Methylenetetrahydrofolate Reductase Research Articles

Can Global DNA Methylation Be Influenced by Polymorphisms in Genes Involved in Epigenetic Mechanisms? A Review

Background: Global methylation refers to the total methylation in the DNA and can also be inferred from the Line 1 and Alu regions, as these repeats are very abundant in the genome. The main function of DNA methylation is to control gene expression and is associated with both normal and pathological mechanisms. DNA methylation depends on enzymes that generate the methyl radical (e.g., methylenetetrahydrofolate reductase—MTHFR) and attach this radical to the DNA (DNA methyltransferases—DNMT). Genetic variants such as single nucleotide polymorphisms (SNP) in these genes can lead to changes in the activity or expression of MTHFR and DNMT proteins and consequently influence the DNA methylation profile. This review focuses on studies investigating inter-individual variations in the global DNA methylation profile associated with genetic polymorphisms in the MTHFR and DNMT genes. Methods: A narrative review was conducted, taking into account articles published in the last 15 years. Results: It was found that the SNPs rs1801131, rs1801133 and rs1537514 in the MTHFR gene, rs2241531, rs2228611, rs2228612, rs21124724 and the haplotype rs2288349, rs2228611, rs2228612, rs16999593 in the DNMT1 gene, rs2424909, rs998382, rs6058891, rs6058897, rs4911256, rs2889703 and rs1883729 in the DNMT3B were associated with the level of global DNA methylation, including LINE and Alu regions in different contexts. No association was found with polymorphisms in the DNMT3A gene. Conclusions: It is concluded that polymorphisms in the MTHFR and DNMT genes may influence the global DNA methylation profile in health, inflammation, tumours and mental illness.

Associations between maternal MTHFR polymorphisms and embryological outcomes in Korean patients with infertility undergoing IVF/ICSI cycles

Objective Methylenetetrahydrofolatereductase (MTHFR) is important for folate metabolism, which is involved in DNA synthesis and cell growth. However, the relationship between Maternal MTHFR polymorphisms and outcomes in assisted reproduction remains controversial. This is the first study to explore the effect of MTHFR polymorphisms on the embryological outcomes in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles in Korean patients with infertility. Materials and methods This retrospective cohort study included 173 women who underwent MTHFR genotyping between July, 2021 and June, 2022. The embryologic outcomes of 301 IVF/ICSI cycles were compared between groups according to MTHFR polymorphisms using ANOVA and Chi-square test. Results Oocyte maturation rates were 80.0%, 75.0%, and 71.4% for MTHFR 677CC, 677CT, and 677TT, respectively. Cleaved embryo formation and transplantable embryo rates were comparable across various maternal MTHFR 677 genotypes. Good-quality embryo (GQE) rate was higher for MTHFR 677CT than those for 677CC and 677TT (40.0% vs. 29.4%, p = 0.001 and 40.0% vs. 33.3%, p = 0.025, respectively). When analyzing the combined MTHFR genotypes, the oocyte maturation rate was significantly lower in 677TT than in 677CC 1298AA/677CC 1298AC and 677CC 1298CC/677CT 1298AA/677CT 1298AC (71.4% vs. 76.7%, p = 0.012 and 71.4% vs. 75.7%, p = 0.029, respectively). The MTHFR 677CC/1298CC, 677CT/1298AA, and 677CT/1298AC genotypes had the highest GQE rates. Conclusions MTHFR 677TT genotype, which had the lowest enzymatic activity, had the lowest oocyte maturation rate. The combined MTHFR 677CC/1298CC, 677CT/1298AA, and 677CT/1298AC genotypes with intermediate enzyme activities had higher GQE rates. However, no differences were observed in the transplantable embryo rate between MTHFR genotypes.

Recurrent Early Pregnancy Loss and Congenital Thrombophilia: A Prospective Study.

Background/Objectives: This study aims to investigate the role of congenital single nucleotide thrombophilia in young females with early recurrent pregnancy loss (RPL). Methods: We studied 120 pregnant females with RPL and 80 matched females as a control with no RPL. Females were aged ≤ 35 years, had at least two consecutive first-trimester RPLs, and the acquired cause of RPL was excluded. A matched control group of 80 pregnant women with no RPL was studied. Coagulation tests included prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), a Factor XIII functional assay, and detecting IgM and IgG anti-beta2-Glycoprotein I (β2GPI) antibodies by an ELISA. The DNA samples were tested for Factor V Leiden, Factor II G20210A, Methylenetetrahydrofolate reductase (MTHFR C677T, A1298C), FXIII V34L, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, endothelial protein C receptor (EPCR) A4600G, and endothelial protein C receptor (EPCR) G4678C. Results: Of the single nucleotide gene mutations investigated, the most relevant mutations were MTHFR C677T, MTHFR A1298C, heterozygous FXIII Val34Leu, and heterozygous FXIII 1694 C>T. Each of them conferred a statistically significant effect. There was a statistically significant protective role for the endothelial protein C receptor (EPCR) A2/A2, wild FXIII Val34Leu, and heterozygousFXIII1694 C>T. Conclusions: Our findings suggest the important role of congenital single nucleotide thrombophilia mutations in young Middle Eastern women with early RPL, particularly MTHFR mutations and FXIII Val34Leu. We found a protective effect of EPCR A2/A2, wild FXIIIVal34Leu, and heterozygous FXIII1694 C>T. We recommend additional studies to explore detrimental factors and protective factors.

The L-Arginine pathway may act as a mediator in the association between impaired one- carbon metabolism and hypertension.

Elevated fasting plasma total homocysteine (tHcy) and the methylenetetrahydrofolate reductase C677T polymorphism (rs1801133) have been associated with hypertension. Whether the L-Arginine pathway is involved, is unclear. We aimed to investigate whether the association between tHcy, the rs1801133 polymorphism and hypertension involves the L-Arginine pathway. THcy, plasma folate and cobalamin, erythrocyte glutathionine reductase activation coefficient, rs1801133 genotype, plasma L-Arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were determined in a cross-sectional study of 788 adults (aged 18 to 75), randomly selected from 2 town population registers. Participants participated in a medical checkup and provided a fasting blood sample. Associations between tHcy, rs1801133 genotype and L-Arginine pathway metabolites were assessed by multiple linear regression analysis and whether the tHcy and rs1801133 genotype are associated with hypertension via the L-Arginine pathway was investigated using mediation analysis. tHcy was positively associated with ADMA (B=0.003; SE=0.001; P<0.001) and SDMA (B=0.007; SE=0.002; P<0.001) and negatively associated with the L-Arginine/ADMA (B=-1.140; SE=0.451; P<0.05) and ADMA/SDMA (B=-0.006; SE=0.003; P<0.05) ratios. The MTHFR 677 CT vs CC genotype was negatively associated with ADMA (B=-0.013; SE=0.007; P<0.05) and with SDMA (B=-0.029; SE=0.013; P<0.05) in participants under 50 years. Each standard deviation increase (37.6) in the L-Arginine/ADMA ratio was associated with reduced hypertension risk (OR [95%CI], 0.6 [0.5, 0.8]). Mediation analysis showed that tHcy and ADMA were mediators in the association between the rs1801133 TT vs CC genotypes and hypertension. Our results support the L-Arginine pathway as a mediator in the association of impaired One-Carbon metabolism and hypertension.

Quorum sensing in Vibrio controls carbon metabolism to optimize growth in changing environmental conditions.

Bacteria sense population density via the cell-cell communication system called quorum sensing (QS). The evolution of QS and its maintenance or loss in mixed bacterial communities is highly relevant to understanding how cell-cell signaling impacts bacterial fitness and competition, particularly under varying environmental conditions such as nutrient availability. We uncovered a phenomenon in which Vibrio cells grown in minimal medium optimize expression of the methionine and tetrahydrofolate (THF) synthesis genes via QS. Strains that are genetically "locked" at high cell density grow slowly in minimal glucose media and suppressor mutants accumulate via inactivating-mutations in metF (methylenetetrahydrofolate reductase) and luxR (the master QS transcriptional regulator). In mixed cultures, QS mutant strains initially coexist with wild type, but as glucose is depleted, wild type outcompetes the QS mutants. Thus, QS regulation of methionine/THF synthesis is a fitness benefit that links nutrient availability and cell density, preventing accumulation of QS-defective mutants.

Correlation of Eight (8) Polymorphisms and Their Genotypes with the Risk Factors of Cardiovascular Disease in a Black Elderly Population.

Single nucleotide polymorphisms (SNPs) have been associated with the development of cardiovascular diseases (CVDs). This study correlated eight SNPs with the risk factors of CVD in a black elderly population. Genotyping was used to detect eight polymorphisms; rs675 (ApoA-IV), rs699 (Angiotensinogen (AGT)), rs247616 and rs1968905 (Cholesteryl ester transfer protein (CETP)), rs1801278 (Insulin receptor substrate 1 (IRS-1)), rs1805087 (Methylenetetrahydrofolate reductase (MTHFR)) and rs28362286 and rs67608943 (Proprotein convertase subtilisin/kexin type 9 (PCSK9)), as well as their genotypes in deoxyribonucleic acid (DNA) extracted from peripheral blood. The cardiovascular risk (CVR) measurements were conducted on a Konelab 20i Thermo Scientific autoanalyzer and an enzyme-linked immunoassay (ELISA) assay. International Business Machines Corporation (IBM)® Statistical Package for the Social Sciences ® (SPSS) version 28 was used for statistical analysis. The heterozygous and homozygous genotypes of the eight polymorphisms were detected with the corresponding CVD risk factors. Subgroup analysis indicated that certain genotype carriers exhibited variations in their concentrations of CVR factors compared to others; however, these differences did not reach statistical significance. For example, carriers of the G genotype of the rs699 polymorphism showed marginally different blood pressure readings compared to the AG genotype carriers. The multiple linear regression analysis indicated that the only significant association was between PCSK9 and the rs28362286 (p = 0.029) polymorphism. The findings of our study show that single nucleotide polymorphisms are disseminated across the human genome. The heterozygous and homozygous genotypes of the SNPs require further investigation as they may have independent and possible collective roles in increasing the risk of CVDs.

Genetic variants in folate metabolism-related genes, serum folate and hepatocellular carcinoma survival: the Guangdong Liver Cancer Cohort study.

Folate metabolism is involved in the development and progression of various cancers. We investigated the association of single nucleotide polymorphisms (SNP) in folate-metabolising genes and their interactions with serum folate concentrations with overall survival (OS) and liver cancer-specific survival (LCSS) of newly diagnosed hepatocellular carcinoma (HCC) patients. We detected the genotypes of six SNPin three genes related to folate metabolism: methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HR) and 95 % CI. This analysis included 970 HCC patients with genotypes of six SNP, and 864 of them had serum folate measurements. During a median follow-up of 722 d, 393 deaths occurred, with 360 attributed to HCC. In the fully-adjusted models, the MTRR rs1801394 polymorphism was significantly associated with OS in additive (per G allele: HR = 0·84, 95 % CI: 0·71, 0·99), co-dominant (AG v. AA: HR = 0·77; 95 % CI: 0·62, 0·96) and dominant (AG + GG v. AA: HR = 0·78; 95 % CI: 0·63, 0·96) models. Carrying increasing numbers of protective alleles was linked to better LCSS (HR10–12 v. 2–6 = 0·70; 95 % CI: 0·49, 1·00) and OS (HR10–12 v. 2–6 = 0·67; 95 % CI: 0·47, 0·95). Furthermore, we observed significant interactions on both multiplicative and additive scales between serum folate levels and MTRR rs1801394 polymorphism. Carrying the variant G allele of the MTRR rs1801394 is associated with better HCC prognosis and may enhance the favourable association between higher serum folate levels and improved survival among HCC patients.

Fluorescent primers amplification refractory mutation system qPCR (FP ARMS-qPCR) for MTHFR C677T SNP genotyping.

The currently used methods for the detection of methylene tetrahydrofolic acid reductase (MTHFR) C677T single nucleotide polymorphism (SNP) are either time-consuming or expensive. In this study, we devised an accurate, rapid and easy-to-use SNP detection system based on fluorescent primers amplification refractory mutation system qPCR, known as FP ARMS-qPCR. Fluorescent primers (FPs) modified by fluorescent dye or quencher near the 3' terminal thymine were designed. The reaction conditions were optimized and the performance was evaluated. Using commercial kits as controls, 242 samples were tested in parallel to verify the feasibility of the FP ARMS-qPCR assay. We demonstrated the good sensitivity and specificity of the FP ARMS-qPCR with optimized conditions. The assay was able to accurately distinguish between different SNP sites of MTHFR C677T in less than 2h using as low as 50 pg of template genomic DNA. Completely consistent genotyping results reveal that FP ARMS-qPCR is concordant with commercial kits. We established a specific, sensitive, and rapid FP ARMS-qPCR method for the detection of MTHFR C677T genotype. This could also serve as a potential diagnostic tool for a variety of diseases.

The effect of hereditary thrombophilia on recurrent pregnancy loss: a retrospective cohort study

ObjectiveThrombophilia screening has been performed in patients with conditions such as previous fetal death, (fetal growth restriction) FGR, preeclampsia, (hemolysis. elevated liver enzyme, low platelet count) HELLP Syndrome, previous abruptio placentae, previous thrombosis in pregnancy, and abnormal placental histology. The actual role of hereditary thrombophilia in recurrent pregnancy loss (RPL) is still debated. This study was intended to determine the incidence of specific gene defects for hereditary thrombophilia and to ascertain their impact on RPL in central Anatolia in Turkey.MethodsThis retrospective cohort study was performed between January 2012 and December 2022. All pregnant women with a complete hereditary screening profile were included. The investigated gene polymorphisms were methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, Factor V Leiden G1691A, and Factor II prothrombin G20210A. Cases of pregnant women at least two or more consecutive pregnancy losses before 22 weeks of gestation were defined as RPL. The rates of genetic screening and their association with RPL were analyzed.ResultsRPL was identified in 224 (27.58%) of the 812 pregnant women with complete genetic screening. Although there was no difference in terms of age, body mass index, numbers of ectopic pregnancies, molar pregnancies, or dilatation & curettage (p > 0.05), gravity (2.0 [2.0–3.0] vs. 4.0 [3.0–5.0]), parity (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), live birth (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), anembryonic pregnancy (0 [0–0] vs. 0 [0–0]), miscarriage (0 [0–1.0] vs. 3.0 [2.0–3.0]), and stillbirth (0 [0–0] vs. 0 [0–0]) numbers differed significantly between the groups (p < 0.05). While no significant differences were determined in MTHFR A1298C, Factor V Leiden, factor II prothrombin G20210A, or homocysteine levels (p > 0.05), the homozygous MTHFR C677T positivity rates differed significantly (6.3% in the non-RPL group vs. 11.6% in the RPL group, p = 0.027) .ConclusionThe homozygous MTHFR C677T polymorphisms was found to be more frequent in women with RPL. Further studies with larger cohorts are needed to confirm our results.

Functional analysis of a S-adenosylmethionine-insensitive methylenetetrahydrofolate reductase identified in methionine-accumulating yeast mutants.

Essential amino acids (EAAs) are important for the maintenance of brain functions. Therefore, the yeast Saccharomyces cerevisiae that accumulate EAAs would help elderly people ingest appropriate levels of EAAs, which in turn could slow neurodegeneration, extend the healthy lifespan and improve quality of life. Here, we isolated two mutant strains, ETH-80 and ETH-129, that accumulate the EAA methionine. Both strains were derived from a diploid laboratory yeast by conventional mutagenesis and carry a novel mutation in the MET13 gene, which encodes the Ser443Phe variant of methylenetetrahydrofolate reductase. Enzymatic analysis revealed that the Ser443Phe substitution abolished the sensitivity to S-adenosyl methionine (SAM)-mediated inhibition even in the presence of 2mM SAM, while increasing the activity for NADPH-dependent reduction. Furthermore, yeast cells expressing the Ser443Phe variant showed a fourfold increase in intracellular methionine content compared to the wild-type Met13. These findings will be useful for the future development of methionine-accumulating yeast strains.

High penetrance and phenotypic landscape of methylenetetrahydrofolate reductase c.665 C>T polymorphism in the absence of folate fortification

BackgroundStudies have linked the methylenetetrahydrofolate reductase (MTHFR) c.665C>T (rs1801133) with hyperhomocysteinemia. Mandatory folate fortification nullified this association. However, its relevance persists in regions with no folate fortification resulting in a relatively low frequency of this variant in healthy population. This study explored the MTHFR variant’s association with 50 clinical manifestations in the absence of folate fortification. MethodsWe performed mutation analysis via whole exome and Sanger sequencing in 2431 cases and 1265 healthy controls and the food frequency-based dietary folate intake assessment. ResultsThe cohort’s average dietary folate intake was 373 ± 141 μg/day. MTHFR rs1801133 variant demonstrated ≥4.49-fold increased risk for respiratory distress, recurrent pregnancy loss (RPL), ischemic stroke, autism, global developmental delay, dysplasia, myoclonic jerks, intellectual disability, aggressive behavior, motor delay, Alzheimer’s, cerebellar atrophy, failure to thrive, cerebral atrophy, increased tendon reflexes, and spasticity (p<0.0001). MTHFR T-allele showed 1.81 – 4.04 folds increased risk for mental retardation, behavioral problems, dystonia, anemia, gait abnormality, hypotonia, recurrent pneumonia, liver disease, cerebral palsy, short stature, hyperactivity, and cognitive decline. The association of this variant with seizures was moderate (OR: 1.51, 95% CI: 1.13 – 2.02, p=0.009). MTHFR TT-genotype was associated with a 5.81-fold risk for the abnormal phenotype (95% CI: 1.39 – 24.28, p=0.005). MTHFR T-allele was associated with low 25-hydroxy vitamin D, Ferritin, TIBC, and elevated total cholesterol. ConclusionThe MTHFR rs1801133 increases the risk for RPL, developmental milestones, neuronal development, autism, ischemic stroke, and late-onset neurological functions. The MTHFR TT-genotype is strongly associated with abnormal phenotypes.

Evaluation of the relationship between thrombophilia gene mutations and demographic data, imaging findings and stroke subtypes in young patients followed up with a diagnosis of stroke

Aims: A stroke is defined as a focal or generalized neurological deficit that develops suddenly, lasts for more than 24 hours, or ends in death within this period, with a cause other than a vascular cause. Stroke is among the leading causes of morbidity and mortality in the general population. In our study, we examined the prevalence of all prothrombotic gene mutations observed in patients with and without predisposing risk factors for young patients with stroke and discussed their roles in stroke formation in the context of existing literature. Methods: In the present study, we conducted a retrospective review of the medical records of 300 patients aged 18 to 49 years who were hospitalized in the neurology clinic of our hospital between June 2023 and June 2024 and diagnosed with acute arterial ischemic stroke based on anamnesis, neurological examination, and radiological imaging (CT and MRI) results. The study cohort comprised 47 patients (23 males, 24 females) aged between 18 and 49 years with a diagnosis of ischemic stroke. In our study, we examined ischemic stroke-related gene polymorphisms in patients with early-onset ischemic stroke (before the age of 50 years). This study aims to investigate the prevalence of Factor V-Leiden, prothrombin-G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, SERPIN 1, and Factor II polymorphisms in young patients with ischemic stroke. Results: A total of 47 patients, comprising 23 males and 24 females, were included in the study. The mean age of the patients was 40.34 ± 6.37 years. According to the TOAST classification system, 17 patients (36.2%) were diagnosed with large artery atherothrombosis, one patient (2.1%) had a cardioembolic infarction, and 29 patients (61.7%) had a small artery occlusion. In our study, when evaluating the thrombophilia mutation subtypes in young ischemic stroke patients, 23.4% (n=11) of the patients were found to be heterozygous for the FVL mutation, while 76.6% (n=36) had no mutation. Concerning the SERPIN 1 mutation, 40.4% (n=19) of the patients were heterozygous, 23.4% (n=11) were homozygous, and 36.2% (n=17) exhibited no mutation. The distribution of patients according to MTHFR C677T mutation revealed that 57.4% (n=27) were heterozygous, 19.1% (n=9) were homozygous, and 23.4% (n=11) had no mutation. Considering the distribution of patients according to the MTHFR A1298C gene mutation, a total of 38.3% (n=18) of the patients were heterozygous, 14.9% (n=7) were homozygous, and 46.9% (n=22) had no mutation. Upon analysis of the distribution of patients according to factor XIII mutation, it was identified that 19.1% (n=9) were heterozygous, 2.1% (n=1) were homozygous, and 78.7% (n=37) of the patients exhibited no mutation. Upon analysis of the distribution of patients according to prothrombin (Factor II) mutation, it was identified that 8.5% (n=4) were heterozygous, while 91.5% (n=43) exhibited no mutation. Conclusion: Although stroke is less prevalent in young adults, the underlying etiology is highly varied. Further research, including the investigation of genetic and prothrombotic mutations, is vital for the prevention of recurrent strokes in young adults.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in Turkish postmenopausal women with osteoporosis

Osteoporosis is a common age-related skeletal disease, characterized by changes in the microarchitectural structure of bone tissue and decreased bone mass, especially affecting postmenopausal women. Genetic and environmental factors affecting bone metabolism play a role in the development of osteoporosis. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene lead to impaired function or inactivation of this enzyme. A decrease in MTHFR enzyme activity and an increase in homocysteine levels affect bone metabolism. In this study, we aimed to investigate the relationship between C677T and A1298C polymorphisms and osteoporosis in Turkish postmenopausal women. DNA samples were extracted from 200 volunteers. The PCR-RFLP technique was used to identify the MTHFR gene polymorphisms C677T and A1298C. The statistical significance of the analysis’s results was assessed. C677T genotype and allele frequency distributions were not statistically different between postmenopausal osteoporosis and healthy control groups (p = 0.249, p = 0.754), while A1298C genotype and allele frequency distributions were found to be statistically significant (p = 0.002, p = 0.013). The results of our study showed that the A1298C polymorphism may be a genetic factor associated with osteoporosis in this specific population. However, the C677T polymorphism did not show a significant connection. To gain a more comprehensive understanding of the genetic basis of osteoporosis, future research with larger sample sizes and the consideration of additional genetic and environmental factors is essential. Additionally, it is crucial to account for ethnic disparities, gene-gene interactions, and gene-environment interplays. These insights can inform the development of personalized preventive and therapeutic strategies for individuals at risk of osteoporosis in diverse populations.

Arabidopsis METHYLENETETRAHYDROFOLATE REDUCTASE 2 functions independently of PENETRATION 2 during primary immunity against rice blast.

Nonhost resistance (NHR) is the most durable and robust form of innate immunity, with a surge of interest in crop improvement. Of the NHR genes identified against rice blast, a devastating disease caused by Magnaporthe oryzae, Arabidopsis PEN2 is indispensable for pre-penetration resistance against M. oryzae, while a consortium of genes orchestrates post-penetration resistance via lesser-known mechanisms. We identified M. oryzae-susceptible mosA (mthfr2 pen2-3) from a randomly mutagenized Arabidopsis pen2-3 population using forward genetics. Analysis of T-DNA inserted mthfr2 lines and pen2-3 complemented mosA lines enunciated that MTHFR2-dependent resistance to M. oryzae is independent of PEN2. MTHFR2-defective plants exhibited higher ROS accumulation and expression of SA-dependent defense markers. MTHFR2-ligand docking revealed that A55V nonsynonymous substitution in mosA altered ligand binding efficiency. This further affected the metabolomic profile of mosA, effectively allowing in vitro germination and development of M. oryzae conidia. Moreover, the loss of function mutation in mthfr2 (involved in 1C metabolic pathway) potentiated mosA immunity against Pst DC3000. In conclusion, our findings assert MTHFR2 as a positive modulator of NHR against M. oryzae. This work documents another layer of conserved yet divergent metabolomic defense in Arabidopsis regulated by folate-mediated 1C metabolism that has the potential to revolutionize crop improvement.

Association between methylenetetrahydrofolate reductase C677T polymorphisms and male oligozoospermia, asthenozoospermia or oligoasthenozoospermia: a case–control study

Mutation of methylenetetrahydrofolate reductase (MTHFR) C677T leads to the decrease of folate utilization and the impairment of spermatogenesis. This study attempts to investigate the association between MTHFR C677T polymorphisms and nonobstructive oligozoospermia, asthenozoospermia or oligoasthenozoospermia in the Chinese population. The study cohort comprised 189 patients diagnosed with oligozoospermia, asthenozoospermia or oligoasthenozoospermia, and 626 controls based on clinical examinations. The MTHFR c.677 genotype of all subjects was determined by fluorescence staining in situ hybridization and the significance of different genotype frequencies was further analyzed by Chi-square test. The results showed that the frequency of MTHFR 677 CT genotype in the oligozoospermia, asthenozoospermia and oligoasthenozoospermia group was 33.3%, 38.3% and 44.0% respectively, whereas it was 47.3% in the control group. The P value of Chi-square test was 0.070, 0.103 and 0.654, respectively. The frequency of MTHFR 677 TT genotype in the oligozoospermia, asthenozoospermia and oligoasthenozoospermia group was 31.1%, 11.7% and 18.0% respectively, while that in the control group was 19.5%. The P value of Chi-square test was 0.061, 0.070 and 0.066, respectively. Collectively, there is a weak association between MTHFR C677T polymorphisms and oligozoospermia, asthenozoospermia or oligoasthenozoospermia within the current Chinese population cohort.

Association of gene polymorphisms with biological features of gastric cancer

Aim of the investigation. To evaluate associations of polymorphic variants of TNF (G308A), XPC (Lys939Gln), MTHFR (Ala222Val) genes with some biological features of gastric cancer. Materials and Methods. We evaluated polymorphic gene variants in 74 patients with verified gastric cancer or gastriesophageal junction cancer (Siewert III). Genotyping was performed by DNA isolation from venous blood leukocytes of the subjects followed by PCR with electrophoretic detection of the result. The association of polymorphic variants of genes with such biological features of the tumor as localization of the process, morphological type, degree of differentiation, type of tumor growth, presence or absence of lymphovascular or perineural invasion was evaluated. Results. Lys/Gln genotype of XPC gene (Lys939Gln) are 3.3 times more likely to develop gastric body cancer (p=0.04). Genotype GG of TNF gene (G308A) 5.3 times increases the development of gastric adenocarcinoma in comparison with other histological types (p=0.018), genotype GA of the same gene 5.2 times more often develop tumor with high-grade differentiation degree (p=0.032). Val/Val genotype of the MTHFR gene (Ala222Val) are significantly less likely to develop lymphatic/vascular invasion compared to carriers of the other genotype (p=0,029). Conclusion. The obtained data suggest that the genetic status of the patient itself may affect the biological characteristics of gastric cancer, which in turn may lead to a change in the patient’s treatment tactics.

Genetic association and computational analysis of MTHFR gene polymorphisms rs1801131 and rs1801133 with breast cancer in the Bangladeshi population

Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating one-carbon metabolism. Polymorphisms within the MTHFR gene have been found to increase the risk of breast cancer in different populations. In this study, we evaluated the association of polymorphisms of the MTHFR gene (rs1801133 and rs1801131) with the risk of breast cancer in the Bangladeshi population. This case‒control study included 202 breast cancer patients and 104 healthy controls. After the organic extraction of DNA, genotyping was performed via the PCR-RFLP method. Sanger sequencing was performed to validate the RFLP data. Statistical analyses were performed to evaluate the associations of the polymorphisms. Different computational tools were used to predict the structural and functional consequences of the SNPs. Our study revealed that the MTHFR gene polymorphism rs1801131 is associated with an increased risk of developing breast cancer (p < 0.001, OR = 3.85, 95% CI = 2.06–7.25 for the AC genotype and p < 0.001, OR = 7.82, 95% CI = 2.69–22.05 for the CC genotype). An association was also observed in the dominant model (AC + CC) (p < 0.001, OR = 4.19, 95% CI = 2.28–7.78). For rs1801131, premenopausal status was significantly associated with breast cancer risk (p < 0.001). For rs1801133, no significant association was found with breast cancer risk (p > 0.05, OR = 1.57, 95% CI = 0.90–2.74 for the CT genotype; p > 0.05, OR = 1.35, 95% CI = 0.36–4.92 for the TT genotype). Computational analyses predicted rs1801131 to be tolerated and rs1801133 to be deleterious. Structural analyses demonstrated no significant changes in protein structure but revealed alterations in neighboring interactions according to both bond distances and angles. In conclusion, rs1801131 but not rs1801133 is significantly associated with breast cancer risk in the Bangladeshi population. Moreover, in silico analyses demonstrated changes in the interaction pattern of polymorphic residues with adjacent amino acids.

Study of the relationships of polymorphisms of the folate cycle genes with the levels of homocysteine and folic acid as risk factors of cardiovascular disorders in the post-covid period

Enzymes of the folate cycle participate in the process of remethylation of homocysteine (HC) to methionine, where folates are coenzymes for methyl transfer. The aim of the work was to identify the interrelationships of gene polymorphisms of associations between folate cycle enzyme gene polymorphisms and cardiometabolic risk factors such as increased serum homocysteine levels and folic acid deficiency in patients in the post-covid period. In 51 patients who suffered from COVID-19, a general clinical and laboratory examination, and assessment of serum homocysteine and folic acid concentrations by immunoenzymatic method was carried out. Polymorphisms of the genes: methylenetetrahydrofolate reductase (677C&gt;T and 1298A&gt;C), methionine synthase-reductase (66A&gt;G) and methionine synthase (2756A&gt;G) were determined by real time polymerase chain reaction. For each of the named polymorphisms, the examined patients were divided into 3 groups according to the nucleotide alleles in the corresponding position: 1) homozygous dominant, 2) heterozygous and 3) homozygous recessive. For the methylenetetrahydro­folatereductase gene at position 677, serum levels of homocysteine and folate did not differ between the groups 1 and 2 with genotypes 677 C/C (n=26) and 677C/T (n=21), (p&gt;0.05); in group 3, the recessive genotype 677 T/T was found in only 4 people (8%), that did not allow comparison of indices. The distribution of patients into 3 groups according to the genotype of the same gene at position 1298 revealed that the recessive 1298 C/C mutation in group 3 (n=9) associated with an increased homocysteine level (19.56±1.89 μmol/l), versus 10.68±0.76 (p=0.012) and 11.63±1.25 μmol/l (p=0.013) in groups 1 and 2, with no difference in folate levels between groups. Group 3 differed by a higher degree of obesity, a higher frequency of hypertension disease and chronic heart failure (in 85% of patients in group 3, against 41 and 50% in groups 1 and 2), a higher number of platelets, a longer duration of hospitalization due to COVID-19, a higher level of D-dimer. The study of groups of patients, divided depending on the genotype of methioninesynthase reductase at position 66, showed that carriers of the recessive homozygous 66 G/G mutation (group 3, n=15) had increased serum homocysteine level (16.56±1.64 μmol/l) in comparison with individuals of group 1 (n=17) 66 A/A (10.28±1.17 μmol/l; p=0.004) and group 2 (n=19) 66 A/G (11.32±1.17 μmol/l, p=0.013). In group 3, a longer duration of hospitalization due to COVID-19 was noted (17.15±1.65 vs. 11.88±0.97 days, p=0.008), higher frequency of hypertension (67% vs. 35%) and heart failure (67% against 29%) compared to group 1. The use of a molecular genetic approach made it possible to establish that the presence of recessive mutations of the folate cycle genes is associated with a potential predisposition to hyperhomocysteinemia, thrombophilia, severe forms of cardiometabolic complications and coronavirus disease.

A case of convexity non-aneurysmal subarachnoid hemorrhage caused by cerebral sinus thrombosis

BackgroundConvexity subarachnoid hemorrhage (cSAH) is an uncommon presentation of subarachnoid bleeding, referring to bleeding more localized to the convexities of the brain. The diagnosis of cerebral venous sinus thrombosis (CVST) can be difficult especially when patients initially present with cSAH. The authors present a case and then discuss the pathophysiology and management.Case presentationA 56-year-old woman with a previous history of hypertension and ischemic heart disease presented to the emergency department after experiencing it. Two seizures following a severe headache. The patient’s history was negative for recent illnesses, head trauma, history of migraines, smoking, alcohol consumption, or intravenous drug use. The patient was diagnosed with CVST based on magnetic resonance venography (MRV). Genetic studies further identified homozygous mutations in the Prothrombin and MTHFR genes. Anticoagulant therapy was initiated with 60 mg of Enoxaparin twice daily and subsequently transitioned to Warfarin after 48 h continued for 3 months, and then replaced by rivaroxaban.ConclusionsThis study highlights the importance of considering CVST as a cause of SAH, emphasizes the role of advanced imaging in diagnosis, and demonstrates a successful treatment approach using both traditional and direct oral anticoagulants. The insights provided in this article can contribute to improving the management of patients with CVST-related SAH.

MTHFR C677T gene polymorphism in patients with coronary heart disease and hypertension treated with enalapril and folic acid: implications for prognosis.

We aimed to investigate the effect of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism on the prognosis of patients with coronary heart disease (CHD) and hypertension treated with enalapril and folic acid. A total of 540 CHD patients diagnosed by coronary angiography in our hospital were selected. According to whether there was folic acid intervention, they were divided into a folic acid group, a non-folic acid group and a control group. The genotypes of the MTHFR C677T locus were detected. Hcy concentration and the folate content were determined. In folic acid group, enalapril and folic acid tablets were used to reduce blood pressure, and clopidogrel or ticagrelor were selected according to CYP2C19 genotypes. In non-folic acid group, enalapril tablets were used, and clopidogrel or ticagrelor were selected based on CYP2C19 genotyping. Routine treatment without intervention was used in control group. Patients were prescribed standardized drug treatment and were followed up by an outpatient service or by telephone for 12 months after discharge. We found that the number and proportion of MTHFR C677T gene mutations in the folic acid group, non-folic acid group and control group were 150 (83.3%), 142 (78.9%) and 144 (80.0%), respectively. The recurrence rate of cardiovascular events in the folic acid and non-folic acid groups was significantly lower, and the degree of reduction in the recurrence rate of cardiovascular events in the folic acid and non-folic acid groups was significantly different. The concentrations of TG, TC, and LDL-C in folate and non-folic groups were lower, while HDL-C was higher than that in control group. To sum up, screening high-risk populations with genotypes has great significance in improving the clinical outcome of CHD patients with H-type hypertension. Folic acid supplementation improves the compliance rate of patients' blood pressure levels and improves their clinical prognosis as well.