Methylenetetrahydrofolate Reductase Genetic Polymorphisms Research Articles

Co-Occurring Methylenetetrahydrofolate Reductase (MTHFR) rs1801133 and rs1801131 Genotypes as Associative Genetic Modifiers of Clinical Severity in Rett Syndrome.

Remethylation disorders such as 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency reduce the remethylation of homocysteine to methionine. The resulting hyperhomocysteinemia can lead to serious neurological consequences and multisystem toxicity. The role of MTHFR genotypes has not been investigated in patients with Rett Syndrome (RTT). In this study, we sought to assess the impact of co-occurring MTHFR genotypes on symptom profiles in RTT. Using pharmacogenomic (PGx) testing, the MTHFR genetic polymorphisms rs1801133 (c.665C>T mutation) and rs1801131 (c.1286A>C mutation) were determined in 65 patients (18.7 years ± 12.1 [mean ± standard deviation]) with RTT as part of routine clinical care within the Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, a National and Specialist Child and Adolescent Mental Health Service (CAMHS) in the UK. The clinical severity of patients was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI). The clinical severity symptom distribution varied between the homozygous and heterozygous MTHFR rs1801133 and rs1801131 genotypes. Those with the homozygous genotype had a narrower spread of severity scores across several domains (language and communication, ambulation, hand-use and eye contact clinical domains). Patients with the homozygous genotype had statistically significantly greater CGI-Severity scores than individuals with a non-homozygous MTHFR genotype (Z = -2.44, p = 0.015). When comparing the ratings of moderately impaired (4), markedly impaired (5), severely impaired (6) and extremely impaired (7), individuals with the homozygous MTHFR genotype were more impaired than those with the non-homozygous MTHFR genotype (Z = -2.06, p = 0.039). There was no statistically significant difference in the number of prescribed anti-epileptic drugs between the genotypes. Our findings show that in those with a pathogenic RTT genetic variant, co-occurring homozygotic MTHFR rs1801133 and rs1801131 polymorphisms may act as associative genetic modifiers of clinical severity in a subset of patients. Profiling of rs1801133 and rs1801131 in RTT may therefore be useful, especially for high-risk patients who may be at the most risk from symptom deterioration.

Association of MTHFR polymorphism, folic acid and vitamin B12 with serum homocysteine levels in pregnant women.

Homocysteine is known to be associated with adverse vascular and metabolic effects, as well as pregnancy complications. Its serum levels are influenced by the function of the enzyme methylenetetrahydrofolate reductase (MTHFR) and the dietary intake of folic acid, vitamin B12, and methionine. In this cross-sectional study, we investigated the association of genetic polymorphisms of the MTHFR gene with vitamin status in pregnant women during mandatory folic acid supplementation. The study included 102 pregnant women between 24 and 28 weeks of gestation who were attending regular outpatient examinations at the maternity clinic. Homocysteine, folic acid, vitamin B12 levels, and MTHFR gene polymorphisms (C677T and A1298C) were analyzed. Significant associations were found between vitamin B12 and folic acid levels with homocysteine (P < 0.001), with lower serum levels of these vitamins being associated with higher homocysteine levels. Surprisingly, there was no significant association between MTHFR genetic polymorphisms and serum homocysteine levels, likely attributed to the supplementation of folic acid and vitamin B12 in vitamin supplements for pregnant women, which counteracts the effect of the mutation. Remarkably, a high prevalence of MTHFR gene mutations was found, with the C677T polymorphism present in 56.9% and the A1298C polymorphism in 87.2% of pregnant women. These findings emphasize the importance of adequate folic acid and vitamin B12 intake during pregnancy to regulate homocysteine levels. Although the MTHFR gene mutations were highly prevalent, their influence on homocysteine levels in this population appears to be mitigated by vitamin supplementation. Further research is warranted to explore the impact of these mutations on other aspects of pregnancy outcomes. The trial is registrated at Clinicaltrail.gov (NCT04952324).

Gender-specific association of SLC19A1 and MTHFR genetic polymorphism with oxidative stress biomarkers and plasma folate levels in older adults

BackgroundPlasma folate levels are closely related to antioxidant capacity and are regulated by folate pathway gene polymorphism. However, few studies have explored the gender-specific association of folate pathway gene polymorphism with oxidative stress biomarkers. The present study was designed to explore the gender-specific independent and combined impacts of solute carrier family 19 member 1 (SLC19A1) and methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms on oxidative stress biomarkers in older adults. MethodsA total of 401 subjects were recruited, including 145 males and 256 females. Demographic characteristics of the participants were collected by using a self-administered questionnaire. Fasting venous blood samples were taken for folate pathway gene genotyping, circulating lipids parameters and erythrocyte oxidative stress biomarkers measurement. The difference of genotype distribution and the Hardy-Weinberg equilibrium was calculated by the Chi-square test. The general linear model was applied to compare the plasma folate levels and erythrocyte oxidative stress biomarkers. Multiple linear regression was used to explore the correlation between genetic risk scores and oxidative stress biomarkers. Logistic regression was used to explore the association of genetic risk scores of folate pathway gene with folate deficiency. ResultsThe male subjects have lower plasma folate and HDL-C levels than the female ones, and the male carrying MTHFR rs1801133 (CC) or MTHFR rs2274976 (GA) genotypes have higher erythrocyte SOD activity. The plasma folate levels, erythrocyte SOD and GSH-PX activities were negatively correlated with genetic risk scores in the male subjects. A positive correlation between the genetic risk scores and folate deficiency was observed in the male subjects. ConclusionsThere was association between folate pathway gene polymorphism of Solute Carrier Family 19 Member 1 (SLC19A1) and Methylenetetrahydrofolate Reductase (MTHFR) with erythrocyte SOD and GSH-PX activities, and folate levels in male but not in female aging subjects. Genetic variant of genes involved in folate metabolism has strong impact on plasma folate levels in the male aging subjects. Our data demonstrated that there was a potential interaction of gender and its genetic background in affecting the body's antioxidant capacity and the risk of folate deficiency in aging subjects.

MTHFR and MTRR Genetic Polymorphism of Methotrexate Therapy Outcomes in Early Rheumatoid Arthritis.

Methotrexate (MTX) is used as an anchor drug for the treatment of rheumatoid arthritis (RA) and there may be differences in drug action between genotypes. The purpose of this study was to investigate the relationship between clinical efficacy response and disease activity of MTX monotherapy with methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms. In the study, a population of 32 patients in East China with early RA fulfilling the diagnostic standards of the American College of Rheumatology (ACR) were enrolled, all of them received MTX monotherapy. Genotyping of patients MTHFR C677T and A1298C, MTRR A66G using tetra-primer ARMS-PCR method and sanger sequencing to verify its accuracy. The distribution of three polymorphic genotypes that were studied is in accordance with the Hardy-Weinberg genetic equilibrium. The patient pathology variables smoke (OR = 0.088, P = 0.037), drink alcohol (OR = 0.039, P = 0.016) and males (OR = 0.088, P = 0.037) were significantly associated with non-response to MTX. Genotype, allele distribution and genetic statistical models were not found to be related to MTX treatment response and disease activity in both the response groups and non-response groups. Our findings suggest that the MTHFR C677T, MTHFR A1298C and MTRR A66G polymorphisms may not predict MTX clinical treatment response and disease activity in patients with early RA. The study revealed that smoke, alcohol, and males were possible influential factors for MTX non-response.

Homocysteine in CAD patients-Does it matter?

Introduction and Aim: Homocysteine (Hcy) is considered as an independent risk factor for coronary artery disease (CAD). Hyperhomocysteinemia (HHcy) may be caused due to the deficiency of vitamin B12, folic acid (FA), and pyridoxine (B6) or due to genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR). A pilot study was undertaken to investigate Hcy levels and its association with lipid profile in patients with CAD. Methods: Lipid profile values were obtained from laboratory reports and the Hcy levels were estimated by enzymatic cycling assay using the commercial kits in autoanalyzer in subjects with CAD (n=12). Results: Hcy (14.58 ± 8.32 µmol/L), LDL (134.75 ± 45.02 mg/dl) and non-HDL (150.25 ± 56.89 mg/dl) levels were found to be elevated in patients with CAD. Conclusion: Dyslipidemia was associated with variable Hcy levels. Few patients with HHcy showed concurrent upsurge in LDL and non-HDL levels.

Association of MTHFR 677C>T polymorphism with pregnancy outcomes in IVF/ICSI-ET recipients with adequate synthetic folic acid supplementation.

Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphism rs1801133 (677C>T) will decrease the utilization of folate. Folate deficiency and its resulting homocysteine (HCY) accumulation can impair female fertility. Folic acid (FA) supplementation is necessary in pregnant women who are undergoing in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) - embryo transfer (ET), and especially in women with MTHFR rs1801133 C-to-T mutations. At present, affordable and accessible synthetic FA is mainly used. However, some studies have suggested that 5-methylenetetrahydrofolate (5-MTHF), a type of active FA, may be more suitable for women with the MTHFR 677C>T polymorphism, since it is safer and more effective. This retrospective study aimed to evaluate whether the MTHFR rs1801133 gene polymorphism is related to the pregnancy outcomes of IVF/ICSI-ET recipients after sufficient supplementation with FA instead of 5-MTHF. Data on 692 women undergoing IVF/ICSI-ET and taking adequate FA were collected. Participant characteristics were compared using the Kruskal-Wallis test and Pearson chi-square test. Logistic regressions were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI), after adjusting for age, BMI, method of fertilization, method of embryo transfer and number of embryos transferred. An additive model (T/T vs. C/C), dominant model (C/T + T/T vs. C/C), and recessive model (T/T vs. C/T + C/C) were evaluated. Analysis revealed that MTHFR rs1801133 in IVF/ICSI-ET women with adequate FA supplementation was not associated with the pregnancy rate but with age (OR = 0.91, 95% CI = 0.88, 0.94, P < 0.001) and BMI (OR = 0.95, 95% CI = 0.90, 0.997, P = 0.037). In 349 clinically pregnant women, no association of the MTHFR 677C>T with pregnancy outcomes was found in the additive model, dominant model, or recessive model. Of the 273 women with positive pregnancy outcomes, 34 had a preterm delivery. MTHFR 677C>T was not associated with a preterm delivery after adjusting for age and BMI. The current results indicated that MTHFR polymorphism rs1801133 was not related to the pregnancy rate or pregnancy outcomes of women undergoing IVF/ICSI-ET with adequate synthetic FA supplementation, suggesting that simple supplementation with less expensive and readily available FA, rather than expensive 5-MTHF, appeared to be appropriate.

The Studies of Prognostic Factors and the Genetic Polymorphism of Methylenetetrahydrofolate Reductase C667T in Thymic Epithelial Tumors.

ObjectiveTo describe the clinical features of a cohort of patients with thymic epithelial tumors (TETs) and to analyze their prognostic factors. In particular, we investigated the correlation between the genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) C667T and the incidence of TETs.MethodsPathological records were reviewed from the database of the Second Affiliated Hospital of Jiaxing University, from January 2010 to December 2020, and 84 patients with TETs were recruited for this study. Univariate and multivariate analyses were performed to determine the prognostic factors. The genetic polymorphism of MTHFR C667T was examined in the patients with TETs and in a group of healthy individuals. The correlation between MTHFR transcriptional levels and methylation was analyzed using The Cancer Genome Atlas (TCGA) thymoma dataset from the cBioPortal platform.ResultsKaplan–Meier univariate survival analysis showed that sex, age, the maximum tumor diameter, surgery, chemotherapy, radiotherapy, WHO histological classification, Masaoka–Koga stage, and 8th UICC/AJCC TNM staging, were statistically significantly correlated with the prognosis of patients with TETs. The Masaoka–Koga stage and 8th UICC/AJCC TNM staging were strongly correlated with each other in this study (r=0.925, P<0.001). Cox multivariate survival analysis showed that the maximum tumor diameter, Masaoka–Koga stage, and 8th UICC/AJCC TNM staging were independent prognostic factors affecting the overall survival (OS) of patients with TETs (P<0.05). The MTHFR C667T genotype (χ 2 = 7.987, P=0.018) and allele distribution (χ 2 = 5.750, P=0.016) were significantly different between the patients and healthy controls. CT heterozygous and TT homozygous genotypes at this MTHFR polymorphism significantly increased the risk of TETs (odds ratio [OR] =4.721, P=0.008). Kaplan–Meier univariate survival analysis showed that there was no correlation between different genotypes and the prognosis of TETs (CC versus CT + TT, χ2 = 0.003, P=0.959). Finally, a negative correlation between the transcriptional and methylation levels of MTHFR was observed in the TCGA thymoma dataset (r=-0.24, P=0.010).ConclusionsThe Masaoka–Koga stage, 8th UICC/AJCC TNM staging, and maximum tumor diameter were independent prognostic factors for TETs. Reduced methylation levels of MTHFR and particular polymorphic variants may contribute to the susceptibility to developing TETs.

Association between Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Risk of Autoimmune Diseases: A Systematic Review and Meta-Analysis.

Methylenetetrahydrofolate reductase (MTHFR) is a critical rate-limiting enzyme in the homocysteine/methionine metabolism pathway that is implicated in the pathogenesis and progression of autoimmune diseases. Previous association studies have been performed to investigate the effect of polymorphisms in MTHFR on the risk of autoimmune diseases with inconsistent results. Therefore, this meta-analysis was designed to assess the association between the MTHFR 677 C/T and 1298 A/C polymorphisms and the susceptibility to autoimmune diseases. We identified reports by a literature search in the following electronic databases: PubMed, Ovid, Web of science, and China National Knowledge Infrastructure. Statistical analyses of the summary odds ratios (ORs) and 95% confidence intervals (CIs) were done using STATA software. In a recessive genetic model, the MTHFR 677 C/T polymorphism was associated with an increased risk of Behcet's disease (OR = 1.97, 95% CI, 1.31-2.97), multiple sclerosis (OR = 1.57, 95% CI, 1.03-2.38), and ankylosing spondylitis (OR = 2.90, 95% CI, 1.92-4.38). The MTHFR 1298 A/C polymorphism was associated an increased risk of multiple sclerosis in a heterozygote comparison (OR = 2.36, 95% CI, 1.29-4.30) and in a dominant model (OR = 2.31, 95% CI, 1.24-4.29). This meta-analysis demonstrated that the MTHFR 677 C/T was a risk factor for Behcet's disease, multiple sclerosis, and ankylosing spondylitis, and the 1298 A/C was a risk factor for multiple sclerosis.

MTHFR Gene Polymorphisms and Cardiovascular Risk Factors, Clinical-Imagistic Features and Outcome in Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) as a severe neurological emergency, is represented by variable conditions in its clinic presentation, onset, risk factors, neuroimagistic features and outcome. The genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C was associated with CVST. We aimed to characterize the prevalence of MTHFR gene polymorphisms associated with cardiovascular risk factors in the group of patients with CVST. Also, we studied additional causes associated with CVST including local infections, general infections, obstetric causes (pregnancy, puerperium) and head injury. This is a retrospective study including 114 patients which referred to our hospital between February 2012–February 2020. The protocol included demographic (age, sex), clinical, neuroimagistic features, paraclinic (genetic polymorphism of MTHFR, factor V G1691A—Leiden, prothrombin G20210A, PAI-1 675 4G/5G; Homocysteine level, the lipid profile, blood glucose and Glycohemoglobin HbA1c, high- sensitive C- reactive protein- hsCRP) data, as well as treatment and outcome. The mean age was 37.55 years with a female predominance (65.79%). In the first group of patients with inherited thrombophilia (60 cases; 52.63%) we found genetic mutation includes MTHFR C677T (38.59%) and A1298C (14.03%), factor V G1691A- Leiden (15.78%), prothrombin G20210A (2.63%), PAI-1 675 4G/5G (42.98%), and hyperhomocysteinemia (35.08%). At the second group with other etiology of CVST, except thrombophilia, we included 54 patients (47.36%). The most common sites of thrombosis were the superior sagittal sinus (52.63%). Headache was the most common symptom (91.22%) and seizures were the main clinical presentation (54.38%). The MTHFR polymorphism was significantly correlated with higher total cholesterol (TC) (p = 0.023), low- density lipoprotein cholesterol (LDL) (p = 0.008), homocysteine level (tHcy) (p < 0.001). Inside the first group with MTHFR polymorphism we have found a significant difference between the levels of homocysteine at the patients with MTHFR C677T versus MTHFR A1298C polymorphism (p < 0.001). The high-sensitive C-reactive protein (hsCRP) was increased in both groups of patients, but the level was much higher in the second group (p = 0.046). Mortality rate was of 2.63%. Demographic, clinical and neuroimagistic presentation of CVST in our study was similar with other studies on the matter, with a high frequency of thrombophilia causes. MTHFR gene polymorphisms (C677T and A1298C) are increased in prevalence in CVST. PAI-1 675 4G/5G gene mutation seems to be involved in CVST etiology. Plasma C-reactive protein level and hyperhomocysteinemia should be considered as a prognostic factor in CVST.

Methylenetetrahydrofolate reductase genetic polymorphism and the risk of diabetic nephropathy in type 2 diabetic patients.

Background:As indicated by numerous studies, there exists a relationship between the polymorphism of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to diabetic nephropathy (DN) in various populations; nonetheless, the findings remain inconsistent. Therefore, we carried out a meta-analysis to determine the relationship between the MTHFR gene polymorphism and DN susceptibility.Materials and method:Related studies were identified from PubMed, Cochrane Library, EMBASE, and the China National Knowledge Infrastructure database (time period: from building the library to October 2019). The strength of the association was examined using odds ratios (ORs) with 95% confidence intervals (95% CIs).Results:The findings illustrated that the C677T gene polymorphism was significantly associated with an enhanced susceptibility to DN compared to that with diabetes mellitus in allelic (OR = 1.64, 95% CI = 1.34–2.00, P < .001), dominant (OR = 1.85, 95% CI = 1.40–2.46, P < .001), codominant (heterozygote: OR = 1.67, 95% CI = 1.27–2.21, P < .001; homozygote: OR = 2.55, 95% CI = 1.82–3.57, P < .001), and recessive (OR = 1.89, 95% CI = 1.50–2.38, P < .001) models of the overall population. Moreover, as compared with the healthy controls, a significantly augmented susceptibility to DN was found in all 5 genetic comparison models (allelic: OR = 2.06, 95% CI = 1.58–2.67, P < .001; dominant: OR = 2.52, 95% CI = 1.73–3.69, P < .001; codominant: OR = 3.78, 95% CI = 2.50–5.70, P < .001; recessive: OR = 2.41, 95% CI = 1.96–2.97, P < .001). Furthermore, stratifying data by ethnicity revealed substantially augmented vulnerability to DN in not only Caucasian but also Asian populations.Conclusion:The present study suggests that the C677T polymorphism was associated with an augmented susceptibility to DN.

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.

Resident Training on Methylenetetrahydrofolate Reductase: a National Survey

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme important in folate metabolism. Genetic polymorphisms of MTHFR have potential clinical implications, particularly in treating mental disorders, where a biologically active form of metafolin is FDA approved in the treatment of major depressive disorder and schizophrenia. Therefore, residents in a variety of specialties must understand the link between genetic polymorphisms of MTHFR and clinical disorders. To identify current gaps in residency curricula with regards to the MTHFR gene. Using a snowball sampling method, a national online survey was sent to residency program directors in family medicine, internal medicine, and psychiatry to be forwarded to their corresponding residents. Data was collected between April 5, 2019, and May 14, 2019. Statistical tests included a Pearson chi-square test. Qualitative content analysis for open item responses was conducted in which recurring keywords and phrases were summarized. The primary outcome of interest was a dichotomous question: Does your curriculum teach about MTHFR? The results showed that many of residency programs surveyed do not include MTHFR in their courses (family medicine 153/166, 92%; internal medicine 135/151, 89%; psychiatry 70/90, 78%) and a majority of residents are unaware of the clinical associations of MTHFR genetic polymorphisms with cardiovascular diseases and psychiatric disorders. While many residents were aware of the MTHFR gene, knowledge about the gene was minimal and many curricula do not include MTHFR as part of their program. Therefore, we recommend residency training programs assess their level of training on MTHFR and its genetic polymorphisms.

Effects of MTHFR genetic polymorphism on inflammatory protein osteopontin in RA patients: A gender based study in North Indian population

BackgroundRheumatoid arthritis (RA) is a systemic chronic inflammatory disease that ultimately damages bone and cartilage of joints leading to disability. Genetic polymorphism in methylene tetrahydrofolate reductase (MTHFR) gene has been identified as potential marker of susceptibility or disease severity in RA. Risk of RA is three times higher in women than men. Several cytokines and proteins play significant role in synovitis of RA patients. Osteopontin (OPN) is the pro-inflammatory cytokine reported to be associated with synovitis in RA, as it generates T-helper-1 (TH1)-mediated cellular immune response. ObjectiveTo study the impact of MTHFR gene polymorphism on the serum levels of OPN in RA patients and to investigate the cause of greater disease severity in women than men. Patients and methodsThe study included sixty RA patients (eleven men and forty-nine women) from different regions of Uttar Pradesh, North India. OPN was estimated by using enzyme-linked immunosorbent assay and other serological parameters such as Serum glutamic oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), C-reactive protein (CRP), triglycerides (TGA), cholesterol, uric acid, albumin and total protein were estimated using commercially available kits. MTHFR A1298C and C677T polymorphism was genotyped using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) based assays. Disease activity score and health questionnaire was assessed in all patients. ResultsMean age of patients was 44.53 ± 1.59 in women and 46.27 ± 4.22 in men with greater duration of morning stiffness in women than men. There were differences in TJC, SJC and DAS-28 score between men and women. OPN levels were found significantly higher in women than men. Other serological parameters were insignificantly higher in women than men. Genotypic study revealed that MTHFR genotypes are not associated with serum OPN levels. However, the disease activity scores (DAS-28), total joint count (TJC) and swollen joint count (SJC) were significantly associated with 1298CC genotype. Frequency distribution of MTHFR gene between men and women indicates that 1298CC genotype was more frequent in women than men and hence it might be one of the factors to cause disease severity more in women than men. ConclusionA1298C polymorphism is a predictor to the disease severity in RA patients. Patients with homozygous mutant CC genotype have a higher DAS-28 score along with TJC and SJC. The significantly higher OPN levels in female subjects suggest that disease severity is more in women than men. However, other parameters such as SGOT, SGPT, CRP, TGA, creatinine, uric acid, albumin and total protein were higher in women but the change was insignificant.

Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice

ABSTRACT Objective: Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C→T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr +/- mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury. Methods: In the present study, three-month-old male Mthfr +/- and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected for histological analysis. Results: Mthfr +/- animals used their non-impaired forepaw more to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr +/- mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia-induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in neurons and astrocytes and neuronal superoxide dismutase 2 (SOD2) levels. Conclusions: Our results suggest that Mthfr +/- mice are more vulnerable to PT-induced stroke damage through the regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.

Association Study of MTHFR Polymorphisms with Nonarteritic Anterior Ischemic Optic Neuropathy in a Spanish Population

Introduction: Nonarteritic anterior ischemic optic neuropathy (NAION), painless loss of central and/or peripheral vision, is a multifactorial disease caused by insufficient blood flow through the posterior ciliary arteries to the optic nerve head. Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene, triggering hyperhomocysteinemia as a consequence of a decreased activity of the codified enzyme, have been considered to be among the risk factors of NAION. Objective: The main aim was to study the association of the most common MTHFR genetic polymorphisms C677T and A1298C with NAION in a Spanish population. Methods: In this case-control study, the association of the most common MTHFR polymorphisms was investigated in 94 unrelated native Spanish patients diagnosed with NAION and 204 healthy controls. Two single nucleotide polymorphisms located in the MTHFR gene, C677T (rs1801133) and A1298C (rs1801131), were analyzed by DNA sequencing and TaqMan assays. Results: The allelic and genotypic frequencies of the MTHFR variants obtained in the NAION group were not significantly different when compared with the control group. A higher frequency of the C677T/A1298C genotype, codifying the nonmutated MTHFR form, was obtained in control subjects (11.27%) compared to NAION patients (4.26%), suggesting a protective effect of the wild-type protein, although this result was not conclusive considering the obtained confidence interval (CI) (95% CI: 0.13–1.06). Study of additional clinical factors including hypertension, diabetes mellitus, and dyslipidemia showed no association with a higher risk of NAION. Conversely, the clinical history of heart or cerebrovascular diseases was significantly higher in NAION patients compared to controls. Over the world, risk variants of the MTHFR gene are highly frequent, excluding African black populations, indicating a racial influence. Conclusions: The MTHFR variants did not significantly increase the risk of suffering from NAION. However, considering that individuals with at least one of the risk variants have the MTHFR enzyme with decreased activity, it cannot be ruled out that these mutations are relevant for the development of NAION in a subgroup of the population with other specific characteristics. These may include high plasma levels of homocysteine along with nutritional deficiencies including low folate or vitamin B12 and the combination of systemic and local risk factors.

Association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C&gt;T and 1298A&gt;C polymorphisms and the risk of diabetic nephropathy; a meta-analysis

Methylenetetrahydrofolate reductase (MTHFR) is involved in the homocysteine metabolism. Two common variants of MTHFR gene (677C&gt;T and 1298A&gt;C), have been reported to reduce the MTHFR enzyme activity and leading to plasma hyperhomocysteinemia. There are a number of recent case-control studies that investigated the association between the MTHFR polymorphism and diabetic nephropathy (DN), albeit with inconsistent results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of MTHFR with susceptibility to DN. A literature search was conducted on PubMed, Embase and Google scholar from inception till March 18, 2019. For MTHFR 677C&gt;T analysis, a total of 23 studies including DM controls (3095 cases and 3187 DM controls) and 12 studies including non-DM controls (1590 cases and 2052 nonDM controls) were taken. For MTHFR 1298A&gt;C analysis, a total of 7 studies using DM controls (959 cases and 1209 DM controls) and 3 studies using non-DM controls (400 cases and 802 nonDM controls) were taken. Meta-analysis showed that mutant genotypes of the 677C&gt;T (OR: 1.58; 95%CI: 1.16-2.14) and 1298A&gt;C (OR: 1.38; 95%CI: 1.16-1.65) polymorphisms in the MTHFR gene were associated with increased risk of DN (diabetic kidney disease). MTHFR 677C&gt;T and 1298A&gt;C polymorphisms revealed significant heterogeneity between studies. Further, there was no evidence for publication bias for these polymorphisms. In conclusion, this meta-analysis provides strong evidence that MTHFR 677C&gt;T and 1298A&gt;C polymorphisms may be associated with increased risks of DN. However, further studies are still needed to accurately determine whether MTHFR genetic polymorphisms are associated with susceptibility to DN.

MTHFR gene polymorphisms in hypothyroidism and hyperthyroidism among Jordanian females.

Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation that is associated with autoimmune pathology. We investigated the association between MTHFR genetic polymorphisms at g.677C>T and g.1298A>C and their haplotypes, and the risk of thyroid dysfunction among Jordanian females. A case-control study involving 98 hypothyroidism cases, 66 hyperthyroidism cases and 100 controls was conducted. Polymerase chain reaction/restriction fragment length polymorphism technique was performed to determine genotypes. Statistical analysis using SPSS software was performed. Genetic analysis showed a significant difference in genotype frequency of g.1298A>C between cases, and controls [hypothyroidism: AA (45.9%), AC (37.8%), CC (16.3%); hyperthyroidism: AA (9.1%), AC (69.7%), CC (21.2%); controls: AA (37.8%), AC (29.6%), CC (32.7%); CChypo vs. AAhypo: 2.55, 95% CI: (1.18-5.52); OR at least on Chypo: 1.79, 95% CI: (1.07-2.99)]; CChyper vs. AAhyper: 4.01, 95% CI: (1.79-9.01); OR at least on Chyper: 0.18, 95% CI: (0.07-0.48)]. There was no significant difference in genotype frequency of g.677C>T between cases and controls [hypothyroidism: CC (50.0%), CT (32.7%), TT (17.3%); hyperthyroidism: CC (77.3%), CT (15.2%), TT (7.6%); controls: CC (55.6%), CT (32.3%), TT (12.1%)]. There was a significant difference of MTHFR haplotypes among hypothyroidism cases and controls. TA and CC had a lower hypothyroidism risk whereas; TC showed a higher risk. g.1298A>C genetic polymorphism of MTHFR may modulate the risk of thyroid disease. CC, TA, and TC haplotypes affect the risk of hypothyroidism. Larger samples should be included in the future to verify the role of MTHFR polymorphisms in thyroid diseases.

Association study between genetic polymorphisms in folate metabolism and gastric cancer susceptibility in Chinese Han population: A case-control study.

BackgroundGastric cancer (GC), the second leading cause of cancer mortality behind lung cancer worldwide, is caused by both genetic and environmental factors. In this study, we evaluated the association between the genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthesis reductase (MTR), and methyltransferase reductase (MTRR) genes and ischemic stroke risk in Chinese population.MethodsA case–control study was conducted including 681 patients with GC and 756 healthy controls. Chi‐squared test/Fisher's exact test and genetic model were used to evaluate associations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression.ResultsIn the allele model, using the chi‐square test, we found that the rs1532268 in MTRR with a minor allele T was significantly associated with increased risk of GC (OR = 1.24, 95% CI, 1.00–1.53; p = 0.048). In the genetic model analysis, we identified that the single‐nucleotide polymorphism of the rs1801133 in MTHFR could increase the GC risk in the recessive model (OR = 1.31, 95% CI, 1.01–1.70; p = 0.042) and log‐additive model (OR = 1.19, 95% CI, 1.02–1.38; p = 0.025). In MTHFR, a strong linkage of rs2274976 and rs1801133 was detected. The haplotype “GC” in the MTHFR gene was found to prominently increase the risk of GC (OR = 1.26, 95% CI: 1.07–1.47; p = 0.005). Other haplotypes did not display the correlativity.ConclusionThis study suggested that MTR and MTHFR polymorphisms may contribute to increase the risk of GC.

Genetic polymorphism of methylenetetrahydrofolate reductase is associated with insulin resistance in Egyptian women with polycystic ovary syndrome.

A common polymorphism (677C to T; Ala to Val) in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased specific MTHFR activity and elevation of homocysteine. The present study aimed to investigate the association between a single nucleotide polymorphism (SNP) in the MTHFR 677C>T gene and insulin resistance in women with polycystic ovary syndrome (PCOS). Two-hundred patients with PCOS were included in this case-control study: 100 patients with insulin resistance and 100 patients without insulin resistance were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The TT genotype for the MTHFR 677C>T polymorphism was significantly more frequent in PCOS patients with insulin resistance than in PCOS patients without insulin resistance (19% versus 6%, p=0.002), whereas there was no significant difference between both groups for CT and there was a statistically significant increase in the T allele in PCOS patients with insulin resistance compared to PCOS patients without insulin resistance (p=0.002, odds ratio=1.95 and 95% confidence interval=1. 29-2.93). Regarding the relationship between MTHFR 677C>T genotypes and the characteristics of insulin resistance in PCOS patients, we found that there was no significant difference in age, waist-hip ratio and total testosterone between the different genotypes of the MTHFR 677C>T polymorphism. The mean values for body mass index and the Homeostatic Model Assessment of Insulin Resistance were significantly higher in the TT genotype of MTHFR 677C>T compared to the CC genotype in PCOS patients with insulin resistance (p<0.001). We have demonstrated an association of the MTHFR 677C>T gene polymorphism with insulin resistance in Egyptian women with PCOS.

Association study of methylenetetrahydrofolate reductase genetic polymorphism C677T with extrapyramidal side effects of antipsychotic treatment

Association study of methylenetetrahydrofolate reductase genetic polymorphism C677T with extrapyramidal side effects of antipsychotic treatment