Reduced Steroid Synthesis in the Follicular Fluid of MTHFR 677TT Mutation Carriers: Effects of Increased Folic Acid Administration.

Objective To compare steroid profiles in the follicular fluid (FF) from women homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation and wildtype controls and to correlate it with the folic acid administration scheme applied at the time of oocyte retrieval. Design Retrospective single center study. Subjects and Methods Infertile patients treated by using assisted reproductive techniques were genotyped routinely for the MTHFR 677C>T mutation. In 2006 they had received folic acid supplementation doses of 400 µg daily per os. This group was designated Group-400 (n = 10). From 2008 onwards, all of our infertility patients received a daily dose of 800 µg folic acid per os. Women from this group were designated Group-800 (n = 28). FF were collected and a panel of steroid hormones (estradiol, estrone, estriol, cortisol, progesterone, 17-OH progesterone, testosterone, androstenedione, aldosterone, DHEA, and DHEA-S) was measured by isotope dilution liquid chromatography-tandem mass spectrometry employing atmospheric pressure photo ionization (APPI). Results In Group-400, the FF hormone profile confirmed a significant reduction of estradiol in homozygous 677TT carriers (0.52 ± 0.08-fold, exact p = 0.032) and for the first time also revealed significantly reduced estriol concentrations in these individuals (0.54 ± 0.05-fold, p = 0.016), as compared to wildtype controls. In Group-800, no significant differences were found for concentrations of any of the steroid hormones between homozygous 677TT carriers and wildtype controls. Conclusions The current findings support and extend previous reports on reduced concentrations of specific steroid hormones in follicular fluids of homozygous MTHFR 677C>T mutation carriers. The restoration of the FF hormone profile by elevated-dose folic acid supplementation might impact performing ART in infertile women with the MTHFR 677TT-genotype. Further adequately powered studies are necessary to verify our finding and to demonstrate the clinical effect of enhanced folic supplementation on ovarian function.

[The effect of various forms of folates on cognitive functions in patients with chronic schizophrenia]. / Vliyanie raznykh form folatov na kognitivnye funktsii u bol'nykh khronicheskoi shizofreniei.

OBJECTIVE: To assess the dynamics of cognitive functions in patients with schizophrenia during intake of various forms of folate as an add-on to antipsychotic therapy. MATERIAL AND METHODS: Using a battery of cognitive tests, the authors evaluated the dynamics of cognitive functions in 3 groups of patients with schizophrenia who received folic acid (n=25), metafolin (n=25) during 4 weeks and in the control group (n=25). Genetic variants of the polymorphism of the folate metabolism enzyme methylenetetrahydrofolate reductase (MTHFR) 677C>T were determined using real-time PCR. Only the carriers of the minor T allele were included in the study. RESULTS AND CONCLUSION: The improvement of certain cognitive functions was noted after folate administration, it was more pronounced and statistically significant in the metapholin group. The results hold promises for further studies of prolonged use of folate in prophylactic doses for schizophrenia.

Frecuencias genotípicas en Niños con Leucemia Linfoblástica Aguda en dos centros Oncológicos / Genotypic frequencies in Children with Acute Lymphoblastic Leukemia in two Oncology centers

Introducción: La leucemia linfoblásticaaguda (LLA) es una de las oncopatologías más frecuentes a nivel infantil, ocupando el primer lugar de los cincos tipos de cáncer con mayor incidencia en Ecuador. El objetivodel estudio fue determinar las frecuencias genotípicas y alélicas delos polimorfismos genéticos de MTHFR 677C>T (rs1801133) y MTHFR 1298A>C(rs1801131) en niños con leucemia linfoblástica aguda de SOLCA ­Loja y SOLCA ­Cuenca. Métodos:Es un estudio transversal, donde se evaluó a 160 pacientes pediátricosdiagnosticados con LLA. La detección de lospolimorfismos MTHFR 677C>T y 1298A>C se realizó mediante la técnica PCR entiempo real. El análisis estadístico descriptivo se desarrolló a través del software IBM SPSS (versión 22) y el programa bioinformático SNPStats. Resultados: Se determinóque las frecuencias genotípicas para el SNP MTHFR 677C>T fueron 25% C/C y 75%C/T con una frecuencia alélica del 38% para el alelo mutado (T). Para el SNP MTHFR1298 A>C se encontró una frecuencia genotípica de 2% A/A, 16% A/C y 82% C/C, entanto que su frecuencia alélica fue del 90% para el alelo mutado (C). No se encontróasociación genotípica ni alélica con ninguna de las variables intervinientes (p>0.05),así como tampoco se manifestó una correlación estadísticamente significativa de lospolimorfismos en mención y el tipo de riesgo de LLA. Conclusión:En la población estudiada con LLA, se evidenció para el SNP de MTHFR 677C>T una frecuencia genotípica del 75% para el heterocigoto C/T. Para el SNP MTHFR 1298A>C se encontró una frecuencia genotípica del 82% para el homocigoto mutado C/C. La distribución de la frecuencia alélica se mostró de la siguiente manera: para MTHFR 677C>T se obtuvo 38% para el alelo mutado T y en cuanto a MTHFR 1298 A>C, 90% correspondió para el alelo mutado C. En el análisis estadístico no se encontró asociación genotípica ni alélica con las variablesdemográficas y clínicas

Introduction:Acute lymphoblastic leukemia (ALL) is one of the most frequent oncopathologiesin childhood, occupying the first place of the five types of cancer with the highest incidence in Ecuador. The objective of the study was to determine the genotypic and allelic frequencies of the genetic polymorphisms of MTHFR 677C> T (rs1801133) and MTHFR 1298A> C (rs1801131) in children with acute lymphoblastic leukemia from SOLCA -Loja and SOLCA -Cuenca. Methods: It is a cross-sectional study, where 160 pediatric patients diagnosed with ALL were evaluated. The detection of MTHFR 677C> T and 1298A> C polymorphisms was performed using the real-time PCR technique. The descriptive statistical analysis was developed using the IBM SPSS software (version 22) and the SNPStats bioinformatics program. Results: It was determined that the genotype frequencies for the SNP MTHFR 677C> T were 25% C / C and 75% C / T with an allele frequency of 38% for the mutated allele (T). For the SNP MTHFR 1298 A> C, a genotype frequency of 2% A / A, 16% A / C and 82% C / C was found, while its allelic frequency was 90% for the mutated allele (C). No genotypic or allelic association was found with any of the intervening variables (p> 0.05), as well as no statistically significant correlation of the mentioned polymorphisms and the type of risk of ALL. Conclusion: In the population studied with ALL, a genotypic frequency of 75% was evidenced for the MTHFR 677C> T SNP for the heterozygous C / T. For the SNP MTHFR 1298A> C, a genotypic frequency of 82% was found for the homozygous mutated C / C. The allelic frequency distribution was shown as follows: for MTHFR 677C> T, 38% was obtained for the mutated allele T and for MTHFR 1298 A> C, 90% corresponded to the mutated allele C. In the statistical analysis No genotypic or allelic association was found with demographic and clinical variables

Interaction between MTHFR 677C>T, PON1 192Q>R and PON1 55L>M polymorphisms and its effect on non-recurrent spontaneous abortion in Mexican women.

MTHFR is a key enzyme in folate metabolism. Some genetic polymorphisms code for a less efficient enzyme, increasing serum concentrations of homocysteine. This has been associated with inadequate feto-maternal circulation and increased risk of spontaneous abortion. Paroxonase 1 (PON1) is a multifunctional enzyme that can detoxify homocysteine through its homocysteine thiolactonase activity. We evaluate the association between MTHFR 677 C>T polymorphisms and non-recurrent spontaneous abortion and its interaction with PON1 polymorphisms involved in homocysteine metabolism in women living in floricultural areas in Mexico. Sociodemographic, reproductive history, folic acid consumption during pregnancy and environmental exposure data of 264 women who had been pregnant sometime during the 10 years prior to study enrolment were collected. MTHFR 677 C>T, PON1 192Q>R and PON1 55L>M genotypes were determined by PCR amplification. Information on pregnancy outcome and maternal genotypes was obtained for 484 pregnancies: 34 non-recurrent spontaneous abortions (gestational age < 20 weeks) and 450 controls. GEE models were used to evaluate the association between MTHFR polymorphism and non-recurrent spontaneous abortion, and its interaction with PON1 polymorphisms. After adjusting for potential confounders, no significant association was found between the MTHFR 677 C>T maternal polymorphism and non-recurrent spontaneous abortion (OR CT vs CC= 0.39, 95% CI: 0.14-1.05; OR TT vs CC = 0.63, 95% CI: 1.22-1.80). No interactions with PON1 192Q>R or PON1 55L>M polymorphisms were identified (p for interaction = 0.88 and 0.41, respectively). PON1 55L>M maternal polymorphism was associated with higher risk of spontaneous abortion (OR LM/MM vs LL = 4.14, 95% CI: 1.49-11.54). Our results do not demonstrate an interaction between the MTHFR 677 C>T and PON1 192Q>R or PON1 55L>M maternal polymorphisms neither an independent association of MTHFR 677 C>T polymorphism with non-recurrent spontaneous abortion, whereas PON1 55LM/MM maternal genotype increase the odds of this event.

5-HTTLPR and MTHFR 677C>T polymorphisms and response to yoga-based lifestyle intervention in major depressive disorder: A randomized active-controlled trial.

BACKGROUND: There is growing evidence suggesting that both genetic and environmental factors modulate treatment outcome in, a highly heterogeneous, major depressive disorder (MDD). 5-HTTLPR variant of the serotonin transporter gene (SLC6A4) and MTHFR 677C>T polymorphisms have been linked to the pathogenesis of MDD, and antidepressant treatment response. The evidence is lacking on the clinical utility of yoga in patients with MDD who have 5-HTTLPR and MTHFR 677C>T polymorphisms and less likely to respond to medications (SSRIs). AIMS: We aimed to examine the impact of YBLI in those who have susceptible 5-HTTLPR and MTHFR 677C>T polymorphisms and are less likely to drug therapy with SSRIs. SETTINGS AND DESIGN: In a 12 week randomized active-controlled trial, MDD patients (n = 178) were randomized to receive YBLI or drug therapy. METHODS: Genotyping was conducted using PCR-based methods. The clinical remission was defined as BDI-II score ≤ 9. STATISTICAL ANALYSIS USED: An intent-to-treat analysis was performed, and the association of genotype with treatment remission consisted of the logistic regression model. A P value of <0.05 was considered statistically significant. RESULTS: Multivariate logistic regression models for remission including either 5-HTTLPR or MTHFR 677C>T genotypes showed statistically significant odds of remission in YOGA arm vs. DRUG arm. Neither 5-HTTLPR nor MTHFR 677C>T genotype showed any influence on remission to YBLI (P = 0.73 and P = 0.64, respectively). Further analysis showed childhood adversity interact with 5-HTTLPR and MTHFR 677C>T polymorphisms to decrease treatment response in DRUG treatment arm, but not in YOGA arm. CONCLUSIONS: YBLI provides MDD remission in those who have susceptible 5-HTTLPR and MTHFR 677C>T polymorphisms and are resistant to SSRIs treatment. YBLI may be therapeutic for MDD independent of heterogeneity in its etiopathogenesis.

Biventricular Thrombi in a Patient With Heart Failure With Severely Reduced Ejection Fraction and Heterozygous Prothrombin 20210G/A and Homozygous Methylenetetrahydrofolate Reductase 677C/T Mutations.

Thrombus in the heart is known to be one of the many sequelae of anterior wall myocardial infarction, atrial fibrillation and coagulation disorders. However, biventricular thrombi are relatively rarely found, even in conditions with a high possibility of thrombus formation. We report the case of a 75-year-old-woman with newly diagnosed systolic heart failure secondary to a nonischemic cardiomyopathy, who was found to have large biventricular thrombi. Further coagulopathy work-up revealed that she was heterozygous for the prothrombin 20210G/A and homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C/T mutations. We, herein, review and discuss previous case reports and published literature regarding ventricular thrombosis and its treatment. To the best of our knowledge, this is the first case of biventricular thrombosis with prothrombin 20210G/A and MTHFR 677C/T mutations.

Association study of methylenetetrahydrofolate reductase genetic polymorphism 677C>T with schizophrenia in hospitalized patients in population of European Russia.

The purpose of the research was to investigate the association of methylenetetrahydrofolate reductase (hereinafter MTHFR) genetic polymorphism 677C>T with schizophrenia in the Russian population in comparison with the control group of healthy blood donors. Also some characteristics of schizophrenia were examined in patients with/without defective T-allele of MTHFR677C>T polymorphism. 500 patients with schizophrenia and 499 blood donors were examined for T-allele carriage of polymorphism MTHFR677C>T by PCR method. 150 archival medical records were studied (in the first patients included in the study). The carriage of T-allele of genetic polymorphism MTHFR677C>T was significantly more common in patients than in healthy donors: 255/500 versus 219/499 (p=0,0287, χ2=4,79; OR=1,33, 95%CI [1037; 1707]). The number of patients with chronic type of schizophrenia onset was significantly more among T-allele carriers (n=77) than among normal CC-genotype carriers (n=73): р=0.038. The number of "incapacitated" persons in the group of patients with defective T-allele (n=77) was significantly higher than in patients with normal genotype (n=73, p=0.0439; OR=2.878, 95%CI=1.111-7.456). The results suggest that T-allele of genetic polymorphism MTHFR677C>T in the population of European Russia may increase the risk of developing schizophrenia and its unfavorable prognosis, which requires further investigation.

Methotrexate elimination and toxicity: MTHFR 677C>T polymorphism in patients with primary CNS lymphoma treated with high-dose methotrexate.

The genetic association of the methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism with methotrexate (MTX)-associated toxicity has been evaluated and conflicting results have been reported. The substantial heterogeneity of the studied population was suggested to be a possible explanation because ethnicity, MTX dose, coadministered chemotherapeutic agents, and folinate rescue dosage regimen could alter the MTX toxicity profile. The patient population was homogenized by limiting the cancer type to primary central nervous system lymphoma and chemotherapy protocol to a high-dose MTX monotherapy regimen. A total of 111 patients with 402 chemotherapy courses were analyzed. MTHFR 677C>T polymorphism was identified as an independent predictive marker for MTX-associated hematologic toxicity (odds ratio, 2.60; 95% confidence interval, 1.32-5.09; P = .0055). Clinically significant nephrotoxicity occurred in patients without delayed elimination, suggesting roles for factors other than serum MTX levels. MTX-induced hepatotoxicity and oral mucositis occurred independently of plasma MTX levels.

A Meta-Analysis of Association between Methylenetetrahydrofolate Reductase Gene (MTHFR) 677C/T Polymorphism and Diabetic Retinopathy.

AIMS: To shed light on the conflicting findings of the association between the methylenetetrahydrofolate reductase gene (MTHFR) 677C/T polymorphism and the risk of diabetic retinopathy (DR), a meta-analysis was conducted. METHODS: A predefined search was performed on 1747 DR cases and 3146 controls from 18 published studies by searching electronic databases and reference lists of relevant articles. A random-effects or fixed-effects model was used to estimate the sizes of overall and stratification effects of the MTHFR 677C/T polymorphism on the risk of DR, as appropriate. RESULTS: Risks were evaluated by odds ratios (OR) with 95% confidence intervals (95% CI). We found a significant association between the MTHFR 677C/T polymorphism and the risk of DR for each genetic model (recessive model: OR = 1.67; 95% CI: 1.19-2.40 and dominant model: OR = 1.71; 95% CI: 1.28-2.28; respectively). In stratified analysis; we further found that the Asian group with both types of diabetes mellitus (DM) showed a significant association with genetic models (recessive model: OR = 2.16; 95% CI: 1.75-2.60 and dominant model: OR = 1.98; 95% CI: 1.42-2.76; respectively). CONCLUSIONS: Our study suggested that the MTHFR 677C/T polymorphism may contribute to DR development, especially in Asian populations. Prospective and additional genome-wide association studies (GWAS) are needed to clarify the real role of the MTHFR gene in determining susceptibility to DR.

MTHFR 677 C/T polymorphism-new ideas about depressive disorder treatment / 中国药理学通报

It has been confirmed that genetic factor plays an im-portant role in the pathogenesis of depression. MTHFR is one of the key enzymes in folate and homocysteine ( Hcy ) metabolism which participates in Alzheimer’ s disease, depression and other mental illnesses. MTHFR-677C/T polymorphism causes the de-crease of enzyme activity and heat resistance, which will lead to lower folate and elevated plasmal Hcy concentration. All of these results put together will cause the central neuronal damage and microvascular damage and affect the synthesis of central neuro-transmitter and methylation of biogenic amines and phospholipids in the central nervous system, which will eventually induce vari-ous mental illnesses like depression, etc. This article reviews the research advancement in the relationship between MTHFR-677C/T polymorphism and depression in recent years on the basis of MTHFR gene mutation and function, lack of folic acid, elevated plasma homocysteine levels and the MTHFR-C677T polymor-phism. Based on which we hope to bring new ideas about treat-ment of depression.

MTHFR C677T polymorphism: association with lymphoid neoplasm and effect on methotrexate therapy.

The aim of this study was to detect the possible role of methylene tetrahydrofolate reductase gene polymorphism (MTHFR C677T) in the pathogenesis of lymphoid neoplasms and to investigate the influence of this polymorphism on methotrexate toxicity in adult ALL patients treated with methotrexate maintenance therapy. There was a statistically significant increase in the risk of non-Hodgkin lymphoma in patients with CT genotype (OR, 2.9; 95% CI, 1.3-6.3; P = 0.007) and combined CT + TT genotype (OR, 3.2; 95% CI, 1.5-6.6; P = 0.006). While no significant association was found between this polymorphism and ALL risk. The patients with ALL treated with methotrexate during maintenance therapy were observed for signs of toxicity. MTHFR 677C>T polymorphism (CT + TT) was significantly overrepresented among cases with hepatic toxicity (OR = 15.6; 95% CI, 2.6-81.3; P = 0.001). In addition, they were overrepresented among cases with mucositis, anemia, thrombocytopenia, and leukopenia. However, it did not reach statistical significance level. Further studies on larger number of subjects are necessary. Additional studies on the role of MTHFR gene polymorphism with environment (folate intake) interaction are needed to confirm the role of these genetic polymorphisms.

Folate-related gene variants in Irish families affected by neural tube defects.

Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative ("risk genotypes") and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms.