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.

Rescue of Methionine Dependence by Cobalamin in a Human Colorectal Cancer Cell Line.

Methionine dependence is a characteristic of most cancer cells where they are unable to proliferate when the essential amino acid methionine is replaced with its precursor homocysteine in the growing media. Normal cells, on the other hand, thrive under these conditions and are referred to as methionine-independent. The reaction that adds a methyl group from 5-methyltetrahydrofolate to homocysteine to regenerate methionine is catalyzed by the enzyme methionine synthase with the cofactor cobalamin (vitamin B12). However, decades of research have shown that methionine dependence in cancer is not due to a defect in the activity of methionine synthase. Cobalamin metabolism has been tied to the dependent phenotype in rare cell lines. We have identified a human colorectal cancer cell line in which the cells regain the ability to proliferation in methionine-free, L-homocystine-supplemented media when cyanocobalamin is supplemented at a level of 1 µg/mL. In human SW48 cells, methionine replacement with L-homocystine does not induce any measurable increase in apoptosis or reactive oxygen species production in this cell line. Rather, proliferation is halted, then restored in the presence of cyanocobalamin. Our data show that supplementation with cyanocobalamin prevents the activation of the integrated stress response (ISR) in methionine-deprived media in this cell line. The ISR-associated cell cycle arrest, characteristic of methionine-dependence in cancer, is also prevented, leading to the continuation of proliferation in methionine-deprived SW48 cells with cobalamin. Our results highlight differences between cancer cell lines in the response to cobalamin supplementation in the context of methionine dependence.

Association of Increased Homocysteine Levels with Impaired Folate Metabolism and Vitamin B Deficiency in Early-Onset Multiple Sclerosis.

The contents of homocysteine (HCy), cyanocobalamin (vitamin B12), folic acid (vitamin B9), and pyridoxine (vitamin B6) were analyzed and the genotypes of the main gene polymorphisms associated with folate metabolism (C677T and A1298C of the MTHFR gene, A2756G of the MTR gene and A66G of the MTRR gene) were determined in children at the onset of multiple sclerosis (MS) (with disease duration of no more than six months), healthy children under 18 years (control group), healthy adults without neurological pathology, adult patients with MS at the onset of disease, and adult patients with long-term MS. A significant increase in the HCy levels was found in children at the MS onset compared to healthy children of the corresponding age. It was established that the content of HCy in children has a high predictive value. At the same time, an increase in the HCy levels was not accompanied by the deficiency of vitamins B6, B9, and B12 in the blood. The lack of correlation between the laboratory signs of vitamin deficiency and HCy levels may be due to the polymorphic variants of folate cycle genes. An increased HCy level should be considered as a marker of functional disorders of folate metabolism accompanying the development of pathological process in pediatric MS. Our finding can be used to develop new approaches to the prevention of demyelination in children and treatment of pediatric MS.

Genetic variants of folate metabolism and the risk of multiple sclerosis.

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.

Whole genome identification, molecular docking and expression analysis of enzymes involved in the selenomethionine cycle in Cardamine hupingshanensis.

BACKGROUND: The selenomethionine cycle (SeMTC) is a crucial pathway for the metabolism of selenium. The basic bioinformatics and functions of four enzymes involved in the cycle including S-adenosyl-methionine synthase (MAT), SAM-dependent methyltransferase (MTase), S-adenosyl-homocysteine hydrolase (SAHH) and methionine synthase (MTR), have been extensively reported in many eukaryotes. The identification and functional analyses of SeMTC genes/proteins in Cardamine hupingshanensis and their response to selenium stress have not yet been reported. RESULTS: In this study, 45 genes involved in SeMTC were identified in the C. hupingshanensis genome. Phylogenetic analysis showed that seven genes from ChMAT were clustered into four branches, twenty-seven genes from ChCOMT were clustered into two branches, four genes from ChSAHH were clustered into two branches, and seven genes from ChMTR were clustered into three branches. These genes were resided on 16 chromosomes. Gene structure and homologous protein modeling analysis illustrated that proteins in the same family are relatively conserved and have similar functions. Molecular docking showed that the affinity of SeMTC enzymes for selenium metabolites was higher than that for sulfur metabolites. The key active site residues identified for ChMAT were Ala269 and Lys273, while Leu221/231 and Gly207/249 were determined as the crucial residues for ChCOMT. For ChSAHH, the essential active site residues were found to be Asn87, Asp139 and Thr206/207/208/325. Ile204, Ser111/329/377, Asp70/206/254, and His329/332/380 were identified as the critical active site residues for ChMTR. In addition, the results of the expression levels of four enzymes under selenium stress revealed that ChMAT3-1 genes were upregulated approximately 18-fold, ChCOMT9-1 was upregulated approximately 38.7-fold, ChSAHH1-2 was upregulated approximately 11.6-fold, and ChMTR3-2 genes were upregulated approximately 28-fold. These verified that SeMTC enzymes were involved in response to selenium stress to varying degrees. CONCLUSIONS: The results of this research are instrumental for further functional investigation of SeMTC in C. hupingshanensis. This also lays a solid foundation for deeper investigations into the physiological and biochemical mechanisms underlying selenium metabolism in plants.

Flexible B12 ecophysiology of Phaeocystis antarctica due to a fusion B12-independent methionine synthase with widespread homologues.

Coastal Antarctic marine ecosystems are significant in carbon cycling because of their intense seasonal phytoplankton blooms. Southern Ocean algae are primarily limited by light and iron (Fe) and can be co-limited by cobalamin (vitamin B12). Micronutrient limitation controls productivity and shapes the composition of blooms which are typically dominated by either diatoms or the haptophyte Phaeocystis antarctica. However, the vitamin requirements and ecophysiology of the keystone species P. antarctica remain poorly characterized. Using cultures, physiological analysis, and comparative omics, we examined the response of P. antarctica to a matrix of Fe-B12 conditions. We show that P. antarctica is not auxotrophic for B12, as previously suggested, and identify mechanisms underlying its B12 response in cultures of predominantly solitary and colonial cells. A combination of proteomics and proteogenomics reveals a B12-independent methionine synthase fusion protein (MetE-fusion) that is expressed under vitamin limitation and interreplaced with the B12-dependent isoform under replete conditions. Database searches return homologues of the MetE-fusion protein in multiple Phaeocystis species and in a wide range of marine microbes, including other photosynthetic eukaryotes with polymorphic life cycles as well as bacterioplankton. Furthermore, we find MetE-fusion homologues expressed in metaproteomic and metatranscriptomic field samples in polar and more geographically widespread regions. As climate change impacts micronutrient availability in the coastal Southern Ocean, our finding that P. antarctica has a flexible B12 metabolism has implications for its relative fitness compared to B12-auxotrophic diatoms and for the detection of B12-stress in a more diverse set of marine microbes.

Genetic Association between the Risk of Dental Caries and MTR Gene Polymorphism in Chinese Children.

Early childhood caries (ECC) is common in children. Little is known about the genetic association of the methionine synthesis reductase (MTRR) gene rs1801394 and methionine synthetase (MTR) gene rs1805087 polymorphisms with ECC, which was examined in the Chinese Han population. Genotyping was performed using the buccal mucosa from 150 normal and 150 ECC children. For genotype and allele distribution comparison, Chi-square test and multiple logistic regression analysis were performed. The odd ratio (OR) and 95% confidence interval (CI) were calculated. MTR gene rs1805087 AG genotype distribution in the ECC group was clearly different from the control group (P = 0.029), and the ECC risk in cases with AG genotype was 0.525 times lower than those carrying AA genotype (95% CI = 0.292-0.942). Logistic regression analysis after adjustment for other clinical indicators determined that the MTR gene rs1805087 AG genotype was still strongly associated with susceptibility to ECC (OR = 0.499, 95% CI = 0.273-0.913, P = 0.024). Significant association was also seen for sugary food intakes (OR = 1.965, 95% CI = 1.162-3.321, P = 0.012), tooth brushing (OR = 0.569, 95% CI = 0.356-0.924, P = 0.023) and sex (OR = 0.562, 95% CI = 0.349-0.907, P = 0.018) with ECC risk. No notable genetic association was found between MTRR gene rs1801394 polymorphism and ECC risk. MTR gene rs1805087 polymorphism may aggrandize the susceptibility to ECC, and AA genotype appeared to be a dangerous element for the development of ECC.

Antimalarial target vulnerability of the putative Plasmodium falciparum methionine synthase.

Background: Plasmodium falciparum possesses a cobalamin-dependent methionine synthase (MS). MS is putatively encoded by the PF3D7_1233700 gene, which is orthologous and syntenic in Plasmodium. However, its vulnerability as an antimalarial target has not been assessed. Methods: We edited the PF3D7_1233700 and PF3D7_0417200 (dihydrofolate reductase-thymidylate synthase, DHFR-TS) genes and obtained transgenic P. falciparum parasites expressing epitope-tagged target proteins under the control of the glmS ribozyme. Conditional loss-of-function mutants were obtained by treating transgenic parasites with glucosamine. Results: DHFR-TS, but not MS mutants showed a significant proliferation defect over 96 h, suggesting that P. falciparum MS is not a vulnerable antimalarial target.

Growth requirement for methionine in human melanoma-derived cell lines with different levels of MMACHC expression and methylation.

Methionine dependence, the inability to grow in culture when methionine in the medium is replaced by its metabolic precursor homocysteine, occurs in many tumor cell lines. In most affected lines, the cause of methionine dependence is not known. An exception is the melanoma-derived cell line MeWo-LC1, in which hypermethylation of the MMACHC gene is associated with decreased MMACHC expression. Decreased expression results in decreased provision of the methylcobalamin cofactor required for activity of methionine synthase and thus decreased conversion of homocysteine to methionine. Analysis of data in the Cancer Cell Line Encyclopedia Archive demonstrated that MMACHC hypermethylation and decreased MMACHC expression occurred more frequently in melanoma cell lines when compared to other tumor cell lines. We further investigated methionine dependence and aspects of MMACHC function in a panel of six melanoma lines, including both melanoma lines with known methionine dependence status (MeWo, which is methionine independent, and A375, which is methionine dependent). We found that the previously unclassified melanoma lines HMCB, Colo829 and SH-4 were methionine dependent, while SK-Mel-28 was methionine independent. However, despite varying levels of MMACHC methylation and expression, none of the tested lines had decreased methylcobalamin and adenosylcobalamin synthesis as seen in MeWo-LC1, and the functions of both cobalamin-dependent enzymes methionine synthase and methylmalonyl-CoA mutase were intact. Thus, while melanoma lines were characterized by relatively high levels of MMACHC methylation and low expression, the defect in metabolism observed in MeWo-LC1 was unique, and decreased MMACHC expression was not a cause of methionine dependence in the other melanoma lines.

Structure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo.

Cobalamin-dependent methionine synthase (MS) is a key enzyme in methionine and folate one-carbon metabolism. MS is a large multi-domain protein capable of binding and activating three substrates: homocysteine, folate, and S-adenosylmethionine for methylation. Achieving three chemically distinct methylations necessitates significant domain rearrangements to facilitate substrate access to the cobalamin cofactor at the right time. The distinct conformations required for each reaction have eluded structural characterization as its inherently dynamic nature renders structural studies difficult. Here, we use a thermophilic MS homolog (tMS) as a functional MS model. Its exceptional stability enabled characterization of MS in the absence of cobalamin, marking the only studies of a cobalamin-binding protein in its apoenzyme state. More importantly, we report the high-resolution full-length MS structure, ending a multi-decade quest. We also capture cobalamin loading in crystallo, providing structural insights into holoenzyme formation. Our work paves the way for unraveling how MS orchestrates large-scale domain rearrangements crucial for achieving challenging chemistries.

Common Variants in One-Carbon Metabolism Genes (MTHFR, MTR, MTHFD1) and Depression in Gynecologic Cancers.

We investigated the association between methylenetetrahydrofolate reductase (gene MTHFR 677C>T, rs1801133), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR 2756A>G, rs1805087), and methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (gene MTHFD1 1958G>A, rs2236225)-well-studied functional variants involved in one-carbon metabolism-and gynecologic cancer risk, and the interaction between these polymorphisms and depression. A total of 200 gynecologic cancer cases and 240 healthy controls were recruited to participate in this study. Three single-nucleotide variants (SNVs) (rs1801133, rs1805087, rs2236225) were genotyped using the PCR-restriction fragment length polymorphism method. Depression was assessed in all patients using the Hamilton Depression Scale. Depression was statistically significantly more frequent in women with gynecologic cancers (69.5% vs. 34.2% in controls, p < 0.001). MTHFD1 rs2236225 was associated with an increased risk of gynecologic cancers (in dominant OR = 1.53, p = 0.033, and in log-additive models OR = 1.37, p = 0.024). Moreover, an association was found between depression risk and MTHFR rs1801133 genotypes in the controls but not in women with gynecologic cancers (in codominant model CC vs. TT: OR = 3.39, 95%: 1.49-7.74, p = 0.011). Cancers of the female reproductive system are associated with the occurrence of depression, and ovarian cancer may be associated with the rs2236225 variant of the MTHFD1 gene. In addition, in healthy aging women in the Polish population, the rs1801133 variant of the MTHFR gene is associated with depression.

Association of MTR and MTRR genes and oral health-related quality of life in children with dental caries.

This study aimed to assess whether genetic polymorphisms in MTR and MTRR are potential biomarkers of oral health-related quality of life (OHRQoL) in children with caries. A cross-sectional study was designed wherein pairs of parents/caregivers and children (aged two-five years) were selected. Clinical examination was used to detect dental caries, which were classified as low-severity and high-severity caries. The Early Childhood Oral Health Impact Scale (ECOHIS) questionnaire was used to assess OHRQoL. Genomic DNA extracted from the saliva was used to analyze two missense genetic polymorphisms: MTR (rs1805087) and MTRR (rs1801394). Mann-Whitney non-parametric test was used to analyze candidate genes with OHRQoL scale and domain, with a significance level of p≤0.05. MTR (rs1805087) was found associated (p = 0.05) with children's OHRQoL subscale scores in the dominant model (GG + AG). Genetic polymorphisms in MTR may increase the risk of poor OHRQoL in children with caries. Further studies are needed to investigate genetics, molecular factors, and OHRQoL.

The role of methionine synthases in fungal metabolism and virulence.

Methionine synthases (MetH) catalyse the methylation of homocysteine (Hcy) with 5-methyl-tetrahydrofolate (5, methyl-THF) acting as methyl donor, to form methionine (Met) and tetrahydrofolate (THF). This function is performed by two unrelated classes of enzymes that differ significantly in both their structures and mechanisms of action. The genomes of plants and many fungi exclusively encode cobalamin-independent enzymes (EC.2.1.1.14), while some fungi also possess proteins from the cobalamin-dependent (EC.2.1.1.13) family utilised by humans. Methionine synthase's function connects the methionine and folate cycles, making it a crucial node in primary metabolism, with impacts on important cellular processes such as anabolism, growth and synthesis of proteins, polyamines, nucleotides and lipids. As a result, MetHs are vital for the viability or virulence of numerous prominent human and plant pathogenic fungi and have been proposed as promising broad-spectrum antifungal drug targets. This review provides a summary of the relevance of methionine synthases to fungal metabolism, their potential as antifungal drug targets and insights into the structures of both classes of MetH.

Conformational switching and flexibility in cobalamin-dependent methionine synthase studied by small-angle X-ray scattering and cryoelectron microscopy.

Cobalamin-dependent methionine synthase (MetH) catalyzes the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate (CH3-H4folate) using the unique chemistry of its cofactor. In doing so, MetH links the cycling of S-adenosylmethionine with the folate cycle in one-carbon metabolism. Extensive biochemical and structural studies on Escherichia coli MetH have shown that this flexible, multidomain enzyme adopts two major conformations to prevent a futile cycle of methionine production and consumption. However, as MetH is highly dynamic as well as both a photosensitive and oxygen-sensitive metalloenzyme, it poses special challenges for structural studies, and existing structures have necessarily come from a "divide and conquer" approach. In this study, we investigate E. coli MetH and a thermophilic homolog from Thermus filiformis using small-angle X-ray scattering (SAXS), single-particle cryoelectron microscopy (cryo-EM), and extensive analysis of the AlphaFold2 database to present a structural description of the full-length MetH in its entirety. Using SAXS, we describe a common resting-state conformation shared by both active and inactive oxidation states of MetH and the roles of CH3-H4folate and flavodoxin in initiating turnover and reactivation. By combining SAXS with a 3.6-Å cryo-EM structure of the T. filiformis MetH, we show that the resting-state conformation consists of a stable arrangement of the catalytic domains that is linked to a highly mobile reactivation domain. Finally, by combining AlphaFold2-guided sequence analysis and our experimental findings, we propose a general model for functional switching in MetH.

The clinical effects of modified tinnitus relieving sound (MTRS) for chronic tinnitus: protocol for a randomized controlled trial.

INTRODUCTION: Chronic subjective tinnitus has become an increasingly serious hazard that affects the health-related quality of life for millions of people. Due to the lack of curative treatment strategies, this study aims to introduce a novel acoustic therapy named the modified tinnitus relieving sound (MTRS) for tinnitus and to evaluate the efficacy of MTRS in comparison with unmodified music (UM) which served as a control. METHODS AND ANALYSIS: A randomized, double-blinded, controlled, clinical trial will be carried out. Sixty-eight patients with subjective tinnitus will be recruited and randomly allocated into two groups in 1:1 ratio. The primary outcome is Tinnitus Handicapped Inventory (THI); the secondary outcomes are the Hospital Anxiety and Distress Scale (HADS; HADS subscales for Anxiety (HADS-A) and Depression (HADS-D)), Athens Insomnia Scale (AIS), the visual analog scale (VAS) for tinnitus, and tinnitus loudness matched by sensation level (SL). Assessment will be performed at baseline and at 1, 3, 9, and 12 months post-randomization. The sound stimulus will be persistent until 9 months after randomization, and be interdictory in the last three months. Data collected during the intervention process will be analyzed and compared to baseline. ETHICS AND DISSEMINATION: This trial received ethical approval from the Institutional Review Board (IRB) of Eye & ENT Hospital of Fudan University (No. 2017048). The study results will be disseminated via academic journals and conferences. FUNDING: This study is supported by the Shanghai Shenkang Development Program (SHDC12019119), the Excellent Doctors-Excellent Clinical Researchers Program (SYB202008), the Shanghai Rising-Star Program (23QC1401200), the Shanghai Rising Stars of Medical Talent Youth Development Program (2021-99), the National Natural Science Foundation of China (81800912), and the National Natural Science Foundation of Shanghai (21ZR1411800). TRIAL REGISTRATION: ClinicalTrials.gov NCT04026932. Registered on 18 July 2019.

B 1 + $$ {\mathrm{B}}_1

PURPOSE: Nuclear Overhauser effect magnetization transfer ratio (NOEMTR ) is a technique used to investigate brain lipids and macromolecules in greater detail than other techniques and benefits from increased contrast at 7 T. However, this contrast can become degraded because of B 1 + $$ {\mathrm{B}}_1^{+} $$ inhomogeneities present at ultra-high field strengths. High-permittivity dielectric pads (DP) have been used to correct for these inhomogeneities via displacement currents generating secondary magnetic fields. The purpose of this work is to demonstrate that dielectric pads can be used to mitigate B 1 + $$ {\mathrm{B}}_1^{+} $$ inhomogeneities and improve NOEMTR contrast in the temporal lobes at 7 T. METHODS: Partial 3D NOEMTR contrast images and whole brain B 1 + $$ {\mathrm{B}}_1^{+} $$ field maps were acquired on a 7 T MRI across six healthy subjects. Calcium titanate DP, having a relative permittivity of 110, was placed next to the subject's head near the temporal lobes. Pad corrected NOEMTR images had a separate postprocessing linear correction applied. RESULTS: DP provided supplemental B 1 + $$ {\mathrm{B}}_1^{+} $$ to the temporal lobes while also reducing the B 1 + $$ {\mathrm{B}}_1^{+} $$ magnitude across the posterior and superior regions of the brain. This resulted in a statistically significant increase in NOEMTR contrast in substructures of the temporal lobes both with and without linear correction. The padding also produced a convergence in NOEMTR contrast toward approximately equal mean values. CONCLUSION: NOEMTR images showed significant improvement in temporal lobe contrast when DP were used, which resulted from an increase in B 1 + $$ {\mathrm{B}}_1^{+} $$ homogeneity across the entire brain slab. DP-derived improvements in NOEMTR are expected to increase the robustness of the brain substructural measures both in healthy and pathological conditions.

Association of MTR gene polymorphisms with the occurrence of non-syndromic congenital heart disease: a case-control study.

To exhaustively explore the association of infant genetic polymorphisms of methionine synthase (MTR) gene with the risk of non-syndromic congenital heart disease (CHD). A hospital-based case-control study involving 620 CHD cases and 620 health controls was conducted from November 2017 to March 2020. Eighteen SNPs were detected and analyzed. Our date suggested that the genetic polymorphisms of MTR gene at rs1805087 (GG vs. AA: aOR = 6.85, 95% CI 2.94-15.96; the dominant model: aOR = 1.77, 95% CI 1.35-2.32; the recessive model: aOR = 6.26, 95% CI 2.69-14.54; the addictive model: aOR = 1.81, 95% CI 1.44-2.29) and rs2275565 (GT vs. GG: aOR = 1.52, 95% CI 1.15-1.20; TT vs. GG: aOR = 4.93, 95% CI 1.93-12.58; the dominant model: aOR = 1.66, 95% CI 1.27-2.17; the recessive model: aOR = 4.41, 95% CI 1.73-11.22; the addictive model: aOR = 1.68, 95% CI 1.32-2.13) were significantly associated with the higher risk of CHD. And three haplotypes of G-A-T (involving rs4659724, rs95516 and rs4077829; OR = 5.48, 95% CI 2.58-11.66), G-C-A-T-T-G (involving rs2275565, rs1266164, rs2229276, rs4659743, rs3820571 and rs1050993; OR = 0.78, 95% CI 0.63-0.97) and T-C-A-T-T-G (involving rs2275565, rs1266164, rs2229276, rs4659743, rs3820571 and rs1050993; OR = 1.60, 95% CI 1.26-2.04) were observed to be significantly associated with risk of CHD. Our study found that genetic polymorphisms of MTR gene at rs1805087 and rs2275565 were significantly associated with higher risk of CHD. Additionally, our study revealed a significant association of three haplotypes with risk of CHD. However, the limitations in this study should be carefully taken into account. In the future, more specific studies in different ethnic populations are required to refine and confirm our findings.Trial registration: Registration number: ChiCTR1800016635; Date of first registration: 14/06/2018.

Cognitive Impairment Is Associated with AMPAR Glutamatergic Dysfunction in a Mouse Model of Neuronal Methionine Synthase Deficiency.

Impairment of one-carbon metabolism during pregnancy, either due to nutritional deficiencies in B9 or B12 vitamins or caused by specific genetic defects, is often associated with neurological defects, including cognitive dysfunction that persists even after vitamin supplementation. Animal nutritional models do not allow for conclusions regarding the specific brain mechanisms that may be modulated by systemic compensations. Using the Cre-lox system associated to the neuronal promoter Thy1.2, a knock-out model for the methionine synthase specifically in the brain was generated. Our results on the neurobehavioral development of offspring show that the absence of methionine synthase did not lead to growth retardation, despite an effective reduction of both its expression and the methylation status in brain tissues. Behaviors were differently affected according to their functional outcome. Only temporary retardations were recorded in the acquisition of vegetative functions during the suckling period, compared to a dramatic reduction in cognitive performance after weaning. Investigation of the glutamatergic synapses in cognitive areas showed a reduction of AMPA receptors phosphorylation and clustering, indicating an epigenomic effect of the neuronal deficiency of methionine synthase on the reduction of glutamatergic synapses excitability. Altogether, our data indicate that cognitive impairment associated with methionine synthase deficiency may not only result from neurodevelopmental abnormalities, but may also be the consequence of alterations in functional plasticity of the brain.

Association of MTR A2756G and MTRR A66G Polymorphisms With Male Infertility: An Updated Meta-Analysis.

The objective of the present study was to find out the association of folate genes MTR A2756G and MTRR A66G polymorphisms with the risk of male infertility. The databases of Google Scholar, PubMed, and Science Direct were searched to find relevant studies. Data were extracted from the eligible studies and were analyzed for pooled up odds ratio (OR) with 95% confidence interval (CI). Review Manager 5.4 was used for statistical analysis. Nineteen case-control studies were included in this meta-analysis which comprised 3621 cases and 3327 controls. Pooled analysis revealed that there is a significant association between MTR A2756G polymorphism with male infertility except for the dominant model. The ORs and 95% CI for each genetic model were as follows: 1.21 [1.03-1.42] for the allele model (G vs. A), 2.31 [1.38-3.96] for the additive model (GG vs. AA), 1.17 [0.98-1.38] for the dominant model (GG+AG vs. AA) and 2.10 [1.55-2.86] for the recessive model (GG vs. AG+AA). MTRR A66G has no noticeable association with male infertility. The current meta-analysis suggests that MTR A2756G polymorphism might be a potential risk factor for male infertility. In the future, the sample size should be increased to confirm the present results.