Methionine Synthase Reductase Research Articles

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>T and 1298A>C), methionine synthase-reductase (66A>G) and methionine synthase (2756A>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>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.

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms and five related serum molecular levels in 2587 patients: Associated differentially with adverse pregnancy.

The aim of the study is to investigate the relationship between Methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) polymorphisms, 5 serum related molecular levels and the risk of adverse pregnancies in different genders. Patients aged from 22 to 38 with a history of adverse pregnancy treated in our genetic eugenics clinic of Henan Provincial People's Hospital are selected. The controls aged from 20 to 34 undergoing eugenics examinations in our genetic eugenics clinic that had no history of adverse pregnancy and at least one healthy child are selected. Sanger sequencing and Chemiluminescence Microparticle Immuno Assay (CMIA) are used for detecting the mutations of MTHFR and MTRR and the 5 serum molecular serum levels. In the female group, MTHFR 677C > T is associated with Recurrent spontaneous abortion (RSA) (P = 0.0017), Chromosomal abnormality (CA) (P = 0.0053), Cleft lip and palate (CLP) (P = 0.0326) and Brain dysplasia (BD) (P = 0.0072); MTHFR 1298A > C is associated with Infertility (P = 0.0026) and BD (P = 0.0382); MTRR 66A > G is associated with CLP (P = 0.0131). In the male group, MTHFR 677C > T is associated with RSA (P = 0.0003), Infertility (P = 0.0013), CA (P = 0.0027) and BD (P = 0.0293). In the female group, the genotype of MTHFR 677C > T is associated with RSA (P = 0.0017), CA (P = 0.0014) and BD (P = 0.0021); MTHFR 1298A > C is associated with Infertility (P = 0.0081) and MTRR 66A > G is associated with Infertility (P = 0.0309). In the male group, the genotype of MTHFR 677C > T is associated with RSA (P = 0.0008), Infertility (P = 0.0096) and CA (P = 0.0165) and MTRR 66A > G is associated with Infertility (P = 0.0158) and congenital heart disease (CHD) (P = 0.0218). In the male group, there is statistically significant difference of the serum Homocysteine (Hcy) levels (P < 0.0001) between adverse pregnancy group and controls.In the female group,there is statistically significant difference of the serum vitamin D levels (P = 0.0015) between adverse pregnancy group and controls. Polymorphic variants in MTHFR and MTRR, serum Folic acid (FA), Hcy and B12 levels in the male group and vitamin D levels in the female group are associated differentially with adverse pregnancy.

Standardization and application of ARMS TaqMan real-time PCR for screening of folate metabolism genes in Han Chinese.

Folate has antioxidant properties, and low concentration in seminal plasma may be associated with increased DNA damage in sperm. Mutations of the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes, including MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), and MTRR A66G (rs1801394), can lead to decreased activity of the encoded folate metabolic enzymes, thereby affecting male reproduction. The current SNP detection methods commonly used in clinical practice have some shortcomings, such as long time-consuming, complex detection steps, or high cost. The purpose of this study was to establish a simple, time-saving, sensitive, accurate, and easy to clinical popularization method for folate metabolism gene detection. We combined ARMS-PCR with TaqMan fluorescent probe to establish an ARMS TaqMan real-time PCR detection method. According to the variation of rs1801131, rs1801133, and rs1801394, two specific primers (one wild type and one mutant) were designed. Mismatched nucleotides were introduced at the penultimate or third position to improve the specificity of the primer. Specific TaqMan probe was introduced to detect PCR products to improve the sensitivity of the method. The results showed that the sensitivity of ARMS TaqMan real-time PCR in SNP genotyping was 1ng, and the accuracy was 100%. A total of 249 clinical samples were detected by the established method, and the correlation between three SNPs and semen quality was analyzed. We found that individuals carrying the AG+GG genotype of rs1801394 had a lower risk of abnormal semen quality. In conclusion, we developed a highly sensitive, accurate, rapid, and easy to be popularized method for detecting SNPs of rs1801394, rs1801131, and rs1801133. ARMS TaqMan real-time PCR is a reliable SNP genotyping method in folate metabolism genes.

Folate and cobalamin status, indicators, modulators, interactions, and reference ranges from early pregnancy until birth: the Reus–Tarragona birth cohort study

BackgroundFolate and cobalamin status, although essential for pregnancy, are not routinely monitored in prenatal care. ObjectivesTo investigate folate and cobalamin status and determinants throughout pregnancy, in the absence of mandatory folic acid (FA) fortification. MethodsIn a cohort study of 831 mothers recruited at <12 gestational weeks (GW), plasma folate, total homocysteine (tHcy), cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA), red blood cell folate (RBCF), and the combined cobalamin status indicator (cB12) were determined at ≤12, 15, 24–27, 34 GW, labor and in the cord. Single nucleotide polymorphisms affecting folate and cobalamin status were determined. FA, cobalamin, micronutrient supplement use, and dietary folate and cobalamin intake (food frequency questionnaire) were recorded. Folate and cobalamin status predictors were assessed by multiple linear regression analysis. ResultsOnly 36.1% of the participants took FA preconceptionally and 47.4% and 7.3% had suboptimal RBCF (<906 nmol/L) and plasma cobalamin status (≤221 pmol/L), respectively, at ≤12 GW. RBCF determinants included planned pregnancy, FA supplementation, plasma cobalamin, and methylenetetrahydrofolate (MTHFR) 677C>T genotype. Cobalamin supplementation was positively associated with plasma cobalamin and early holoTC. Smoking and BMI were inversely associated with plasma cobalamin and early holoTC, but none were associated with MMA. Only participants with the MTHFR 677TT genotype, exceeding FA supplement recommendations, improved their folate status (interaction term: B (95% CI):0.15 (0.01, 0.29), P = 0.032). Smoking was inversely associated with plasma cobalamin status in participants with the methionine synthase reductase (MTRR) 524CC genotype only (interaction term:0.07 (0.01, 0.04), P = 0.014). Mothers with low early pregnancy cobalamin status and also those with bigger newborns, had lower cobalamin status at labor. ConclusionsSuboptimal early pregnancy folate or cobalamin status affected 47.4% and 7.3% of the participants, respectively. The MTHFR 677TT genotype predicted folate status throughout pregnancy. Smoking and BMI were negatively associated with cobalamin status throughout pregnancy.Clinical Trial Registry number and website where it was obtained: NCT01778205. www.clinicaltrials.gov

Chlorquinaldol Alleviates Lung Fibrosis in Mice by Inhibiting Fibroblast Activation through Targeting Methionine Synthase Reductase.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Thus, it is essential to investigate potential druggable targets to improve IPF treatment outcomes. By screening a curated library of 201 small molecules, we have identified chlorquinaldol, a known antimicrobial drug, as a potential antifibrotic agent. Functional analyses have demonstrated that chlorquinaldol effectively inhibits the transition of fibroblasts to myofibroblasts in vitro and mitigates bleomycin-induced pulmonary fibrosis in mice. Using a mass spectrometry-based drug affinity responsive target stability strategy, we revealed that chlorquinaldol inhibited fibroblast activation by directly targeting methionine synthase reductase (MTRR). Decreased MTRR expression was associated with IPF patients, and its reduced expression in vitro promoted extracellular matrix deposition. Mechanistically, chlorquinaldol bound to the valine residue (Val-467) in MTRR, activating the MTRR-mediated methionine cycle. This led to increased production of methionine and s-adenosylmethionine, counteracting the fibrotic effect. In conclusion, our findings suggest that chlorquinaldol may serve as a novel antifibrotic medication, with MTRR-mediated methionine metabolism playing a critical role in IPF development. Therefore, targeting MTRR holds promise as a therapeutic strategy for pulmonary fibrosis.

Polymorphism of Folate Metabolism Genes among Ethnic Kazakh Women with Preeclampsia in Kazakhstan: A Descriptive Study.

Preeclampsia is a severe multifactorial complication of pregnancy. Studies found associations between folate metabolism genes' polymorphisms and preeclampsia. However, investigations in this field are limited among Asian populations. Thus, the study's aim was to evaluate the prevalence of methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) genes' polymorphisms among ethnic Kazakh women with preeclampsia. This was a retrospective study involving 4246 patients' data for the period of 2018-2022. Identification of MTR, MTRR, and MTHFR genes' polymorphism was performed via PR-PCR. Peripheral blood samples were obtained for the analyses. In total, 4246 patients' data of Kazakh ethnicity with preeclampsia at >20 weeks gestational age who had undergone an investigation to identify polymorphisms of the folate metabolism pathway genes for the period of 5 years were included in this study. The most common and prevalent mutation was the MTRR A66G polymorphism: 24.5% of all tested patients with preeclampsia had the MTRR A66G polymorphism. It was highest among the 35-39 age group participants. The second most prevalent was the MTHFR C677T polymorphism: 9% of women with preeclampsia had the MTHFR C677T mutation. It was highest among women aged 30-34. There was a rare association of the MTR A2756G mutation with preeclampsia among the study participants. The identified levels of MTRR A66G and MTHFR C677T polymorphisms among the study participants suggest the importance of evaluating MTRR and MTHFR polymorphisms in women with preeclampsia. The role of the MTR A2756G polymorphism in the development of preeclampsia needs to be further investigated.

Effect of Methylfolate, Pyridoxal-5'-Phosphate, and Methylcobalamin (SolowaysTM) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial.

Exploring the link between genetic polymorphisms in folate metabolism genes (MTHFR, MTR, and MTRR) and cardiovascular disease (CVD), this study evaluates the effect of B vitamin supplements (methylfolate, pyridoxal-5'-phosphate, and methylcobalamin) on homocysteine and lipid levels, potentially guiding personalized CVD risk management. In a randomized, double-blind, placebo-controlled trial, 54 patients aged 40-75 with elevated homocysteine and moderate LDL-C levels were divided based on MTHFR, MTR, and MTRR genetic polymorphisms. Over six months, they received either a combination of methylfolate, P5P, and methylcobalamin, or a placebo. At the 6 months follow-up, the treatment group demonstrated a significant reduction in homocysteine levels by 30.0% (95% CI: -39.7% to -20.3%) and LDL-C by 7.5% (95% CI: -10.3% to -4.7%), compared to the placebo (p < 0.01 for all). In the subgroup analysis, Homozygous Minor Allele Carriers showed a more significant reduction in homocysteine levels (48.3%, 95% CI: -62.3% to -34.3%, p < 0.01) compared to mixed allele carriers (18.6%, 95% CI: -25.6% to -11.6%, p < 0.01), with a notable intergroup difference (29.7%, 95% CI: -50.7% to -8.7%, p < 0.01). LDL-C levels decreased by 11.8% in homozygous carriers (95% CI: -15.8% to -7.8%, p < 0.01) and 4.8% in mixed allele carriers (95% CI: -6.8% to -2.8%, p < 0.01), with a significant between-group difference (7.0%, 95% CI: -13.0% to -1.0%, p < 0.01). Methylfolate, P5P, and methylcobalamin supplementation tailored to genetic profiles effectively reduced homocysteine and LDL-C levels in patients with specific MTHFR, MTR, and MTRR polymorphisms, particularly with homozygous minor allele polymorphisms.

Gestational diabetes mellitus is associated with distinct folate-related metabolites in early and mid-pregnancy: A prospective cohort study.

This study aimed to evaluate the association between gestational diabetes mellitus (GDM) and circulating folate metabolites, folic acid (FA) intake, and the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genotype. A prospective pregnancy cohort study was conducted in Beijing, China, from 2022 to 2023. Circulating folate metabolites, including red blood cell (RBC) 5-methyltetrahydrofolate (5-MTHF), 5, 10-methylene-tetrahydrofolate (5,10-CH2-THF), 5- formyltetrahydrofolate (5-CHO-THF), and unmetabolised folic acid (UMFA), and plasma homocysteine (HCY), 5-MTHF, and methylmalonic acid (MMA), were determined at 6-17weeks and 20-26weeks of gestation. FA intake and the MTHFR and MTRR genotype were also examined. GDM was diagnosed between 24 and 28weeks of pregnancy by a 75-g oral glucose tolerance test (OGTT). The association between the folate status and GDM was ascertained using multivariate generalised linear models, logistic regression models, and restricted cubic spline regression, adjusting for potential confounders. The study included 2032 pregnant women, of whom 392 (19.29%) developed GDM. UMFA above the 75th percentile (≥P75) [adjusted OR (aOR) (95% confidence interval [CI])=1.36 (1.01-1.84)], UMFA≥P90 [aOR (95% CI)=1.82 (1.23-2.69)], and HCY≥P75 [aOR (95% CI)=1.40 (1.04-1.88)] in early pregnancy, and RBC 5-MTHF [aOR (95% CI)=1.48 (1.10-2.00)], RBC 5,10-CH2-THF [aOR (95% CI)=1.55 (1.15-2.10)], and plasma 5-MTHF [aOR (95% CI)=1.36 (1.00-1.86)] in mid-pregnancy≥P75 are associated with GDM. Higher UMFA levels in early pregnancy show positive associations with the 1-h and 2-h glucose levels during the OGTT, and higher HCY levels are associated with increased fasting glucose levels during the OGTT. In comparison, RBC 5- MTHF and 5,10-CH2-THF, and plasma 5- MTHF in mid-pregnancy are positively associated with the 1-h glucose level (p<0.05). The MTHFR and MTRR genotype and FA intake are not associated with GDM. Elevated levels of UMFA and HCY during early pregnancy, along with elevated RBC 5-MTHF and 5,10-CH2-THF and plasma 5-MTHF during mid-pregnancy, are associated with GDM. These findings indicate distinct connections between different folate metabolites and the occurrence of GDM.

Association of MTHFR (C677T, A1298C) and MTRR A66G polymorphisms with fatty acids profile and risk of neural tube defects.

This study aims to determine if 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms were associated with fatty acid (FA) levels in mothers of fetuses with neural tube defects (NTDs) and whether these associations were modified by environmental factors. Plasma FA composition was assessed using capillary gas chromatography. Concentrations of studied FA were compared between 42 mothers of NTDs fetuses and 30 controls as a function of each polymorphism by the Kruskal-Wallis nonparametric test. In MTHFR gene C677T polymorphism, cases with (CT + TT) genotype had lower monounsaturated FAs (MUFA) and omega-3 polyunsaturated FA (n-3 PUFA) levels, but higher omega-6 polyunsaturated FAs (n-6 PUFA) and omega-6 polyunsaturated FAs: omega-3 polyunsaturated FAs (n-6:n-3) ratio levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype had lower MUFA levels, but higher PUFA and n-6 PUFA levels. Controls with (AG + GG) genotype had lower n-6 PUFA levels. In MTHFR gene C677T polymorphism, cases with smoking spouses and (CT + TT) genotype had lower MUFA and n-3 PUFA levels, but higher PUFA, n-6 PUFA, and n-6:n-3 ratio levels. Cases with (CT + TT) genotype and who used sauna during pregnancy had lower n-3 PUFA levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype and who used sauna during pregnancy had higher PUFA and n-6 PUFA levels. Further research is required to clarify the association of FA metabolism and (MTHFR, MTRR) polymorphisms with NTDs.

E034 Drug-induced accelerated nodulosis in a patient with rheumatoid arthritis

Abstract Background/Aims Drug-induced accelerated nodulosis (DIAN) is characterized by the occurrence or progression of multiple subcutaneous nodules in a patient treated for rheumatoid arthritis (RA). It was first and most commonly reported with methotrexate in RA patients. Methods A 37-year-old normotensive, non-diabetic, seropositive rheumatoid arthritis female presented with complaints of nodules over the bilateral hands and feet from the last three months. The treatment history included methotrexate therapy (10 mg/week) for one year. Methotrexate-induced rheumatoid accelerated nodulosis (MIAN) was suspected. Methotrexate was stopped and hydroxychloroquine was added considering the low disease activity. The nodules decreased in number as well as size. On follow-up, she presented with increased multiple joint pain and swelling with ESR 60 mm/hour, CRP 13.6 mg/L, and leflunomide was added. After six months of leflunomide use, she again developed multiple bilateral nodules on the extensor and palmar surface of fingers and feet, ranging from 0.5 to 1 cm. The CRP was 9.2 mg/L, ESR 80 mm/hour, complete blood count showed mild anaemia with normal renal and liver function tests. The nodule biopsy showed palisading granuloma consisting of lymphocytes and histiocytes in mid and deep reticular dermis with large foci of fibrin deposition and collagen degeneration s/o rheumatoid nodule. Leflunomide was stopped. Results The leflunomide was switched to sulfasalazine along with colchicine, and hydroxychloroquine was continued. The patient is doing well on follow-up in terms of disease activity and nodule size. Palmeiro. A.G., et al. 2022 reviewed 39 studies from 1st Jan 1988 to 1st Jan 2022 and found 109 cases of accelerated nodulosis. 99 patients had RA, methotrexate was the culprit drug in 89, followed by etanercept in 7 and leflunomide was in just 3 patients. Although there are no exact treatment guidelines, tumour necrosis factor inhibitors were avoided due to increased nodulosis risk. Recently, Valor-Méndez. L., et al 2020 reported improved nodulosis with Janus Kinase inhibitors like baricitinib, which seems to be a future option. Histologically, rheumatoid nodules and accelerated nodulosis are indistinguishable. The exact pathogenesis is unknown but, polymorphic variants of methionine synthase reductase or haplotype HLA-DRB1*0401, and adenosine A1 receptor promotion in multinucleated giant cells are associated. Conclusion Drug-induced accelerated nodulosis (DIAN) and MIAN are not that rare but diagnosis is challenging. It causes significant morbidity and affects the quality of life because of the predominant involvement of hands and feet. It should be suspected especially when disease activity is low or rapidly progressive nodules with a change in immunotherapy. Partial to total improvement can be achieved by identifying and stopping the culprit drug. We need specific guidelines, more treatment options, and a specific national registry to report such adverse effects with biologics and non-biologic disease-modifying antirheumatic drugs. Disclosure H. Singh: None. R. Kaur: None. G. Mohan: None.

Genetic variants of folate metabolism and the risk of multiple sclerosis

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

Pre-pregnancy training of women with early pregnancy loss and adenomyosis, taking into account folate cycle gene polymorphisms

Polymorphisms in folate cycle genes (methylene tetrahydrofolate reductase – MTHFR, methionine synthase reductase – MTRR and methionine synthase – MTR) and associated hyperhomocysteinemia and folate deficiency play an important role among multiple genetic causes early pregnancy loss.The results of studies examining the influence of polymorphic variants of the folate cycle genes in women with pregnancy losses are quite contradictory. It has been proven that prescribing folic acid preparations or in combination with other vitamins and trace elements at the stage of preparation for pregnancy and during pregnancy significantly reduces the risk of miscarriage and pregnancy loss, is an important prevention of defects in the development of the nervous system of the fetus and disorders of the autistic spectrum in newborns and children. Adenomyosis remains a complex and urgent problem in obstetrics and gynecology, as today there is convincing evidence of the negative impact of adenomyosis both on fertility and on the course and outcomes of pregnancy.The objective: to study the prevalence of folate cycle gene polymorphisms and to assess the effectiveness of vitamin-mineral complex use in the pre-gravid preparation taking into account the genetic peculiarities of folate metabolism in women with early pregnancy loss (EPL) and adenomyosis.Materials and methods. Data from the examination at the stage of pre-gravid preparation of 40 women with early pregnancy loss – EPL (5–13 weeks of gestation) and adenomyosis, which were included in the main group, and 34 women with adenomyosis without a history of EPL (control group) were analyzed.Resuts. In 73,5% of women of the control group, the C/C genotype of the MTHFR 677 C&gt;T gene prevailed, in women with EPL and adenomyosis, a significant increase in the frequency (50%) of the heterozygous polymorphism for this C/T allele of the MTHFR 677 gene and a decrease in the frequency of detection of neutral A/A allele and increased frequency (80%) of MTHFR 1298 gene allele polymorphism (A/C and C/C). In women with EPL and adenomyosis, a significant increase in homocysteine (12,8±2,3мμmol/l) and a deficiency of folic acid (5,0±0,9 ng/ml) in blood serum compared to reference values were found.Conclusions. The use of vitamin-mineral complex, which includes betaine (200 mg), cystine (200 mg), zinc (10 mg), niacin (16 mg), folic acid (in the form of 5-MTHF-glucosamin – 400 mcg), vitamin B12 (in the form of methylcobalamin – 2.5 mcg), vitamin B6 (1.4 mg) and riboflavin (1.4 mg), 1 tablet 1-2 times a day for 3 months for the pre-gravid preparation leaded to significant decrease of homocysteine concentration, normalization of folic acid concentration. This formed favorable conditions for pregnancy course and for risk reduction of possible obstetrical complications.

MTRR gene rs1801394 polymorphism is associated with neonatal birth weight in pregnant women with fetal growth retardation

Aim: to assess associations between folate cycle gene polymorphism and neonatal birth weight in pregnant women with fetal growth retardation (FGR) and related functional effects in population of the Central Black Earth Region.Materials and Methods. 98 cases of women with FGR were enrolled to a retrospective molecular and genetic screening to assess prevalence 5 SNPs (single nucleotide polymorphisms) in genes involved in folic acid cycle and methionine metabolism (rs699517 TYMS, rs2790 TYMS, rs1979277 SHMT1, rs1805087 MTR, rs1801394 MTRR).Results. It was found out that allele A of the rs1801394 MTRR was associated with a lower neonatal birth weight (recessive model: β = –0.34 ± 0.13; p = 0.009). This polymorphic locus exerts crucial functional effects by determining the amino acid substitution in methionine synthase reductase (Ile22Met) localized in the region of modified histones, which mark enhancers and promoters in ectoderm, endoderm and mesoderm cell cultures, primary osteoblast cells, brain, fat nuclei, skeletal muscles, etc. In addition, rs1801394 MTRR is found DNA sites (motifs) responsible for sensitivity to transcription factors STAT and TBX5 being also related to MTRR gene mRNA expression level in subcutaneous and visceral adipose tissue, thyroid gland, fibroblast cell culture as well as various brain regions.Conclusion. Thus, the allele A of the rs1801394 polymorphism in MTRR gene is a risk factor for a lower neonatal birth weight.

Level of homocysteine and polymorphism of genes involved in folate metabolism in women with polycystic ovary syndrome

Background. Polycystic ovary syndrome (PCOS) is a multifactorial disease in the development of which gene polymorphism plays an important role. In recent years, data on the role of homocysteine (Hcy) in the formation of PCOS have appeared, and hyperhomocysteinemia is even considered one of the main symptoms of this disease. The causes of an impaired Hcy metabolism are varied and mainly depend on the condition of the genes encoding enzymes of the folate cycle. At the same time, available data on the effect of the 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) gene polymorphisms on the development of hyperhomocysteinemia and the risk of PCOS are few and contradictory. The purpose of the study was to investigate the polymorphisms of the main genes encoding enzymes of the folate cycle (MTHFR, MTR, MTRR) and to reveal their relationship with the level of Hcy in PCOS. Material and methods. One hundred and twenty-nine women aged 20–28 years were examined: the main group — 98 patients with PCOS, the control group — 31 healthy women. The serum content of Hcy was evaluated and a molecular genetic study was conducted to identify the MTHFR, MTR, and MTRR genes. Results. Polymorphic variants of genes involved in folate metabolism were found in both patients with PCOS and in healthy women. However, serum concentration of Hcy was significantly higher in PCOS. Analysis of the MTHFR C677T polymorphism gene showed that the presence of the mutant T allele was associated with an increased Hcy level (12.9 ± 0.2 μmol/l) and the risk of PCOS (odds ratio (OR) = 1.19; 95% confidence interval (CI) 0.52–2.71). In the presence of two T alleles, the level of Hcy (14.6 ± 0.3 µmol/L) and the risk of deve­loping PCOS (OR = 7.69; 95% CI 0.98–59.87) increased even further compared to the functionally “normal” C677C genotype. There was also an association between the MTHFR gene polymorphism at locus 1298 and PCOS whose strength depended on the number of pathological C alleles and was mediated by Hcy content, although this mutation was accompanied by a less significant increase in the level of Hcy than the mutation at locus 677. Compared to carriers of the homozygous A1298A genotype, the risk of developing PCOS was 5.7 times higher in patients with one C allele, and 7.3 times higher in the presence of two C alleles. The MTRR A66A and A66G genotypes were associated with a significant increase in the level of Hcy compared to that of the control group and were associated with an increased risk of PCOS. The mutant homozygous G66G genotype was more common in the control group and had no significant effect on Hcy concentration. It is not proved that the MTR gene is a candidate gene for the development of PCOS, and its polymorphic variants have a negative effect on the level of Hcy. The combination of MTHFR C677T and A1298C, MTHFR C677T and MTR A2756G, MTR A2756G and MTRR A66G gene mutations are associated with a greater increase in Hcy and the risk of developing PCOS compared to any individual monomutation. Conclusions. The MTHFR gene polymorphism and the synergistic effect of the MTHFR, MTR, MTRR gene mutations can be important genetic determinants for homocysteine levels and the risk of PCOS.

Folic acid blocks ferroptosis induced by cerebral ischemia and reperfusion through regulating folate hydrolase transcriptional adaptive program

Cerebral ischemia-reperfusion (I/R) injury is notably linked with folic acid (FA) deficiency. The aim of our investigation was to explore the effects and underlying mechanisms by which FA mitigates I/R, specifically through regulating the GCPII transcriptional adaptive program. Initially, we discovered that following cerebral I/R, levels of FA, methionine synthase (MTR), and methylenetetrahydrofolate reductase (MTHFR) were decreased, while GCPII expression was elevated. Secondly, administering FA could mitigate cognitive impairment and neuronal damage induced by I/R. Thirdly, the mechanism of FA supplementation involved suppressing the transcriptional factor Sp1, subsequently inhibiting GCPII transcription, reducing Glu content, obstructing cellular ferroptosis, and alleviating cerebral I/R injury. In summary, our data demonstrate that FA affords protection against cerebral I/R injury by inhibiting the GCPII transcriptional adaptive response. These findings unveil that targeting GCPII might be a viable therapeutic strategy for cerebral I/R.

Association of maternal genetic polymorphisms with fetal growth restriction syndrome in Russian pregnant women from Rostov region

BackgroundFetal growth restriction (FGR) is one of the main syndromes causing fetal morbidity and mortality. It was known to be associated with different factors including maternal, fetal, and environmental. However, the effect of genetic factors in FGR is not totally understood. Recently, researchers have focused on investigating genetic variants as possible markers of FGR. This especially concerns maternal genetic polymorphisms since they could serve as prenatal prognostic biomarkers. Accordingly, we aimed to study the association of several polymorphisms affecting vital processes of pregnancy with FGR in pregnant women. Targeted polymorphisms include methylenetetrahydrofolate reductase (MTHFR) 677C > T; methionine synthase reductase (MTRR) 66A > G; methionine synthase (MTR) 2756A > G; angiotensinogen (AGT) 704 T > C; and vascular endothelial growth factor A (VEGFA) 634C > G. In addition, this study examined SNP–SNP interactions, linkage disequilibrium (LD), and haplotypes association for these polymorphisms in the studied population.ResultsAccording to our data, MTRR 66(GG) carriers had increased FGR risk (OR = 3.18, 95% CI 1.31–7.72) while (AG) genotype was associated with lower FGR risk (OR = 0.37, 95% CI 0.17–0.84). AGT 704T > C also showed significant association with FGR with allele (T) as a risk factor. SNP–SNP interactions analysis revealed antagonistic relationship between these two polymorphisms and haplotypes association confirmed this finding. High LD possibility was shown between MTHFR 677C > T and MTR 2756A > G (D′ = 0.999) located on chromosome 1.ConclusionWe suggest MTRR 66A > G and AGT 704T > C as associated with FGR susceptibility with antagonistic interaction. Result will help to expand our understanding of FGR as a multifactorial syndrome and improve prenatal prognosis using maternal genetic biomarkers, but further studies in different populations are needed to confirm findings.

Optic disc edema during strict 6° head-down tilt bed rest is related to one-carbon metabolism pathway genetics and optic cup volume.

Some astronauts on International Space Station missions experience neuroophthalmological pathologies as part of spaceflight associated neuro-ocular syndrome (SANS). Strict head-down tilt bed rest (HDTBR) is a spaceflight analog that replicates SANS findings and those who had 3-4 risk alleles (G and C alleles from the methionine synthase reductase [MTRR] A66G and serine hydroxymethyltransferase [SHMT1] C1420T, respectively) as compared to 1-2 risk alleles, had a greater increase in total retinal thickness (TRT). The objective of this study was to identify factors that contribute to the individual variability of the development of SANS in a 60d HDTBR at the German Aerospace Center's:envihab facility, Cologne Germany. 22 of 24 subjects who participated in the HDTBR study provided blood samples for genetic analysis. Total retinal thickness and optic cup volume were measured before and after bed rest. Subjects with 3-4 versus 0-2 risk alleles had greater ΔTRT during and after bed rest, and the model improved with the addition of baseline optic cup volume. This bed rest study confirms that variants of MTRR and SHMT1 are associated with ocular pathologies. Subjects with more risk alleles had the greatest HDTBR-induced ΔTRT, reaffirming that genetics predispose some individuals to developing SANS. Preflight optic cup volume and genetics better predict ΔTRT than either one alone. Whether nutritional supplements can override the genetic influences on biochemistry, physiology, and pathophysiology remains to be tested. These findings have significant implications for both aerospace and terrestrial medicine.

Association of methionine synthase reductase (MTRR A66G) polymorphism with susceptibility to acute lymphoblastic leukemia

Background and Objectives. The enzyme methionine synthase reductase is involved in cellular methylation reactions, DNA synthesis, and epigenetic processes. It is encoded by the MTRR gene, which garnered a lot of attention in current medical genetics research. This study was conducted to study the association between MTRR (A66G) polymorphism and the risk of developing acute lymphoblastic leukemia among Sudanese patients. Materials and Methods. This is a case-control study in which 150 patients with acute lymphoblastic leukemia (ALL) and 150 healthy participants as a control group were enrolled. DNA was extracted and analyzed for the MTRR (A66G) polymorphism using the real-time polymerase chain reaction. Results. Based on flow cytometry results, B-ALL was more common (79%) than T-ALL (21%). The comparison of hematological parameters in acute lymphoblastic leukemia subtypes showed a statistically significant high mean total white blood count (P=0.000) and mean blast percentage (P=0.050) in patients with T-ALL. The molecular analysis showed that the incidence of the MTRR homozygous genotypes AA and GG were higher in the patients (44% and 9.3%, respectively) compared to the control group (40% and 6.7%, respectively). In comparison, the heterozygous genotype AG was lower in the patients (46.7%) than in the control group (53.3%). However, the association between the polymorphism and acute lymphoblastic leukemia risk was not statistically significant (OR: 1.179, 95% CI 0.7459-1.865, P=0.445). Conclusions. This study concluded that MTRR A66G polymorphism was not associated with the risk of acute lymphoblastic leukemia among the Sudanese population.

Genetic polymorphisms of the folate cycle and hyperhomocysteinemia in children from areas bordering the Chоrnobyl exclusion zone

The aim of the work is to establish a relationship between polymorphisms of the FC and the state of hyperhomocysteinemia in children living in areas bordering the ChEZ). Research methods: laboratory, genetic, mathematical-statistical. Results: The levels of homocysteine (Hcy) in blood and genetic polymorphisms of the folate cycle (FC) were determined in 690 children (322 boys and 368 girls) aged 8-17 years old living near the ChEZ. It was found that 97.8% of the children had genotypes with risk alleles of FC polymorphisms. The most common combinations of 2 and 3 polymorphic variants. The proportion of hyperhomocysteinemia cases was recorded in 62.5% of those examined and did not generally depend on the number of FC polymorphisms with risk alleles. Unlike their mothers, there was no correlation between blood Hcy concentration and the number of FC polymorphisms with risk alleles in children. The frequency of hyperhomocysteinemia cases in boys was likely higher than in girls. Hyperhomocysteinemia was detected in 40% of cases among children with no risk alleles for FC genetic polymorphisms. Genotypes with allele variants of one FC polymorphism were found in 15% of cases. High frequency of hyperhomocysteinemia was recorded both in the subgroup with T/T MTHFR:677 genotype and in most genetic subgroups. A high frequency of hyperhomocysteinemia, with four polymorphisms with risk alleles, was associated with compound heterozygotes A/CMTHFR:1298 and C/TMTHFR:677 in combination with A/G MTR genotypes: A2756G and G/G A66G. The homozygous variant of the neutral allele A of the MTRR:A66G genetic polymorphism, which controls methionine synthase reductase, contributed to the improvement of Hcy methylation processes in risk allele variants of three FC polymorphisms. Conclusions: The conducted studies indicate that in children of the second Chоrnobyl generation, who have been living in conditions of constant radiation exposure in areas affected by the Chоrnobyl accident since birth, the occurrence of hyperhomocysteinemia is not associated with a specific genotype and the number of FC polymorphisms with risk alleles. The results obtained indicate the participation of genetic and environmental factors in the occurrence of hyperhomocysteinemia in the population of children living in areas located near the ChEZ.

Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency?

In early-onset (EO) cblC deficiency (MMACHC), hydroxocobalamin dose-intensification (OHCBL-DI) improved biochemical and clinical outcome. In mammals, Cobalamin is reduced, in a reaction mediated by MMACHC. Pathogenic variants in MMACHC disrupt the synthesis pathway of methyl-cobalamin (MetCbl) and 5′-deoxy-adenosyl-cobalamin (AdoCbl), cofactors for both methionine synthase (MS) and methyl-malonyl-CoA mutase (MCM) enzymes. In 5 patients (pts.), with EO cblC deficiency, biochemical and clinical responses were studied following OHCbl-DI (mean ± SD 6,5 ± 3,3 mg/kg/day), given early, before age 5 months (pts. 1, 2, 3 and 4) or lately, at age 5 years (pt. 5). In all pts., total homocysteine (tHcy), methyl-malonic acid (MMA) and Cob(III)alamin levels were measured. Follow-up was performed during 74/12 years (pts. 1, 2, 3), 33/12 years (pt. 4) and 34/12 years (pt. 5). OHCbl was delivered intravenously or subcutaneously. Mean ± SD serum Cob(III)alamin levels were 42,2 × 106 ± 28, 0 × 106 pg/ml (normal: 200–900 pg/ml). In all pts., biomarkers were well controlled. All pts., except pt. 5, who had poor vision, had central vision, mild to moderate nystagmus, and with peri-foveolar irregularity in pts. 1, 2 and 4, yet none had the classic bulls' eye maculopathy and retinal degeneration characteristic of pts. with EO cblC deficiency. Only pt. 5, had severe cognitive deficiency. Both visual and cognitive functions were better preserved with early than with late OHCBL-DI. OHCBL-DI is suggested to bypass MMACHC, subsequently to be rescued by methionine synthase reductase (MSR) and adenosyl-transferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO cblC deficiency.