Folate Metabolism Research Articles

Polymorphism of folate metabolism genes and thrombotic complications in patients with functionally single ventricle

Aim. To analyze the relationships between the carriage of polymorphic variants in the folate metabolism genes and the development of thrombotic complications in patients with single ventricle (SV) during surgical treatment.Material and Methods. A total of 102 children with SV were examined in the performed research. All patients underwent surgical hemodynamic correction of congenital heart disease (CHD). According to a retrospective chart review, thrombosis was diagnosed in 12.7 % of the examined patients with SV. The analysis of polymorphism in the MTR A2756G enzyme gene revealed significant differences between the groups of patients with a history of thrombosis and without it.Results. We found that the risk of developing thrombosis was associated with the carriage of homozygous genotype 2756AA of the MTR enzyme gene (OR = 11.21; 95% CI: 1.39–89.96; p = 0.023).

GENETIC VARIATION OF FOLATE METABOLIC PATHWAY IN RECURRENT PREGNANCY LOSS- A SYSTEMATIC REVIEW

Introduction: Recurrent pregnancy loss (RPL) is a discrete disorder, which is defined as loss of two or more clinically recognized pregnancies. The increasing incidence of RPL in recent days may be due to, chromosomal and congenital abnormalities, antiphospholipid syndrome, uterine anomalies, hereditary thrombophilia, autoimmunity and environmental factors, but the cause of RPL still remains undetermined in the majority of cases.Folate deficiency is one the causes for congenital abnormalities which may leads to pregnancy losses. Any deficiency in the folate metabolic pathway leads to low levels of folate, which has been associated with abnormalities in both mothers (anemia) and fetuses (congenital abnormalities). Also it is associated with increased homocysteine levels which may contribute in these conditions1. Objectives: Study of folate metabolism status in RPL by correlating the association between 5, 10-methylenetetrahydrofolate reductase gene (MTHFR) Data Sources: Data from Pubmed, EMBASE, MEDLINE and many other data baseswere searched. Similar strategy were applied for each article search. Study selection: the review was restricted to studies on recurrent pregnancy loss, Folate metabolism, MTHFR gene and study statistics. Results:A hypothesis was drawn from different studies and a positive link was observed in MTHFR gene alleles mutation, hyperhomocysteinaemia and recurrent pregnancy loss. Conclusion:Understanding the molecular genetics of folate metabolic pathway will provide newer avenues in the effective management of pregnancy losses due to low folate level (in MTHFR gene polymorphism) with supplementation of folic acid or L-methylfolate.

Железодефицитные состояния в практике акушера-гинеколога

Deficiency or excess of microelements and vitamins significantly affects the vital activity at each step of human life. This is particularly significant during pregnancy because of immediate and long-term effects on the fetus and newborn. Iron is one of the essential microelements and plays an important role in the mechanisms of biological oxidation. Iron metabolism in the human body is quite complex and impossible without synergy with other metals and vitamins. Iron is most closely related to folic acid and is critical for many vital processes, including embryogenesis. Considering that iron and folic acid deficiencies (leading to anemias in extreme cases) negatively affect pregnancy course, its favorable outcome, and prognosis for a newborn, these conditions are to be addressed. Medications are diverse, they should be selected based on the specificity of iron and folic acid metabolism. Among preparations currently available in Russia, combined ones best meet the requirements (iron valence, iron compounds, association with synergid components, dosage form). KEYWORDS: iron, folic acid, iron-deficiency anemia, folate-deficiency anemia, therapy, combined preparations. FOR CITATION: Mikhelson Ar.A., Lebedenko E.Yu., Gayda O.V. et al. Iron deficiencies in obstetric-gynecologic practice. Russian Journal of Woman and Child Health. 2022;5(2):129–137 (in Russ.). DOI: 10.32364/2618-8430-2022-5-2-129-137.

Folate Metabolism in Hepatocellular Carcinoma. What Do We Know So Far?

Cancer cells are characterized by accelerated proliferation and an outstanding adaptation of their metabolic pathways to meet energy demands. The folate cycle, also known as folate metabolism or one-carbon metabolism, through enzymatic interconversions, provides metabolites necessary for nucleotide synthesis, methylation, and reduction power, helping to maintain the high rate of proliferation; therefore, the study of this metabolic pathway is of great importance in the study of cancer. Moreover, multiple enzymes involved in this cycle have been implicated in different types of cancer, corroborating the cell's adaptations under this pathology. During the last decade, nonalcoholic fatty liver disease has emerged as the leading etiology related to the rise in the incidence and deaths of hepatocellular carcinoma. Specifically, cholesterol accumulation has been a determinant promoter of tumor formation, with solid evidence that an enriched-cholesterol diet plays a crucial role in accelerating the development of an aggressive subtype of hepatocellular carcinoma compared to other models. In this review, we will discuss the most recent findings to understand the contribution of folate metabolism to cancer cells and tumor microenvironment while creating a link between the dynamics given by cholesterol and methylenetetrahydrofolate dehydrogenase 1-like, a key enzyme of the cycle located in the mitochondrial compartment.

MTHFR C677T and MTR A2756G Gene Polymorphism in Neural Tube Defect Patients and Its Association with Red Blood Cell Folate Level in Eastern Indian Population.

Single-nucleotide polymorphism (SNP) is a single-nucleotide change in a deoxyribose nucleic acid (DNA) sequence that occurs in >1% of population. Methylene tetra hydro folate reductase (MTHFR) C677T (rs1801133) and methionine synthase enzyme (MTR) A2756G (rs1805087) are two such SNPs occurring in coding sequence of the respective genes, which are frequently seen with neural tube defects (NTDs). MTHFR and MTR genes are involved in folate metabolism. The folate level in the course of pregnancy is treated as vital in the etiopathogenesis of NTDs. This study aims to explore the association of SNPs of both genes and red blood cell (RBC) folate levels in the predisposition to NTDs. The purpose of this investigation was to determine the relationship of NTDs with polymorphisms in MTHFR and MTR genotype and to estimate and compare the RBC folate levels in NTD patients and controls. A total of 397 individuals were enrolled (163 patients and 234 controls) for this observational study. Genotyping to find out MTHFR C677T and MTR A2756G was performed by polymerase chain reaction-restriction fragment length polymorphism technique from DNA extracted from the subject's blood. RBC folate level was estimated by chemiluminescence immunoassay method with the same blood sample. The total RBC folate levels were significantly less among cases compared to controls (P = 0.020). A significant difference for RBC folate was observed between case and control groups of various genotypes of MTHFR C677T, except heterozygote CT (P = 0.459). Among MTR A2756G, genotypes with only homozygous AA have significant difference (P = 0.003) for RBC folate levels. Among different types of NTDs, there were no significant differences for RBC folate levels. Among MTHFR C677T, T allele possessed 1.9 times risk compared to C allele for the occurrence of NTDs. In MTR A2756G polymorphism, the odds of developing NTDs were 1.6 times in heterozygous AG compared to homozygous AA. Similarly, the risk for NTDs was three times higher in subjects with both heterozygous AG and CT genotypes compared to wild-type homozygous AA and CC genotypes. The total RBC folate levels were significantly less among cases compared to controls, and the genotypes had no such effect in decrease in RBC folate levels. The presence of mutant allele in homozygous or heterozygous condition for both SNPs had increased risk associated with NTDs.

THYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISMS AND SUSCEPTIBILITY TO ESOPHAGEAL CANCER: A CASE-CONTROL STUDY.

ABSTRACTBACKGROUND:The enzyme methylenetetrahydrofolate reductase is engaged in DNA synthesis through folate metabolism. Inhibiting the activity of this enzyme increases the susceptibility to mutations, and damage and aberrant DNA methylation, which alters the gene expression of tumor suppressors and proto-oncogenes, potential risk factors for esophageal cancer.AIMS:This study aimed to investigate the association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and susceptibility to esophageal cancer, by assessing the distribution of genotypes and haplotypes between cases and controls, as well as to investigate the association of polymorphisms with clinical and epidemiological characteristics and survival.METHODS:A total of 109 esophageal cancer patients who underwent esophagectomy were evaluated, while 102 subjects constitute the control group. Genomic DNA was isolated from the peripheral blood buffy coat followed by amplification by polymerase chain reaction and real-time analysis. Logistic regression was used to assess associations between polymorphisms and the risk of developing esophageal cancer.RESULTS:There was no association for methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and haplotypes, with esophageal cancer susceptibility. Esophageal cancer patients carrying methylenetetrahydrofolate reductase 677TT polymorphism had higher risk of death from the disease. For polymorphic homozygote TT genotype, the risk of death significantly increased compared to wild-type genotype methylenetetrahydrofolate reductase 677CC (reference) cases (p=0.045; RR=2.22, 95%CI 1.02–4.83).CONCLUSIONS:There was no association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and esophageal cancer susceptibility risk. Polymorphic homozygote genotype methylenetetrahydrofolate reductase 677TT was associated with higher risk of death after surgical treatment for esophageal cancer.

Neuropsychiatric manifestations in vitamin B12 deficiency.

Vitamin B12 deficiency can have distressing neuropsychiatric symptoms. It can have an etiological role in clinical presentations like depression, anxiety, psychosis, dementia, and delirium, requiring screening of at-risk populations. Few mechanisms that underlie the neuropsychiatric manifestations of B12 deficiency include alteration in one-carbon metabolism, genetic vulnerability, and alteration in folate metabolism. Maintaining a high serum B12 level in elderly can be protective against Alzheimer's disease (AD). In an established AD, its deficiency is associated with higher cognitive decline and risk for delirium. The other mental changes associated with B12 deficiency include apathy, agitation, impaired concentration, insomnia, persecutory delusions, auditory and visual hallucinations, and disorganized thought-process. Besides serum vitamin B12, plasma methylmalonic acid (MMA) and homocysteine helps in diagnosis. The chapter focuses on early recognition and effective treatment of these neuropsychiatric manifestations of vitamin B12 deficiency.

Quantitation of 5-Methyltetrahydrofolate in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray-Tandem Mass Spectrometry.

We describe a simple stable isotope dilution method for accurate and precise measurement of cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF) as a clinical diagnostic test. 5-MTHF is the main biologically active form of folate and is involved in the regulation of homocysteine and numerous methylation reactions, including synthesis of neurotransmitters, lipids, DNA, and RNA. Measurement of 5-MTHF in CSF provides diagnostic information regarding disorders affecting folate metabolism within the central nervous system, in particular inborn errors of folate metabolism and cerebral folate deficiency. Determination of 5-MTHF in CSF (50μL) was performed utilizing high-performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). 5-MTHF in CSF is determined by a 1:2 dilution with internal standard (5-MTHF-13C5) and injected directly onto the HPLC-ESI-MS/MS system. Each assay is quantified using a five-point standard curve (25-400nM) and has an analytical measurement range of 3-1000nM.

Selective nanosensor based on folic acid imprinted nanostructures.

Folic acid, which provides the transfer of single carbon atoms in synthesis reactions and metabolic cycles in metabolism, is very important for metabolism. Folic acid also plays an important role in nucleotide synthesis and methylation reactions. There are many disorders caused by defective folic acid metabolism and lack of folic acid. Today, innovative, cost-effective methods are needed to develop folic acid determination methods. The main objective of this study is the development of surface-printed carbon electrodes (SPCE) modified with folic acid imprinted nanostructures (FA-Imp-poly(MPTS-rGO-co-NAT), which will be used for the first time for folic acid determination in commercially human blood serum. For this purpose, the synthesis of nanostructures has been carried out and characterized by FTIR, SEM-EDS, and AFM. Then, a new chemically modified nanosensor was fabricated for the determination of folic acid using folic acid imprinted nanostructures. Differential pulse voltammetry (DPV) and circular voltammetry (CV) methods were used as electrochemical methods in the FA-imprinted-nanosensor studies. Measurements in differential pulse voltammetry were performed at an application speed of 0.005 volts per second in the potential range of -0.4 to 0.6 volts. As a result of the circular voltammetric method, an idea about the surface was obtained with the voltammograms obtained. The detection limit (LOD) of the developed FA-imprinted-nanosensor was 7.54 ng/mL and the determination limit (LOQ) was 25.14 ng/mL. FA analytical (10 and 20 ng/mL) was added to commercial synthetic serum samples by the standard adding method and RSD values of 0.092% and 0.734% were found in the DPV technique and measurements respectively. This manuscript demonstrated a novel, simple, selective, and rapid FA-imprinted-nanosensor for determining the FA in the biological samples.

Methylenetetrahydrofolate reductase C677T polymorphism across acute leukemia

Background Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for folate metabolism and also plays a role in DNA biosynthesis and the epigenetic process of DNA methylation. MTHFR gene polymorphisms, mainly the C677T, have been implicated as risk factors for several types of cancers such as the acute leukemia (AL). Main body of the abstract This study was conducted to examine the extent of the association between MTHFR C677T polymorphism and AL across a comprehensive literature of meta-analysis. Relevant English-language literature was searched and retrieved from PubMed using the terms MTHFR, the C677T polymorphism, and AL. Several parameters have been studied in the assessment of correlation between AL and the MTHFR polymorphism, such as folate intake, ethnicity, age, and sex. Nevertheless, the results are contrasting. Short conclusion Comprehensive analysis of MTHFR C677T in AL may be helpful and provide new insights for a personalized therapy based on the human genotype.

MTHFD1 c.1958G>A and TCN2 c.776G>C polymorphisms of folate metabolism genes and their implication for oral cavity cancer

Abstract Background Cancers of the head and neck can damage the brain, spinal cord, and nerves, as well as the sense organs responsible for contact with the outside world. Oncogenic transformation occurs following mutations that change the function of specific genes, such tumor suppressor genes or oncogenes, and their encoded protein products. Therefore, the aim of this study was to evaluate the relationship between the occurrence of MTHFD1 c.1958G>A and TCN2 c.776G>C gene polymorphisms and the risk of oral cavity cancer. Materials and methods The study population consisted of 439 patients and 200 healthy subjects. Genomic DNA was extracted from peripheral blood and from paraffin-embedded tissue. Analysis of the gene polymorphisms was performed using polymerase chain reaction–restriction fragment length polymorphism. Results Statistically significant differences were found in the distribution of genotypes of the rs2236225 and rs1801198 polymorphisms between patients and controls. Regarding MTHFD1 c.1958G>A, the GA genotype (p<0.0001, OR = 2.91, 95% CI = 1.88–4.49-GA) was more common among patients than healthy subjects. Regarding TCN2 c.776G>C, the frequency of CC genotype (p< 0.0001, OR = 0.17, 95% CI = 0.10–0.33-CC) was significantly less common among patients than healthy subjects. Tobacco smoking, alcohol use, and male gender (p<0.0001) were found to be predictors of the disease. Conclusion The results suggest that the MTHFD1 c.1958G>A polymorphism may be associated with a greater risk of oral cavity cancer, whereas a protective effect has been found for the TCN2 c.776G>C polymorphism.

Relationship between Methylenetetrahydrofolate Reductase C677T Homozygous Mutation and Cerebral Small Vessel Disease Subtypes

Background: Neuroimaging detects cerebral small vessel disease (CSVD) subtypes, including infarction, asymptomatic lacunes, cerebral microbleeds, white matter hyperintensities (WMHs), and enlarged perivascular space. Methylenetetrahydrofolate reductase (MTHFR) plays an essential role in the metabolism of folic acid and homocysteine. The purpose of this study was to investigate the relationship between the MTHFR C677T mutation and CSVD subtypes.Methods: A total of 144 patients with acute ischemic stroke who visited the Korea University Guro Hospital between April 2020 and August 2020 were retrospectively reviewed. After excluding 24 patients, due to missing laboratory, clinical, or imaging information, a total of 120 patients were analyzed.Results: Among the 120 participants, 25% were included in the MTHFR C677T homozygous mutation group, which had significantly lower folic acid levels (6.24±4.21 ng/mL vs. 8.24±4.21 ng/mL, p=0.03) and higher total homocysteine levels (17.09±14.07 μmol/L vs. 9.65±3.19 μmol/L, p<0.01). Using multiple logistic regression analysis, the homozygous mutation (adjusted odds ratio [aOR]=4.29; 95% confidence interval [CI]=1.16–15.90) and age (aOR=1.06; 95% CI=1.01–1.11) were independently associated with moderate to severe WMHs. Additionally, moderate to severe WMHs were more frequent in the homozygous mutation group (86.7% vs. 66.7%, p=0.01). In a detailed analysis, the homozygous mutation group showed a significantly higher rate of moderate to severe periventricular WMH (PWMH) (86.7% vs. 65.6%, p<0.01).Conclusion: The MTHFR C677T homozygous mutation was positively correlated with moderate to severe PWMH subtypes of CSVD.

MATERNAL GENE POLYMORPHISMS OF VITAMIN B12 METABOLIC PATHWAY AND THEIR ASSOCIATION WITH CONGENITAL HEART DISEASES

Congenital heart disease (CHD) describes a huge set of structural and functional abnormalities that arises during cardio embryogenesis. Low levels of maternal vitamin B12 can disturb the homeostasis of the fetal folate metabolism pathway. The gene CUBN encodes for the intrinsic factor– cobalamin receptor (cubilin), which acts as a receptor for intrinsic factor to many compounds such as vitamin B12.Main aim of our study was to analyze association of CUBN G253A (rs1801222) variant with maternal serum folate, vitamin B12 and homocysteine (Hcy) levels and thereby its link with congenital heart defects. 110 pregnant women with vitamin B12 deficiency and carrying fetuses with CHD and equal number of age matched healthy women were selected as cases and control subjects respectively. Maternal serum folate, vitamin B12 and homocysteine levels as well as genetic polymorphism CUBN G253 → A were assessed. In the present study, it was observed that cases with GA genotype, A allele under the dominant (p=<0.001) and allelic models (p<0.001) respectively and cases with AA genotype under the co-dominant (p<0.01) and recessive models (p<0.001) demonstrated an increased risk of an offspring with CHD. Furthermore, while cases with GA and AA genotypes of CUBN G253A variant showed significantly elevated Homocysteine, it was observed that all the CHD case mothers were vitamin B12 deficient irrespective of the CUBN genotype.

Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish

Simple SummaryFolic acid is an essential vitamin for human beings. It has become a consensus to supplement folic acid during pregnancy. It is reported that 15~20% of people in the world supplement folic acid excessively. We found that excessive folic acid supplementation or insufficient folic acid intake could lead to abnormal heart development in zebrafish embryos. We elucidated the mechanism of folic acid on early cardiac development for the first time. These results provide a scientific basis for the important reasonable supplement dose of folic acid. At the same time, we constructed zebrafish mutants with abnormal folate metabolism, which provide a novel biological model for the study of folate acid metabolism.Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. Moreover, we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid and mthfr−/− mutant all gave rise to early pericardial edema and cardiac defect at 3 days post fertilization (dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5 dpf. The expression levels of cardiac marker genes hand2, gata4, and nppa changed in the abnormality of folate metabolism embryos and mthfr−/− mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. Furthermore, our results reveal that folic acid has a dose-dependent effect on early cardiac development. Precise dosage of folic acid supplementation is crucial for the embryonic development of organisms.

Levels of Folate and Vitamin B12, and Genetic Polymorphisms Involved in One-Carbon Metabolism May Increase the Risk of Cervical Cytological Abnormalities

To analyze the association of cervical cytological abnormalities with genetic polymorphisms of enzymes involved in folate metabolism, and the effect of micronutrients on association of polymorphisms with cervical carcinogenesis. Our samples were divided in Control (120 women with normal cytology), and Cases: 37 women with Atypical Squamous Cells of Undetermined Significance(ASC-US), 33 participants presenting Low-Grade Squamous Intraepithelial Lesion(LSIL), and 24 women presenting High-Grade cervical lesions(HSIL/ASC-H). We obtained cervical samples for cytological analysis, HPV detection, and analysis of polymorphisms and cervical cell folate. Blood samples were obtained for serum folate and vitamin B12 evaluation. To analyze all polymorphisms simultaneously, we calculated Genetic Risk Score(GRS). Median concentrations were used as cutoff for determination of micronutrient levels. We observed no differences of genotype or allelic frequencies of polymorphisms according to cervical lesions. However, high levels of cervical cell folate and high number of genetic alterations increased risk of High-Grade lesions [OR(IC95%):1.85(0.42–8.11)]. Instead, women with vitamin B12 ≤ 274 pg/ml and GRS ≥ 3 presented even greater risk of HSIL/ASC-H [OR(IC95%):2.91(0.46–18.62)]. High frequency of genetic polymorphisms involved in one-carbon metabolism associated with high levels of cell folate or low levels of serum vitamin B12, increased the risk of High-Grade lesion in uterine cervix.

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.

Supramolecular complexation between cucurbit[7]uril and folate and analytical applications

Folate (FA) plays a key role in the biosynthesis of amino acids, purines, and pyrimidines in the human body, and intracellular folate metabolism has become an attractive target of tumor chemotherapy. In this work, an inclusion interaction was found between FA and cucurbit[7]uril (CB[7]), and the formation of a CB[7]-FA 2:1 supramolecular inclusion complex was confirmed by fluorescence spectra, UV-Vis absorption spectroscopy, 1H NMR, and molecular modeling calculations. In addition, FA is generally determined through the indirect fluorescent method because it shows weak fluorescence in aqueous solution. Therefore, a simple, direct fluorescence probe method for rapidly measuring FA was investigated, and the linear equation of FA was ΔF = 14.691C + 37.366 within the concentration ranges of 0.82 ~ 18.31 µg mL–1. The proposed direct fluorescence method was applied to the determination of spiked plasma. We demonstrated that this method could provide an experimental basis for the targeted administration of the CB[7]-FA complex, and it could be extended as a promising fluorescence detection method for drugs in vivo.

Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks

The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD.

Polymorphisms in vitamin B12 and folate metabolising genes and their association with adverse pregnancy outcome: secondary analysis of a population based case control study

Vitamin B12 and folate deficiency leads to accumulation of homocysteine that increases the risk of adverse pregnancy outcomes like preterm birth and low birth weight (LBW) of the neonate. We explored the association of genetic variants of key vitamin B12 and folate metabolising enzymes (MTHFR C677T and A1298C, MTR A2756G, TCN-2 C776G) with preterm birth and LBW in South Indian women. MTHFR A1298C heterozygotes (AC) were at higher risk for preterm delivery, whereas TCN-2 C776G heterozygotes (CG) were at higher risk for both preterm delivery and LBW. MTHFR C677T, A1298C and MTR A2756G haplotype CAG was protective for preterm delivery (p=.036, OR = 0.475; 95% CI: 0.233–0.97), whereas, haplotype CCG increasing the risk of preterm birth by 1.8 folds (p=.018, OR = 1.81; 95% CI: 1.09–2.98). These results underscore the significance of vitamin B12 and folate in the pathophysiology of preterm birth and LBW. Impact Statement What is already known on this subject? Polymorphisms of vitamin B12 and folate metabolising genes have been reported to influence preterm birth and LBW, but the reports are not consistent. What do the results of this study add? We observed a relationship of MTHFR A1298C and TCN-2 C776G with preterm birth, and significant association of TCN-2 C776G with LBW in infants. What are the implications of these findings for clinical practice and/or further research? Identification of women carrying these polymorphic risk alleles may benefit from early nutritional modifications.

Disruption of Folate Metabolism Causes Poor Alignment and Spacing of Mouse Conceptuses for Multiple Generations.

Abnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with the hypomorphic Mtrr gt mutation. MTRR is necessary for methyl group utilisation from folate metabolism, and the Mtrr gt allele disrupts this process. We show that the spectrum of phenotypes previously observed in Mtrr gt/gt conceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes. Notably, we report misalignment of some Mtrr gt conceptuses within their implantation sites from E6.5. The degree of misorientation occurs across a continuum, with the most severe form visible upon gross dissection. Additionally, some Mtrr gt/gt conceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Skewed growth likely influences embryo development since developmental delay and heart malformations (but not defects in neural tube closure or trophoblast differentiation) associate with severe misalignment of Mtrr gt/gt conceptuses. Typically, the uterus is thought to guide conceptus orientation. To investigate a uterine effect of the Mtrr gt allele, we manipulate the maternal Mtrr genotype. Misaligned conceptuses were observed in litters of Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt mothers. While progesterone and/or BMP2 signalling might be disrupted, normal decidual morphology, patterning, and blood perfusion are evident at E6.5 regardless of conceptus orientation. These observations argue against a post-implantation uterine defect as a cause of conceptus misalignment. Since litters of Mtrr +/+ mothers display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of the Mtrr gt model, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe conceptus skewing associates with the Mtrr genotype of either maternal grandparent. Moreover, the presence of conceptus skewing after embryo transfer into a control uterus indicates that misalignment is independent of the peri- and/or post-implantation uterus and instead is likely attributed to an embryonic mechanism that is epigenetically inherited. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. This study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.