Folate Cycle Genes Research Articles

The role of single nucleotide variants of folate cycle genes of a mother with epilepsy in the occurrence of congenital malformations of the fetus

Aim - To study the frequency of single-nucleotide variants (ONV) rs1801133 and rs1801131 of the MTHFR gene; rs1801394 of the MTRR gene, rs1805087 of the MTR gene and rs1051266 of the SLC19A1 gene in women with epilepsy and to evaluate their associations with major congenital malformations (MCM) of the fetus. Material and methods. The study included 61 women with epilepsy who have children: 20 had different fetal MCM (main group), 41 patients had children born without MCM (comparison group). DNA was extracted from blood, and the genotyping of five ONV into four genes was analyzed by polymerase chain reaction. The frequencies of genotypes and alleles in the mothers of the main and the comparison group were determined, the differences were assessed using Pearson's chi-squared criterion (χ2) and Fisher's exact criterion. Results. There were no statistically significant differences in the frequencies of genotypes and alleles for all analyzed ONV between the main group and the comparison group. There were no statistically significant differences in the frequencies of genotypes and alleles of ONV genes of the folate cycle in mothers of children with malformations (n = 14) and without malformations (n = 22), taking valproic acid. A statistically significant relationship was revealed between the carrier of a certain haplogroup of the mother and the formation of fetal MCM. Conclusion. The MCM in a child is a multifactorial phenomenon in which genetic factors with a small effect size can play a significant role only in the case of certain unfavorable combinations.

Analysis of the contribution of polymorphisms of hemostasis system genes and folate cycle genes to the genetic presposition to the development of thrombosis in patients with Ph-negative myeloproliferative neoplasia in the Republic of Uzbekistan

Thrombotic complications often complicate the course of the underlying disease in patients with chronic myeloproliferative neoplasia. However, a thromboembolic condition is not observed in all patients.The aim of the study was to assess the carriage frequency of polymorphic genes of the blood coagulation system and folate metabolism genes and the contribution of genetic variants to the development of thrombosis in patients with chronic Ph-negative myeloproliferative neoplasia (CMPN).Materials and methods. Molecular genetic testing for the presence of genetic variants with an assessment of their frequency of occurrence and allelic load was carried out in 142 patients with CMPN. We studied polymorphisms of the folate cycle genes – A2756G (Asp919Gly) of the MTR gene, C677T (Ala22Val) of the MTHFR gene, A66G (ILe22Met) of the MTRR gene (rs1801394), as well as mutations of the genes of blood coagulation factors – G(455)A of the FGB gene, G20210A of the F2 gene, G10976A (Arg353Gln) of the F7 gene, G1691A (Arg506Gln) of the F5 gene. The study was carried out using real-time polymerase chain reaction (PCR); The biological material for the test was whole blood.Results and discussion. The study showed that only 6 out of 50 (12%) patients with thrombotic complications had no changes in the genes studied, while 88% of patients had one or another genotypic variant, which may indicate a high probability of involvement of a hereditary genetic factor in the development of hypercoagulability and thrombotic complications in patients with chronic MPN.Conclusions. A comprehensive study of the role, interaction and operating conditions of genes that control blood coagulation processes in patients with Ph-negative chronic MPN will make it possible to understand the causes of hemostatic system disorders and develop effective measures to prevent thrombotic complications in this category of patients.

Changes in <i>DNMT1</i> expression as a marker of epigenetic regulation disturbanses in multiple sclerosis patients

BACKGROUND: Multiple sclerosis is a chronic neurodegenerative autoimmune disease characterized by the presence of foci of inflammation and demyelination in the central nervous system. The initiation of pathological processes in multiple sclerosis is caused by a complex interaction of genetic factors, unfavorable environmental factors and epigenetic influences. Progressive neurological symptoms caused by axonal conduction disorders, axonal death and neurodestruction lead to a significant decreased patients’ quality of life and disability. The search for a new markers to improve diagnostic and therapeutic methods, including taking into account the genetic background and epigenetic interactions, is an urgent task.
 AIM: The work was aimed to study the changes in DNMT1 mRNA expression in multiple sclerosis patients with different disease duration, to analyze methylation of DNMT1 promoter, and compare the changes in the level of DNMT1 expression with the homocysteine content in the blood, and the presence of polymorphic variants in genes coding the key folate cycle enzymes.
 MATERIALS AND METHODS: The level of DNMT1 mRNA expression in peripheral mononuclear blood cells was assessed by reversed transcription followed by polymerase chain reaction. Fluorescent polymerase chain reaction followed by methyl-sensitive analysis of high-resolution melting curves was used to analyze methylation of the DNMT1 promoter. The content of homocysteine in the blood was determined by chemiluminescence immunoassay. The real-time polymerase chain reaction was used for genotyping by polymorphism of folate cycle genes; the fluorescent probes with the LNA modifications were used to discriminate alleles.
 RESULTS: It has been shown that in multiple sclerosis patients, including those at the onset of the disease, the level of DNMT1 mRNA expression is significantly lower than in the control group. No relationship was found between the decrease in DNMT1 expression and the level of promoter methylation. Strong positive relationship between the level of DNMT1 mRNA expression and homocysteine content in patients with multiple sclerosis and the combined effects of the genotypes of MTR A2756G and MTHFR C677T polymorphism on the expression of DNMT1 have been shown. These findings suggest that genetically determined features of folate metabolism may contribute to the disruption of epigenetic regulation in multiple sclerosis.
 CONCLUSIONS: The obtained results indicate the promise of research aimed to identifying the factors causing epigenetic changes in multiple sclerosis. Studying the mechanisms of the folate cycle genes polymorphic variants contribution to the pathogenesis of multiple sclerosis could be one of the possible ways to improve diagnostic and therapeutic approaches.

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>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.

Polymorphic substitutions in folate cycle genes as predictors of hyperhomocysteinemia in children

Introduction. Mutant alleles of genes of folate cycle enzymes can lead to the significant deterioration of its function and varying severity of pathology. Several defects in these genes lead to severe hyperhomocysteinemia, the most common form of which is a deficiency of cystathionine beta-synthase B. 
 Aim: to establish polymorphic substitutions in the genes of folate cycle enzymes that contribute to the formation of hyperhomocysteinemia in children.
 Materials and methods. Two hundred seventy one children aged of 13–18 years were examined. The analysis of genetic polymorphisms of the folate cycle was carried out using a molecular genetic method. Quantitative determination of the blood homocysteine and folic acid level was performed by chemiluminescent immunoassay on microparticles. Statistical data processing was carried out using Statistica 6.1 application programs (StatSoft Inc., USA). 
 Results. The frequency of the T allele of the MTHFR 677 gene was revealed to be higher in adolescents of the main group compared with the control (p = 0.043). The frequency of the homozygous genotype 66 AA of the MTRR gene in children of the comparison group was significantly higher (p = 0.049), however, the heterozygous genotype 66 AG of the MTRR gene was significantly more often detected in adolescents of the main group (p = 0.008). The average concentrations of homocysteine in children of the main group were 11.6 mmol/L, in adolescents of the control group 9.3 mmol/L (p = 0.021). Hyperhomocysteinemia in children of the main group was detected in 217 (80.1%) adolescents, and in 57 (49.6%) children of the control group (p < 0.001). The baseline serum folate level was determined in the children of the main group. The average amount of vitamin B9 in the blood of children of the main group was 3.7 ng/ml, and in 145 (53.5%) children this indicator was significantly reduced.
 Conclusion. Low levels of folic acid contribute to an increase in homocysteine in blood plasma. Taking vitamin B9 and vitamin folate complexes significantly reduces the level of homocysteine in blood plasma (p < 0.001).

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.

РОЛЬ ПОЛИМОРФИЗМА ГЕНОВ ФОЛАТНОГО ЦИКЛА В РАЗВИТИИ АТЕРОСКЛЕРОЗА И САХАРНОГО ДИАБЕТА 2-ГО ТИПА

Cardiovascular diseases are still the leading causes of death in the world. Atherosclerosis of the arteries of the lower extremities is one of them. A risk factor for the development of atherosclerosis is diabetes mellitus, particularly type 2. The fact that these diseases are systemic and multifactorial is generally recognized. Considering the progress of genetics and gene therapy in recent decades, the search for genes responsible for the development of both lower limb atherosclerosis and type 2 diabetes mellitus is relevant. Their identification can probably help to improve the prognosis of the course of these diseases, personalize the system of prevention and treatment. Homocysteine is an amino acid involved in the pathogenesis of both obliterative atherosclerosis and diabetes mellitus. In this context, folate cycle genes, which play a major role in the development of hyperhomocysteinemia, are of particular interest.

Assessment of the physical development of children with and without high thrombogenic risk factors in the Health Center for Children

BACKGROUND: Up to 65% diseases associated with pathological thrombus have been described; more than 100 thrombogenic risk factors leading to vascular accidents have been studied. It is known that physical development is an important indicator of health in children. The relationship between the presence of thrombogenic risk factors in various disorders of physical development in children has been studied.
 AIM: To determine the relationship between physical development disorders in children and the presence of thrombogenic risk factors.
 MATERIALS AND METHODS: The study included 396 children aged 14–18 years, who underwent physical growth assessment using the sigma deviation method and genetic testing to determine polymorphisms of folate cycle genes and polymorphisms of thrombophilia genes. Statistical processing was carried out using the application package Statistica 10.0 (StatSoft, Inc., USA).
 RESULTS: The analysis of anthropometric indicators in children showed that in the group of the patients with thrombogenic risk factors, height and body weight values with average physical disharmonious development due to excess weight were statistically significantly higher than age-reference indicators.
 CONCLUSIONS: Based on the results of the study, it has been shown that disharmony in physical development in children with high thrombogenic risk factors may be one of the risk factors for the development of thrombotic conditions.

Allelic variants of folate metabolism genes among students in Arctic Russia

AIM: To assess the prevalence of allelic variants of folate metabolism genes in Russian and Indian students living in the Arctic region of Russia.
 METHODS: A cross-sectional study was performed on a sample of ethnic Indians, students at the Faculty of General Practitioner of the Northern State Medical University, living in Arkhangelsk and ethnic Russians who were born in Arkhangelsk region. The study included 117 ethnic Indians and 195 Russian participants. A survey of participants and a molecular genetic study of the nucleotide sequence in the genes involved in the exchange of folate by real-time PCR were carried out. A group of ethnic Indians was compared with Russians according to 4 variants of the nucleotide sequence in the genes involved in folate metabolism.
 RESULTS: Statistically significant differences were observed in the frequency distribution of the T allele of the MTHFR gene polymorphism (rs1801133) (p=0.001). Among Russians, the occurrence of the T allele was found to be 26.3%, whereas among Indians, it was only 7.7%. At the same time, no statistically significant differences were found in the distribution of other polymorphic variants of the folate cycle genes between the groups. The mutant allele G of the MTRR gene polymorphism (rs1801394) was the most frequently occurring polymorphism among the participants.
 CONCLUSION: Greater prevalence of the unfavorable allele T of the MTHFR gene (rs1801133) compared to the group of ethnic Indians may suggest an elevated susceptibility to folate metabolism disorders in the Russian population

Fortified foods with methylated forms of B vitamin for the prevention of hyperhomocysteinemia

Aim. To study the relationship between blood homocysteine levels and genetic and epigenetic factors and assess the possibility of correcting homocysteine levels using products enriched with methylated forms of B vitamin.Material and methods. The study included 20 people (6 men and 14 women) aged 24-67 years (mean age — 41,5 years). Muscleto-fat ratio was determined by bioelectrical impedance analysis. The plasma concentration of homocysteine was measured using an immunochemistry analyser. Polymorphism analysis of folate cycle genes was performed using polymerase chain reaction. Statistical processing of the material, training and data prediction was performed using artificial neural networks (ANNs). Homocysteine levels before a 3-month consumption of fortified products are presented as Hc1, after — Hc2.Results. The blood level of homocysteine before taking fortified fruitberry bars varied from 6,5 to 24,2 µmol/l, averaging 12,45±2,9 µmol/l. After 3 months of use, the blood homocysteine level decreased to the range of 7,1-18 µmol/l and, on average, amounted to 10,87±2,6 µmol/l (p=0,028). Hyperhomocysteinemia was detected in two women (19,7 and 24,2 µmol/l) and one man (17,1 µmol/l). After consuming fruitberry bars, a significant decrease in blood homocysteine levels was observed from 19,7 to 14,3 µmol/l, from 24,2 to 14,1 µmol/l and from 17,1 to 15,5 µmol/l, respectively. A significant average correlation was revealed between Hc1 and Hc2 (r=0,579; p<1×10-5). Correlations were noted between blood homocysteine levels and body mass index, as well as responses about elevated blood glucose levels and the frequency of desire to reduce body weight (p<6,74×10-5).Conclusion. The results demonstrate a significant decrease in blood homocysteine in all participants when taking food products fortified with methylated forms of B vitamin (p=0,028). Individuals adhering to dietary restrictions showed a more pronounced decrease in homocysteine levels (p<6,74×10-5).

Relationship between folate cycle genes polymorphisms and development of chronic heart failure in patients with hypertension and type 2 diabetes mellitus

Relationship between folate cycle genes polymorphisms and development of chronic heart failure in patients with hypertension and type 2 diabetes mellitus

Polymorphism of folate metabolism genes in breast cancer patients

Breast cancer is a widespread oncological disorder, which is considered one of the leading causes of mortality among women. DNA repair processes a well as its methylation involving genes of folate cycle play a crucial role in cancerogenesis. The aim of the study is to generalize the current data about association between polymorphic variants of folate cycle genes MTHFR С677Т (rs1801133), MTR A2756G (rs1805087), MTRR А66G (rs1801394) with risk of breast cancer development. The search of scientific papers has been conducted using PubMed and elibrary.ru sources. Original and randomized surveys published from 2008 till 2022 have been included in this review.
 The study has accumulated sufficient data on MTHFR С677Т polymorphic variant in breast cancer patients, having significant influence on disease development. However, the data about MTR A2756G and MTRR A66G variants is quite limited. According to the findigs of many scientific papers, there is no link between polymorphic variants of these genes and breast cancerogenesis manifestation. Such factors like ethniсity and sufficient consumption of folates with nutrition can have significant impact on results and conclusions of studies about role of folate cycle genes in breast cancer patients.
 Further investigation of MTHFR С677Т (rs1801133), MTR A2756G (rs1805087) and MTRR А66G (rs1801394) genetic polymorphic variants with consideration of gene-environment and gene-gene interactions could explain the presence of individual differences of breast cancer risk.

Concentrations of vitamin B12 and folate in maternal serum and fetal fluids, metabolite interrelationships, and hepatic transcript abundance of key folate and methionine cycle genes: the impacts of maternal nutrition during the first 50 d of gestation.

Adequate maternal nutrition is key for proper fetal development and epigenetic programming. One-carbon metabolites (OCM), including vitamin B12, folate, choline, and methionine, play a role in epigenetic mechanisms associated with developmental programming. This study investigated the presence of B12 and folate in maternal serum, allantoic fluid (ALF), and amniotic fluid (AMF), as well as how those concentrations in all three fluids correlate to the concentrations of methionine-folate cycle intermediates in heifers receiving either a control (CON) or restricted (RES) diet for the first 50 d of gestation and fetal hepatic gene expression for methionine-folate cycle enzymes. Angus cross heifers (n = 43) were estrus synchronized, bred via artificial insemination with semen from a single sire, and randomly assigned to one of two nutrition treatments (CON = 20, RES = 23). Heifers were ovariohysterectomized on either day 16 (n = 14), 34 (n = 15), or 50 of gestation (n = 14), where samples of maternal serum (n = 42), ALF (n = 29), and AMF (n = 11) were collected and analyzed for concentrations of folate and B12. Concentrations of B12 and folate in ALF were greater (P < 0.05) in RES compared to CON. For ALF, folate concentrations were also greater (P < 0.01) on day 34 compared to day 50. There was a significant (P = 0.04) nutrition × fluid interaction for B12 concentrations where concentrations were greatest in restricted ALF, intermediate in control ALF, and lowest in CON and RES serum and AMF. Folate concentrations were greatest (P < 0.01) in ALF, intermediate in serum, and lowest in AMF. Additionally, positive correlations (P < 0.05) were found between ALF and AMF folate concentrations and AMF concentrations of methionine, serine, and glycine. Negative correlations (P < 0.05) between AMF folate and serum homocysteine were also observed. Both positive and negative correlations (P < 0.05) depending on the fluid evaluated were found between B12 and methionine, serine, and glycine concentrations. There was a downregulation (P = 0.05) of dihydrofolate reductase and upregulation (P = 0.03) of arginine methyltransferase 7 gene expression in RES fetal liver samples compared with CON fetal liver on day 50. Combined, these data show restricted maternal nutrition results in increased B12 and folate concentrations present in fetal fluids, and increased expression of genes for enzymes within one-carbon metabolism.

Influence of polymorphism of folate cycle genes in assisted reproductive technologies programs in women with infertility and miscarriage

Influence of polymorphism of folate cycle genes in assisted reproductive technologies programs in women with infertility and miscarriage

Assessment of the role of nutritional and genetic determinants in the formation of the risk of diseases associated with folate cycle disorders in the population of the Omsk region

A number of essential nutrients are involved in the folate cycle, and its effectiveness depends on the sufficient intake of them. In addition, polymorphic variants of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) and methionine synthase (MTR) genes affect a wide range of biochemical reactions of the folate cycle and should also be considered as a risk factor for the development of a number of diseases. The purpose of this research was to study the prevalence of these risk factors. Material and methods. The prevalence of polymorphisms of the folate cycle genes: C677T polymorphism of the MTHFR gene and A66G polymorphism of the MTRR gene in a random stratified (by sex and age) sample of the adult population of the Omsk region [n=139, 51 men, 88 women, aged 18 to 75 years, median age 37 (26; 48) years] was studied. The identification of polymorphisms was carried out by the method of allele-specific polymerase chain reaction with an electrophoretic detection scheme. Using the food intake frequency questionnaire, the dietary intake of nutrients involved in the folate cycle was determined: B vitamins (B6, B2, B9, B12), methionine, choline, in a representative stratified sample of residents of the Omsk region [n=421, 177 men, 244 women, aged 18 to 83 years, median age 37 (23; 57) years]. Results. MTHFR genotypes (A222V С677T C>T) were distributed as follows: CC-type - 51.3%, CT - 41.0%, TT - 7.7%; MTRR genotypes (I22M A>G): AA type - 57.9%, AG - 30.3%, GG - 11.8%. The analysis of actual nutrition showed consumption below the recommended dietary intake of folates in 88.2% persons, vitamin B2 and choline - in 40.5%, vitamin B6 - in 29.2%, methionine - in 22.0%. Vitamin B12 intake was within the recommended range. Conclusion. The totality of the data presented indicates the combined influence and wide distribution of factors that determine the low efficiency of the folate cycle, and, as a result, a high risk of developing a characteristic pathology for the adult population of the region, which determines the need and priorities for prevention measures, including healthy nutrition.

Hyperhomocysteinemia in children is an indicator of environmental problems associated with the chоrnobyl exclusion zone

The aim of study: determination of the genetic factor’s involvement (MTHFR:C677T polymorphism), which affects the activity of the main enzyme of the folate cycle, methylenetetrahydrofolate reductase, and environmental exposure, including the radiation factor, in the occurrence of hyperhomocysteinemia in children which living near the Chornobyl Exclusion Zone (ChEZ). Research methods. Immunochemical, mathematical and statistical. Results. Within the framework of international projects, the levels of homocysteine (Hcy) and allelic variants of the genetic polymorphism MTHFR:C677T were determined in 624 children aged 13-17 years old from Ivankivskyi and Poliskyi districts of the Kyiv region. It has been established that an increase in the level of Hcy in the blood and an increase in the number of cases of hyperhomocysteinemia in the examined groups of children are associated with forest fires in the ChEZ in 2015 and 2020. Under conditions of pronounced exposure to radioactive agents and combustion products of forest trees, the proportion of cases of hyperhomocysteinemia in groups of children with and without the T allele of the MTHFR:677 polymorphism in the genome did not have statistical differences. An indicator of ecological trouble in the ChEZ and adjacent areas is an increase, above the physiological level, in the concentration of Hcy in the blood of adolescent children with the absence of the T allele of the MTHFR:677 polymorphism in the genome. Conclusion. In areas affected by the accident at the Chornobyl nuclear power plant, it is necessary to constantly conduct regular monitoring studies of the health of children, using tests for the content of Hcy in the blood and the state of the folate cycle genes.

Associations of variants of folate cycle genes with features of the clinical course of severe intraventricular hemorrhages in premature infants.

Summary data indicate that it has increased attention to the study of the role of the folate cycle and the genes encoding its key components in the complicated course of the neonatal period in premature infants. Therefore, the aim of our study was to investigate the relationship of folate cycle gene variants with the features of the neonatal course in premature infants with severe intraventricular hemorrhages (IVH). The study included 24 preterm infants with with IVHs of 3d and 4th degree that received standard clinical, laboratory and instrumental examination. Apgar scores at 1 and 5 minutes were significantly lower in patients with AA genotype according to variant A1298C of the MTHFR gene. The concentration of total protein on 6th day after birth was negatively correlated with the A66G variant of the MTRR gene. The mean concentration of ionized calcium in the first day after birth was higher in the subgroup of patients with the AA genotype (according to variant A1298C of the MTHFR gene). In the subgroup of patients requiring mechanical ventilation, the frequency of AA genotype according to variant A2756G of the MTR gene was significantly increased. The presence of respiratory disorders and oxygen dependence was negatively correlated with variant A1298C MTHFR. The day of surfactant administration was positively correlated with variant A1298C of the MTHFR gene. The results of this study indicate that gene variants MTHFR (C677T, A1298C), MTRR (A66G), MTR (A2756G), RFC1 (G80A) may affect the neonatal course in premature infants with severe IVH.

Role of intergenic interactions among folate cycle genes in the development of fetal growth retardation

Objective: Metabolic disturbances in the folate cycle in mothers can lead to fetal growth retardation (FGR). This study was to analyze the role of intergenic interactions among maternal folate cycle genes in the development of FGR. Methods: This case-control study recruited 365 women in the third trimester of pregnancy, including 122 FGR patients and 243 controls. The women were genotyped for 5 polymorphisms of the 4 folate cycle genes: MTR (rs1805087), MTRR (rs1801394), serine hydroxymethyl transferase (SHMT1; rs1979277), and TYMS (rs699517 and rs2790). The SNP × SNP interactions in the two-, three-, and four-locus models were analyzed using the multifactor dimensionality reduction method and a modification of it (the model-based multifactor dimensionality reduction method). Results: Four loci of maternal folate cycle genes (rs1805087 MTR, rs2790 TYMS, rs1801394 MTRR, and rs1979277 SHMT1) were associated with FGR in 3 significant models of single nucleotide polymorphism (SNP) × SNP interactions (two-, three-, and four-locus models) (P &lt;0.05). The highest contribution to FGR was made by polymorphic loci rs1979277 SHMT1 (1.70% of entropy), rs1805087 MTR (0.96%), and interactions between rs1979277 SHMT1 × rs1805087 MTR (-1.11%) and rs1801394 MTRR × rs1979277 SHMT1 (−0.64%). The four-locus maternal genotype combination AG rs1801394 MTRR × AA rs1805087 MTR × CT rs1979277 SHMT1 × AG rs2790 TYMS was associated with an increased risk of FGR (β = 2.69, P = 0.012). FGR-associated SNPs were correlated with the expression of 16 genes (MTR, MTRR, SHMT1, ALKBH5, CTD-2303H24.2, ENOSF1, FAM106A, FOXO3B, LGALS9C, LLGL1, MIEF2, NOS2P2, RP11-806L2.6, SMCR8, TOP3A, and USP32P2) in various tissues and organs related to FGR pathophysiology. Conclusion: SNP × SNP interactions of maternal folate cycle genes (MTR, MTRR, SHMT1, and TYMS) are associated with the development of FGR.

Genetic control of homocysteine metabolism in children living near the chоrnobyl exclusion zone

The aim of study: to determine the involvement of folate cycle genes in the occurrence of hyperhomocysteinemia in children from Ivankivskyi district of Kyiv region of Ukraine 35 years after the accident at the Chornobyl nuclear power plant. Research methods. Immunochemical, mathematical and statistical. Results. Homocysteine levels were determined in 217 children aged 12-17 from Ivankivskyi district of Kyiv region, as well as genetic polymorphisms of the folate cycle. An excess of homocysteine in the blood over 10 µmol/l (a state of hyperhomocysteinemia) was detected in 65.44 % (142 out of 217) of those examined, among boys – 69.79 % (67 out of 96), among girls – 61.98 % (75 out of 121). The largest proportion of hyperhomocysteinemia cases was registered in the subgroup of children with the basic polymorphism MTHFR: 677TT – 94.44 % of cases. In most cases, hyperhomocysteinemia in children was associated with an environmental factor, including radioactive elements and their decay products. The system for the prevention of hyperhomocysteinemia and its consequences in children living in areas affected by the accident at the Chornobyl nuclear power plant should include regular monitoring of the content of radionuclides in the body of children and locally produced food, the content of homocysteine in the blood, and assessment of the state of folate cycle genes.

Gene polymorphism in blood coagulation system and folate cycle affecting heart condition in patients with hemorrhagic fever and renal syndrome

One of the typical manifestations of hemorrhagic fever with renal syndrome (HFRS) is a damage to the cardiovascular system. The most promising direction of studying the causes of cardiac complications in HFRS should be considered the genetic patient characteristics, particularly taking into account the disease pathogenesis, study of polymorphism of the genes in the blood coagulation system and the folate cycle. The aim of the study was to find out an effect of polymorphism of the blood coagulation system and folate cycle genes on heart damage in hemorrhagic fever with renal syndrome. A case-control study was conducted by enrolling 19 patients in the 2019 summerautumn period at the Republican Clinical Infectious Hospital in the City of Izhevsk. The study of polymorphism of the blood coagulation system and folate cycle genes was performed by using a set of reagents RealBest-Genetics Hemostasis (12) on the CFX96 amplifier (Bio-Rad, USA). DNA was extracted from peripheral blood leukocytes with reagents RealBest Extraction 100. Transthoracic echocardiography was performed on a Vivid 7 Dimension ultrasound scanner (GE Healthcare, USA) with a matrix sector sensor M4S with a phased array at scanning frequency of 1.54.3 MHz. Statistical analysis was performed using Statistica 12, IBM SPSS 22. The group parameters were calculated and depicted as median and interquartile range (ME [Q25; Q75]). Comparison of such parameters was carried out by using the MannWhitney criterion. Comparison of the frequency distribution for genotypes and alleles in the study groups was carried out using the criterion 2. The association of alleles/genotypes with a predisposition to detectable changes was assessed by the risk ratio (OR) additionally calculating 95% confidence interval (CI). The p 0.05 was considered as statistically significant. During the study, 7 patients were found to have floating echoes on the aortic valve in the outlet of the left ventricle signs of thrombotic endocarditis. In the group of patients with signs of thrombotic endocarditis, there was revealed a higher frequency of the allele A for the F7:10976 G/A gene compared to patients lacking signs of thrombotic endocarditis (p = 0.0357). All study patients had a normal left ventricular ejection fraction (more than 50%), but during the speckle-tracking study assessing the index of averaged peak longitudinal contractility (GLPS AVG), 11 patients with impaired myocardial contractility were identified. In patients with decreased GLPS AVG, the genotype G/G of the FGB:-455 G/A gene was detected more often compared to patients with preserved myocardial contractility (p = 0.0397). In 8 patients, signs of grade 1 diastolic left ventricular dysfunction were revealed, the prognostic importance of the gene polymorphism related to the blood coagulation system and folate cycle in developing this complication has not been determined.