MTHFR C677T Research Articles

Clinical characteristics of H-type hypertension and its relationship with the MTHFR C677T polymorphism in a Zhuang population from Guangxi, China.

ObjectiveThis study was designed to assess the clinical presentation of patients with H‐type hypertension who were of Zhuang nationality in Guangxi, China. The relationship between the C677T polymorphism in the MTHFR gene and H‐type hypertension was also assessed.MethodsThis was a case‐control study in which 185 Zhuang nationality patients with hypertension that had been hospitalized at the Wuming Hospital of Guangxi Medical University between February 2018 and December 2018 were assessed for plasma homocysteine (Hcy) levels. These levels were used to divide patients into H‐type (>15 μmol/L) and non‐H‐type (≤15 μmol/L) hypertension groups. Patient clinical data were then analyzed, and PCR was used to analyze samples from all patients for the presence of the C677T polymorphism in the MTHFR gene. Differences between these two groups of hypertension patients were then compared using appropriate statistical methods.ResultsWe found that relative to patients in the non‐H‐type hypertension group, patients in the H‐type hypertension group exhibited significant differences in sex, age, urea nitrogen levels, creatinine levels, and uric acid levels. There were, however, no significant differences between these two groups with respect to interventricular septum thickness, left ventricular posterior wall thickness, or ejection fraction. We did not detect any association between the MTHFR gene C677T polymorphism and H‐type hypertension in Zhuang nationality individuals in Guangxi.ConclusionRisk of H‐type hypertension is not associated with the MTHFR C677T polymorphism in hypertensive individuals of Guangxi Zhuang nationality in China.

Increased homocysteine expression associated with genetic changes in the folate pathway as a key determinant of preeclampsia: A prospective study from lower Assam, India

Lacunae exist in the scientific understanding of preeclampsia (PE) pathogenesis, which is a global issue and a clinical challenge during pregnancy and contributes to both maternal and fetal morbidity and mortality. We aim to understand the significance of homocysteine levels and folate pathway parameters in PE pathogenesis involving pregnancy cases from lower Assam, India. PE cases {N = 145, mild-PE (n = 108), severe-PE (n = 37)} and 192 normal full-term delivery cases were evaluated for Hcy expression and Vitamin B12 levels and evaluated for association with MTHFR and TYMS polymorphisms in PE pathogenesis. Hcy level was significantly higher in PE cases with negative pregnancy outcomes (p = 0.003) and was higher in PE-preterm delivery compared to PE-term delivery cases (p = 0.301). The VitaminB12 levels were not associated with higher tHcy concentration. Distribution of MTHFRC677T variant genotype was significantly higher in severe-PE cases compared to mild-PE cases (p = 0.050) and was associated with an increased risk of severe PE. The combined variant genotype of MTHFR and TYMSdel6 polymorphism resulted in significant increase (p = 0.014) in the risk of severe-PE compared to mild-PE. Within the PE delivery group, the combined variant genotypes showed association with higher homocysteine levels both in live birth cases as well in the PE cases with negative pregnancy outcomes. Increased homocysteine levels were associated with combined variant genotypes and were consistent in both term and preterm delivery in PE cases. The study points out the prognostic significance of MTHFR C677T, TYMS 1494del6 genotype and tHcy levels as a risk factor for PE, negative pregnancy outcome and preterm delivery.

Pharmacogenetic aspects of methotrexate in a cohort of Colombian patients with rheumatoid arthritis.

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). However, over time, ~40% of patients may experience therapeutic failure or drug toxicity. The genetic variability of the enzymes involved in the MTX metabolic pathway seem to serve an important role in the eventual therapeutic failure or drug toxicity. Depending on the enzymes affected, the toxicity or the therapeutic response may change. The present study reports some of the polymorphisms identified in enzymes in the MTX metabolic pathway that are present in a group of Colombian patients with RA, and assesses the associations of these polymorphisms with toxicity or therapeutic response to the medication. A total of 400 patients with RA were evaluated, of which 76% were women. the average age was 60.7±13.9 years and the duration of the disease was 13.2±10.9 years. The disease activity scoring method, DAS28-CRP, was used to evaluate the therapeutic response. Toxicity was determined based on reports of adverse events during the evaluation of the patients. The single nucleotide polymorphisms (SNPs) assessed using reverse transcription-PCR in the present study were MTHFR C677T, A1298C, ATIC C347G, RFC-1-G80A, FPGS-AG and DHFR-CT. The SNPs of MTHFR C677T (P=0.05) and A1298C (P=0.048) were significantly associated with the efficacy of MTX, and DHFR-CT (P=0.01) and ATIC C347 (P=0.005) were significantly associated with documented toxicity. Haematological, hepatic or renal toxicity was not associated with any of the SNPs. The results obtained in Colombian patients with RA receiving MTX are similar to those reported in other populations; however, the SNPs associated with a lack of response previously reported in the literature were not observed in our data. The SNPs identified in the present study may be used as biomarkers to predict response to MTX in terms of efficacy and toxicity in Colombian patients with RA.

Maternal folate, one-carbon metabolism and pregnancy outcomes.

Single nucleotide polymorphisms and pre‐ and peri‐conception folic acid (FA) supplementation and dietary data were used to identify one‐carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 μg daily FA at 15‐week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 μg (5.4%) (P < .0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L−1 vs. 31.9 ± 11.2, P = .007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre‐ and early‐pregnancy dietary factors, are independent risk factors for pregnancy complications.

Association of ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with Coronary Artery Disease (CAD)

BackgroundCoronary artery disease (CAD) is a complex disease resulting from the cumulative and interactive effects of large number of genes along with environmental exposure. Therefore, the present study was envisaged as an effort to study the association of candidate genes ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with the risk of CAD, targeting the populations of Jammu (JandK).MethodA total of 400 confirmed CAD patients and 400 healthy controls were enrolled for the present study. Genotyping was done by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP).ResultsESR1 gene (rs9340799) polymorphism was found to be associated with CAD in all the genetic models. The haplotype analysis of ESR1 (rs2234693 and rs9340799) gene revealed that C-G haplotype was conferring approximately 5-fold risk and T-A haplotype was adding 1.4-fold risk towards the disease. ‘T’ allele of MTHFR rs1801133 SNP was observed to be responsible for development of CAD in our study population (p < 0.0001). In case of MTHFR (rs1801133 and rs2274976) gene, the haplotype T-G was observed to confer 4.7-fold risk towards CAD whereas haplotype C-G provided nearly a 1.7 fold protection towards development of CAD. For MS gene, rs185087 was also found to be associated with CAD in a co-dominant (p = 0.003 and p = 0.03), dominant (p = 0.001) and allelic models (p = 0.001). The gene-gene interaction revealed strong epistasis between single nucleotide polymorphisms (SNPs), ESR1 rs9340799 and MTHFR rs2274976. Furthermore, the dendrogram for gene-environment dataset indicated moderately synergistic interaction between CETP rs708272 and physical inactivity.ConclusionIn the study under reference, a significant association of ESR1-XbaI (rs9340799), MTHFR C677T (rs1801133) and MS A2756G (rs185087) gene polymorphisms with the susceptibility of CAD in the population of Jammu region (JandK) has been observed.

Effectiveness of the preventive use of folic acid and complex with active folates in women with MTHFR C677T genetic polymorphism and with history of embryonic loss

Objective: to evaluate the clinical efficacy and safety of Femibion Natalcare vitamin complex containing metafolin in women of late reproductive age with MTHFR C677T genetic polymorphism who had anamnestic embryonic losses.Materials and methods. Study included 100 women of late reproductive age with MTHFR C677T genetic polymorphism and anamnestic embryonic losses. Patients of main group were divided in subgroups: first – 45 women who received folic acid (400 mcgper day) and second – 55 patients who received vitamin complex Femibion Natalcare 1 tablet daily. Prescription of medications began before preconception (6–8 weeks), intake ended at 28 weeks of gestation. Control group included 40 healthy women with physiological pregnancy. The studied parameters reflected information about the features of the pregnancy and birth.Results. After a course of prophylactic supplementation with Femibion Natalcare compared with monotherapy of folic acid, it was possible to reliably reduce cases of early pregnancy loss (p =0.03), anemia in I trimester (p =0.009), preeclampsia (p =0.014), anemia in II and III trimesters (p =0.001), placental dysfunction (p =0.0005), decrease in the level of placental hormones (p =0.014), pathology of placental development and localization (p =0.0499), fetal growth retardation (p =0, 0499), premature maturation of placenta (p =0.02), induction of labor (p =0.015), disorders of neonatal adaptation (p =0.03), neonatal jaundice (p =0.018), postpartum anemia (p =0.015). There were no cases of side effects of drugs on the mother and child.Conclusions. The use of a vitamin complex containing active folate metapholine for women of late reproductive age with MTHFR C677T genetic polymorphism and anamnestic embryonic losses had a positive effect on clinical symptoms, helps to reduce cases of perinatal pathology and impaired early neonatal adaptation.

Pregnancy outcomes in patients with MTHFR gene polymorphism: A case series

Aim: Based on the literature, MTHFR polymorphism is common among the general population and is controversial in terms of treatment, as it is poorly associated with pregnancy complications. In this study, we aimed to investigate the relationship between treatment and pregnancy outcomes in patients with MTHFR polymorphism.Methods: The data of 48 patients who were diagnosed with MTHFR C677T and A1298C polymorphism between June 2012 and April 2020 and followed up during their pregnancy were reviewed retrospectively. Demographic and clinical features of patients, pregnancy history, diagnosis, and perinatal complications were examined. Pre- and post-treatment clinical features of the patients were compared.Results: Comparison of pre- and post-treatment pregnancy data of the patients revealed that live birth rates were significantly higher (pre-treatment: 9.4% post-treatment: 68.7%, P=0.001) and abortion rates were significantly lower after treatment (pre-treatment: 81.2%, post-treatment: 32.1%, P=0.001). Pregnancy complications were observed in 9 (18.3%) patients. It was observed that among patients with MTHFR gene mutation, live birth rates increased by 24.12-fold and by 3.76-fold for each year of decrease in the age of conception following treatment. Conclusion: In pregnant women with MTHFR polymorphism, methionine-poor diet and medical treatment had a positive effect on pregnancy outcomes. It was also observed that among those with MTHFR gene polymorphism, young patients with MTHFR A1298C heterozygotes had the best treatment results.

Association of methylenetetrahydrofolate reductase C677T gene polymorphism and polycystic ovary syndrome in the South Indian cohort

The polycystic ovarian syndrome is the utmost common endocrinopathy state in women. It is related to both reproductive and metabolic disorders. The MTHFR gene associated with the ovarian follicular action encodes the 5-MTHFR (methylenetetra-hydrofolate reductase) enzyme, tangled in folate metabolism. MTHFR gene C677T polymorphism declines the enzyme activity and thus folate deficit and increases the level of homocysteine, which affects the progress of oocytes. Here, we evaluated the association of MTHFR gene C677T polymorphism withPolycystic ovary syndrome (PCOS) inthe South Indian cohortof women. About 129 PCOS women with following Rotterdam criteria and 90 women controls were studied. PCR-RFLP technique was carried out on all PCOS women in this study. Dissimilarities in hormone levels in PCOS patients were detected. MTHFR gene polymorphism CC, CT, TT genotype was found to be 74, 16, 9.30% in patients correspondingly. However, in controls, it was 44.4, 24, 31%, respectively. A substantial difference was detected in the genotype frequency distributions among the patients and controls. Also, allele frequency was shown as 82.95% C allele and 17.83% T allele and 56.67%, 43.33% for C, and T allele in controls correspondingly. Our resultsindicate a possible association and suggest that MTHFR C677T polymorphism can be used as a potential biomarker for PCOS progress in the South Indian women.

Surveillance analysis of the effects of dietary and lifestyle determinants on plasma homocysteine levels by combining the MTHFR C677T polymorphism in a rural North Indian population

AimThe objective of the present study was to understand the effect of dietary and lifestyle determinants on plasma homocysteine levels by combining the MTHFR C677T polymorphism in a rural North Indian population. MethodsA total of 1634 participants were recruited under a major government sponsored research project through door to door survey. The participants (both men and women and aged 30–65 years) were recruited from a Mendelian population. Of these 1459 participants were considered for the present analysis, as they were neither on any kind of medication for high blood pressure, CAD, diabetes or any other disorder nor did they have any missing data. Informed written consent was obtained from all the participants. Data on dietary and other lifestyle factors was collected in face-to-face interview through structured interview schedules. 5 ml of intravenous blood was collected from all the participants for biochemical and molecular analysis. Homocysteine, folate and vitamin B12 analysis was estimated through Immulite 1000 by chemiluminescence technique. Genetic variation in the MTHFR C677T genotype was analyzed using PCR-RFLP technique. ResultThe prevalence of hyperhomocystenemia (Hyphcy), folate and vitamin B12 deficiency was found to be 69.92%, 32.53% and 57.86% respectively. 677 T allele of MTHFR was found to be associated with Hyphcy. Men had significantly higher levels of homocysteine, folate and vitamin B12 as compared to the women. Age was found to be positively associated with homocysteine levels among women. Lifestyle determinants were found to be associated with increased risk for Hyphcy among the men. ConclusionThe findings reveal that there is high frequency of vitamin B12 levels deficiency and Hyphcy in the studied population. This is likely to contribute to increased susceptibility to numerous disorders. Therefore, it is the need of the hour that the general population is made aware of the benefits of consumption of vitamin B12 rich foods and the same is promoted in the population.

Interactive effect of MTHFR C677T polymorphism and sex on symptoms and cognitive functions in Chinese patients with chronic schizophrenia.

The etiology of schizophrenia is still unknown, and the MTHFR gene has been shown to be associated with SCZ. Previous studies have shown that patients with schizophrenia exhibit sex differences in symptoms and cognitive function. However, no study has been conducted to investigate the sex difference in the association between C677T polymorphism and symptoms and cognitive impairment in Chinese patients with schizophrenia. The C677T polymorphism was genotyped in 957 patients with schizophrenia and 576 controls. Patients were also rated on the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The results showed that there were significant differences in MTHFR C677T genotype and allele distributions between male patients and male controls (both p<0.05), while there was no significant difference between female patients and female controls (both p>0.05). Further analysis showed that there were significant sex differences in the association between C677T genotype and negative symptoms, immediate memory or attention index score in schizophrenia (p<0.05). This study suggests that the complex interactive effect between MTHFR C677T polymorphism and sex plays an important role in some clinical characteristics of patients with schizophrenia.

Expression of the C677T Polymorphism of the 5, 10-Methylenetetrahydrofolate Reductase (MTHFR) Gene in Patients with Carotid Artery Atherosclerosis.

BackgroundThe C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism has been associated with hypertension and coronary heart disease, but its relationship with carotid artery remains unknown. This study aimed to investigate the association between the C677T polymorphism of the MTHFR gene in patients with confirmed carotid artery atherosclerosis.Material/MethodsThis retrospective study included 210 patients with carotid artery atherosclerosis (the patient group) and 210 controls (the control group). Color Doppler ultrasound was used to identify carotid artery intimo-medial thickness and atherosclerotic plaques. Sanger sequencing using the polymerase chain reaction (PCR) was used to detect the MTHFR C677T gene polymorphism. Systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), glycosylated hemoglobin (HbA1c), and other laboratory indicators were measured.ResultsSBP, DBP, FPG, TC, LDL-C, HbA1c, and intimo-medial thickness were significantly increased in the patient group compared with the control group, and HDL-C was significantly lower. The allele frequencies of the C667T locus of MTHFR gene were significantly different between the two groups (P<0.05), and the TT genotype and the T allele frequencies in the patient group were higher than in the control group. Logistic regression analysis showed that SBP, TC, LDL-C, and the C667T MTHFR gene polymorphism were risk factors for carotid artery atherosclerosis.ConclusionsThe C677T polymorphism of the MTHFR gene was expressed in patients with carotid artery atherosclerosis.

Influence of plasma methotrexate level and MTHFR genotype in Korean paediatric patients with acute lymphoblastic leukaemia

Whether plasma MTX concentrations and MTHFR C677T and A1298C polymorphisms could be used as a predictor of occurrence of MTX-related toxicities in Korean paediatric patients with acute lymphoblastic leukaemia (ALL) were assessed. HD-MTX related toxicities, MTHFR polymorphisms and MTX plasma concentrations following 337 HD-MTX cycles to 117 children with ALL on maintenance therapy were analyzed. A significantly higher frequency of hyperbilirubinemia (P = 0.0443) and renal toxicity (P = 0.0107) were associated with high MTX concentrations by Fisher’s exact test. Moreover, high MTX concentrations at 24 h, 48, and 72 h were significantly associated with increased frequency of vomiting (P < 0.05) and hyperbilirubinemia (P < 0.05) by Mann-Whitney U test. There was a significantly higher frequency of mucositis in patients with the MTHFR 677 TT genotype (P = 0.0273) and a significantly higher frequency of MTX dose reduction in patients with the 677 TT genotype (P = 0.0217), compared to the CC/CT genotype. Independently, plasma MTX concentrations and MTHFR C677T genotype could be useful markers for tailoring MTX dosing and monitoring adverse effects in childhood ALL HD-MTX therapy in Korean patients.

Genetic risk factors for venous thromboembolism among infertile men with Klinefelter syndrome

BackgroundKlinefelter syndrome (KS) is one of the commonest sex chromosome disorders. Affected males become infertile and highly susceptible to several health problems, including vascular thromboembolism (VTE). The risk of VTE may be exacerbated by an underlying genetically inherited thrombophilia. In this study, we aimed to investigate the genotype and allele frequencies of common gene polymorphisms related to hereditary thrombophilia in infertile males with KS compared to normal, fertile men. MethodsEighty-five infertile males with KS and 75 healthy control males were included in this case-control study. Genetic testing was done using an extended thrombophilia gene panel by Multiplex PCR reverse hybridization method. ResultsThere was an increased frequency of mutant alleles and heterozygous genotypes of FV Leiden, FV H 1299R, Pro G20210A, MTHFR C677T and PAI-1 4G/5G thrombophilic gene polymorphisms in KS patients compared to the control group. It was shown that 10.7% of KS patients had the A3 haplotype of the EPCR gene in comparison to 5.3% of control patients. The A3/A3 genotype was found only in KS patients (7.1%). Carriers of more than one mutant allele in KS patients exceeded the control (p < 0.001). ConclusionA high prevalence of thrombophilic gene polymorphisms and the coexistence of different mutant alleles were evident in infertile KS males. These data highlight the importance of conducting further studies to understand the role of hereditary thrombophilia in predicting venous thrombosis in patients with Klinefelter syndrome.

Association Between MTHFR C677T Polymorphism and Congenital Heart Disease.

Many published studies have evaluated the association between the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) polymorphism and the risk of congenital heart disease (CHD); however, the specific conclusion is still controversial.To get a more accurate conclusion, we used a meta-analysis to evaluate the association between the MTHFR gene C677T polymorphism and the risk of CHD.Based on the design-based search strategy, a comprehensive literature search was conducted on PubMed, OVID, Cochrane Library, Embase, Wanfang, CNKI, and Web of Science. We selected the Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies. We performed a heterogeneity test on the results of the study and calculated the combined odds ratios (ORs) and its corresponding 95% confidence intervals (95% CIs) under a random- or fixed-effect model. Subgroup analyses were conducted by ethnicity, source of controls, sample size, and genotyping method. Sensitivity analysis was used to insure authenticity of this meta-analysis result. Egger's test and Begg's funnel plot were performed to detect publication bias.Eventually, our meta-analysis included 15 eligible studies. We observed a significant correlation between the MTHFR C677T polymorphism and the development of CHD in the recessive model (OR: 1.35, 95% CI: 1.06-1.71, P = 0.006) for the overall population. In subgroups stratified by ethnicity and source of controls, subgroup analyses indicated similar associations in Asians and hospital-based groups, but not for Caucasians and population-based groups. Egger's test and Begg's funnel plot demonstrated no significant publication bias in our study.Our analysis identified that MTHFR C677T allele is a risk genetic for CHD development, especially in Asians compared with Caucasians.

Promoter Hypermethylation of Wnt/β-catenin Signaling Pathway Inhibitor WIF-1 Gene and its Association with MTHFR C677T Polymorphism in Patients with Colorectal Cancer.

ObjectivesColorectal cancer (CRC) is a common malignancy with a high rate of mortality. The dysregulation of genes involved in the Wnt/β-catenin signaling pathway is a common finding in cancers. Wnt-inhibitory factor-1 (WIF-1) suppresses the Wnt/β-catenin signaling pathway and its inactivation by genetics and epigenetic changes may cause cancer. We investigated the DNA methylation status of the WIF-1 gene in patients with CRC and its interaction with MTHFR C677T polymorphism, a known modifier of methylation reaction.MethodsWe investigated 50 cancerous tissues and the adjacent non-cancerous tissue. Genomic DNA was extracted using a commercial kit and was treated by sodium bisulfite. Methylation-specific PCR was used for methylation analysis, and restriction fragment length polymorphism PCR to analyze the C677T polymorphism of the MTHFR gene.ResultsThe frequency of WIF1 promoter DNA methylation was significantly higher in cancerous tissue than adjacent non-cancerous tissue (52.0% vs. 8.0%; p < 0.001). WIF1 promoter DNA methylation status showed a significant association only with tumor location (p = 0.009). Carriers of TT genotype and T allele of MTHFR C677T polymorphism had a significantly higher frequency of unmethylated WIF1 gene than methylated WIF-1 gene in cancerous tissue (p = 0.025 and p = 0.001, respectively).ConclusionsPromoter DNA hypermethylation of the WIF-1 gene is a significant risk factor for CRC development, which was significantly associated with tumor location only. The significant association of TT genotype and T allele of MTHFR C677T polymorphism with unmethylated WIF-1 gene suggests a protective role for this common polymorphism against methylation-induced development of CRC.

Interaction of thrombophilic SNPs in patients with unexplained infertility-multifactor dimensionality reduction (MDR) model analysis.

Our aim was to evaluate the frequency and SNP-SNP interactions between factor V Leiden (FVL) G1691A, prothrombin G20210A mutation, and C677T MTHFR and PAI-1 4G/5G gene polymorphisms in female IVF patients with unexplained infertility (UI) by using a multifactor dimensionality reduction (MDR) model analysis. A total of 225 subjects were enrolled in the study. There were 105 females in UI group and 120 healthy controls. Designated SNPs were determined by using allele-specific PCR methods. The difference in thrombophilia prevalence was assessed by a chi-square test and logistic regression analysis. Four-locus SNP interaction model was tested using the MDR approach. A ten-fold cross-validation consistency (CVC) and permutation testing were performed. There was a significant difference of MTHFR C677T polymorphism frequency between the groups. Significantly less UI patients had MTHFR CC genotype (p = 0.005), while the risk allele T was more frequent (OR = 1.83, p = 0.0018). Logistic regression determined a significant association only for MTHFR C677T in our patients (TT genotype OR = 2.99). The MDR analysis confirmed the significance of a single-locus model for MTHFR C677T polymorphism (p = 0.015; OR = 2.93). However, the best, significant predictive model was the two-locus model comprising MTHFR C677T and FVL (CVC = 10/10, testing accuracy = 60.95%, p = 0.013; OR = 3.02). The MTHFR C677T polymorphism was significantly associated with UI, with minor allele T being more frequent. Additionally, there was a significantly increased presence of MTHFR C677T with FVL mutation in these patients. Therefore, MTHFR and its interaction with FVL should be recognized as contributing factors in the pathogenesis of infertility.

Homocysteine, but not MTHFR gene polymorphism, influences depressive symptoms in patients with schizophrenia

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is the key enzyme of folate metabolism in the process of one-carbon cycle and its deficiency results in elevated homocysteine concentration. In this study, we hypothesized that MTHFR C677T polymorphism and homocysteine concentration may play important roles in the development of depressive symptoms in schizophrenia. MethodsWe recruited 715 patients with stable schizophrenia, and among them, 197 schizophrenia patients under olanzapine monotherapy were enrolled for homocysteine concentration analysis. The Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) were employed to evaluate psychiatric and depressive symptoms. ResultsWhen the 715 schizophrenia patients were evaluated by CDSS, 326 individuals (45.6%) had depressive symptoms. No significant differences were observed in C677T genotype and allele distributions between the schizophrenia with or without depression groups. Schizophrenia patients with depression have higher levels of homocysteine than those without depression (P = 0.019). There was a positive correlation between the homocysteine levels and CDSS score (r = 0.22, P = 0.002). ConclusionOur findings suggested that higher levels of homocysteine may be a risk factor for the development of depressive symptoms in schizophrenia patients.

Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation

Homozygosity for the C677T polymorphism in MTHFR (TT genotype) is associated with a 24–87% increased risk of hypertension. Blood pressure (BP) lowering was previously reported in adults with the TT genotype, in response to supplementation with the MTHFR cofactor, riboflavin. Whether the BP phenotype associated with the polymorphism is related to perturbed one-carbon metabolism is unknown. This study investigated one-carbon metabolites and their responsiveness to riboflavin in adults with the TT genotype. Plasma samples from adults (n 115) screened for the MTHFR genotype, who previously participated in RCTs to lower BP, were analysed for methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), betaine, choline and cystathionine by liquid chromatography tandem mass spectrometry (LC-MS/MS). The one-carbon metabolite response to riboflavin (1.6 mg/d; n 24) or placebo (n 23) for 16 weeks in adults with the TT genotype was also investigated. Plasma SAM (74.7 ± 21.0 vs 85.2 ± 22.6 nmol/L, P = 0.013) and SAM:SAH ratio (1.66 ± 0.55 vs 1.85 ± 0.51, P = 0.043) were lower and plasma homocysteine was higher (P = 0.043) in TT, compared to CC individuals. In response to riboflavin, SAM (P = 0.008) and cystathionine (P = 0.045) concentrations increased, with no responses in other one-carbon metabolites observed. These findings confirm perturbed one-carbon metabolism in individuals with the MTHFR 677TT genotype, and for the first time demonstrate that SAM, and cystathionine, increase in response to riboflavin supplementation in this genotype group. The genotype-specific, one-carbon metabolite responses to riboflavin intervention observed could offer some insight into the role of this gene-nutrient interaction in blood pressure.

3\u2019UTR polymorphism of Thymidylate Synthase gene increased the risk of persistence of pre-neoplastic cervical lesions

BackgroundCervical cancer is caused by high-risk Human Papillomavirus (hr-HPV) infection associated with cofactors that has been analyzed as predictors of the remission or persistence of cytological abnormalities remission or persistence. These cofactors can be either environmental, epigenetic, or genetic. Polymorphism in genes of enzymes that act on one-carbon metabolism alter their activity and also may be associated with cervical carcinogenesis because they affect DNA synthesis and repair, and gene expression. Therefore, this study aimed to analyze the risk of persistence of pre-neoplastic cervical lesions according to genetic polymorphisms involved in one-carbon metabolism.MethodsOur sample consisted of 106 women, divided into two groups – Remission (n = 60), i.e., with the presence of pre-neoplastic lesions at first meeting (T1) and normal cytology after 6 months of follow-up (T2), and Persistence (n = 46), i.e., with the presence of pre-neoplastic lesions at T1 and T2. We obtained cervical samples for cytological analysis (T1 and T2), HPV detection (T1), and evaluation of polymorphism C667T of Methylenetetrahydrofolate Reductase (MTHFR C677T), A2756G of Methionine Synthase (MS A2756G), A66G of Methionine Synthase Reductase (MTRR A66G), double or triple 28 bp tandem repeat in 5′-untranslated enhanced region of Thymidylate Synthase (TSER), and 6 bp deletion at nucleotide 1494 in TS 3′-untranslated region (TS3’UTR). To analyze all genetic polymorphisms simultaneously, we calculated the Genetic Risk Score (GRS).ResultsWe observed no differences between the Remission and Persistence groups regarding the GRS. Also, there were no differences in the genotypic and allelic distribution of MTHFR C677T and MS A2756G polymorphisms. However, the risk of persistence was higher among women with the heterozygote genotype - ins/del [OR (IC95%): 3.22 (1.19–8.69), p = 0.021], or the polymorphic genotype – del/del [OR (IC95%): 6.50 (1.71–24.70), p = 0.006] of TS3’UTR. Conclusions: The presence of the TS3’UTR polymorphism increased the risk of persistence of cervical abnormalities. This genetic variant could be a potential marker of cervical carcinogenesis and therefore assist the follow-up of women with persistent pre-neoplastic cervical lesions.

Polymorphism in folate cycle genes in patients with gout in the Russian population of Trans-Baikal Territory

Objective. To study the frequency distribution of genotypes and alleles of polymorphic loci of folate cycle genes ( MTHFR C677T, MTHFR A1298G, MTR A2756G, MTRR A66G) in patients with gout and to evaluate their association with the risk of the disease. Material and Methods. 80 patients (69 men and 11 women) with gout were examined. The diagnosis of gout was made according to the classification criteria ACR/EULAR, 2015. DNA isolated from white blood cells of whole peripheral blood was the material used in the genetic analyses. All patients were genotyped to detect polymorphisms of the MTHFR C677T, MTHFR A1298G, MTR A2756G, MTRR A66G gene loci. Statistical data processing was performed using the software package Statistiсa 10.0. Results. Genetic polymorphisms of the MTHFR C677T and MTR A2756G genes are involved in the development of gout in individuals of Russian ethnicity in the population of the Trans-Baikal Territory. Minor T allele (χ 2 = 4.65, p = 0.03, OR = 1.83, CI95% = 1.05–3.17) and the T/T genotype (χ 2 = 6.5, p = 0.01, OR = 5.94, CI95% = 1.3–27.00) of the C677T locus of the MTHFR gene, minor G allele (χ 2 = 6.46, p = 0.01, OR = 2.38, CI95% = 1.2–4.69) and the A/G genotype of the MTR A2756G gene (χ 2 = 5.78, p = 0.01, OR = 2.66, CI95% = 1.18–5.98 ) were identified as alleles and genotypes having increased risk for developing gout. While the C allele (χ 2 = 4.65, p = 0.03, OR = 0.55, CI95% = 0.31–0.94) of the MTHFR C677T gene, and allele A (χ 2 = 6.46, p = 0.01, OR = 0.42, CI95% = 0.21–0.83) and genotype A/A (χ 2 = 7.58, p = 0.006, OR = 0.33, CI95% = 0.15–0.74) of the A2756G locus of the MTR gene were determined as genotypes and alleles having a protective effect. Conclusion. Significant differences were found in the frequency distribution of genotypes and alleles of the MTHFR C677T and MTR A2756G genes in gout patients compared with the control group. The presence of minor T allele and the T/T genotype of MTHFR C677T gene, the minor G allele and the A/G genotype of MTR A2756G gene was associated with an increased risk of gout. In contrast, the carriage of the C allele of MTHFR C677T gene, allele A and the genotype A/A of MTR A2756G gene had a potentially protective effect.