MTHFR C677T Research Articles

812 FOLATES-RELATED ERYTHROCYTE DIVERSION LEAD TO ATRIAL CARDIOMYOPATHY/FIBRILLATION THROUGH EPCS DYSFUNCTION

Abstract Background Recent advances support the concept that pre-persistent Atrial Fibrillation (AF) and paradoxical embolism do not explain the wholeness of embolic strokes, thus suggesting a broad Atrial Cardiomyopathy (AC). Pathogenic mechanisms underlying AC are still largely unknown. Folate cycle disorders are a yet underrated dysmetabolism. MTHFR-inherited defects could hinder both endothelial and circulating endothelial progenitor cell (EPCs) functioning, therefore providing one-shot explanation to both atrial stasis (increasing atrial fibrosis and generating atrial hypocontractility even in sinus rhythm) and endothelial dysfunction (ED). Purpose This study aims to enquire for the hypothesis that: 1) atrial fibrosis (AFib – intended as a relative percentage of low voltage area in the context of left atrial endocavitary voltage mapping) would relate to folate cycle disorders (intended as both: a)MTHFR C677T inherited mutations and b)bone-marrow function disorders, here referring to erythropoiesis diversions) and 2) AF patients would show dysfunctional EPCs. Methods We studied 59 consecutive patients admitted to the cardiology Unit of the General Hospital “F.Miulli”, with preserved EF, subjected to AF ablation. AFib was quantified by bipolar peak-to-peak voltage areas (<0,5 mV) with respect to the wholeness of the picked voltage points. Blood count cell was evaluated by a commercial laboratory test. EPCs isolation and characterization were performed by Ficoll-Hypaque gradient and following flow cytometry analysis for cell surface antigens: CD45, CD34, CD133, VEGFR2 and KDR. EPCs functional wound healing assay was performed to determine the number of EPCs migrated to the “wound”, measuring the percentage of relative wound closure compared with matched-controls. Results Baseline characteristics did not differ between Sample and Control groups. % of Afib significantly differs between C677T MTHFR homozigosis patients (n=15) with respect to non-C&//T MTHFR homozygosis patients (n=44 p < 0,02). Once univariate analysis was performed, subsequent multivariate analysis highlights highest fit once merged RBC, RDW-SD and folates values were inputed: Goodness of fit was proper, modelling good (Low figure - R2=0,39; p=0,0001). Either RBC, RDW-SD and folates coefficient reached significance (p < 0,0001; p < 0,01; p < 0,05 respectively). Number of EPCs significantly differs between AF patients and matched controls (p < 0,001). Conclusions Our findings support the hypothesis that genetically determined folates dysmetabolism (MTHFR dysfunction) promotes AFib via a complex cardiac-bone marrow networking involving circulating EPCs and unraveled by erythropoiesis diversions. Such results suggest a pathogenic role of folate cycle disorders in the AC development

H-Type Hypertension among Black South Africans and the Relationship between Homocysteine, Its Genetic Determinants and Estimates of Vascular Function.

Elevated homocysteine (Hcy) increases cardiovascular disease (CVD) risk. Our objective was to emphasize Hcy’s contribution in hypertension and CVD management by determining H-type hypertension (hypertension with Hcy ≥ 10 µmol/L) and associations between Hcy, blood pressure (BP) and estimates of vascular function among Black South Africans. We included 1995 adults (63% female). Plasma Hcy and cardiovascular measures (systolic and diastolic BP (SBP, DBP), pulse pressure, heart rate (HR), carotid-radialis pulse wave velocity (cr-PWV), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1) were quantified. Five Hcy-related polymorphisms (cystathionine β-synthase (CBS 844ins68, T833C, G9276A); methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase (MTR A2756G)) were genotyped. Hcy was >10 µmol/L in 41% (n = 762), and of the 47% (n = 951) hypertensives, 45% (n = 425) presented with H-type. Hcy was higher in hypertensives vs. normotensives (9.86 vs. 8.78 µmol/L, p < 0.0001, effect size 0.56) and correlated positively with SBP, DBP, cr-PWV and ICAM-1 (r > 0.19, p < 0.0001). Over Hcy quartiles, SBP, DBP, HR, cr-PWV and ICAM-1 increased progressively (all p-trends ≤ 0.001). In multiple regression models, Hcy contributed to the variance of SBP, DBP, HR, cr-PWV and ICAM-1. H-type hypertensives also had the lowest MTHFR 677 CC frequency (p = 0.03). Hcy is positively and independently associated with markers of vascular function and raised BP.

Evaluation of homocysteine, folic acid and methylenetetrahydrofolate reductase C677T gene polymorphism associated with recurrent spontaneous miscarriage

This study was aimed to assess the association between evaluation of homocysteine level, folic acid and methylenetetrahydrofolate reductase MTHFR C677T gene polymorphism and recurrent pregnancy loss RSA. Sixty four women diagnosed with RSA and 41 normal fertile female, who had at least one or more child, 21 of them were pregnant women while 20 were non-pregnant. The level of homocysteine was high in women with RSA (11.41+3.75) (p&lt;0.05) compared to normal fertile women either pregnant (7.02+2.13) or non-pregnant (6.84+2.08), low levels of folic acid was observed (6.35+2.09) in women with RSA (p&lt;0.05) compared to fertile women either pregnant(10.08+3.08) or non-pregnant(11.27+3.15). No statistically significant difference was observed in the distribution of genotypes between cases and controls for MTHFR polymorphism. In conclusion, the present study reveals to lack of association of MTHFR C677T polymorphism in RSA women.

GLOBAL DNA METHYLATION LEVELS IN MIGRAINE PATIENTS FROM GEORGIA

Introduction: Migraine is a common, complex neurological disease characterized by the presence of a strong genetic component. Genome-wide association studies (GWAS) have identified gene variants involved in migraine development. In addition, it is known that epigenetic mechanisms, such as DNA methylation, play an important role in inflammation disorders. The aim of our study was to investigate global DNA methylation levels in migraine patients with C677T polymorphism of the MTHFR gene. Materials and methods: MTHFR C677T genotyping analysis (36 patients and 32 controls) was performed using TaqMan technology (Thermo Scientific, USA). Global DNA methylation was determined by the quantitative analysis of 5-methylcytosine (Zymo Research, Germany). Results: In individuals with TT genotypes, the percentage of methylated cytosine (5mC) was significantly lower in the migraine group compared to the control group (P=0.001). Conclusions: Our results suggest that epigenetic approaches can be used to study the migraine pathogenesis. In addition, reduced methylation levels can be ameliorated by the dietary supplementation with vitamins B6, B9, B12, which may be a strategy for migraine prevention and management in patients with MTHFR C677T polymorphism.

Protective effect of metafolin in pregnant patients with MTHFR polymorphism, under heparin and aspirin protect treatment

Introduction: Thrombophilias during pregnancy are associated with maternal-fetal morbidity and mortality. In addition to this, the physiological changes that arise during pregnancy also generate a state of hypercoagulability, which can lead to complications during pregnancy such as Fetal Growth Restriction (FGR), Preeclampsia and Gestational Loss (GL). The objective was to evaluate the efficacy of Metafolin (MF) against Folic Acid (FA), in pregnant women with MTHFR-C677T mutation. Material and method: Retrospective, observational and cross-sectional study, which included 73 pregnant women. Groups: 1) GAF-T: Treatment with Folic Acid (FA, 400 mcg/24h) and 2) GMf-T: Treatment with Metafolin (Mf, 0.71 g/24h). In all cases, the women had the MTHFR C677T mutation and were treated with Heparin (5000 IU/12h) and Aspirin Protect (100 mg/24h), from the first trimester of pregnancy. Anthropometric data collection (in mothers and their newborns), presence of complications during pregnancy, MTHFR-C677T single nucleotide polymorphism (SNP) study and placental pathology were evaluated. Results: The prevalence of Fetal Growth Restriction (FGR) (15.3 vs 11.1%), placental abruption (PA) (7.6 vs 5.5%), hypertension (7.6 vs 0%) and preeclampsia (7.6 vs 5.5%) in GAF-T and GMf-T was low. GMf-T presented fewer small villi (61.5 vs 22.2%), ischemic changes (76.9 vs 22.2%), erythrocyte extravasation (61.5 vs 22.2%) and hematomas (46.1 vs 11.1%). Conclusion: The application of Mf from the beginning of pregnancy decreases the probability of developing placental pathologies. In addition, the joint application of Heparin and Aspirin Protect reduces the risk of developing complications during pregnancy such as Fetal Growth Restriction (FGR), Placental Abruption (PA), Hypertension and Preeclampsia.

Targeted genetic analysis unveils novel associations between ACE I/D and APO T158C polymorphisms with D-dimer levels in severe COVID-19 patients with pulmonary embolism

Only a percentage of COVID-19 patients develop thrombotic complications. We hypothesized that genetic profiles may explain part of the inter-individual differences. Our goal was to evaluate the genotypic distribution of targeted DNA polymorphisms in COVID-19 patients complicated (PE+) or not (PE−) by pulmonary embolism. We designed a retrospective observational study enrolling N = 94 consecutive patients suffering severe COVID-19 with pulmonary embolism (PE+, N = 47) or not (PE−, N = 47) during hospitalization. A panel of N = 13 prothrombotic DNA polymorphisms (FV R506Q and H1299R, FII G20210A, MTHFR C677T and A1298C, CBS 844ins68, PAI-1 4G/5G, GPIIIa HPA-1 a/b, ACE I/D, AGT T9543C, ATR-1 A1166C, FGB − 455G > A, FXIII103G > T) and N = 2 lipid metabolism-related DNA polymorphisms (APOE T 112C and T158C) were investigated using Reverse Dot Blot technique. Then, we investigated possible associations between genotypic subclasses and demographic, clinical, and laboratory parameters including age, obesity, smoking, pro-inflammatory cytokines, drug therapy, and biomarkers of thrombotic risk such as D-dimer (DD). We found that 58.7% of PE+ had homozygous mutant D/D genotype at ACE I/D locus vs. PE− (40.4%) and 87% of PE+ had homozygous mutant C/C genotype at APOE T158C locus vs. PE− (68.1%). In PE+ group, DD levels were significantly higher in D/D and I/D genotypes at ACE I/D locus (P = 0.00066 and P = 0.00023, respectively) and in C/C and T/C genotypes at APOE T158C locus (P = 1.6e−06 and P = 0.0012, respectively) than PE− group. For the first time, we showed significant associations between higher DD levels and ACE I/D and APOE T158C polymorphisms in PE+ vs. PE− patients suggesting potential useful biomarkers of poor clinical outcome.

Association of gene polymorphism MTHFR C677T and MTHFR A1298C with atrial fibrillation

Association of gene polymorphism MTHFR C677T and MTHFR A1298C with atrial fibrillation

CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women.

Cystathionine-gamma-lyase (CSE) in the transsulfuration pathway generates hydrogen sulfide (H2S), suggested regulating cardiovascular function. The G1208T polymorphism in the CTH gene, rs1021737, has, in addition toMTHFR, been found to increase homocysteine, related to myocardial infarction (MI) risk. This study aimed, for the first time, to investigate the associations of the polymorphisms CTH G1208T, MTHFR C677T, and A1298C with the prospective risk of developing a fatal or non-fatal first MI. This case-referent study included 545 cases later developing a first-ever MI and 1,054 referents from the Northern Sweden Health and Disease Study. Fatal MI was defined as death within 28days after MI symptoms. Women, but not men, had a positive association between fatal MI and the CTH G1208T, odds ratio [95% confidence interval] 3.14 [1.16-8.54] for heterozygotes, and the dominant model 3.22 [1.22-8.51], and for the MTHFR A1298C heterozygotes 3.24 [1.26-8.34] and the dominant model 2.63 [1.06-6.50]. The MTHFR C677T polymorphism was not related to MI. This study indicates that the minor alleles of CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk for a fatal MI among women but not for non-fatal MI. No association was found in men.

Highly sensitive genotyping of MTHFR C677T polymorphisms using a novel RPA-LDR-qPCR assay.

The 5,10-methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in the metabolism of folic acid, synthesis of DNA, and DNA methylation. The genetic polymorphisms of MTHFR caused by the C677T mutation have become an important clinical indicator related to folic acid intake in relevant populations. The most widely used method in clinical practice for genotyping of MTHFR C677T polymorphisms was fluorescence probe PCR, but several flaws of the method hampered its accuracy. This study established a highly sensitive RPA-LDR-qPCR assay for genotyping of MTHFR C677T polymorphisms. It provides an alternative tool for more accurate and reliable diagnosis of folic acid metabolism disorders, and supports the relevant personalized medicine.

A Hypertrophic Spinal Pachymeningitis Patient With Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, Glycoprotein IIIa L33P Gene Mutations

Hypertrophic pachymeningitis (HP) is a rare clinical entity of diverse etiology, characterized by a chronic inflammation that causes dura thickening. Reports of Idiopathic hypertrophic cranial pachymeningitis (IHCP) were related to infections, trauma, tumors, and rheumatologic conditions. It was first described by Charcot and Joffroy regarding spinal meninges in 1869. HP has three stages; progressive radicular symptoms begin first, then muscle weakness and atrophy start. Findings such as paraplegia, loss of bladder and bowel control, and respiratory distress caused by intercostal and diaphragmatic denervation are considered the third stage of the disease. Especially in the cranial form of the disease, nerve ischemia and various cranial neuropathic findings may occur. Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, and PAI-1 4G-5G gene mutation analysis were measured with an ABI Prism. In this case report, the authors present a case of hypertrophic mutations pachymeningitis with Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, Glycoprotein IIIa L33P gene. In conclusion, we report a case of HP with Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, and Glycoprotein IIIa L33P gene mutations. We emphasize that the identification of pachymeningitis can be easily bypassed with the application of limited laboratory techniques. As in this case report, we think that these mutations should be analyzed in patients diagnosed with pachymeningitis.

Association between MTHFR polymorphism and seizure control in epileptic patients with hyperhomocysteinaemia

The aim of this study was to investigate possible associations between MTHFR polymorphism and seizure control of epileptic patients with hyperhomocysteinaemia. A total of 81 epileptic patients with hyperhomocysteinaemia treated with oxcarbazepine monotherapy were enrolled in this study. All patients were offered vitamin B supplementation (2.5 mg/d folate and 1.5 mg/d mecobalamine) for six months. MTHFR C677T and A1298C polymorphisms, serum homocysteine, folate and vitamin B12 levels as well as seizure frequency and score based on the Hamilton depression scale (HAMD) were evaluated at baseline and after six months of follow-up. Spearman correlation analysis showed that the extent of decline of seizure frequency positively correlated with a dynamic change in serum homocysteine concentration between baseline and after six months of follow-up (t=0.241, p=0.015 [Spearman’s coefficient]). For the MTHFR C677T polymorphism, compared to the CC genotype, the TT genotype was associated with a significant downtrend of homocysteine (19.69 vs 10.28 mmol/L, p=0.006) and uptrend of folate (6.21 vs 2.49 ng/mL; p=0.004). The decrease in homocysteine (17.94 vs 12.52 mmol/L, p=0.001) and increase of folate (5.08 vs 2.86 ng/mL; p=0.003) were significantly greater in patients with the T allele compared to those with the C allele. Also, the TT genotype (2.33 vs 1.4, p=0.056) and T allele (1.95 vs 1.38, p=0.037) were associated with a greater decrease in seizure frequency compared to the CC genotype or C allele. The A1298C polymorphism alone was not associated with elevated homocysteine or decreased folate levels at baseline, and showed little association with response to vitamin B supplementation in epileptic patients with hyperhomocysteinaemia. However, in patients with combined 677TT/1298AA or 677TT/1298AC polymorphisms, the changes in homocysteine and folate levels and seizure frequency were more obvious. MTHFR C677T polymorphism was associated with seizure control in epileptic patients with hyperhomocysteinaemia; individuals with the 677TT genotype or T allele demonstrated better seizure control.

Methodological and Biological Factors Influencing Global DNA Methylation Results Measured by LINE-1 Pyrosequencing Assay in Colorectal Tissue and Liquid Biopsy Samples.

Long interspersed nuclear element 1 (LINE-1) bisulfite pyrosequencing is a widely used technique for genome-wide methylation analyses. We aimed to investigate the effects of experimental and biological factors on its results to improve the comparability. LINE-1 bisulfite pyrosequencing was performed on colorectal tissue (n = 222), buffy coat (n = 39), and plasma samples (n = 9) of healthy individuals and patients with colorectal tumors. Significantly altered methylation was observed between investigated LINE-1 CpG positions of non-tumorous tissues (p ≤ 0.01). Formalin-fixed, paraffin-embedded biopsies (73.0 ± 5.3%) resulted in lower methylation than fresh frozen samples (76.1 ± 2.8%) (p ≤ 0.01). DNA specimens after long-term storage showed higher methylation levels (+3.2%, p ≤ 0.01). In blood collection tubes with preservatives, cfDNA and buffy coat methylation significantly changed compared to K3EDTA tubes (p ≤ 0.05). Lower methylation was detected in older (>40 years, 76.8 ± 1.7%) vs. younger (78.1 ± 1.0%) female patients (p ≤ 0.05), and also in adenomatous tissues with MTHFR 677CT, or 1298AC mutations vs. wild-type (p ≤ 0.05) comparisons. Based on our findings, it is highly recommended to consider the application of standard DNA samples in the case of a possible clinical screening approach, as well as in experimental research studies.

MTHFR C677T polymorphism and cerebrovascular lesions in elderly patients with CSVD: A correlation analysis.

Plasma homocysteine (Hcy) has been identified as a potential risk factor for cerebral small vessel disease. Cerebral small vessel disease (CSVD) leads to cognitive impairment, depression, and other symptoms and is a common disease in middle-aged and elderly people. To investigate the relationship between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and CSVD in elderly patients, plasma levels of homocysteine (Hcy) and MTHFR genotyping were assessed. MRI and MRA were performed at the same time to analyze the relationship between different genotypes and cerebrovascular lesions. We showed that Hcy plasma levels in the TT group were significantly higher than those in the CC and CT groups. Moreover, we observed that the severity of white matter lesions was associated with women and positively correlated with age, previous coronary heart disease, luminal infarction, and MTHFR polymorphism. The multivariate logistic regression analysis showed that age, TT genotype, and lacunar infarction were independent risk factors for white matter hyperintensity (WMH). Importantly, we showed that there was a significant correlation between Hcy plasma levels and MTHFR gene polymorphism, with the TT genotype constituting an independent risk factor for WMH. Therefore, we recommended early detection of MTHFR gene polymorphisms with concomitant early intervention concerning risk factors to delay the occurrence of cognitive impairment in CSVD elderly patients.

Non-functional bladder paraganglioma in a patient with complex hematological disorders: case report

BackgroundAlthough bladder cancer is quite a common cancer, most common encounter being transitional cell carcinomas, paragangliomas with such localization, is a very rare histopathological finding. In addition, hematuria in a patient with a theoretically "hypercoagulable" condition is uncommon; in our case it was the single symptom.Case presentationWe report the case of a 44-year-old female referred to our hospital for gross hematuria. The CT scan revealed an intraluminal enhancing bladder mass. Also, the XIII coagulation factor level was 36% and surprisingly genetic mutations suggesting inherited thrombophilia were found: MTHFR C677T negative, A1298C positive and PAI-1 gene polymorphism (675 4G/5G). The hematologist recommended folic acid 5 mgs daily. A TURBT was performed (macroscopically no residual tumor tissue). The immunohistochemical examination revealed tumor cells intensely positive to chromogranin and synaptophysin, negative for cytokeratin AE1/3, p63, 7, 20 or CDX2, and slight (less than 5%) positive for Ki-67. The combined examinations correspond to a bladder paraganglioma. Six months after surgery, the patient had no clinical symptoms and no relapse sonographically and cystoscopically.ConclusionsAlthough a very rare entity, bladder paraganglioma should be suspected in patients with hematuria and unexplained hyperadrenalism symptoms such as hypertension, serious dizziness, headache or palpitation. The immunohistochemical examination is important not only for diagnosis but also for identifying the functionality of the tumors. In such cases the therapeutic management could be different as in transitional cell carcinomas.

Analysis of polymorphisms in recurrent pregnancy loss: Factor V Leiden G1691A, Factor II G20210A, MTHFR C677T and Factor V H1299R

The distribution of factor V Leiden G1691A, factor II G20210A, MTHFR C677T, and factor V H1299R polymorphisms known to predispose to thrombophilia in 215 cases and 40 controls admitted with indication of recurrent pregnancy loss (RPL) was investigated. Genotyping was performed by melting curve analysis using simultaneous PCR (RT-PCR). There was no difference between genotype and allele frequencies in the case and control groups in terms of the polymorphisms examined (p>0.05). In the genotype distribution of the Factor V gene G1691A polymorphism, 12.6% GA in the case group and 90.0% GG (wild) genotypes in the control group were found to be higher than the other genotypes. In the genotype distribution of the factor II gene G20210A polymorphism, the GG (wild) genotype was found to be higher in 94.5% and 97.5%, respectively, in the case group and control group than the other genotypes. In the genotype distribution of MTHFR gene C677T polymorphism, 43.7% CC (wild) in the case group and 40.0% CT genotype in the control group were found to be higher than the other genotypes. In the genotype distribution of the factor V gene A4070G polymorphism, 87.4% AA (wild) in the case group and 80% AA (wild) genotype in the control group were found to be higher than the other genotypes. However, the frequency of risk allele A for factor V Leiden G1691A (6.8% and 5%), the frequency of risk allele A for factor II gene G20210A (3% and 1.2%), MTHFR gene C677T were determined in the case and control groups. The frequency of the T allele (35.9% and 42.5%), which is the risk allele for A4070G, and the frequency of the G allele (6.5% and 16.6%), which is the risk allele for the factor V gene A4070G, were determined. When our study results were evaluated, no relationship was found between RPL and factor V Leiden G1691A, factor II G20210A, MTHFR C677T, and factor V A4070G polymorphisms.

Maternal Thrombophilic and Hypofibrinolytic Genetic Variants in Idiopathic Recurrent Pregnancy Loss: a Continuing Mystery.

Despite the fact that multiple recurrent pregnancy loss (RPL) etiologies have been identified, 50-70% of RPL cases remain enigmatic, and idiopathic RPL is still a serious medical challenge. A plethora of studies have investigated the correlation of RPL with variations in coagulation and/or fibrinolytic factors-encoding genes. Notwithstanding, evidence for a link between these variations and RPL remains discordant. We aimed to explore the association of thrombophilic and hypofibrinolytic gene variations with RPL development. Two hundred Saudi women were recruited in this study, comprising 150 women experiencing RPL and 50 healthy women. Thirteen genetic variants, including FV G1691A, FV A4070G, F2 G20210A, F13A1 G103T, FGB - 455G > A, PAI-1 - 675 4G/5G, ITGB3 T1565C, MTHFR C677T, MTHFR A1298C, ACE I/D, APOB G10708A, APOE T388C, and APOE C526T were genotyped using ViennaLab StripAssay. Women experiencing RPL harbor significantly higher frequencies of the F13A1 103T, FGB - 455A, and ITGB3 1565C alleles than control women (p < 0.001). No differences in the prevalence of other investigated variants were identified between control women and those with RPL. No considerable link of F5 1691G > A/4070A > G, MTHFR 677C > T/1298A > C, and APOE 388T > C/526C > T haplotypes with RPL risk was demonstrated. F13A1 G103T, FGB - 455G > A, and ITGB3 T1565C variants are connected to a higher likelihood of developing RPL and, hence, may have the potential to identify those women at risk of RPL, thereby, improving RPL susceptibility prediction. Incorporating molecular testing of thrombophilic and hypofibrinolytic genetic variants into routine workup could confer a promising approach for refined RPL risk assessment.

Developing a Sensitive Platform to Measure 5-Methyltetrahydrofolate in Subjects with MTHFR and PON1 Gene Polymorphisms.

Inadequate levels of 5-methyltetrahydrofolate (5-MTHF) and the T variant of MTHFR C677T have been suggested to be associated with an increased risk of developing mental illness, whereas the PON1 SNP variant provides a protective role. However, reports validating the methodology for plasma 5-MTHF levels in schizophrenia patients are limited. A sensitive LC–MS/MS system using an amide column and calibration curve was determined by dialyzed human plasma, and applied to schizophrenia patients and healthy controls in Taiwan, and the differences between the subgroups were discussed. This analysis system meets regulation criteria, and the lower limit of quantification for 5-MTHF levels was 4 nM from 200 μL plasma, within 7 min. The mean plasma 5-MTHF levels in schizophrenia patients (n = 34; 11.70 ± 10.37 nM) were lower than those in the healthy controls (n = 42; 22.67 ± 11.12 nM) significantly (p < 0.01). 5-MTHF concentrations were significantly lower in male carriers than in female carriers (18.30 ± 10.37 nM vs. 24.83 ± 11.01 nM, p < 0.05), especially in subjects who were MTHFR CT/PON1 Q allele carriers. In conclusion, this quantitative system, which employed sensitive and simple processing methods, was successfully applied, and identified that schizophrenic patients had significantly lower levels of 5-MTHF. Lower plasma 5-MTHF concentrations were observed in male subjects.

Association of factor V Leiden R506Q, FXIIIVal34Leu, and MTHFR C677T polymorphisms with acute myocardial infarction

BackgroundAcute myocardial infarction (AMI) is a leading cause of death and morbidity around the world. Although the association between thrombophilia and AMI is well-established, controversial data are present on the association between thrombophilic polymorphisms and AMI. The aim of this study was to investigate the association of three thrombophilic polymorphisms including factor V Leiden (FVL), MTHFRC677T (methylenetetrahydrofolate reductase), and Coagulation factor XIIIVal34Leu with AMI in East of Iran.ResultThere were no statistically significant differences between the patients and control groups in terms of the distributions of allelic and genotypic frequencies of FVL and FXIIIVal34Leu polymorphisms (P-value > 0.05). Subjects who carried CT genotype of MTHFR C677T polymorphism were at a 2.03-fold higher risk for AMI (P-value: 0.02, OR 1.76, 95% CI 1.07–2.75). Furthermore, patients with MTHFR 677CT (P-value < 0.001, β = - 0.90, 95% CI − 1.33, − 047) or 677CC (P-value < 0.001, β = - 1.04, 95% CI − 1.47, − 0.61) genotypes showed significantly Lower creatinine levels compared with patients having the MTHFR 677TT. No association was observed between the other remaining polymorphisms and AMI (P-value > 0.05).ConclusionOur findings showed that MTHFRC677T polymorphism could contribute to AMI susceptibility and increase creatinine levels in east Iran population. This was the first study to examine the association of these three polymorphisms with AMI in east Iran.

Impact of Factor V Leiden G1691A, MTHFR C677T, and Prothrombin G20210 A mutations on the development of neonatal thrombosis

Impact of Factor V Leiden G1691A, MTHFR C677T, and Prothrombin G20210 A mutations on the development of neonatal thrombosis

MTHFR Gene-Polymorphism and Infertile Men in Indian Population: A Systematic Literature Review

Single nucleotide polymorphisms (SNPs) in the genetic makeup of the methylenetetrahydrofolate reductase gene (MTHFR C677-T, A1298-C, and G1793-A) alongside environmental and lifestyle component has shown some links as a potential factor responsible for male infertility across the globe posing huge genetic vulnerability to the gender. However, SNPs in the MTHFR gene implicated in male infertility are not without their own controversial results even within the same population. The goal of this study was to provide comprehensive insights into the controversial nature of MTHFR gene polymorphism on male infertility across all Indian populations as well as other ethnicities. The electronic PubMed database was utilized to conduct and select eligible studies for this systematic review (update to December 2021). Only high-quality studies with a link between MTHFR polymorphisms and male infertility were included based on our exclusion and inclusion criteria. The connection between the MTHFR gene polymorphism and male infertility in Indian population studies was evaluated using odds ratios (ORs) with a 95% confidence interval (CI). A total of five studies presenting 1,237 cases and 1,044 controls were assessed for this study. The collective results revealed that MTHFR C667-T and A1298-C gene polymorphism were significantly linked with an increased chance of male infertility both in south India and north India, however, with some conflicting results. Interestingly, no study has been carried out to investigate the impact of G1793-A polymorphism on infertile males in the Indian population at the time of our report. Results generated from the few case-control evaluated on MTHFR gene polymorphism in the Indian population are found to conflict with some extrinsic factors (such as nutritional status-folate metabolism, lifestyle, varying recruitment procedures, and epigenetic elements) identified to have played some critical roles. Therefore, broader studies across all regions in India addressing the grave impact of MTHFR gene polymorphism on male infertility are of utmost importance.