Individualized Folic Acid Supplementation based on Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR), Compared with Traditional Folic Acid Supplementation, Reduces Gestational Diabetes Mellitus

Backgroud: Folic Acid (FA) may contribute to the development of gestational diabetes mellitus (GDM), but existing studies are inconsistent. We examined the genotype distributions and allele frequencies of methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms of pregnant women in China, and compared the effects of individualized folate supplementation and traditional FA supplementation on GDM.Methods: The genotype distributions and allele frequencies of MTHFR C677T, A1298C and MTRR A66G polymorphisms in 968 pregnant women (case group) were tested. FA metabolism was ranked at four levels, and then pregnant women of different levels are supplemented with different doses of FA at different periods. The case group was followed up for pregnancy complications and compared with 1,940 pregnant women traditionally supplemented with FA in the same hospital (control group).Results: The allele frequencies of MTHFR C677T were 63.3% (C) and 36.7% (T), those of MTHFR A1298C were 79.3% (A) and 20.7% (C), and those of MTRR A66G were 75.0% (A) and 25.0% (G). Compared with control group, the incidence of GDM in the case group were significantly lower, especially in high-risk pregnant women after FA supplementation.Conclusion: Traditional FA supplementation based on personal habits is controversial, but the use of polymorphisms of genes to clarify the FA metabolism of pregnant women, appropriate, timely and accurate supplementation of FA can effectively reduce gestational diabetes, especially for high-risk pregnant women.

Electroencephalogram Signatures of Agitation Induced by Sevoflurane and Its Association With Genetic Polymorphisms

Background: Volatile anesthetic-induced agitation, also called paradoxical excitation, is not uncommon during anesthesia induction. Clinically, patients with agitation may lead to self-injury or disrupt the operative position, increasing the incidence of perioperative adverse events. The study was designed to investigate clinical features of sevoflurane-induced agitation and examined whether any gene polymorphisms can potentially be used to predict agitation.Methods: One hundred seventy-six patients underwent anesthesia induction with sevoflurane were included in this study. Frontal electroencephalogram (EEG), electromyography (EMG), and hemodynamics were recorded continuously during anesthesia induction. DNA samples were genotyped using the Illumina Infinium Asian Screening Array and the SNaPshot technology. Genetic association was analyzed by genome-wide association study. Logistic regression analysis was used to determine the role of variables in the prediction of agitation.Results: Twenty-five (14.2%) patients experienced agitation. The depth of anesthesia index (Ai index) (p < 0.001), EMG (p < 0.001), heart rate (HR) (p < 0.001), and mean arterial pressure (MAP) (p < 0.001) rapidly increased during the agitation. EEG exhibited a shift toward high frequencies with spikes during agitation. The fast waves (alpha and beta) were more pronounced and the slow rhythms (delta) were less prominent during the occurrence of agitation. Moreover, three SNPs in the methionine synthase reductase (MTRR) gene were correlated to the susceptibility to agitation (p < 5.0 × 10−6). Carrying rs1801394 A > G (odds ratio 3.50, 95% CI 1.43–9.45) and/or rs2307116 G > A (3.31, 1.36–8.95) predicted a higher risk of agitation.Discussion: This study suggests that the agitation/paradoxical excitation induced by sevoflurane is characterized as increases in Ai index, EMG, HR and MAP, and the high frequency with spikes in EEG. Moreover, our results provide preliminary evidence for MTRR genetic polymorphisms, involving folate metabolism function, may be related to the susceptibility to agitation.Clinical Trial Number and Registry URL: ChiCTR1900026218; http://www.chictr.org.cn/showproj.aspx?proj=40655.

Association between Maternal and Fetal MTHFR C677T and MTRR A66G Polymorphisms with the Risk of NTDs: A Systematic Review and Meta-Analysis Study

Background: Neural tube defects (NTDs) are classed as multifactorial birth defects of the brain and spinal cord that arise during embryonic development. Although the etiology is not well understood, NTDs are reported to be prevented by maternal folic acid supplementation before and during early pregnancy. This meta-analysis study aimed to assess the association between fetal and maternal methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with the risk of NTDs. Methods: The PubMed, Scopus, and Springer Link databases were searched (from March 2000 to November 2020) for the literature on the association between MTHFR C677T and MTRR A66G polymorphisms with the risk of NTDs. Results: In total, 33 studies were reviewed in the present study, and it was revealed that, unlike MTRR A66G polymorphism, MTHFR C677T was statistically associated with the risk of NTDs in the overall population. The results of subgroup analysis showed that the Indian subcontinent subgroup with maternal MTHFR C677T polymorphism and the European subgroup with fetal MTHFR C677T polymorphism was significantly susceptible to NTDs. Conclusion: The obtained results revealed that, unlike MTRR A66G, maternal and fetal MTHFR C677T polymorphism was significantly associated with NTDs. Subgroup analysis also demonstrated that folic acid deprivation can be considered the main cause of MTHFR C677T polymorphism in some areas.

Vitamin B Mitigates Thoracic Aortic Dilation in Marfan Syndrome Mice by Restoring the Canonical TGF-β Pathway

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms have been correlated with TAA severity in MFS patients. However, the detailed relationship between the folate-methionine cycle and MFS pathogenesis remains unclear. Fbn1C1039G/+ mice were reported to be a disease model of MFS. To study the role of the folate-methionine cycle in MFS, Fbn1C1039G/+ mice were treated orally with methionine or vitamin B mixture (VITB), including vitamins B6, B9, and B12, for 20 weeks. VITB reduced the heart rate and circumference of the ascending aorta in Fbn1C1039G/+ mice. Our data showed that the Mtr and Smad4 genes were suppressed in Fbn1C1039G/+ mice, while VITB treatment restored the expression of these genes to normal levels. Additionally, VITB restored canonical transforming-growth factor β (TGF-β) signaling and promoted Loxl1-mediated collagen maturation in aortic media. This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients.

Methionine synthase reductase A66G polymorphism and ischemic stroke in younger patients

In the past decade, stroke incidence in younger adults increased. Methionine synthase reductase (MTRR) A66G polymorphism is one of the risk factors for ischemic stroke (IS). However, clinical features of IS in MTRR A66G polymorphism are not yet studied.Objective: to investigate clinical features of IS in MTRR A66G polymorphism.Patients and methods. One hundred forty-one younger patients with IS, hospitalized in the neurological department of Sverdlovsk Regional Clinical Hospital №1, were included in the study. MTRR A66G polymorphism was detected by the real-time polymerase chain reaction in all participants.Results and discussion. MTRR A66G polymorphism was present in 83.7% of younger patients with IS. Participants with MTRR A66G polymorphism had a significantly higher prevalence of arterial hypertension (р=0.029). In addition, protein C level was significantly lower in patients with MTRR A66G mutation (р=0.001).Conclusion. The majority of younger patients with IS have MTRR A66G polymorphism. Therefore, the inclusion of MTRR A66G polymorphism screening in the diagnostic algorithm of stroke in young adults seems necessary.

Significant Interaction of MTHFR C677T, A1298C and MTRR A66G Polymorphisms on the Risk of Low Birth Weight Infants

Background: To explore the relationship between maternal methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C, Methionine Synthase Reductase (MTRR) gene A66G and the recurrence of low birth weight(LBW) in offspring. Methods: Allele-specific polymerase chain reaction (ASPCR) assay combined with TaqMan probe technique were used to detect the mother’s MTHFR and MTRR genotypes respectively. And unconditional logistic regression analysis was used to evaluate the associations of MTHFR and MTRR polymorphisms, and gene-gene interaction with low birth weight.Results: MTHFR 677TT and 1298CC were independently associated with a higher risk of LBW (OR:2.22, 95%CI:1.14-4.34 and OR:2.82, 95% CI:1.15-6.87,respectively). The MTRR A66G polymorphism was associated with an significant association of LBW when combined with the MTHFR 677TT genotype, although there was no association found between LBW and MTRR A66G alone.Moreover, two or more risk genotypes carriers showed higher odds of LBW than null risk genotype one.Conclusion: Maternal MTHFR gene 677TT, 1298CC can increase the risk of LBW in the offspring.The MTRR A66G polymorphism was not associated with LBW alone. But it may exacerbate the effect of the MTHFR C677T variant.

Factors associated with rs1801394 of the methionine synthase reductase gene polymorphism in patients with rheumatoid arthritis

Clinical response to methotrexate (MT) therapy in rheumatoid arthritis (RA) can be predicted on the basis of some single nucleotide polymorphisms (SNPs) of genes, involved in folate metabolism. One of these SNPs is the rs1801394 (A66G) polymorphism of the methionine synthase reductase gene (MTRR). We investigated the association of this polymorphism with the clinical characteristics of RA patients after 6 months of MT therapy. Studies of the relationship between the response to MT therapy and the rs1801394 polymorphism have not been carried out in Russia previously.Objective: to study the possible association of the rs1801394 polymorphism with the clinical characteristics of patients with RA after 6 months of MT therapy.Patients and methods. The study included 60 patients with RA who met the ACR / EULAR criteria (2010) and received≥20 mg MT per week continuously. Based on the EULAR criteria, patients were divided into two groups: group 1 (n=30) with a good (DAS28>1.2) and group 2 (n=30) with an unsatisfactory (DAS28 <1.2) response to MT therapy. Genotyping of the rs1801394 polymorphism was performed by allelic discrimination using real-time polymerase chain reaction.Results and discussion. The frequency distribution of the A66G polymorphism genotypes in both groups was similar, however, in the 2nd group with an unsatisfactory response, there was a tendency towards a higher frequency of the mutant GG genotype (p=0.067). An association of the A66G polymorphism with gender and disease duration was found. In group 1, the AG genotype was more often detected in men than in women (p=0.017). In group 2, the AG genotype was also more common in men (p=0.075). In addition, in this group, carriers of the G allele (genotypes AG and GG) had a longer duration of the disease than carriers of the AA genotype (p=0.003 and p=0.005, respectively).Conclusion. In the present study, the relationship of the studied polymorphism rs1801394 of the MTRR gene with gender and duration of RA disease was established.

THE STUDY OF SOCIAL-MEDICAL AND GENETIC RISKS OF REPRODUCTIVE LOSSES

Object of research: homozygous and heterozygous disorders of genes encoding the enzymes of the folate cycle, methylenetetrahydrofolate reductase (MTHFR) and methionine-synthase-reductase (MTRR). Solved problem: an in-depth study of genetically determined risk factor’s influence for reproductive losses associated with homozygous and heterozygous disorders of folate cycle genes. Main scientific results: in-depth study of genetically determined reproductive losses as a systemic phenomenon was held. The structural characteristics of reproductive losses in population and significant predominance of pathology in the pedigrees of those examined with a burdened obstetric history of reproductive losses were determined. Also, a significant increase in the chances of reproductive loss in patients with heterozygous and homozygous inheritance of MTHFR and MTRR genes was determined. A correlation effect on the degree of genomic polymorphism of the MTHFR and MTRR gene was noted. Area of practical use of research results: medical-genetic institutions. Innovative technological product: determination of genetically risk factors for growth of reproductive losses of the population associated with homozygous and heterozygous disorders of genes encoding the enzymes of the folate cycle (MTHFR C677T and MTRR A66G). Timely adjustment of folic acid levels allows to prevent birth defects and reduce reproductive losses Scope of application of the innovative technological product: clinical medical-genetic practice using the ability to determine the polymorphism of genes MTHFR and MTRR, which makes it possible to timely adjust the level of folic acid and prevent the reproductive losses.

The effect of polymorphic markers of genes of proteins involved in the folate metabolism on the course and outcomes of the viral lung damage associated with SARS-CoV-2 infection

Introduction. Infection with human coronavirus 2 (SARS-CoV-2) associated with severe acute respiratory syndrome, forms polymorphous pattern of the infectious disease (COVID-19) in the range from mild acute respiratory infection to severe and life-threatening variations of systemic infection with respiratory tract involvement. Among significant predictors of the severe course and lethal outcome in the individuals with lung affection associated with COVID-19 infection, the increase of plasma levels of D-dimer, homocysteine, and some single-nucleotide polymorphisms (SNPs) of genes of the folate cycle proteins are singled out. Aim. To assess the role of genetic markers of folic acid metabolic disorders in the development of symptoms and the outcomes of viral lung damage associated with SARS-CoV-2 infection in the hospitalized patients. Materials and methods. In an open prospective comparative study the assessment of outcomes depending on polymorphic markers of protein genes of the folate cycle and the use of fixed combination of folic acid and vitamins В6, В12 in comprehensive therapy was performed in 117 patients with lung damage associated with SARS-CoV-2 infection. Results. Patients showed an increased relative risk of the heterozygous minor G-allele carriage of 66AG SNP of the methionine synthase reductase gene (MTRR). The homozygous MTRR G66G genotype was associated with indicators of anemia and thrombocytopenia. A statistically significant decrease in the odds ratio in achieving negative results for SARS-CoV-2 RNA detection by the 14th day of therapy in patients with the heterozygous 677CT genotype and the homozygous 677TT genotype of the MTHFR (methylenetetrahydrofalate reductase) gene was established. Conclusion. Lung damage caused by SARS-CoV-2 infection is associated with an increased risk of genetic metabolic disorder of folate and vitamin B12.