279 hospitalised patients with hypertension were selected and grouped according to their homocysteine (Hcy) level. If their blood Hcy level was ≥ 10 µmol/L they were assigned to the H-type hypertensive group, and if it was < 10 µmol/L they were assigned to the non-H-type hypertensive group. Blood lipid indexes, renal function indexes and blood glucose indexes were collected, and the differences between the two groups were compared. Furthermore, MTHFR C677T genotype distribution and allele frequency and Hcy level of MTHFR C677T genotype were compared, and logistic multiple regression analysis was conducted for the correlation of different genotypes of MTHFR C677T and the early kidney injury marker NGAL.ResultsIn the non-H-type hypertensive group, the levels of Hcy and NGAL, cystatin, blood urea nitrogen, serum creatinine, uric acid, serum β2-microglobulin and urinary microalbumin-to-creatinine ratio increased significantly, and the glomerular filtration rate level decreased significantly, when compared with the H-type hypertensive group, with statistical differences (p < 0.05). The H-type hypertensive group and the non-H-type hypertensive group had significant differences in the CC, CT and TT genotypes and allele frequencies at the MTHFR C677T locus. The MTHFR C677T gene mutation rate of the H-type hypertensive group was significantly higher than that of the non-H-type hypertensive group. The H-type hypertensive group had higher levels of the TT genotype and CT genotype Hcy. There was a statistical difference (p < 0.05).ConclusionMethylenetetrahydrofolate reductase C677T polymorphism is correlated with the Hcy level, and its gene polymorphism will affect the Hcy level. Methylenetetrahydrofolate reductase C677T polymorphism has an interactive effect with NGAL. Screening NGAL and reducing Hcy levels are valuable methods for the prevention and treatment of early renal injury in patients with H-type hypertension and help improve the prognosis of patients and their quality of life.

763 ACTIVATION OF SIRT1 ATTENUATES VASCULAR DYSFUNCTION AND THROMBOSIS IN MTHFR DEFICIENCY

Abstract Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.

SIRT1 pharmacological activation rescues vascular dysfunction and prevents thrombosis in MTHFR deficiency

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/–) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/– mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.

Correlation Analysis Between MTHFR C677T Polymorphism and Uterine Fibroids: A Retrospective Cohort Study.

BackgroundUterine fibroids(UF) are the most common benign tumors in women, with high incidence and unknown causes. We aimed to explore the correlation between Methylenetetra-hydrofolate reductase (MTHFR) C677T polymorphism and UF.MethodsThis is a retrospective cohort study. Data were collected from 2411 women detected for MTHFR C677T polymorphism in the Fifth Affiliated Hospital of Sun Yat-sen University from 2018 to 2020. B-ultrasound (BU) and the first page of medical records were used to analyze whether they had ever been diagnosed with UF. The collected data were analyzed. Using the chi-square test and regression analysis to explore the correlation, and the risk factors was screened by multifactor logistic regression analysis.ResultsA total of 2411 pregnant women were in the MTHFR C677T polymorphism detection. Among them, 226(9.37%) were diagnosed as UF by BU or clinical diagnosis. The allele and genotype of MTHFR C677T were significantly different between the case and control group (p<0.05), and the distribution of the allele was following Hardy-Weinberg (H-W) equilibrium. Comparing with the wild-type (C/C), the mutant group (C/T+T/T) was more likely to form UF(OR,1.43;OR95%CI,1.07-1.89). After adjusting for confoundings, the heterozygous mutant (C/T) was more susceptible to UF than the wild-type (aOR,1.41;aOR95%CI,1.41-1.91). In the case group, BMI, gravidity and parity were not associated with the size and number of UF and the MTHFR C677T polymorphism (p>0.05). However, older maternal age was associated with the incidence of UF, especially the multiple UF (p<0.05).ConclusionOur results found that MTHFR C677T polymorphism was associated with UF occurrence for the first time. This could imply that it may increase the risk of forming UF in women of gestational age.

Relationship between Methylenetetrahydrofolate Reductase C677T Gene Polymorphism and Autism Susceptibility: A Meta-Analysis

To explore the correlation between 5,10-methylenetetrahydrofolate reductase C677T gene polymorphism and autism susceptibility and to provide the evidence-based medicine for the prevention and treatment of autism. The retrieval database includes the VIP Chinese Science and Technology journal database, China National Knowledge Infrastructure, Wanfang database, PubMed, Wiley online library and Web of science. Chinese retrieval form: “Autism” and “methylenetetrahydrofolate reductase”. English retrieval form: “methylenetetrahydrofolate reductase”) and (“autism” or “autism spectrum disorders”) and (“C677T” or “polymorphism” or “genotype”). The retrieved time was till June 30, 2020 and the languages were limited to Chinese or English. Stata 12.0 software was used for meta-analysis, the evaluation indexes including heterogeneity test, merged effect, sensitivity analysis and publication bias evaluation. Based on the inclusion and exclusion criteria, 11 articles were included in the analysis. The meta-analysis shows that T/C allele odds ratio=0.56 (p<0.001), indicating that the T allele of methylenetetrahydrofolate reductase C677T may be an Autism spectrum disorder risk factor. The odds ratio of genotype CT vs. CC was 1.44 (p<0.001), the odds ratio of genotype TT vs. CC was 3.05 (p<0.001), the odds ratio of genotype TT+CT vs. CC was 1.81 (p<0.001), the odds ratio of genotype TT vs. CT+CC was 2.52 (p<0.001). CT, TT and TT+CT genotypes were positively correlated with autism susceptibility, indicating that CT, TT and TT+CT genotypes may increase the risk of autism susceptibility. Methylenetetrahydrofolate reductase C677T gene polymorphism has a positive correlation with autism susceptibility.

Prenatal Multivitamin Use and MTHFR Genotype Are Associated with Newborn Cord Blood DNA Methylation.

Background: Fetal development involves cellular differentiation and epigenetic changes—complex processes that are sensitive to environmental factors. Maternal nutrient levels during pregnancy affect development, and methylene tetrahydrofolate reductase (MTHFR) is important for processing the nutrient folate. Hypothesis: We hypothesize that supplement intake before pregnancy and maternal genotype are associated with DNA methylation in newborns. Methods: In the pregnancy cohort, Early Autism Risk Longitudinal Investigation (EARLI), health history, and genotype information was obtained (n = 249 families). Cord blood DNA methylation (n = 130) was measured using the Illumina HumanMethylation450k array and global DNA methylation levels were computed over 455,698 sites. Supplement use preconception and during pregnancy were surveyed at visits during pregnancy. We evaluated associations between maternal preconception supplement intake and global DNA methylation or DNA methylation density distributions of newborn cord blood, stratified by the presence of a variant maternal MTHFR C677T allele. Results: Maternal preconceptional multivitamin intake was associated with cord blood methylation, dependent on maternal MTHFR genotype (interaction term p = 0.013). For mothers without the MTHFR variant allele, multivitamin intake was associated with 0.96% (95% CI: 0.09, 1.83) higher global cord blood methylation (p = 0.04) and was also associated with the cumulative density distribution of methylation (p = 0.03). For mothers with at least one variant allele, multivitamin intake had a null −0.06% (95% CI: −0.45, 0.33) association with global cord blood DNA methylation, and was not associated with the cumulative density distribution (p = 0.37). Conclusions: We observed that cord blood DNA methylation was associated with maternal supplement exposure preconception and maternal genotype. Genetic context should be considered when assessing DNA methylation effects of modifiable risk factors around the time of pregnancy.

Methylenetetrahydrofolate Reductase C677T Gene Polymorphism as a Risk Factor for Hypertension in a Rural Population.

Hypertension remains a public health burden despite advances in its management. Hence, the search for further risk stratification tools and prevention and new treatment approaches continues. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with hypertension. Interestingly, riboflavin, as a cofactor of MTHFR, may control blood pressure in patients with mutant MTHFR variants. These double benefits of a risk stratification tool and treatment approach make it interesting. Because this polymorphism depends on ethnicity and geographic region, we aimed to determine the association between MTHFR C677T gene polymorphism and hypertension in a rural Indonesian-Sundanese population. This population-based case-control study included 213 hypertensive subjects and 202 nonhypertensive subjects as controls. The TaqMan assay was used to determine the MTHFR C677T genotypes. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the risk of association. There was a significant difference in MTHFR C677T allele frequencies between the hypertensive and control groups (62.9% CC, 34.3% CT, 2.8% TT vs. 77.7% CC, 20.8% CT, 1.5% TT; p=0.004) and between mutant (TT and CT) and wild-type genotypes (CC) (p=0.001). The mutant genotype was associated with a risk of hypertension (OR 2.1; 95% CI 1.3–3.5) when adjusted for age, body mass index, waist circumference, and diabetes mellitus. The mutant of the MTHFR C677T gene increases the risk of hypertension in rural Indonesian-Sundanese population. These findings may be used in future studies to evaluate the effect of riboflavin supplementation in this population.

Methylenetetrahydrofolate reductase C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus

Background Type 2 diabetes mellitus (T2DM) is becoming increasingly prevalent throughout the world. Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes mellitus. The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been reported to cause reduced MTHFR enzyme activity and impaired homocysteine metabolism, leading to hyperhomocysteinemia. Aim The aim of the study was to evaluate the role of MTHFR C677T gene polymorphism in the susceptibility to DN in type 2 diabetic patients. Patients and methods The study was conducted on 180 adult Egyptian participants (60 healthy controls, 60 patients with T2DM without nephropathy, and 60 patients with T2DM complicated with nephropathy). C677T genotypes were determined by PCR-RFLP analysis, and homocysteine levels were measured by enzyme-linked immunosorbent assay. Results The prevalence of polymorphic genotype of CT and TT and T allele was statistically significantly increased in diabetic patients than in controls (P&lt;0.001). There was a statistically significant increase in polymorphic genotypes (CT and TT) and T allele in T2DM with nephropathy in comparison to T2DM without nephropathy group (P&lt;0.001, 0.05, respectively). Serum homocysteine levels were significantly higher in patients with nephropathy than in patients without nephropathy or controls with P less than 0.001. The higher serum homocysteine level was observed with polymorphic genotypes TT and CT compared with CC genotypes (P&lt;0.001). Conclusion The TT genotype and T allele of MTHFR C677T may represent a significant genetic molecular marker to predict the risk of DN in T2DM.

Methylenetetrahydrofolate reductase C677T variant and hyperhomocysteinemia in subarachnoid hemorrhage patients from India.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T, A1298C) has been implicated in increased plasma homocysteine (Hcy) levels. The present study was designed to investigatethe association between MTHFR polymorphism and increased Hcy levels in subarachnoid haemorrhage (SAH) patients. A total of 150 subjects from North India were included in the study, comprising of 100 SAH patients and 50 healthy controls. Plasma Hcy levels was determined and MTHFR polymorphism (C677T, A1298C) was screened by High resolution melting (HRM) analysis. Plasma Hcy levels were found to be significantly higher (p < 0.001) in SAH patients than in healthy controls. No significant difference in the genotype and allele frequency of MTHFR A1298C was observed. However, frequency of MTHFR C677T genotype, CT (53% vs. 20%; p < 0.001) and TT (15% vs. 2%; p < 0.05) was significantly higher in SAH group as compared to healthy controls. The frequency of T allele (41.5% vs. 12%; p < 0.001) was also found to be higher in SAH patients in comparison to healthy controls. Furthermore, Hcy levels were higher in SAH patients with TT genotype than in patients having CT genotype, whereas CC genotype had lower Hcy levels. The study suggests that higher frequency of MTHFR C677T allele may contribute to etiopathology of SAH through increase in Hcy levels.

MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort.

Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine (Hcy) metabolism. We aimed to evaluate a possible relationship between MTHFR gene C677T (rs 1801133), A1298C (rs 1801131) variants and susceptibility to FMF in a Turkish cohort. This case-control study included 198 Turkish FMF patients and 100 healthy subjects as controls. MTHFR C677T and A1298C were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. The genotype distribution and allele frequency of the MTHFR C677T were statistically different between the patients and the control group (P=.006, P=.001, respectively). The frequency of the TT genotype and T allele of MTHFR C677T was significantly higher in the patients than in the controls. The genotype distribution of MTHFR A1298C variant did not show any statistically significant difference between the patients and the controls (P›.05). The patients had statistically different frequencies in allele C of MTHFR A1298C variant compared with the control (P=.032). We also examined the risk associated with inheriting the combined genotypes for the two MTHFR variants. According to these results, individuals who were CC homozygous at C677T locus and AA homozygous at A1298C locus have a lower risk of developing FMF (P=.002). Individuals who were TT homozygous at C677T locus and AC heterozygous at A1298C locus have higher risk of developing FMF (P=.033). Our findings clearly showed there was an association the MTHFR C677T/A1298C variants and susceptibility to FMF in the Turkish sample.

The MTHFR C677T mutation is not a risk factor recognized for HBV-related HCC in a population with a high prevalence of this genetic marker

BackgroundPolymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene can affect disease progression in HBV infection. However, the results from different reports are inconsistent. The aim of this study was to investigate the association between the MTHFR C677T polymorphism and the outcome of HBV infection in a Tianjin Han population. MethodsTaqMan SNP genotyping was employed to determine the alleles and genotypes of MTHFR C677T in 2511 subjects from various stages of HBV infection and 549 healthy controls. ResultsOf the 3060 subjects, the genotypic frequencies were CT 48.9%, TT 29.3% and CC 21.8%; the allelic frequencies were T 53.8% and C 46.2%. There was no significant difference in genotypic or allelic distribution among the different disease groups. When either healthy subjects or self-limited subjects were used as controls, the TT genotype and the T allele conferred protective effects against hepatocellular carcinoma (HCC) (HCC vs healthy subjects: OR=0.588, 95% CI=0.413–0.836, P=0.003; OR=0.768, 95% CI=0.645–0.915, P=0.003, respectively. HCC vs self-limited subjects: OR=0.598, 95% CI=0.404–0.886, P=0.010; OR=0.772, 95% CI=0.635–0.940, P=0.010, respectively). After sub-stratification by gender, the prevalence of the TT genotype or T allele was the lowest in the male HCC group (TT 23.5%, T 49.8%). The protective effects of the TT genotype and the T allele were observed in male HCC and cirrhotic subjects (HCC vs self-limited subjects: OR=0.470, 95% CI=0.288–0.766, P=0.002; OR=0.681, 95% CI=0.535–0.866, P=0.002, respectively. Liver cirrhosis vs self-limited subjects: OR=0.624, 95% CI=0.392–0.992, P=0.046; OR=0.791, 95% CI=0.627–0.998, P=0.048, respectively), but not in female. When the subjects were stratified according to the clinical features, no statistically significant difference in the genotypic distribution was observed (P>0.05). ConclusionsThe TT genotype and T allele of MTHFR C677T may confer a protective effect on disease progression to HCC in HBV-infected individuals, especially among male patients, in a population with a high prevalence of this genetic marker.

Association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with primary glaucoma in Saudi population.

BackgroundMethylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism is involved in DNA synthesis, DNA repair and DNA methylation. The functional polymorphism of MTHFR gene, C677T has been shown to impact various diseases and implicated as a risk factor for the development of various neurodegenerative disorders including glaucoma.MethodsWe investigated MTHFR C677T genotypes and alleles frequencies in primary glaucoma [primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG)] patients and matched healthy controls in a case-control study. Two hundred ten primary glaucoma cases were studied for MTHFR C677T polymorphism and compared with 280 controls taken from the healthy population, employing the polymerase chain reaction-restriction fragment length polymorphism technique (PCR-RFLP). The MTHFR gene was amplified using specific primers. The PCR products (294 bp) was subsequently digested with HinfI (New England Biolabs) at 37 °C for 12 h, separated by electrophoresis on 2 % agarose gels, and visualized with ethidium bromide staining. The restriction digestion yielded 168 and 126 bp fragments for TT, 294, 168 and 126 bp fragments for CT and undigested PCR product 294 bp indicating CC genotype.ResultsWe found the frequency of the genotypes and alleles of MTHFR C677T differ significantly between cases and controls. The frequencies of allele T and genotype CT were significantly higher while the frequencies of allele C and genotype CC were lower in primary glaucoma patients as compared to controls (p <0.05). Upon stratification of our results into POAG and PACG, significantly higher frequencies of allele T (19.44 %) and genotype CT (38.89 %) were found in POAG patients compared to controls (12.5 % and 25 % respectively). The frequencies of alleles and genotypes were almost similar in PACG and controls (p = 0.8).ConclusionThis study indicates that the allele T and genotype CT of MTHFR C677T polymorphism are significantly associated with POAG while allele C and CC genotype may be protective for it. We conclude that the MTHFR C677T polymorphism increases the risk for POAG development in Saudi population and can be a genetic marker however, further studies are needed with multiple-ethnic populations affected with POAG to strengthen these findings.

Role of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in polycystic ovary syndrome risk

Polycystic ovary syndrome is one of the most frequently encountered endocrine malfunctions. Methylenetetrahydrofolate reductase (MTHFR) plays a vital role in folate metabolism, DNA methylation, and RNA synthesis. We carried out a study to investigate the association between MTHFR C677T and A1298C genetic variations and the risk of polycystic ovary syndrome in a Chinese population. We recruited 244 patients and 257 control subjects from an Inner Mongolian Medical University to this hospital-based, case-control study. The genotyping of the MTHFR C677T and A1298C polymorphisms was carried out using polymerase chain reaction coupled with restriction fragment length polymorphism. Using multiple logistic regression analysis, we found that the TT genotype and the T allele of MTHFR C677T carriers showed increased risk of polycystic ovary syndrome compared with the wild-type genotype or allele carriers. The adjusted ORs for the TT genotype and the T allele of MTHFR C677T were 1.84 (1.05-3.26) and 1.38 (1.06-1.81), respectively. Subjects carrying the CC genotype (OR = 3.98, 95%CI = 1.60-11.23) and the C allele (OR = 1.46, 95%CI = 1.07-2.00) of MTHFR A1298C had an elevated risk of polycystic ovary syndrome compared with the AA genotype and A allele carriers. In conclusion, our study suggests that the MTHFR C677T and A1298C polymorphisms may have contributed to the risk of polycystic ovary syndrome in the Chinese women investigated. Further research involving a greater number of individuals is warranted to confirm our results.

Association between the MTHFR C677T polymorphism and gastric cancer susceptibility: A meta-analysis of 5,757 cases and 8,501 controls.

Current data regarding the association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of developing gastric cancer are insufficient to draw definite conclusions. Therefore, the present meta-analysis was conducted to achieve a more precise estimation of the association. MEDLINE, EMBASE and Wanfang database searches resulted in the identification of 28 eligible studies describing 5,757 cases and 8,501 controls. The strength of the association between the MTHFR C677T polymorphism and gastric cancer risk were evaluated using crude odds ratios (ORs), with 95% confidence intervals (CIs). The pooled ORs were determined using homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (TT+CT vs. CC) and recessive (TT vs. CC+CT) models. When all studies were pooled into the meta-analysis, significant associations were identified between the MTHFR C677T polymorphism and the risk of gastric cancer (homozygous model: OR, 1.39; 95% CI, 1.20-1.62; heterozygous model: OR, 1.18; 95% CI, 1.05-1.32; dominant model: OR, 1.23; 95% CI, 1.10-1.38; recessive model: OR, 1.26; 95% CI, 1.12-1.42). Stratification of the data by ethnicity identified a statistically significantly elevated risk of gastric cancer in Asian MTHFR C677T polymorphism populations (homozygous model: OR, 1.64; 95% CI, 1.43-1.90; heterozygous model: OR, 1.30; 95% CI, 1.16-1.45; dominant model: OR, 1.39; 95% CI, 1.25-1.54; recessive model: OR, 1.41; 95% CI, 1.25-1.51), but not in Caucasian populations (homozygous model: OR, 1.15; 95% CI, 0.89-1.48; heterozygous model: OR, 1.03; 95% CI, 0.84-1.25; dominant model: OR, 1.05; 95% CI, 0.86-1.28; recessive model: OR, 1.09; 95% CI, 0.91-1.31). Following adjustment for heterogeneity, the current meta-analysis demonstrated that the MTHFR C677T polymorphism was not associated with the risk of gastric cancer in Caucasian individuals. Furthermore, no evidence of publication bias was observed. Thus, the current meta-analysis indicates that the MTHFR C677T allele may be a low-penetrant risk factor for the development of gastric cancer in Asian populations.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and susceptibility to acute lymphoblastic leukemia in a cohort of Egyptian children

This case–control study was planned to investigate the possible role of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as a risk factor for the development of acute lymphoblastic leukemia (ALL) in a cohort of Egyptian children. Typing of MTHFR C677T and A1298C polymorphisms was done using restriction fragment length polymorphism (RFLP) for 100 children with ALL and 100 age- and sex-matched healthy controls. No significant differences were found between patients with ALL and controls for the frequency of MTHFR C677T and A1298C alleles, genotypes, combined genotypes or haplotypes. The C677T and A1298C genotype frequency was different from that in Korean and Chinese populations (p < 0.5) and was similar to that in British, French-Canadian and German-Caucasian populations (p > 0.5). Our findings suggest that MTHFR C677T and A1298C polymorphisms are unlikely to affect the development of childhood ALL in an Egyptian population from Delta.

The MTHFR C677T Polymorphism Is Related to Plasma Concentration of Oxidized Low-Density Lipoprotein in Adolescents with Cardiovascular Risk Factors

Aim: The aim of this study was to investigate possible relationships among the A1298C (rs1801131) and C677T (rs1801133) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and levels of homocysteine, vitamins B₆, B₁₂, folic acid and lipid profile, including oxidized low-density lipoprotein (ox-LDL), of adolescents at cardiovascular risk. Methods: We recruited 115 adolescents (10-19 years old), 58.3% (n = 67) female, from a public school in Brazil who underwent anthropometric, biochemical and genetic tests as well as food consumption evaluation. Results: An important prevalence of hyperhomocysteinemia (19.1%) and alterations in triacylglycerol (17.4%), total cholesterol (26.9%) and high-density lipoprotein (HDL) cholesterol (48.0%) concentrations were observed, as well as low vitamin B₆ concentrations (23.5%). The categorization of homocysteine concentrations into tertiles revealed significant differences in serum concentrations of folate, vitamin B₁₂ and HDL, waist circumference and intake of total and saturated fat among the tertiles. The presence of variant alleles regarding the MTHFR C677T polymorphism interfered with vitamin B₆ and ox-LDL cholesterol concentrations. There was a trend for higher waist circumference values in T carriers (C677T), but not in C carriers (A1298C). Conclusions: The MTHFR C677T allele was associated with higher plasma vitamin B₆ and ox-LDL compared to the CC genotype.

Dissociable genetic contributions to error processing: a multimodal neuroimaging study.

BackgroundNeuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.MethodsWe measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.ResultsWe replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.Conclusions DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.

Methylenetetrahydrofolate reductase gene C677T, A1298C polymorphisms and pre-eclampsia risk: a meta-analysis.

To determine whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with pre-eclampsia susceptibility. Literature searches of the Pubmed, Embase, BIOSIS Previews and Web of Science were conducted to identify all eligible articles up to January 18th, 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) of five genetic models were calculated by fixed-effects or random-effects model. Publication bias, subgroup analysis, meta-regression and sensitivity analysis were also performed. A number of 49 studies including 51 samples consisted of 18,009 subjects (6,238 patients and 11,771 controls) were finally included. MTHFR C677T allele (TT or CT) carriers were 1.12 times more likely to develop pre-eclampsia (95% CI 1.04-1.21) compared with 677CC homozygous individuals. Similar results were obtained under other genetic models. Restricted to severe pre-eclampsia, there was an increased risk for 677TT homozygotes compared with 677CC homozygotes (OR 1.43; 95% CI 1.12-1.83). Subgroup analysis revealed a significant positive association between the C677T polymorphism (TT or CT) and pre-eclampsia in Asians (OR 1.41; 95% CI 1.11-1.79) and white population (OR 1.14; 95% CI 1.03-1.25). Meta-regression showed that study population, blinded genotyping, matching of cases and controls were not substantial sources of heterogeneity. For the MTHFR A1298C, ORs for all genetic models yielded a null association. This meta-analysis suggests that the MTHFR 677T allele might be associated with increased pre-eclampsia risk in Asian and white ethnicity and the subgroup of severe pre-eclampsia, while no association is observed between the MTHFR A1298C polymorphism and pre-eclampsia.

MTHFRC677T variant reduces risk of sporadic Parkinson's disease in ethnic Chinese

Genetic variability of methylenetetrahydrofolate reductase (MTHFR) may be associated with Parkinson's disease (PD). Its role in ethnic Chinese population is still unclear. Our study aimed to investigate whether MTHFR C677T variation was linked to PD risk in a Han Chinese population from mainland China. To investigate the association with the risk of PD, we analyzed the single-nucleotide polymorphism C677T in MTHFR gene using a case-control methodology. A total of 1482 subjects included 765 patients with idiopathic PD, and 717 age- and sex-matched controls were recruited in this study. The T allele of MTHFR C677T was associated with a decreased risk of PD (OR = 0.80, 95% CI: 0.688-0.926, P = 0.003). Patients with CT + TT genotypes have a decreased risk of PD compared with those with CC genotypes (OR = 0.66, 95%CI: 0.532-0.813, P = 0.000). CT + TT subjects cannot be differentiated from CC subjects based on their clinical features. We showed that the C677T polymorphism in MTHFR gene was associated with decreased PD susceptibility in a Han Chinese population from mainland China. Efforts to fully elucidate the pathophysiologic role of the variant in PD should be necessary.