Methionine Synthase Reductase Gene Research Articles

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.

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.

Association of maternal methionine synthase reductase gene polymorphisms with the risk of congenital heart disease in offspring: a hospital-based case-control study

Background Evidence suggests that periconceptional folic acid supplementation may prevent congenital heart disease (CHD). Methionine synthase reductase (MTRR) is one of the key regulatory enzymes in the folate metabolic pathway. This study aimed to comprehensively evaluate the association of single nucleotide polymorphisms (SNPs) in the maternal MTRR gene with CHD risk in offspring. Methods A hospital-based case-control study involving 740 mothers of CHD cases and 683 health controls was conducted. Results The study showed that maternal MTRR gene polymorphisms at rs1532268 (C/T vs. C/C: aOR = 1.524; T/T vs. C/C: aOR = 3.178), rs1802059 (G/A vs. G/G: aOR = 1.410; A/A vs. G/G: aOR = 3.953), rs2287779 (G/A vs. G/G: aOR = 0.540), rs16879334 (C/G vs. C/C: aOR = 0.454), and rs2303080 (T/A vs. T/T: aOR = 0.546) were associated with the risk of CHD. And seven haplotypes were observed to be associated with the risk of CHD, T-G-A haplotype (OR = 1.298), C-A-C-C (OR = 4.824) and A-G haplotype (OR = 1.751) were associated with increased risk of CHD in offspring; A-A-A (OR = 0.773), T-A-A (OR = 0.557), G-A-C-C (OR = 0.598) and G-C (OR = 0.740) were associated with decreased risk of CHD in offspring. Conclusions Maternal MTRR gene polymorphisms were associated with CHD in offspring, and its haplotypes have affected the occurrence of CHD. Furthermore, given the complexity and heterogeneity of CHD, the mechanisms by which these factors influence offspring cardiac development remain unknown, and studies in larger samples in an ethnically diverse population are needed.

Genetic Polymorphisms of Gene Methionine Synthase Reductase (MTRR) and Risk of Urinary Bladder Cancer.

Methionine synthase reductase (MTRR) gene involved in the signaling for production of enzyme called methionine synthase reductase that use for the synthesis of methionine, which further used in DNA replication and repair. Genetic variation in MTRR gene may alter the susceptibility of developing urinary bladder cancer. The present study undertaken to identify the contribution of genetic polymorphisms in the MTRR gene on the selected polymorphic sites including c.66A>G and c.524C>T towards urinary bladder cancer risk. Direct-DNA sequencing method was applied for the observation of genotyping distribution of MTRR c.66A>G and c.524C>T polymorphisms in 232 histopathological confirmed cases of transitional cell carcinoma (TCC) of urinary bladder cancer and 250 age-, sex- and ethnicity-matched cancer free controls. With significant difference (p = 0.05) of genotype analysis further corresponding Odds ratio (OR) and 95% confidence interval (CI) were calculated. Multivariable logistic regression analysis was applied for adjusting significant confounder variables. Haploview software (version 4.2) was used to perform pairwise Linkage Disequilibrium (LD) analysis. Age (p = 0.01), Habit of smoking (p = 0.05), tobacco consumption (p = 0.001) and diet (p = 0.02) were significantly differed between cases and controls. Both the MTRR substitution showed higher risk of developing urinary bladder cancer (p = <0.001), although this effect alters in multivariable logistic regression analysis in a protective association for both the substitution. No LD observed between the c.66A>G and c.524C>T substitutions. In conclusion, MTRR c.66A>G and c.524C>T substitutions showed a joint effect with the other associated risk factors. Further studies with a greater number of subjects of different ethnicity and polymorphisms are recommended for the better understanding urinary bladder cancer etiology and to screen the population who are at higher risk of developing urinary bladder cancer.

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.

Association of methylenetetrahydrofolate reductase polymorphism and male infertility in type 2 diabetes mellitus patients

Introduction: As per World Health Organization, Infertility is a condition which is characterized by not getting conceived with more than 1-year of unprotected sexual intercourse without usage of any contraceptive aids. Folate has a significant role in the metabolism of the cells, like nucleic acids synthesis, gene expression by means of remethylation of the homocysteine into methionine. In the males, deficiency of folate leads to reduced proliferation of the sperm cells. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase genes result in alterations of the methylations resulting pathological conditions being a potential risk factor for male infertility. Materials and MethodS: A total of 100 diabetic infertile males were selected as the study group and 100 nondiabetic fertile males were included as the control group. Blood samples were analyzed for the MTHFR polymorphisms. DNA extraction was done and the extract is subjected to polymerase chain reaction amplification. The resultant is subjected to electrophoresis for MTHFR gene allele confirmation. Statistical analysis was done using IBM SPSS Statistics 20 package. Chi-square test, odds ratio has been done and P < 0.05 is considered statistically significant. Results: Genotype frequencies of MTHFR C677T, A1298C in all the subjects were analyzed for the Hardy–Weinberg law of genetic equilibrium. Mutant polymorphisms of MTHFR C677T, i.e., thymine-thymine and cytosine-thymine were increased significantly. Similarly, MTHFR A1298C mutant polymorphisms, i.e. adenine-cytosine, cytosine-cytosine were increased significantly in the infertile group than in the fertile group. Discussion: Mutations of both MTHFR C677T, A1298C are found to be linked with lowered enzyme activity. We found that the occurrence of mutant homozygous and mutant heterozygous genotypes was increased in a diabetic male infertile group when compared to nondiabetic fertile group. Hence, it can be concluded that presence of single-nucleotide polymorphisms of MTHFR will increase the risk of infertility in diabetic male population.

MTRR rs1532268 polymorphism and gastric cancer risk: evidence from a meta-analysis.

ObjectiveThe methionine synthase reductase (MTRR) gene encodes the MTRR enzyme involved in the metabolic pathway of homocysteine. Several studies investigated the effect of the MTRR rs1532268 gene polymorphism on the risk of gastric cancer (GC), but the results have been inconsistent.MethodsWe performed a comprehensive and systematic search of PubMed, Google Scholar, MEDLINE, Science Direct, Scopus, CNKI, and Web of Science. Five studies were included in this meta-analysis to determine whether MTRR rs1532268 polymorphism contributes to the risk of GC.ResultsPooled data indicated that the MTRR rs1532268 polymorphism significantly increased GC risk under the allele comparison model (odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.01–1.29) and dominant model (OR = 1.14, 95% CI = 1.00–1.30). In the analysis stratified by ethnicity, no relationship was found in Whites or Asians.ConclusionOur meta-analysis suggests a positive correlation between MTRR rs1532268 polymorphism and GC development.

Analysis of the frequency distribution of five single-nucleotide polymorphisms of the MTRRgene in a Chinese pediatric population with acute lymphoblastic leukemia.

The objective of the present study was to examine the frequency distribution of five single-nucleotide polymorphisms (SNPs; rs1801394 A>G, rs1532268 C>T, rs162036 A>G, rs10380 C>T, and rs9332 C>T) of the methionine synthase reductase (MTRR) gene, their effects on methotrexate (MTX) concentration, and the risk of relapse in a Chinese pediatric population with acute lymphoblastic leukemia (ALL). This was a retrospective single-center study, and all analyses were exploratory. Pediatric Department of Beijing Shijitan Hospital, Capital Medical University, Beijing, China. One hundred and forty pediatric patients with ALL. All patients were treated according to the Chinese Children's Leukemia Group (CCLG)-ALL 2008 protocol. Serum MTX concentrations were measured using fluorescence polarization immunoassay. Genotyping of five SNPs was performed using the Sequenom MassARRAY iPLEX platform. Chinese children with ALL had a significantly lower frequency of rs1801394 G than European (EUR) and South Asian (SAS) populations; significantly lower frequency of rs1532268 T than American (AMR), EUR, and SAS populations; and significantly lower frequencies of rs162036 G, rs10380 T, and rs9332 T than African and AMR populations (p<0.01). Seven haplotypes were observed, with the ACACC being the most common haplotype (49.9%) in our study. The median dose-normalized concentrations of MTX in serum at 24h in children with rs1532268 CT and TT genotypes were significantly higher than those with CC genotype (p=0.04). Compared with children with AA-CC-AA-CC-CC diplotype, a significantly higher risk of relapse was observed in children with AG-CC-AA-CC-CC and AG-CC-AG-CC-CC diplotypes (p=0.03 and 0.003, respectively). The present study confirmed the ethnic differences in the distribution of MTRR rs1801394, rs1532268, rs162036, rs10380, and rs9332 polymorphisms. The rs1532268 polymorphism had greater effects on MTX disposition. The AG-CC-AA-CC-CC and AG-CC-AG-CC-CC diplotypes were significantly associated with higher risk of relapse of ALL.

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.

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&gt;1.2) and group 2 (n=30) with an unsatisfactory (DAS28 &lt;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.

Влияние полиморфных маркеров генов белков — участников фолатного метаболизма на течение и исходы вирусного поражения легких, связанного с инфицированием коронавирусом SARS-CoV-2

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.

Genetic predictors of vascular complications in adolescents involved in sports

Introduction. The urgency of the problem is because the carriage of genetic predictors of thrombogenic risk in adolescents can be a significant factor in the formation of arterial and venous thromboses, leading to disability and even death, especially after significant sports overloads. Materials and methods. DNA genotyping was carried out in 259 boys aged 14 to 17 years who were professionally involved in sports for a long time. The reference group consisted of 228 students who were not additionally involved in sports sections at the age of 14-17 years of I-II health groups. Genetic testing was performed using the Real-Time PCR method using competing TagMan probes. 12 genetic allelic DNA polymorphisms were studied. The analysis of laboratory and instrumental methods of research. The results were statistically processed using the STATISTICA 10.0 software package. Results. Among adolescent athletes, a group of children with a high risk of vascular complications was identified on the basis of the studied thrombogenic DNA polymorphisms and folate metabolism genes. The frequency of the minor C1565 allele of the GPIIIa gene was significantly more often determined in adolescent athletes, while the variant of the minor 4G allele (-675) of the PAI-I gene was significantly more often detected in relatively healthy schoolchildren. The heterozygous genotype 1565 TC of the GPIIIa gene, the heterozygous genotype 1298 of the AC MTHFR gene, and the heterozygous genotype 66 AG of the methionine synthase reductase gene (MTRR) were found to be more pronounced in adolescent athletes. The frequency of associations of 4 (17.4%), 5 (28.6%), 6 (25.8%), 7 (10.8%) and 8 (5.4%) genetic polymorphisms was significantly increased in adolescent athletes, which may have pathogenetic significance. Moreover, in athletes, combinations of C677T polymorphisms of the MTHFR gene, 4G (-675) 5G of the PAI-I gene, G (-455) A of the FGB gene were unfavorable for the implementation of vascular lesions. Conclusion. For the first time, criteria have been formulated for the selection of teenage athletes in the high-risk group for vascular complications, taking into account genetic factors. It has been established that the most informative predictors of the risk of vascular complications are the variants of the GPIIIa T1565C, MTRR A66G genes, and gene gene associations of polymorphisms.

Contribution of MTR A2756G polymorphism and MTRR A66G polymorphism to the risk of idiopathic male infertility.

Background:Methionine synthase reductase gene (MTRR A66G) polymorphism and methionine synthase gene (MTR A2756G) polymorphism have shown an association with idiopathic male infertility risk in several ethnic populations. However, their small sample sizes and inconsistent outcomes have prevented strong conclusions. We performed a meta-analysis with published studies to evaluate the associations of the 2 single nucleotide polymorphisms (SNPs) and idiopathic male infertility risk.Methods:A thorough literature search was performed up to Jun 21, 2019 with Medline, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), China Biology Medical literature (CBM), China Science and Technology Journal Database (VIP), and Chinese literature (Wan Fang) databases. Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the strength of associations.Results:Seventeen studies including 3269 cases and 3192 controls met the inclusion criteria. Our meta-analysis showed that the MTR A2756G mutation may contribute to genetic susceptibility to the risk of idiopathic male infertility in Non-Asians, but not to Asian population, whereas the MTRR A66G polymorphism may be unrelated to idiopathic male infertility in both Non-Asian and Asian populations. In the stratified analysis by infertility type, the MTR A2756G polymorphism was a risk factor for both non-obstructive azoospermia (NOA) and oligoasthenoteratozoospermia (OAT) patients. However, the MTRR A66G polymorphism is associated with risk for OAT in Asian, but not in Non-Asian population.Conclusion:This meta-analysis suggested that the MTR A2756G and MTRR A66G polymorphisms were risk factors for idiopathic male infertility. Studies with larger sample sizes and representative population-based cases and well-matched controls are needed to validate our results.

Distribution of Methionine Synthase Reductase (MTRR) Gene A66G Polymorphism in Indian Population.

Methionine synthase reductase (MTRR) is an important enzyme of the folate/homocysteine pathway. It is responsible for regulation of methionine enzyme by reductive methylation. A common variant A66G is reported in the FMN-binding domain of the MTRR gene, which leads to substitution of isoleucine by methionine (I22M) in MTRR enzyme with reduced activity. Reduced catalytic activity of enzyme leads to high homocysteine concentration in blood and increases risk for numerous diseases. The frequency of A66G polymorphism varies in different ethnic groups. The present study has been designed to evaluate the frequency of MTRR A66G gene polymorphism in the Eastern UP population by PCR-RFLP method. Along with this we also performed a meta-analysis to evaluate the global prevalence of this polymorphism. Databases were screened to identified the eligible studies. The prevalence of the G allele and GG genotype was determined by the use of prevalence proportion with 95% CI. Open meta-analyst software was used for the meta-analysis. Total 1000 blood samples were analyzed, the frequencies of A and G alleles were 0.35 and 0.65 respectively. Meta-analysis results revealed that the prevalence of G allele and GG genotype were 49.4% (95% CI 40.6-58.1, p ≤ 0.001) and 24.3% (95% CI 17.8-30.9, p ≤ 0.001) respectively. In sub-group meta-analysis, the lowest frequency of G allele was found in South America (32.7%; 95% CI 14.1-51.3, p ≤ 0.001), and highest in Asia (56.4%; 95% CI 39.5-73.3, p ≤ 0.001). The results of the meta-analysis showed that the Asian population has the highest frequency of G allele and highest frequency of the GG genotype was found in the European population.

Association of MTHFR C677T, MTHFR A1298C, and MTRR A66G Polymorphisms with Neural Tube Defects in Tunisian Parents

Objective: This study aims to investigate the association of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms with neural tube defects (NTDs) in a Tunisian population. Methods: Genotyping was performed by polymerase chain reaction with restriction fragment length polymorphisms (PCR-RFLPs) using the restriction enzymes. Allele and genotype frequencies were compared between mothers and fathers of fetuses with NTDs with matched controls based on an association analysis using SPSS software. Results: MTHFR (C677T, A1298C) and MTRR A66G polymorphisms were found to be protector factors for NTD fetuses in the mother group. In addition, a combination of the three wild-type alleles C677/A1298/A66 has increased four-fold the incidence of NTDs (p = 0.004, OR = 3.96, 95% CI: 1.53–10.23). In the father group, MTHFR C677T was a risk factor for NTDs. However, no association was found between MTHFR A1298C, MTRR A66G, and the occurrence of this anomaly. The analysis of MTHFR C677T and MTRR A66G polymorphisms has demonstrated a significant difference in vitamin B₁₂ levels between recessive and dominant genotypes in case mothers (p < 0.05). Conclusion: Additional studies are required to better understand the roles of parental gene polymorphisms related to folate-homocysteine metabolism in the pathogenesis of NTD.

Methionine Synthase Reductase-A66G and -C524T Single Nucleotide Polymorphisms and Prostate Cancer: A Case-Control Trial

Purpose:Some variations in the sequence of methionine synthase reductase (MTRR) gene can increase the risk of various cancers such as prostate cancer. The aim of this study was to investigate the association between prostate cancer and the MTRR A66G and C524T gene single nucleotide polymorphisms (SNPs) using an in silico analysis.Methods:In this case-control study, 218 Iranian men, including 108 men with prostate cancer and 110 prostate cancer-free men, were enrolled. The MTRR A66G and C524T genotyping was performed by PCR-RFLP. Some of the bioinformatics tools were employed for the evaluation of polymorphism on the molecular aspects of the MTRR.Results:With regard to the MTRR A66G polymorphism, the genotype AG (OR: 0.85, 95% CI: 0.47-1.54, p= 0.6014), genotype GG (OR: 0.89, 95% CI: 0.42-1.87, p= 0.7512), and allele G (OR: 0.92, 95% CI: 0.63-1.35, p= 0.6686) were not associated with prostate cancer risk. However, the data for C524T SNP showed that the genotype CT was associated with prostate cancer risk (OR: 1.92, 95% CI: 1.06-3.47, p= 0.0308). Further, carriers of the allele T (OR: 1.80, 95% CI: 1.04-3.13, p= 0.0358) were associated with high risk of prostate cancer. In addition, bioinformatics analysis revealed that C524T SNP could affect some molecular aspects of the protein structure, while having no effect on the mRNA structure.Conclusion:The MTRR C524T is a genetic risk factor for prostate cancer; however, the MTRR A66G is not suggested as a suitable biomarker for prostate cancer. To obtain more reliable results, further studies are recommended to use larger sample sizes and investigate the effects of environmental factors.

The roles of MTRR and MTHFR gene polymorphisms in congenital heart diseases: a meta-analysis.

Background: We performed the present study to better elucidate the correlations of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms with the risk of congenital heart diseases (CHD).Methods: Eligible articles were searched in PubMed, Medline, Embase and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations of MTHFR and MTRR gene polymorphisms with CHD.Results: A total of 47 eligible studies were finally included in our meta-analysis. Our overall analyses suggested that MTRR rs1801394, MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms were all significantly associated with the risk of CHD in certain genetic models. Further subgroup analyses according to ethnicity of study participants demonstrated that the MTRR rs1801394 polymorphism was significantly correlated with the risk of CHD only in Asians, whereas MTRR rs1532268, MTHFR rs1801133 and MTHFR rs1801131 polymorphisms were significantly correlated with the risk of CHD in both Asians and Caucasians.Conclusions: Our findings indicated that MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may affect the risk of CHD in Asians and Caucasians, while the MTRR rs1801394 polymorphism may only affect in risk of CHD in Asians.

Association of Single Nucleotide Polymorphisms (SNPs) in Genes Encoding for Folate Metabolising Enzymes with Glioma and Meningioma in Indian Population

Background:The association of primary brain tumors with Single Nucleotide polymorphisms (SNPs) in genes of folate metabolising enzymes have been reported to vary among different ethnic population. Here, we have studied the association of SNPs of folate metabolizing genes with the primary brain tumors (glioma and meningioma) in North Indian population.Methods:SNPs of genes coding for folate metabolizing enzymes was carried out in 288 study population from North India [Glioma (n=108), Meningioma (n=76) and healthy-control (n=104)]. The allele-specific polymerase chain reaction (ARMS-PCR) was used to analyse the SNP A1298C of the MTHFR (Methylenetetrahydrofolate-reductase) and the SNP A66G of the methionine synthase reductase (MTRR) genes. The PCR-RLFP (Restriction Fragment Length Polymorphism) was used to analyse the SNP C677T of the Methylene tetrahydrofolate-reductase and the SNP A2756G of the methionine-synthase (MTR) genes. Serum homocysteine, vitamin B12 and folate levels were evaluated in controls/patients serum using Chemiluminescence immunoassay and the levels were correlated with SNPs genotype.Results:The CC genotype of MTHFR A1298C was observed to have reduced risk of having meningioma than AA genotype (odd ratio=0.62, 95%CI 0.32-0.97, p=0.03). Similarly, the AG genotype of MTRR A66G showed reduced risk of glioma than AA genotype (odd ratio=0.56, 95%CI 0.32-0.97, p=0.039). Furthermore, in patients with AA genotype of MTR A2756G and CT genotype of MTHFR C677T showed higher serum homocysteine level than GG genotype (8.6 µmol/L, p=0.048) and CC genotype (11.2µmol/L, p=0.039) respectively.Conclusion:Our findings provide an insight into the risk association of SNPs in MTHFR A1298C and MTRR A66G genes with glioma/meningioma patients. Further studies are needed to evaluate their clinical implications.

ПРОГНОЗИРОВАНИЕ РИСКА ВОЗНИКНОВЕНИЯ ПРОТРОМБОТИЧЕСКИХ ИЗМЕНЕНИЙ У ПОДРОСТКОВ С ЭССЕНЦИАЛЬНОЙ АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИЕЙ

Today, the problem of early diagnosis of hematological changes predisposing to the development of thrombotic complications in patients with essential hypertension (EH) is an urgent problem that requires close attention not only of physicians, but also of pediatricians. The aim of the study was the development of prognostic criteria for risk of prothrombotic changes (PC) in adolescents with EH, timely preventive measures and prevention of thrombotic complications. Sixty adolescents with EH without PC and 37 adolescents with EH and PC were examined. We used the following methods: clinical anamnestic (including genealogy), functional and ultrasound, laboratory, mathematical and statistical. To create a mathematical model of forecasting, discriminant analysis was used, with the help of which from the 59 proposed predictors the algorithm selected 8 most informative features: the C777T polymorphism of the 5,10-methylenetetrahydrofolate reductase gene, the A66G gene of the methionine synthase reductase gene, the daily diastolic blood pressure level, the level of the nocturnal systolic arterial pressure-time index of hypertension, systolic blood pressure during the day, weighed down by thrombotic genealogically history, early onset of thrombosis, burdened thrombotic genealogical history. Our method for predicting the risk of developing PC allows to place adolescents with EH having an increased risk of developing these coagulation shifts in a separate group, to identify thrombogenic risk in adolescence and, if necessary, to initiate preventive measures in time to reduce the incidence of thrombotic complications of EH and mortality of patients.

A66G and C524T polymorphisms of methionine synthase reductase gene are linked to the development of acyanotic congenital heart diseases in Egyptian children

Methionine synthase reductase (MTRR) is one of the main regulatory enzymes in the homocysteine/folate pathway. Genes involved in this pathway may play an important role in the development of congenital heart diseases (CHDs). C524T and A66G polymorphisms of MTRR gene may play an imperative role in the development of acyanotic CHDs. This study carried out on 200 children equally divided into 2 groups: group I: 100 children with acyanotic CHDs; and group II: 100 healthy children served as controls. PCR-RFLP method carried out to amplify the A66G and C524T polymorphisms of MTRR gene digested with Xho1and NdeI enzymes. A significant difference(P=0.015) in genotype frequencies of C524T polymorphism between cases and controls, where CC, CT, and TT were 14.0%, 40.0% and 46.0% in patients compared to 38.0,36.0% and 26.0% in controls. Again, a significant difference (P=0.010) in genotype frequencies of A66G polymorphism between the two groups as AA, AG and GG were 26.0%, 32.0% and42.0% in patients compared to 48.0, 36.0% and 16.0% in controls. Also, MTRR A66G and C524T polymorphisms were associated with a higher CHD risk in the homozygote comparison of wild and mutant genotypes and also in heterozygote and mutant comparison. So A66G and C524T polymorphisms of MTRR gene are associated with increased risk of acyanotic CHDs.