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Project description:RATIONALE: The development and progression of asthma are strongly influenced by environmental exposures. We have demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. OBJECTIVES: Since there is conflicting evidence on the role of folate in modifying allergic airway disease risk, we hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (MTHFR) activity would reduce the allergic airway disease phenotype. METHODS: Using a house dust mite (HDM) induced model of allergic airway disease, we tested the effect of MTHFR on disease severity. MEASUREMENTS AND MAIN RESULTS: Loss of MTHFR alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6MTHFR-/- mice demonstrate significantly less airway hyerreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6MTHFR-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and IL-4/IL-5 cytokine concentrations. The effect of MTHFR loss on HDM-induced allergic airway disease was reversed by betaine supplementation. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6MTHFR-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations. CONCLUSION: Collectively, these findings indicate that single carbon metabolism warrants further investigation as a disease modifier in allergic airway disease.
2018-01-31 | GSE71822 | GEO
Project description:RATIONALE: The development and progression of asthma are strongly influenced by environmental exposures. We have demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. OBJECTIVES: Since there is conflicting evidence on the role of folate in modifying allergic airway disease risk, we hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (MTHFR) activity would reduce the allergic airway disease phenotype. METHODS: Using a house dust mite (HDM) induced model of allergic airway disease, we tested the effect of MTHFR on disease severity. MEASUREMENTS AND MAIN RESULTS: Loss of MTHFR alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6MTHFR-/- mice demonstrate significantly less airway hyerreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6MTHFR-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and IL-4/IL-5 cytokine concentrations. The effect of MTHFR loss on HDM-induced allergic airway disease was reversed by betaine supplementation. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6MTHFR-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations. CONCLUSION: Collectively, these findings indicate that single carbon metabolism warrants further investigation as a disease modifier in allergic airway disease.
2018-01-31 | GSE71821 | GEO
Project description:RationaleEnvironmental exposures strongly influence the development and progression of asthma. We have previously demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. There is conflicting evidence on the role of folate (one of the primary methyl donors) in modifying allergic airway disease.ObjectivesWe hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (Mthfr) activity would reduce the allergic airway disease phenotype through epigenetic mechanisms.MethodsAllergic airway disease was induced in C57BL/6 and C57BL/6Mthfr-/- mice through house dust mite (HDM) exposure. Airway inflammation and airway hyperresponsiveness (AHR) were measured between the two groups. Gene expression and methylation profiles were generated for whole lung tissue. Disease and molecular outcomes were evaluated in C57BL/6 and C57BL/6Mthfr-/- mice supplemented with betaine.Measurements and main resultsLoss of Mthfr alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6Mthfr-/- mice demonstrated significantly less airway hyperreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6Mthfr-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and Il-4/Il-5 cytokine concentrations. Betaine supplementation reversed parts of the HDM-induced allergic airway disease that are modified by Mthfr loss. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6Mthfr-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations.ConclusionCollectively, these findings indicate that the loss of folate as a methyl donor is a modifier of allergic airway disease, and that epigenetic and expression changes correlate with this modification. Further investigation into the mechanisms that drive this observation is warranted.
| S-EPMC5766142 | biostudies-literature
Project description:Allergic Airway Disease is Dependent on Methylene-Tetrahydrofolate Reductase
| PRJNA292134 | ENA
Project description:BackgroundMethylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been found to be related with many diseases. Systemic inflammation is now considered as a major predisposition factor for diseases including diabetes mellitus (DM), coronary arterial disease (CAD), stroke, and cancer. This study aimed to investigate whether systemic inflammation is a possible underlying pathogenesis for MTHFR gene polymorphism-related disease.MethodsA total of 292 patients were enrolled, and single nucleotide polymorphisms for MTHFR C667T and A1298C were genotyped. Systemic inflammation markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were collected.ResultsIn our study population, MTHFR 677 variants had significant higher NLR level than MTHFR 677 wild type (3.77 ± 0.26 vs 3.06 ± 0.18, P = .028). Logistic regression analysis showed that MTHFR 677 variants were significantly associated with increased NLR level. MTHFR 1298 variants showed the opposite effects which tended to have lower level of NLR (3.21 ± 0.16 vs 3.79 ± 0.34, P = .087) and PLR (137.0 ± 4.8 vs 157.7 ± 9.4, P = .052) than MTHFR 1298 wild type. General linear model showed that there was no statistically significant interaction between MTHFR C667T and A1298C gene polymorphism on NLR or PLR.ConclusionsThis study indicates that MTHFR C677T and MTHFR A1298C gene polymorphisms have opposite effect on systemic inflammation, and systemic inflammation may contribute to the pathogenesis for diseases associated with MTHFR C667T gene polymorphism.
| S-EPMC6817214 | biostudies-literature
Project description:This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy.
| S-EPMC8087097 | biostudies-literature
Project description:BACKGROUND:Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. METHODS AND RESULTS:We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03-1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91-1.03]) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. CONCLUSIONS:The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.
| S-EPMC3855044 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-10-01 | E-GEOD-40889 | biostudies-arrayexpress
Project description:This study aimed to investigate whether the single nucleotide polymorphism C677T (rs1801133) of the methylene-tetrahydrofolate reductase (MTHFR) gene was associated with the risk of coronary artery disease (CAD) and circulating homocysteine (Hcy) levels in Tunisian population. 310 angiografically diagnosed CAD patients and 210 controls were enrolled in this study. The MTHFR C677T (rs1801133) polymorphism was genotyped, and the Hcy concentrations were measured. The severity of CAD was evaluated using the Gensini scoring system. Compared to the CC genotype, the TT genotype confers a higher risk for CAD severity with an OR = 9.07 and 95% CI = 3.78-21.8. The T allele was the predisposing allele for CAD and that it was probably associated with CAD severity. The area under the ROC curve for Hcy was 0.764 (95% CI 0.660 to 0.868, p = 0.001). The receiver operating characteristics curve (ROC) for Hcy showed its useful prediction of CAD. Hcy levels were not significantly associated with CAD severity expressed by Gensini Score (GS). The MTHFR C677T (rs1801133) polymorphism influences circulating Hcy levels. The MTHFR C677T polymorphism and hyperhomocysteinemia could have an important role in the prediction of the presence and not the severity expressed by GS of CAD.
| S-EPMC7308346 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-07-09 | E-GEOD-59219 | biostudies-arrayexpress