Homocysteine concentration in coronary artery disease and severity of coronary lesions.

Our previous study reckons that the impact of the rs1801133 variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) on coronary artery disease (CAD) is possibly mediated by cardiometabolic disorder. This study is performed to verify this hypothesis. Four hundred and thirty CAD patients and 216 CAD-free individuals were enrolled in this case-control study. The rs1801133 variant was genotyped by PCR-RFLP. Severity of coronary lesions was evaluated by number of stenotic coronary vessels and extent of coronary stenosis. The rs1801133 T allele significantly increased homocysteine levels in patients with CAD and CAD-free individuals. Individuals with the T allele of rs1801133 had an increased risk of developing CAD. In contrast, individuals with the TT genotype of rs1801133 were at high risk of multiple vessel lesions. The carriers of CT genotype had higher levels of systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP), and lower levels of apolipoprotein A1 (APOA1) than those with CC genotype in male patients with CAD. The receiver operating characteristic (ROC) curve and precision-recall (PR) curve indicated that hyperhomocysteinemia was sensitive to predict the severity of CAD. Multivariate logistic regression revealed that homocysteine, rs1801133, age, smoking, weight, body mass index (BMI), lipoprotein(a) [Lp(a)], and hs-CRP were independent risk factors for CAD. The increased risk of CAD and severity of coronary lesions associated with rs1801133 in the Chinese Han population were attributed, at least partly, to high homocysteine levels. Hyperhomocysteinemia had a high predictive value for severe CAD or multiple vessel lesions.

5-Formyltetrahydrofolate promotes conformational remodeling in a methylenetetrahydrofolate reductase active site and inhibits its activity.

The flavoprotein methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of N5, N10-methylenetetrahydrofolate (CH2-H4folate) to N5-methyltetrahydrofolate (CH3-H4folate), committing a methyl group from the folate cycle to the methionine one. This committed step is the sum of multiple ping-pong electron transfers involving multiple substrates, intermediates, and products all sharing the same active site. Insight into folate substrate binding is needed to better understand this multifunctional active site. Here, we performed activity assays with Thermus thermophilus MTHFR (tMTHFR), which showed pH-dependent inhibition by the substrate analog, N5-formyltetrahydrofolate (CHO-H4folate). Our crystal structure of a tMTHFR•CHO-H4folate complex revealed a unique folate-binding mode; tMTHFR subtly rearranges its active site to form a distinct folate-binding environment. Formation of a novel binding pocket for the CHO-H4folate p-aminobenzoic acid moiety directly affects how bent the folate ligand is and its accommodation in the active site. Comparative analysis of the available active (FAD- and folate-bound) MTHFR complex structures reveals that CHO-H4folate is accommodated in the active site in a conformation that would not support hydride transfer, but rather in a conformation that potentially reports on a different step in the reaction mechanism after this committed step, such as CH2-H4folate ring-opening. This active site remodeling provides insights into the functional relevance of the differential folate-binding modes and their potential roles in the catalytic cycle. The conformational flexibility displayed by tMTHFR demonstrates how a shared active site can use a few amino acid residues in lieu of extra domains to accommodate chemically distinct moieties and functionalities.

Shifting landscapes of human MTHFR missense-variant effects.

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.

Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase 677C>T variant and correction with moderate dose folic acid supplementation.

5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C>T) results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2 mg folic acid/kg diet) and assess the effects of folic acid supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing and whole-genome bisulfite sequencing (WGBS). Reproductive parameters and locus-specific imprinted gene methylation were unaffected by genotype or diet. Using WGBS, sperm from 677TT mice had 360 differentially methylated tiles as compared to 677CC mice, predominantly hypomethylation (60% of tiles). Folic acid supplementation mostly caused hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.

Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.

AIMS: The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. MATERIALS AND METHODS: In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. RESULTS: Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large-for-gestational age (LGA), preterm birth (PTB), and reduced gestational age (p < 0.05). Pregnant women with MTHFR A1298C AA or C677T CT + TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32-times and reduced the gestational age by 0.11 weeks (p < 0.05). For MTHFR C677T CC + TT genotype carriers, higher HbA1c levels were associated with 1.49-, 1.24-, and 1.23-times increased risks of macrosomia, LGA, and PTB, respectively (p < 0.05). A U-shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC + TT participants, with a cut-off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT + TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37-times increased risks of LGA and PTB, respectively. CONCLUSIONS: Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large-scale studies are required to confirm these findings.

Geographical distribution of MTHFR C677T gene polymorphisms among the reproductive-age women in Chinese Han populations: based on migration.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is essential for the metabolism of folic acid and homocysteine. The MTHFR C677T polymorphism is associated with several disorders. Our study aims to explore the geographical distributions of the MTHFR C677T polymorphism of women in China and how migration affected the polymorphism in Suzhou. METHODS: A total of 7188 women of reproductive age were recruited in Suzhou of the study. Subjects were classified according to their native places after data extraction. MTHFR C677T gene polymorphisms were detected by quantitative PCR with genomic DNA isolated from blood samples. RESULTS: The frequencies of the 677T allele and 677TT genotype were higher in northern China than that in southern China and decreased in geographical gradients from north to south. The frequencies were considerably higher in the migrant population than that in the indigenous population of Suzhou. The migrant population have gradually changed the prevalence in Suzhou. CONCLUSIONS: Our study suggested that the prevalence of MTHFR C677T polymorphisms among women varied across different geographical regions in Chinese Han populations. The 677T allele frequencies of the northern populations were significantly higher than those of the southern populations. The migrant population gradually changed the prevalence of the MTHFR C677T polymorphism in Suzhou.

Association between MTHFR C677T Gene Polymorphisms and the Efficacy of Vitamin Therapy in lowering Homocysteine Levels among Stroke Patients with Hyperhomocysteinemia.

BACKGROUND: The impact of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation on the relationship between plasma homocysteine (Hcy) levels and stroke has been extensively studied and documented in previous study. However, it remains unclear whether the MTHFR C677T mutation can affect the response to Hcy lowering treatment in stroke patients with hyperhomocysteinemia (HHcy). Understanding the impact of genetic factors on treatment response can help optimize personalized treatment strategies for stroke patients with HHcy. We aimed to investigate the potential association between the MTHFR C677T gene polymorphisms and the effectiveness of Hcy lowering treatment using vitamin therapy in stroke patients with HHcy. METHODS: The MTHFR C677T genotype polymorphisms were identified using polymerase chain reaction-restriction fragment length polymorphism, and the distribution of three genotypes in the MTHFR C677T gene locus was compared. The treatment effects of Hcy lowering agents were compared among patients with different genotypes. RESULTS: Among the 320 stroke patients enrolled in the study, 258 (80.6%) were diagnosed with HHcy. Of these, 162 patients (Effective Group) responded well to the clinical Hcy lowering treatment, while 96 patients (Invalid Group) failed to achieve sufficient response even after taking combination supplements of folic acid, Vitamin B6, and methylcobalamin for one month. Significant differences were observed in terms of age (p < 0.001), hypertension (p = 0.034), dyslipidemia (p = 0.022), hyperuricemia (p = 0.013) and genotype distribution of MTHFR C677T gene polymorphism (p < 0.001) between the Invalid group and the Effective group. The multivariate regression analysis revealed that the T allele (odd rations [OR], 1.327; 95% confidence interval [CI], 1.114-1.580; p = 0.0015) was independently associated with an insufficient Hcy lowering treatment effect. Additionally, the TT genotype was independently associated with insufficient response in both the codominant model (OR, 1.645; 95% CI, 1.093-2.476; p = 0.017) and the recessive model (TT versus CC + CT; OR, 1.529; 95% CI, 1.145-2.042; p = 0.004). However, no relationship was observed between CT + TT genotypes and poor treatment effect in the dominate model. CONCLUSIONS: Our findings suggested that the TT genotype and T allele of MTHFR C677T polymorphism were independently associated with an insufficient Hcy lowering treatment effect in stroke patients with HHcy.

Cerebral venous thrombosis with hyperhomocysteinemia due to loss of heterozygosity at methylenetetrahydrofolate reductase (MTHFR) locus: a case report.

BACKGROUND: Loss of heterozygosity (LOH) at methylenetetrahydrofolate reductase (MTHFR) locus has been reported in tumor tissue. But the mutation was never reported in cerebral venous thrombosis (CVT) with hyperhomocysteinemia (HHcy) before. CASE PRESENTATION: A 14-year-old girl was admitted with an intermittent headache and nausea for 2 months. The plasma homocysteine level was 77.2 µmol/L. Lumbar puncture revealed an intracranial pressure > 330 mmH2O. Cerebral MRI and MRV revealed superior sagittal sinus thrombosis. Whole-exome sequencing revealed LOH at Chr1:11836597-11,867,232 affects exons 10-21 of C1orf167, the entire MTHFR, and exons 1-2 of the CLCN6 gene. The normal allele was the c.665 C > T/677 C > T variant in MTHFR. The patient was treated with nadroparin for 2 weeks, followed by oral rivaroxaban. Supplemental folate and vitamins B12 and B6 were prescribed. One month later, she had no headache and the intracranial pressure had decreased to 215 mmH2O. MRI showed shrinkage of the thrombosis in the superior sagittal sinus, the degree of stenosis had significantly decreased. CONCLUSIONS: Rare LOH at the MTHFR locus should be analyzed in CVT with HHcy. With anticoagulation treatment, the prognosis was good.

Maternal pre-pregnancy BMI, MTHFR polymorphisms, and the risk of adverse pregnancy outcomes in pregnant women from South China: a retrospective cohort study.

BACKGROUND: Increasing evidence suggests an association between maternal pre-pregnancy body mass index (pre-BMI) and adverse pregnancy outcomes. However, the effects of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on these relationships require further investigation. This study aimed to investigate whether the relationship between pre-BMI and the risk of adverse pregnancy outcomes was influenced by MTHFR gene polymorphisms. METHODS: A total of 5614 mother-fetus pairs were included in the study. The odds ratios (OR) of adverse pregnancy complications, including gestational diabetes mellitus (GDM), gestational hypertension (GHT), cesarean delivery (CS), and premature rupture of membranes (PROM), were estimated using adjusted logistic regression models and subgroup analysis. RESULTS: Pregnant women with higher pre-BMI values were positively related to the risk of GDM, GHT, and CS. In the subgroup analysis, underweight BMI was associated with a decreased risk of CS and GDM in pregnant women with the MTHFR A1298C AA or C677T CC genotype, while overweight/obese BMI was associated with an increased risk of GDM and CS in different MTHFR variants. Moreover, pregnant women with MTHFR A1298C AC + CC or C667T CC were found to have an increased risk of GHT in the MTHFR A1298C AA or C667T CT + TT genotype. A remarkable association was observed between the obesity group with MTHFR A1298C AC + CC (OR = 6.49, CI: 2.67-15.79) and the overweight group with the C667T CC genotype (OR = 4.72, CI: 2.13-10.45). CONCLUSIONS: MTHFR gene polymorphisms exert a modifying effect on the association between maternal pre-BMI and the risk of GHT, CS, and GDM. Pregnant women with a high pre-BMI with specific MTHFR genotypes should be considered for GHT development.

MTHFR 677C>T (rsRS1801133) variant is associated with hyperhomocysteinemia but not with clinical severity in patients with peripheral arterial disease.

Background: The MTHFR 677C>T variant's involvement with hyperhomocysteinemia and peripheral arterial disease (PAD) is still unclear. Objectives: To evaluate associations between the MTHFR 677C>T (rs1801133) variant and susceptibility to and severity of PAD and homocysteine (Hcy) levels. Methods: The study enrolled 157 PAD patients and 113 unrelated controls. PAD severity and anatomoradiological categories were assessed using the Fontaine classification and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC), respectively. The variant was genotyped using real-time polymerase chain reaction and Hcy levels were determined using chemiluminescence microparticle assay. Results: The sample of PAD patients comprised 60 (38.2%) females and 97 (61.8%) males. Patients were older and had higher Hcy than controls (median age of 69 vs. 45 years, p<0.001; and 13.66 µmol/L vs. 9.91 µmol/L, p=0.020, respectively). Hcy levels and the MTHFR 677C>T variant did not differ according to Fontaine or TASC categories. However, Hcy was higher in patients with the CT+TT genotypes than in those with the CC genotype (14.60 µmol/L vs. 12.94 µmol/L, p=0.008). Moreover, patients with the TT genotype had higher Hcy than those with the CC+CT genotypes (16.40 µmol/L vs. 13.22 µmol/L, p=0.019), independently of the major confounding variables. Conclusions: The T allele of MTHFR 677C>T variant was associated with higher Hcy levels in PAD patients, but not in controls, suggesting a possible interaction between the MTHFR 677C>T variant and other genetic, epigenetic, or environmental factors associated with PAD, affecting modulation of Hcy metabolism.

Contexto: O envolvimento da variante MTHFR 677C>T na hiperhomocisteinemia e na doença arterial periférica (DAP) ainda não está claro. Objetivos: Avaliar a associação da variante MTHFR 677C>T (rs1801133) com suscetibilidade e gravidade da DAP e valores séricos de homocisteína (Hcy). Métodos: Este estudo caso-controle envolveu 157 pacientes com DAP e 113 controles não relacionados. A gravidade e as categorias anatomorradiológicas da DAP foram avaliadas pela classificação de Fontaine e pelo Inter-Society Consensus for the Management of Peripheral Arterial Disease, respectivamente. A genotipagem foi realizada por meio de reação em cadeia da polimerase em tempo real, e os valores de Hcy foram determinados por ensaio de micropartículas de quimioluminescência. Resultados: Entre os pacientes com DAP, 97 (61,8%) eram homens e 60 (38,2%) eram mulheres, com mediana de idade de 69 anos. Os pacientes com DAP eram mais velhos e apresentaram valores mais elevados de Hcy do que os controles (mediana de 69 vs. 45 anos de idade, p < 0,001; 13,66 µmol/L vs. 9,91 µmol/L, p = 0,020, respectivamente). Os valores de Hcy foram mais elevados em pacientes com os genótipos CT+TT do que aqueles com o genótipo CC (14,60 µmol/L vs. 12,94 µmol/L, p = 0,008). Além disso, os pacientes com o genótipo TT apresentaram valores mais elevados de Hcy do que aqueles com os genótipos CC+CT (16,40 µmol/L vs. 13,22 µmol/L, p = 0,019, respectivamente), independentemente das principais variáveis confundidoras. Conclusões: O alelo T da variante MTHFR 677C>T foi associado a valores mais elevados de Hcy nos pacientes com DAP, mas não em controles, sugerindo uma possível interação entre a variante genética MTHFR 677C>T e outros fatores genéticos, epigenéticos ou ambientais associados com a DAP na modulação do metabolismo da Hcy.

MicroRNA-22-3p and MicroRNA-149-5p Inhibit Human Hepatocellular Carcinoma Cell Growth and Metastasis Properties by Regulating Methylenetetrahydrofolate Reductase.

microRNAs are small endogenous noncoding RNAs that have emerged as key negative regulators that target gene expression through RISC. Our previous study showed that the methylenetetrahydrofolate reductase gene (MTHFR) plays a key role in one carbon metabolism, which is downregulated by miR-22-3p and miR-149-5p, and that it could exert a potential anti-cancer effect. Whether miR-22-3p/miR-149-5p can regulate MTHFR to exert anti-cancer effects has become the focus of our research. Normal (HL-7702 cells) and cancerous (QGY-7703/HepG2 cells) human hepatocellular cells were transfected with 100 nM hsa-miR-22-3p/hsa-miR-149-5p mimic or controls. After 24, 48, and 72 h, cell proliferation ability was tested using CCK-8. The changes in MTHFR expression at both the transcriptional and translational levels were determined by RT-qPCR and Western blotting, respectively. Cancerous cell invasion and migration ability were confirmed by means of a transwell assay. We found that ectopic miR-22-3p/miR-149-5p inhibits hepatocellular carcinoma cell proliferation but does not inhibit normal human hepatocyte proliferation. The transfection of ectopic miR-22-3p/miR-149-5p downregulated the MTHFR expression in QGY-7703 and HepG2 but not in HL-7702. QGY-7703 and HepG2 migration and invasion were inhibited by ectopic miR-22-3p/miR-149-5p. Additionally, we found that ectopic miR-22-3p/miR-149-5p significantly increased the expression of TP53INP1 and PDCD4 in QGY-7703. The results of the study suggest that miRNA-22-3p and miRNA-149-5p inhibit tumor growth and metastasis properties may be by regulating MTHFR and that they exert anticancer effects in hepatocellular carcinoma cells.

Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and H-type hypertension: A systematic review and meta-analysis.

PURPOSE: The polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene C677T has been linked to H-type hypertension. But the conclusion remained controversial. To elucidate this issue, we performed a comprehensive meta-analysis to analyze the MTHFR C677T polymorphism and H-type hypertension. MATERIALS AND METHODS: The English and Chinese databases were systematically searched to identify relevant studies until November 2020. RevMan 5.3 and Stata 12.0 software were used for meta-analysis. The odds ratio (ORs) and 95% confidence intervals (95% CIs) were used to assess the relationship between the MTHFR C677T polymorphism and H-type hypertension. RESULTS: A total of 14 studies involving 1769 cases and 1443 controls were included. The meta-analysis results showed the association between MTHFR C677T polymorphism and H-type hypertension with the homozygous codominant model (OR = 3.30, 95% CI = 1.94-5.60), heterozygous codominant model (OR = 2.34, 95% CI = 1.53-3.58), dominant model (OR = 1.79, 95% CI = 1.33-2.41), recessive model (OR = 2.70, 95% CI = 1.73-4.21),and the allelic model (OR = 1.82, 95% CI = 1.41-2.35). All p-values were less than 0.05. Therefore, MTHFR C677T polymorphism has a positive correlation with the risk of H-type hypertension. Among them, TT mutation has the greatest impact on the activity of this enzyme, which causes Hcy to rise and leads to H-type hypertension. CONCLUSION: In summary, our results provide sufficient data to support the hypothesis that the MTHFR C677T polymorphism is related to H-type hypertension susceptibility.

Decreased Methylenetetrahydrofolate Reductase Activity Leads to Increased Sensitivity to para-Aminosalicylic Acid in Mycobacterium tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the most fatal diseases in the world. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the production of 5-methyltetrahydrofolate (5-CH3-THF), which is required for the de novo biosynthesis of methionine in bacteria. Here, we identified Rv2172c as an MTHFR in M. tuberculosis through in vitro and in vivo analyses and determined that the protein is essential for the in vitro growth of the bacterium. Subsequently, we constructed rv2172c R159N and L214A mutants in M. tuberculosis and found that these mutants were more sensitive to the antifolates para-aminosalicylic acid (PAS) and sulfamethoxazole (SMX). Combining biochemical and genetic methods, we found that rv2172c R159N or L214A mutation impaired methionine production, leading to increased susceptibility of M. tuberculosis to PAS, which was largely restored by adding exogenous methionine. Moreover, overexpression of rv2172c in M. tuberculosis could increase methionine production and lead to PAS resistance. This research is the first to identify an MTHFR in M. tuberculosis and reveals that the activity of this enzyme is associated with susceptibility to antifolates. These findings have particular value for antitubercular drug design for the treatment of drug-resistant TB.

Effect of methylenetetrahydrofolate reductase C677T polymorphism on serum folate but not vitamin B12 levels in patients with H-type hypertension.

BACKGROUND: Hyperhomocysteinemia (HHcy) is a common complication in Chinese hypertensive patients and associated with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, folate, and vitamin B12 (Vit B12) status. This study evaluated the associations of MTHFR C677T polymorphism, folate, and Vit B12 with H-type hypertension. METHODS AND RESULTS: 887 eligible patients with essential hypertension were included. Patients were divided into two groups according to the Hcy level, the H-type hypertension group and the normal hypertension group. Related risk factors such as MTHFR polymorphism, folate and Vit B12 status were analyzed in the two groups. Age, gender, SBP, DBP, MTHFR C677T genotype, folate and Vit B12 differed significantly between H-type hypertension and normal hypertension groups (P < 0.05). MTHFR 677TT variant, gender, folate, and Vit B12 were independent risk factors for the occurrence of H-type hypertension. The risk for TT carriers was 8 times higher than that of CC and CT carriers [OR (95% CI) 8.248 (5.274-12.899)]. Male patients had almost fivefold higher odds than female patients [OR (95% CI) 4.923 (2.741-8.842)]. Folate level of patients with H-type hypertension decreased with the C to T substitution of MTFHR C677T gene (P < 0.05), while Vit B12 level was not associated with the gene (P > 0.05). CONCLUSIONS: MTHFR 677TT variant, gender, folate, and Vit B12 were risk factors for the occurrence of H-type hypertension. Folate but not Vit B12 was associated with MTFHR C677T polymorphism in patients with H-type hypertension. Accordingly, the above factors may be considered in the prevention and treatment of hypertension.

Association of ALDH2 rs671 and MTHFR rs1801133 polymorphisms with hypertension among Hakka people in Southern China.

BACKGROUND: Genetic factors play an important role in susceptibility to hypertension. Herein, the association between acetaldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and hypertension was analyzed among Hakka population in southern China. METHODS: A total of 3057 hypertensive patients and 2215 controls were enrolled. The ALDH2 rs671 and MTHFR rs1801133 genotyping were analyzed using gene chip. Relevant information and medical records of these subjects were collected. RESULTS: Hypertensive patients with ALDH2 rs671 G/A heterozygous had lower systolic blood pressure (SBP) than other genotypes (P < 0.001), while hypertensive patients with A allele had lower diastolic blood pressure (DBP) than patients with G allele (P < 0.001). The level of plasma homocysteine (Hcy) in patients with MTHFR CC, CT and TT genotypes showed an increasing trend (P < 0.001). The ALDH2 G/A genotype in the co-dominant model (adjusted OR 1.251, 95% CI 1.024-1.528, P = 0.028) and ALDH2 A/A genotype in the recessive model (adjusted OR 1.221, 95% CI 1.008-1.478, P = 0.041) were significant risk factors for the presence of hypertension. The MTHFR C/T genotype in the co-dominant model (adjusted OR 1.307, 95% CI 1.039-1.643, P = 0.022) and MTHFR C/T and T/T genotypes in the dominant model (adjusted OR 1.281, 95% CI 1.146-1.430, P < 0.001) were significant risk factors for the presence of hypertension. Further, logistic regression analysis showed that age, smoking, alcohol consumption, hyperhomocysteinemia, and high level of serum TG, Apo-A1, Apo-B were significant risks for hypertension. CONCLUSIONS: In summary, ALDH2 rs671 G/A, A/A genotypes and MTHFR rs1801133 C/T, T/T genotypes may be risk factors for hypertension in this Chinese Hakka population.

Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice.

Objective: Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C→T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/- mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury.Methods: In the present study, three-month-old male Mthfr+/- and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected for histological analysis.Results: Mthfr+/- animals used their non-impaired forepaw more to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/- mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia-induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in neurons and astrocytes and neuronal superoxide dismutase 2 (SOD2) levels.Conclusions: Our results suggest that Mthfr+/- mice are more vulnerable to PT-induced stroke damage through the regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.

Dark Green Leafy Vegetable Intake, MTHFR Genotype, and Risk of Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Evidence suggests that consumption of dark green leafy vegetables may influence the decrease in the risk of cutaneous squamous cell carcinoma (SCC). Dark green leafy vegetables contain folate as a main component among other nutrients; thus, we hypothesised that their possible observed protective effect on SCC, observed in previous studies, would be more evident in persons with specific genotypes related to folate metabolism. METHODS: Genotyping of methylenetetrahydrofolate reductase (MTHFR) gene variants rs1801133 (C677T) and rs1801131 (A1298C) was carried out for 1,128 participants in an Australian community-based longitudinal study of skin cancer. Dietary intakes were assessed through repeated Food Frequency Questionnaires (1992-1996), and all incident skin cancers were recorded in 1992-2007 and histologically confirmed. We assessed associations between intake of dark green leafy vegetables and SCC development in strata defined by genotype, by calculating relative risks (RRs) with 95% confidence intervals (CIs) using generalised linear models with negative binomial distribution and person-years of follow-up as offset. RESULTS: High versus low intake of dark green leafy vegetables was associated with a lower risk of SCC tumours in carriers of the C677T variant allele (RR = 0.42, 95% CI = 0.23-0.75), and within wild-type A1298C homozygotes (RR = 0.43, 95% CI = 0.22-0.85). CONCLUSION: The protective effect of dark green leafy vegetables on cutaneous SCC may be genotype-dependent. Folate metabolism-related gene polymorphisms should be considered when assessing the relation of green leafy vegetables to cancer risk.

MTHFR 677TT is associated with decreased number of embryos and cumulative live birth rate in patients undergoing GnRHa short protocol: a retrospective study.

BACKGROUND: Whether MTHFR C677T genotype affects pregnancy outcomes following assisted reproductive technology is conflicting. And the role of MTHFR C677T genotype on cumulative live birth has not been reported. This study aims to investigate the effect of MTHFR C677T genotype on cumulative live birth following in-vitro fertilization and embryo transfer (IVF-ET). METHODS: This is a retrospective cohort study that includes 1173 women undergoing their first IVF-ET. We retrospectively compared the reproductive outcomes among the groups stratified by MTHFR C677T genotypes (677CC, 677CT, 677TT). We performed interaction analysis to detect the factor that interacts with the MTHFR C677T genotype. Poisson regression analyses were used to evaluate the associations between MTHFR C677T genotypes with the number of transferable embryos and the number of good-quality embryos. Cox regression analysis was used to evaluate the association between MTHFR C677T genotypes with cumulative live birth. All regression analyses were adjusted with the confounding factors which may independently impact reproductive outcomes. RESULTS: There is a significant interactive effect of MTHFR 677TT genotype with GnRHa protocol on reproductive outcomes (P for interaction<0.05). MTHFR 677TT homozygous mutation was found to impact reproductive outcomes under GnRHa short protocol but not GnRHa long protocol. MTHFR 677TT is significantly associated with decreased number of transferable embryos (p-value=0.028), decreased number of good-quality embryos (p-value=0.005), and decreased cumulative live birth rate (p-value=0.024) in patients undergoing GnRHa short protocol. However, the clinical pregnancy rate, miscarriage rate and live birth rate at the first embryo transfer cycle were not significantly different between the groups under both protocols (p-values>0.05). CONCLUSIONS: MTHFR 677TT genotype is associated with decreased number of transferable embryos, decreased number of good-quality embryos, and decreased cumulative live birth rate in the first complete cycle in patients undergoing GnRHa short protocol.

MTHFR 677T-1298C haplotype in acute lymphoblastic leukemia: Impact on methotrexate therapy.

INTRODUCTION: Functional variants of the Methylenetetrahydrofolate reductase (MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients. METHODS: Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype. RESULTS: The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity's score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92). CONCLUSION: Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker.

Folic Acid Supplementation in Early Pregnancy, Homocysteine Concentration, and Risk of Gestational Diabetes Mellitus.

We used a prospective cohort of pregnant women at 12 to 20 weeks gestation between 2002 and 2008 in Ottawa and Kingston to evaluate the impact of early pregnancy folic acid supplementation on the risk of gestational diabetes mellitus. Among 7552 eligible women, 84 (1.11%) were diagnosed of gestational diabetes mellitus. Non-significant associations were observed between gestational diabetes mellitus and folate supplementation, homocysteine levels, and methylenetetrahydrofolate reductase 677 TT genotype. Although we found no significant associations between folic acid supplementation and the risk of gestational diabetes mellitus, genetic associations were not confounded by lifestyle or socioeconomic factors, which may have biased previous studies.