MTHFR C677T、MTHFR A1298C、MTRR A66G and MTR A2756G polymorphisms and male infertility risk: a systematic review and meta-analysis.

BACKGROUND: Epidemiological studies have reported that polymorphisms of folate-metabolizing genes have a significant impact on male infertility. However, the results of published studies have come to different conclusions. OBJECTIVE: To determine an association between folate-metabolizing gene polymorphisms and the risk of male infertility. METHODS: The meta-analysis was conducted according to the PRISMA 2020 statement. The protocol was registered with PROSPERO (CRD42023412251). Studies were searched from PubMed, Google Scholar, Embase, Scopus, and the Cochrane Library up to 24st October2023. Articles that satisfied the inclusion criteria were evaluated for their quality using the Newcastle-Ottawa Scale. Data were extracted from the eligible studies and were analyzed for pooled up odds ratio (OR) with 95% confidence interval (CI). Meta-analysis was conducted using STATA 12. RESULTS: Forty-six case-control studies were included in the meta-analysis which comprised 20,639 participants. The pooled analysis revealed that the MTHFR C677T polymorphism was significantly associated with male infertility and abnormospermia.Three-fifths of the model showed there was a significant association between the MTR A2756G polymorphism and male infertility. Both MTHFR A1298C and MTRR A66G polymorphisms were not significantly associated with male fertility. Furthermore, subgroup analysis revealed a significant association between the MTHFR C677T polymorphism and male fertility in Asian countries. CONCLUSION: This meta-analysis suggests that the MTHFR C677T and MTR A2756G polymorphisms may be a potential risk factor for male infertility.

Association of MTHFR C677T, MTHFRA1298C, and MTRRA66G Gene Polymorphisms with Hyperhomocysteinemia and Its Modulation by the Combined Effect of Vitamin B12 and Folate in Chinese Population with Hypertension.

BACKGROUND: In China, the MTHFR 677T allele, unlike in most Western populations, is a rare genetic variant linked to various disorders. The contributing nutritional and genetic factors to this genetic risk remain unclear. OBJECTIVE: This study aimed to elucidate the interactions between genetic variations in total homocysteine (tHcy) pathway genes, serum tHcy concentrations, and nutritional factors in a Chinese population with hypertension. METHODS: This study analyzed 1304 Chinese adults with hypertension aged ≥18 y enrolled in the China Precision Nutrition and Health KAP Real World Study (CPNAS). Serum concentrations of vitamin B12 and folate were measured using the magnetic microparticle chemiluminescence method, and tHcy concentrations were measured using Hcy Assay kits. Identification of the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms was performed via time-of-flight nucleic spectrometry. RESULTS: Our findings revealed significant sex differences in tHcy concentrations, with males exhibiting higher tHcy concentrations than females (13.95 µmol/L vs. 11.15 µmol/L, P < 0.001). Individuals deficient in both vitamin B12 and folate had an increased risk of hyperhomocysteinemia (H-Hcy) (57.4%). In contrast, the prevalence of H-Hcy was lower among those deficient in either vitamin B12 (31.1%) or folate (23.2%) alone. Significant associations were identified between the MTHFR C677T and A1298C polymorphisms and elevated serum tHcy concentrations, particularly in individuals homozygous for the T allele. Conversely, the MTRR A66G genotype did not show a significant correlation with tHcy concentrations. Optimal vitamin B12 concentrations significantly modulated the genotypic effect on tHcy concentrations, with individuals having adequate vitamin B12 and folate exhibiting low tHcy concentrations, even among high-risk genotypes (TT). CONCLUSIONS: Adequate concentrations of folate and vitamin B12 significantly reduce serum tHcy concentrations and mitigate the genotypic impact on tHcy concentrations, highlighting the potential for targeted nutritional interventions to manage cardiovascular risks associated with H-Hcy. This trial was registered at clinicaltrials.gov as ChiCTR2100051983.

ATR1 A1166C (rs5186), FII G20210A (rs1799963), FV G1691A (rs6025), FXIII 97G > T (rs11466016) and MTHFR A1298C (rs1801131) polymorphisms and the risk of ST-elevation myocardial infarction in young Mexican individuals.

BACKGROUND: Previous studies had identified genetic variants associated with Myocardial Infarction, but results are inconclusive. We examined the association between FII G20210A (rs1799963), FV G1691A (rs6025), FXIII 97G > T (rs11466016), ATR1 A1166C (rs5186) and MTHFR A1298C (rs1801131) polymorphisms and ST elevation Myocardial Infarction in young Mexican individuals. METHODS: We included a total of 350 patients with Myocardial Infarction <45 years old and 350 controls matched by age and gender. The polymorphisms were analyzed by PCR-RFLP using specific restriction enzymes. DNA fragments were separated by electrophoresis in 2% gel of agarose and visualized using SYBR green. RESULTS: The A1166C (p = 0.004) but not FXIII 97G > T (p = 0.19), G20210A (p = 0.32), G1691A (p = No significant) and A1298C (p = 0.21) polymorphisms were associated with increased risk for ST elevation Myocardial Infarction. Moreover, dyslipidemia, hypertension, smoking and family history of atherothrombotic disease were associated. CONCLUSIONS: We found that A1166C represented increased risk for ST elevation Myocardial Infarction. However, G20210A, G1691A, 97G > T, and A1298C were not associated. In addition, we had determined that Glu298Asp, PLA1/A2, TAFI Thr325Ile, ACE I/D, AGT M235T and PAI-1 4G/5G polymorphisms represented increased risk in the same group of patients. However, MTHFR C677T, AGT T174M, FV G1691A, TSP-1 N700S, MTHFR C677T and TAFI 174 M polymorphisms were no associated. Our results suggest that in young patients with ST Myocardial Infarction, those polymorphisms could contribute to premature endothelial dysfunction, atherothrombosis, vasoconstriction, increased platelet aggregation, muscle cell migration and proliferation. Further studies are required to try to better assess gene-gene and gene-modifiable factors interaction.

MTHFR and MTRR gene polymorphisms in patients with chronic hepatitis B virus infections in Zigong, Sichuan Province.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is a severe disease affecting the physical and economic well-being of patients. The relationship between polymorphisms in the MTHFR gene and disease progression following HBV infection remains a controversial topic. AIM: To study MTHFR and MTRR gene polymorphisms in patients with chronic HBV infections in Zigong, Sichuan Province. SUBJECTS AND METHODS: One hundred and ninety-one patients with chronic HBV infections were divided into three groups: the chronic hepatitis B (CHB) group (n = 71), the hepatitis B-induced liver cirrhosis (LC) group (n = 56), and the hepatitis B-related primary liver cancer (PLC) group (n = 64). The gene polymorphisms were detected using the PCR-melt curve method and analysed. RESULTS: The distributions of MTHFR C677T (CC: 41.2% vs. 41.8%; CT: 50% vs. 45.5%; TT: 8.8% vs. 12.7%; p = 0.714), MTHFR A1298C (AA: 70.6% vs. 72.7%; AC: 26.5% vs. 25.5%; CC: 2.9% vs. 1.8%; p = 1.000), and MTRR A66G (AA: 58.1% vs. 65.5%; AG: 39.0% vs. 29.1%; 2.9% vs. 5.5%; p = 0.353) genetic polymorphisms did not vary between male and female patients from Zigong. In addition, there were no differences in the distributions of MTHFR C677T (CC: 43.4% vs. 38.8%; CT: 49.1% vs. 48.2%; TT: 7.5% vs. 12.9%; p = 0.444), MTHFR A1298C (AA: 76.4% vs. 64.7%; AC: 20.8% vs. 32.9%; CC: 2.8% vs. 2.4%; p = 0.155), and MTRR A66G (AA: 62.3% vs. 57.6%; AG: 34.0% vs. 38.8%; 3.8% vs. 3.5%; p = 0.353) genetic polymorphisms between the patients <60 and >60 years of age. The distributions of MTHFR C677T (CHB vs. LC, p = 0.888; CHB vs. PLC, p = 0.661; PLC vs. LC, p = 0.926), MTHFR A1298C (CHB vs. LC, p = 0.12; CHB vs. PLC, p = 0.263; PLC vs. LC, p = 0.550), and MTRR A66G (CHB vs. LC, p = 0.955; CHB vs. PLC, p = 0.645; PLC vs. LC, p = 0.355) gene polymorphisms were comparable between the CHB, LC, and PLC groups. CONCLUSION: The distributions of MTHFR and MRRR genetic polymorphisms in the population with HBV infections in Zigong, Sichuan Province did not differ in age and sex. The MTHFR and MRRR genetic polymorphisms were comparable between the CHB, LC, and PLC groups.

Association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms with serum folate, cobalanin and homocysteine concentrations in Greek adults.

Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme of homocysteine metabolism participating in the folate cycle. The aim of this study was to investigate the association of MTHFR C677T and MTHFR A1298C gene polymorphisms with serum folate, cobalamin (Cbl) and homocysteine (Hcy) concentrations in healthy Greek adults. The MTHFR C677T and A1298C gene polymorphisms were genotyped in 383 healthy Greek adults (199 men and 184 women) using polymerase chain reaction and reverse hybridization. Serum folate, Cbl and total Hcy (tHcy) levels were determined using immunoassays methods. Among the 383 individuals, 73 (19.1%) were normal (CC), 202 (52.7%) were heterozygous (CT) and 108 (28.2%) were homozygous (TT) regarding the MTHFR C677T gene polymorphism, while 263 (68.7%) were normal (AA), 105 (27.4%) were heterozygous (AC) and 15 (3.9%) were homozygous (CC) regarding the MTHFR A1298C gene polymorphism. The overall C and T allele frequency for the MTHFR C677T gene polymorphism was 45.4% and 54.6%, respectively, while the overall A and C allele frequency for the MTHFR A1298C gene polymorphism was 82.3% and 17.6%, respectively. The MTHFR C677T and not the A1298C gene polymorphism had a significantly influence on serum folate and tHcy levels. The individuals with 677TT genotype had significantly lower serum folate and significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. Serum folate and tHcy levels are influenced by the existence of the MTHFR C677T gene polymorphism (mainly 677TT genotype). Individuals with low serum folate levels and/or high serum tHcy levels should be further investigated for a possible existence of MTHFR C677T and not A1298C gene polymorphisms, with aim to determine the suitable treatment.

Association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with vitamin B12 deficiency and adverse perinatal outcomes among pregnant women of rural South India - a cross sectional longitudinal study.

OBJECTIVES: To determine the occurrence of MTHFR gene polymorphisms and to study their association with vitamin B12 deficiency and adverse perinatal outcomes among a cohort of pregnant women from Kaniyambadi block, Tamil Nadu. METHODS: 120 consecutive pregnant women who were ≤20 weeks of gestational age from the 82 villages of Kaniyambadi block were recruited. Genomic DNA was isolated from the peripheral blood. PCR amplification was done followed by Sangers sequencing. Maternal and neonatal outcomes were extracted. Data was entered and analysed. RESULTS: Our study found the occurrence of c.1298A>C variant in homozygous state in 14.2% and c.677C>T heterozygous state in 15%. Sanger sequencing of exon 7 identified another pathogenic variant c.1262G>T in heterozygous state in two of them. Both the mothers who harboured that variant had preterm delivery and one of them gave birth to a low-birth-weight neonate. In the entire cohort, 5% of the mothers had abortion, 4.2% of them had preterm delivery and 8.8% of the neonates had low birth weight. Presence of c.1298A>C or c.677C>T variants were associated with vitamin B12 deficiency [Pearson Chi squared value (χ2)=7.9 and 7.6 respectively; p=0.02]. Heterozygous pathogenic variant c.1262G>T was associated with both adverse maternal [χ2=11.5; p=0.001] and neonatal [χ2=18.3; p=0.009] outcomes. CONCLUSIONS: MTHFR gene polymorphisms could be associated with several adverse perinatal outcomes and vitamin B12 deficiency. Further larger studies are needed to prove the pathogenicity of c.1262G>T variant on pregnancy.

Association of MTHFR C677T (rs1801133) and A1298C (rs1801131) Polymorphisms with Serum Homocysteine, Folate and Vitamin B12 in Patients with Young Coronary Artery Disease.

C677T (rs1801133) and A1298C (rs1801131) MTHFR gene polymorphisms and/or nutritional deficiency of folate/vitamin B12 leading to hyperhomocysteinemia is an established risk factor for CAD. The objective of this study was to evaluate the clinical usefulness of association between MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms with serum homocysteine, folate and vitamin B12 in addition to conventional cardiovascular risk factors in patients with young CAD. Genomic DNA was isolated from the whole blood. Genotyping of MTHFR C677T (rs1801133) and MTHFR A1298C (rs1801131) polymorphisms in young CAD patients and healthy controls was performed by ARMS-PCR method. Serum homocysteine, vitamin B12 and folate were estimated by CMIA and lipid profile parameters were measured by automated chemistry analyzers. Serum homocysteine levels were significantly higher but serum folate and vitamin B12 levels were not significantly different among young CAD group as compared to control group. Statistically significant hyperhomocysteinemia was observed in carriers of T allele for MTHFR 677C/T (rs1801133) genotype in young CAD group but this association was not significant for MTHFR 1298A/C (rs1801131) polymorphism. The association between hyperhomocysteinemia and CAD in young group was not independent of conventional cardiovascular risk factors. Risk of hyperhomocysteinemia and young CAD could be monitored by MTHFR polymorphism detection followed by serum homocysteine, folate and vitamin B12 measurements. The findings could help to prevent or delay the occurrence of young CAD through appropriate measures.

MTHFR (C677T, A1298C), FV Leiden polymorphisms, and the prothrombin G20210A mutation in arterial ischemic stroke among young tunisian adults.

Arterial ischemic stroke (AIS) in young adults is less common in older adults, but the underlying pathogenesis and risk factors are more multi-faceted. The role of inherited thrombophilia such as 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, (C677T and A1298C), factor V of Leiden (FVL) polymorphism, and the prothrombin G20210A mutations remains unclear. This study aims to evaluate the role of prothrombin genetic factor in AIS among young adults in Tunisia and to assess the synergistic effect between thrombogenic mutations in the pathogenesis of AIS. In this case-control study, blood samples were collected from patients and healthy controls, all matched for age and gender. The difference between them is evaluated by using the chi-square test. The odds ratio (OR) was carried out to evaluate the associations between each polymorphism and AIS risk using a binary logistic regression model. Values were considered statistically significant when p < 0.05. Patients carrying simultaneously the MTHFR polymorphisms (677T and 1298C) have a higher risk to develop AIS compared to controls. The heterozygous variants FVL increased the risk of AIS only when it is associated with MTHFR C677T or MTHFR A1298C polymorphisms. In conclusion, our study confirmed the involvement of MTHFR polymorphisms as AIS's important risk factors. The existence of FVL polymorphism or prothrombin G20210A mutation alone doesn't correlate with the occurrence of stroke. We assume that the presence of both MTHFR and FVL polymorphisms has a synergistic effect and increased the risk of the AIS.

The effect of A1298c polymorphism of the MTHFR gene on anti-Müllerian hormone levels: experimental and Web-based analysis.

BACKGROUND: The 5,10-methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, which is expressed in human oocytes and preimplantation. Due to the involvement of MTHFR in female reproduction, we tend to evaluate the influence of MTHFR A1298C polymorphism on ovarian marker reserves such as serum anti-Müllerian hormone (AMH) levels in women after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). METHODS: A total of 100 women, who underwent ART treatment due to male factor infertility, were recruited into this study. MTHFR A1298C polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, and serum AMH concentrations were measured by an ultrasensitive enzyme-linked immunosorbent assay (ELISA). RESULTS: Women with the CC genotype had higher AMH levels (4.15 ± 1.67 ng/ml), albeit not significant, than carriers with other genotypes after ovarian stimulation. No significant differences existed in terms of miscarriage and live birth rates among different genotype groups. CONCLUSION: The presence of the C mutant allele of the 1298 polymorphism in the MTHFR gene led to an increasing trend in serum AMH concentrations; however, the numbers of oocytes retrieved decreased in women with mutated genotypes. The influence of the MTHFR C677T polymorphism on embryo quality and pregnancy rate after ART cycles remains unclear.

Hyperbaric oxygen treatment results in a group of Turkish central retinal artery occlusion patients with a combined presence of thrombophilic mutations.

Background: Central retinal artery occlusion (CRAO) is a rare ocular-ischemic syndrome causing irreversible blindness. Its pathophysiology has not been clarified, and no targeted therapies are available yet. Hyperbaric oxygen (HBO2) therapy is already an approved therapy for CRAO and has been shown to improve the visual acuity of CRAO patients safely. However, further clinical data are required to classify HBO2 therapy as a type-I general agreement for CRAO. Materials and Methods: Eleven patients with non-arteritic CRAO were enrolled. Patient demographics, medical history, detailed eye examinations, HBO2 therapy results, pre-/post HBO2 therapy visual acuity measurements and genotypes for common thrombophilic mutations (Factor V G1691A Leiden, Factor II G20210A, MTHFR A1298C, MTHFR C677T, and PAI-1-675 4G/5G) were obtained. Result: Six patients (54%) responded to HBO2 therapy compared to five non-responders (46%). Patients admitted before 12 hours responded well to HBO2 therapy. No systemic diseases nor advanced age were statistically correlated to CRAO. A combination of mutations rather than single mutations for each patient could be seen as responsible for CRAO. No Factor V G1691A Leiden mutations and only one FII G20210A mutation were observed. Eight patients (72%) had MTHFR 677T allele, five patients (45%) had MTHFR 1298C allele, and 10 patients (91%) had the PAI-1-675 4G allele. Conclusion: Not a single mutation but a combination of mutations and other unknown factors probably lead to CRAO, and if intervention is timely, HBO2 therapy offers improvement in visual acuity safely.

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.

Interactions between genetic variants involved in the folate metabolic pathway and serum lipid, homocysteine levels on the risk of recurrent spontaneous abortion.

BACKGROUND: The interaction between folate pathway gene polymorphisms and homocysteine, serum lipid leverls are poorly understood in patients with recurrent spontaneous abortion (RSA). The aim of this study is to explore the effects of folate pathway gene polymorphisms (the 5-10-methylenetetrahydrofolate reductase, MTHTR C677T, MTHFR A1298C and the methionine synthase reductase, MTRR A66G) and their interactions with homocysteine on serum lipid levels in patients with RSA. METHODS: A total of 403 RSA women and 342 healthy women were randomly selected. Genotyping of the MTHFR C677T, A1298C and MTRR A66G were performed by TaqMan-MGB technique. Serum homocysteine, folate, fasting glucose, fasting insulin, Interleukin 6, Tumor necrosis factorα (TNFα) and lipid profiles were measured according to the kits. Continuous variables were analyzed using 2-sample t-tests. Categorical variables were analyzed and compared by χ2 or Fisher's exact tests. Unconditional logistic regression model was applied to test the interactions of gene polymorphisms on RSA. RESULTS: The distribution of genotype of CC, CT TT and T allele of MTHFR C677T, genotype of AA and C allele of MTHFR A1298C, and genotype of AA, AG and G allele of MTRR A66G were different between cases and controls (all p were < 0.05). There were significant interactions between MTHFR C677T-A1298C and MTHFR A1298C-MTRR A66G in RSA group and control group, with ORs of 1.62 (95%CI: 1.28-2.04, p < 0.001) and 1.55 (95%CI: 1.27-1.88, p < 0.001), respectively. Serum TNFα level and insulin resistant status (HOMR-IR) were higher in RSA group than in control group (p = 0.038, 0.001, respectively). All the three gene SNPs except MTRR 66AG gene variant had detrimental effects on HOMA-IR (all p were < 0.05). RSA group who carried the MTHFR 677CT, TT, CT/TT genotypes and MTRR 66AG, AG/GG genotypes had detrimental effects on serum homocysteine levels, the MTHFR 677CT, CT/TT genotype carriers had favorable effects on serum folate levels, the MTHFR 677TT, CT/TT, 1298 AC, AC/CC genotype carriers had detrimental effects on serum low-density lipoprotein cholesterol (LDL-C) levels, and the MTRR 66AG genotype carriers had lower high-density lipoprotein cholesterol (HDL-C) levels than the AA genotype carriers (all p were < 0.05). CONCLUSIONS: Interaction between the MTHFR C677T, A1298C and MTHFR A1298C, MTRR A66G are observed in our RSA group. Besides, all the three gene SNPs except MTRR 66AG gene variant had detrimental effects on HOMA-IR. MTHFR C677T and MTRR A66G gene variants had detrimental effects on serum homocysteine levels and insulin resistance status, while MTHFR C677T, A1298C and MTRR A66G gene variants had detrimental effects on certain serum lipid profiles.

Methylenetetrahydrofolate reductase C677T variant and hyperhomocysteinemia in subarachnoid hemorrhage patients from India.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T, A1298C) has been implicated in increased plasma homocysteine (Hcy) levels. The present study was designed to investigate the association between MTHFR polymorphism and increased Hcy levels in subarachnoid haemorrhage (SAH) patients. A total of 150 subjects from North India were included in the study, comprising of 100 SAH patients and 50 healthy controls. Plasma Hcy levels was determined and MTHFR polymorphism (C677T, A1298C) was screened by High resolution melting (HRM) analysis. Plasma Hcy levels were found to be significantly higher (p < 0.001) in SAH patients than in healthy controls. No significant difference in the genotype and allele frequency of MTHFR A1298C was observed. However, frequency of MTHFR C677T genotype, CT (53% vs. 20%; p < 0.001) and TT (15% vs. 2%; p < 0.05) was significantly higher in SAH group as compared to healthy controls. The frequency of T allele (41.5% vs. 12%; p < 0.001) was also found to be higher in SAH patients in comparison to healthy controls. Furthermore, Hcy levels were higher in SAH patients with TT genotype than in patients having CT genotype, whereas CC genotype had lower Hcy levels. The study suggests that higher frequency of MTHFR C677T allele may contribute to etiopathology of SAH through increase in Hcy levels.

Determining the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and genomic DNA methylation level: A meta-analysis.

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) polymorphism is a risk factor for neural tube defects. C677T and A1298C MTHFR polymorphisms produce an enzyme with reduced folate-related one carbon metabolism, and this has been associated with aberrant methylation modifications in DNA and protein. METHODS: A meta-analysis was conducted to assess the association between MTHFR C677T/A1298C genotypes and global genomic methylation. RESULTS: Eleven studies met the inclusion criteria. Of these, 10 were performed on C677T MTHFR genotypes and 6 were performed on A1298C MTHFR genotypes. Our results did not indicate any correlation between global methylation and MTHFR A1298C, C677T polymorphisms. CONCLUSION: The results of our study provide evidence to assess the global methylation modification alterations of MTHFR polymorphisms among individuals. However, our data did not found any conceivable proof supporting the hypothesis that common variant of MTHFR A1298C, C677T contributes to methylation modification. Birth Defects Research (Part A) 106:667-674, 2016. © 2016 Wiley Periodicals, Inc.

Association of Mycobacterium infections in patients with Mendelian susceptibility to mycobacterial disease with venous thromboembolism.

An association between a hypercoagulable state and Mendelian susceptibility to mycobacterial disease (MSMD) has been established in a few studies; resultant thrombosis is considered rare. In a case-control study, the prevalence of factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C mutations were investigated in mycobacterium-infected patients. The study comprised 30 patients with mycobacterial infections (invasive, disseminated and/or recurrent infections with Bacille Calmette-Guerin or non-tuberculosis mycobacteria and Mycobacterium Tuberculosis with positive results for acid-fast bacilli and tuberculin skin tests) and 30 normal healthy controls. Forty female (66.7%) and 20 male subjects (33.3%) aged from 3 to 70 years were recruited into this study. Genotyping of targeted genes was performed by RT-PCR and cytokine TNF-α concentrations were quantified using a commercially available ELISA kit. Significant associations between mycobacterial infection and TNF-α production after stimulating peripheral blood mononuclear cells with LPS alone and with IFN-γ plus LPS were identified. Moreover, genotyping analysis in the studied population revealed a significant association between MTHFR c.677C>T (OR, 3.28; 95% CI, 1.35-7.92; P < 0.05), MTHFR c.1298A>C (OR, 2.33; 95% CI, 1.10-4.93; P < 0.05) and mycobacterial infection in affected patients, indicating susceptibility to venous thromboembolism according to previous studies. Additionally, mycobacterium-infected patients had a significantly greater prevalence of MTHFR C677T and A1298C mutations than controls.

Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancer disease.

Breast cancer (BC) represents a highly heterogeneous tumour at both the clinical and molecular levels. Single-nucleotide polymorphisms (SNPs) of the folate-metabolising enzyme methylenetetrahydrofolate-reductase (MTHFR) may modify the association between folate intake and BC and influence plasma folate concentration. The role of folate in BC is equivocal, association studies between the common MTHFR SNPs C677T and A1298C and BC risk are controversial. In this study, I have reviewed observed associations between folate intake, as well as its blood levels, and BC. The purpose of this review is to analyse the role of folate and the two SNPs associated with reduced enzyme activity in BC. I explored the most relevant and updated work that emphasises positive and negative associations among these variables. My findings indicate that no definitive conclusions can be drawn from the studies on this topic. However, this manuscript highlights variables that could be useful to explore in further association analyses.

Interrelationships among MTHFR gene polymorphisms, MTRR gene polymorphisms, and HBV gene BCP 1762/1764 mutations with disease progression in Chronic hepatitis B virus infection patients.

OBJECTIVE: Chronic hepatitis B virus (HBV) infection is a major disease that seriously affects the health of patients. In this paper, the relationship among MTHFR gene polymorphism, MTRR gene polymorphism and 1762/1764 mutation in the BCP region of HBV gene with disease progression in chronic HBV patients was studied. METHODS: A total of 144 chronic HBV infection patients from January 2021 to June 2022 in the Third People's Hospital of Zigong City, were included as the study subjects. These patients were divided into hepatitis B primary liver cancer patients group (PLC) in 51 cases, Non-primary liver cancer patients group (Non-PLC) in 93 cases, Non-PLC is also divided into chronic hepatitis B virus carriers (CHC) in 49 cases, hepatitis B Live cirrhosis(LC) in 44 cases. MTHFR (C677T), MTRR (A66G) and MTHFR (A1298C) genes polymorphisms were detected by PCR-dissolution curve. The level of HBV-DNA was quantified by real-time PCR, and the 1762/1764 mutation site in the BCP region of the HBV gene were detected by ARMS-PCR. Data were statistically analyzed using the SPSS statistical software. RESULTS: The proportion of HBV mutations in BCP region 1762/1764 in PLC group was 82.4%, which was higher than that in LC group (63.6%) and CHC group (51.0%), and the differences were statistically significant (p < 0.05). There were no significant differences in the distribution of MTHFR C677T, MTHFR A1298C and MTRR A66G polymorphisms among CHC, LC and PLC (p > 0.05). The polymorphism distribution of MTHFR C677T, MTRR A66G and MTHFR A1298C genes in patients with chronic hepatitis B virus infection at different stages (CHC, LC and PLC) showed no gender or age differences between and within groups (p > 0.05). Among the patients with MTHFR 677CT + TT, MTRR 66AG + GG and MTHFR 1298AA genotype, the proportion of HBV mutation in BCP region 1762/1764 in PLC group was higher than that in CHC group and LC group, and the differences were statistically significant (p < 0.05). Folate levels in the PLC group were lower than those in the non-PLC group (CHC and LC patients), and the difference was statistically significant compared with the CHC group (p < 0.05). In different MTHFR C677T and MTRR A66G genotypes, the serum GGT activity were statistically significant between mutant PLC and mutant Non-PLC (p < 0.05). CONCLUSION: MTHFR C677T, MTRR A66G and MTHFR A1298C gene polymorphisms distribution have no gender and age differences in chronic hepatitis B virus infection patients. The mutation of HBV gene BCP region 1762/1764 may be associated with the occurrence and development of liver cancer in patients with chronic HBV infection. Single difference of MTHFR C677T, MTHFR A1298C and MTRR A66G gene polymorphisms may have little effect on the disease progression in patients with chronic HBV infection. MTHFR 677CT + TT, MTRR 66AG + GG and MTHFR 1298AA genotype combined with HBV gene BCP region 1762/1764 mutation may be closely related to the occurrence and development of hepatitis B liver cancer.

Associations between one-carbon metabolism and valproic acid-induced liver dysfunction in epileptic patients.

Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually associated with hepatotoxicity. However, the underlying mechanisms of VPA-caused hepatotoxicity remain unclear. In this study, a total of 157 pediatric patients with epilepsy were recruited and divided into normal liver function (NLF, 112 subjects) group and abnormal liver function (ABLF, 45 subjects) group. We observed that MTHFR A1298C and MTHFR C677T variants may be linked to VPA-induced liver dysfunction (p = 0.001; p = 0.023, respectively). We also found that the MTHFR A1298C polymorphism was associated with a higher serum Hcy level (p = 0.001) and a lower FA level (p = 0.001). Moreover, the serum Hcy levels was strongly correlated with the GSH and TBARS concentrations (r = -0.6065, P < 0.001; r = 0.6564, P < 0.001, respectively). Furthermore, logistic analysis indicated that MTHFR A1298C/C677T polymorphisms and increased Hcy concentrations may be risk factors for VPA-induced liver dysfunction. These results suggested that individual susceptibility to VPA-induced liver dysfunction may result from MTHFR A1298C/C677T polymorphisms and increased Hcy levels. This study may be helpful for the prevention and guidance of VPA-induced liver dysfunction.

Involvement of the ABCB1 C3435T Variant but Not the MTHFR C677T or MTHFR A1298C Variant in High-Dose Methotrexate-Induced Toxicity in Pediatric Acute Lymphoblastic Leukemia Patients in China.

Purpose: It remains unclear whether the MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genetic variants are associated with methotrexate (MTX) elimination delay and high-dose MTX (HD-MTX) toxicities in the treatment of pediatric acute lymphoblastic leukemia (ALL). The aim of our study was to analyze the potential predictive role of MTHFR C677T, MTHFR A1298C and ABCB1 C3435T in toxicities and the relationship between these variants and MTX elimination delay during HD-MTX therapy in pediatric ALL patients. Patients and Methods: We conducted a retrospective study on ALL patients receiving HD-MTX treatment with available MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genotype and 44-h plasma MTX levels. Logistic regression analyses and chi-square tests were used to assess the relationship between the variants and HD-MTX toxicities and MTX elimination delay. Results: Genotype frequencies were in Hardy-Weinberg equilibrium. MTX elimination delay did not significantly differ between MTHFR C677T and MTHFR A1298C or ABCB1 C3435T. Leukopenia (P=0.028), neutropenia (P=0.034) and oral mucositis (P=0.023) were 6.444-fold, 4.978-fold and 9.643-fold increased, respectively, in ABCB1 C3435T homozygous genotype (TT) patients compared to wild-type (CC) patients. No significant association was found between the toxicities investigated and MTHFR C677T or MTHFR A1298C. Conclusion: This study showed that the ABCB1 C3435T homozygous allele genotype (TT) is associated with increased MTX-related toxicities (leukopenia, neutropenia and oral mucositis). These results may help to distinguish pediatric ALL patients with a relatively high risk of MTX-related toxicities before HD-MTX infusion and optimize MTX treatment.