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1.
The roles of MTRR and MTHFR gene polymorphisms in congenital heart diseases: a meta-analysis.
Xu, A, Wang, W, Jiang, X
Bioscience reports. 2018;(6)
Abstract
Background: We performed the present study to better elucidate the correlations of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms with the risk of congenital heart diseases (CHD).Methods: Eligible articles were searched in PubMed, Medline, Embase and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations of MTHFR and MTRR gene polymorphisms with CHD.Results: A total of 47 eligible studies were finally included in our meta-analysis. Our overall analyses suggested that MTRR rs1801394, MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms were all significantly associated with the risk of CHD in certain genetic models. Further subgroup analyses according to ethnicity of study participants demonstrated that the MTRR rs1801394 polymorphism was significantly correlated with the risk of CHD only in Asians, whereas MTRR rs1532268, MTHFR rs1801133 and MTHFR rs1801131 polymorphisms were significantly correlated with the risk of CHD in both Asians and Caucasians.Conclusions: Our findings indicated that MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may affect the risk of CHD in Asians and Caucasians, while the MTRR rs1801394 polymorphism may only affect in risk of CHD in Asians.
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The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: Findings from the CSPPT.
Yang, X, Zhang, M, Song, R, Liu, C, Huo, Y, Qian, G
Cardiovascular therapeutics. 2018;(6):e12473
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Abstract
OBJECTIVE In a subgroup analysis of the China Stroke Primary Prevention Trial, we aimed to explore the impact of folic acid supplementation on arterial stiffness and assess the modifying effect of the methylenetetrahydrofolate reductase (MTHFR) gene in Chinese patients with hypertension. METHODS This prospective study enrolled 2529 hypertensive Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) was measured by trained medical staff using PWV instruments at both baseline and exit visits, approximately 5 years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). RESULTS During the follow-up, change in folate was significantly and independently correlated with change in ba-PWV in study patients (β = -1.31, P < 0.001). Individuals with CC genotype had a significantly greater PWV response to folic acid supplementation than did carriers of the T allele (β = -2.79, P < 0.001 for CC homozygotes compared with β = -0.56, P = 0.464 for TT homozygotes). The positive effect of folic acid on improved PWV was modified by the MTHFR genotype (P for interaction = 0.034). CONCLUSION In a subgroup of Chinese hypertensive patients who had received 5-year antihypertensive therapy, increases in folate status were associated with higher reductions in PWV, and individuals with the CC genotype showed greatest PWV response to folic acid supplementation.
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MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment.
Huang, X, Qin, X, Yang, W, Liu, L, Jiang, C, Zhang, X, Jiang, S, Bao, H, Su, H, Li, P, et al
Arteriosclerosis, thrombosis, and vascular biology. 2018;(3):679-685
Abstract
OBJECTIVE This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.
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[Meta-analysis on relationship between the Chinese maternal MTHFR gene polymorphism(C677T) and neural tube defects in offspring].
Zhang, C, Huo, J, Sun, J, Huang, J, Piao, W, Yin, J
Wei sheng yan jiu = Journal of hygiene research. 2018;(2):312-317
Abstract
OBJECTIVE To explore the association between maternal MTHFR gene polymorphism( C677T) and neural tube defects in offspring through Meta-analysis in China. METHODS CNKI, Pub Med, Web of Science, Chinese Wan Fang Data databases, CBM, VIP for published articles were searched from the time of Database establishment to July 5 th 2017. The search strategy was based on combinations of the English and/or Chinese keywords, 'MTHFR'and 'folate pathway'and 'polymorphism'or 'SNP'and'NTDs or Neural Tube Defects'. References of reviews and retrieved studies were also scanned. All the case-control studies about MTHFR gene C677T polymorphism and susceptibility of neural tube defect were collected, which were fulfilled the followinginclusion criteria: case-control study and cohort study design, presentation of data necessary for calculating odds ratios( ORs). Data were extracted from studies and analyzed by Rev Man 5. 3 software. RESULTS A total of 13 papers were selected, including1500 patients and 1654 controls. Meta-analysis result showed that the combined odds ratio values of neural tube defect for offspring with maternal TT, TT + CT and T allele genotypes were 1. 94, 1. 65 and 1. 39, respectively. CONCLUSION The present Meta-analysis suggests that MTHFR C677T is significantly associated with maternal risk for NTDs in the Chinese population, supplemental folic acid supplementation based on MTHFR polymorphisms will be an important means to further reduce the birth defects of newborns.
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Methylomic changes in response to micronutrient supplementation and MTHFR genotype.
Stevens, AJ, Rucklidge, JJ, Darling, KA, Eggleston, MJ, Pearson, JF, Kennedy, MA
Epigenomics. 2018;(9):1201-1214
Abstract
UNLABELLED Exposure times and dosage required for dietary components to modify DNA methylation patterns are largely unknown. AIM: This exploratory research represents the first genome-wide analysis of DNA methylation changes during a randomized-controlled-trial (RCT) for dietary supplementation with broad spectrum vitamins, minerals and amino acids in humans. METHODS Genome-wide changes in methylation from paired, peripheral blood samples were assessed using the Infinium Methylation EPIC 850 K array. RESULTS Methylation increased at 84% of the most significant differentially methylated CpGs; however, none showed significance after adjustment for genome-wide testing. CONCLUSION Micronutrient supplementation is unlikely to have a substantial biological effect on DNA methylation over 10 weeks; however, the trend toward hypermethylation that we observed is likely to become more marked with longer exposure periods.
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Methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to epilepsy.
Rai, V, Kumar, P
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(12):2033-2041
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism was reported as risk factor for multiple diseases due to its role in conversion of homocysteine to methionine. The aim of the present meta-analysis was to find out the validity of association of C677T polymorphism with epilepsy susceptibility. METHODS Pubmed, Science Direct, Springer Link and Google Scholar, databases were searched for relevant studies up to January, 31, 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed using five genetic models. All statistical analysis was done by MetaAnalyst and Mix programs. RESULTS Except recessive model, significant association was found between MTHFR C677T polymorphism and epilepsy risk in other four genetic models (T vs C: OR = 1.29, 95% CI = 1.08-1.52, p = 0.004; TT vs CC: OR = 1.48, 95% CI = 1.19-1.82, p = 0.0003; TT + CT vs CC: OR = 1.20, 95% CI = 1.05-1.38, p = 0.008; TT vs CT + CC: OR = 1.35, 95% CI = 1.11-1.62, p = 0.002). Similarly, in the subgroup analysis based on ethnicity, significant association was found in Asian (T vs C: OR = 1.85; 95% CI = 1.15-2.99; p = 0.03) and Caucasian populations (TT vs CC: OR = 1.38; 95% CI = 1.10-1.1.73; p = 0.005). No evidence of heterogeneity and publication bias was detected in present meta-analysis. CONCLUSION In conclusion, results of present meta-analysis suggested that 677T allele of MTHFR is significantly increases the epilepsy susceptibility.
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A Meta-Prediction of Methylenetetrahydrofolate-Reductase Polymorphisms and Air Pollution Increased the Risk of Ischemic Heart Diseases Worldwide.
Chen, ZF, Young, L, Yu, CH, Shiao, SPK
International journal of environmental research and public health. 2018;(7)
Abstract
Ischemic heart disease (IHD) is among the leading causes of death worldwide. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been associated with IHD risk, but the findings presented with heterogeneity. The purpose of the present meta-analysis was to provide an updated evaluation by integrating machine-learning based analytics to examine the potential source of heterogeneity on the associations between MTHFR polymorphisms and the risk of various subtypes of IHD, as well as the possible impact of air pollution on MTHFR polymorphisms and IHD risks. A comprehensive search of various databases was conducted to locate 123 studies (29,697 cases and 31,028 controls) for MTHFR C677T, and 18 studies (7158 cases and 5482 controls) for MTHFR A1298C. Overall, MTHFR 677 polymorphisms were risks for IHD (TT: Risk ratio (RR) = 1.23, p < 0.0001; CT: RR = 1.04, p = 0.0028, and TT plus CT: RR = 1.09, p < 0.0001). In contrast, MTHFR 677 CC wildtype was protective against IHD (RR = 0.91, p < 0.00001) for overall populations. Three countries with elevated IHD risks from MTHFR C677T polymorphism with RR >2 included India, Turkey, and Tunisia. Meta-predictive analysis revealed that increased air pollution was associated with increased MTHFR 677 TT and CT polymorphisms in both the case and control group (p < 0.05), with the trend of increased IHD risk resulting from increased air pollution. These results associate the potential inflammatory pathway with air pollution and the folate pathway with MTHFR polymorphism. Future intervention studies can be designed to mitigate MTHFR enzyme deficiencies resulting from gene polymorphisms to prevent IHDs for at-risk populations.
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Association between 5,10-methylenetetrahydrofolate, gene polymorphism and congenital heart disease.
Wang, HL, Sun, L, Zhou, S, Wang, F
Journal of biological regulators and homeostatic agents. 2018;(5):1255-1260
Abstract
This article is to investigate the association between C677T polymorphism of 5, 10-methylenetetrahydrofolate (MTHFR) gene and congenital heart defects (CHD). Two hundred thirty-five nuclear families (father, mother and child) with CHD were enrolled in the study (experimental group), and two hundred thirty-five healthy nuclear families were selected as a control group. Under the case-control study, the C677T polymorphism of MTHFR gene was detected with polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. The distribution of genotype frequency in the CHD group and control group were analyzed. SPSS 13.0 software was used to analyze the data. The distribution of genotype frequency at C677T polymorphism site was significantly different between the CHD group (including ventricular septal defect, atrial septal defect, tetralogy of fallot, double outlet right ventricle, patent ductus arteriosus) (child and mother) and healthy control group (child and mother). There were no differences between CHD group-fathers and healthy control group-fathers. Analyses of the MTHFR genotypes of CHD nuclear family data with transmitted disequilibrium test (TDT) and haplotype-based haplotype relative risk statistical method both revealed significant indications that the parents transmitted more T allele of MTHFR to their CHD children. TT genotype of MTHFR gene is associated with CHD, and a mother or a child with T allele has a much higher risk of CHD.
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MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.
Visani, G, Loscocco, F, Ruzzo, A, Galimberti, S, Graziano, F, Voso, MT, Giacomini, E, Finelli, C, Ciabatti, E, Fabiani, E, et al
The pharmacogenomics journal. 2018;(3):444-449
Abstract
We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.
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Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis.
Luo, Z, Lu, Z, Muhammad, I, Chen, Y, Chen, Q, Zhang, J, Song, Y
Lipids in health and disease. 2018;(1):191
Abstract
BACKGROUND The associations of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) rs1801133 polymorphism with coronary artery disease (CAD) and plasma lipid levels have been widely investigated, but the results were inconsistent and inconclusive. This meta-analysis aimed to clarify the relationships of the rs1801133 polymorphism with CAD and plasma lipid levels. METHODS By searching in PubMed, Google Scholar, Web of Science, Cochrane Library, Wanfang, VIP and CNKI databases, 123 studies (87,020 subjects) and 65 studies (85,554 subjects) were identified for the CAD association analysis and the lipid association analysis, respectively. Odds ratio (OR) and standardized mean difference (SMD) were used to determine the effects of the rs1801133 polymorphism on CAD risk and lipid levels, respectively. RESULTS The variant T allele of the rs1801133 polymorphism was associated with increased risk of CAD under allelic model [OR = 1.11, 95% confidence interval (CI) = 1.06-1.17, P < 0.01], additive model (OR = 1.25, 95% CI = 1.14-1.37, P < 0.01), dominant model (OR = 1.11, 95% CI = 1.04-1.17, P < 0.01), and recessive model (OR = 1.22, 95% CI = 1.12-1.32, P < 0.01). The T carriers had higher levels of total cholesterol (TC) (SMD = 0.04, 95% CI = 0.01-0.07, P = 0.02) and low-density lipoprotein cholesterol (LDL-C) (SMD = 0.07, 95% CI = 0.01-0.12, P = 0.01) than the non-carriers. CONCLUSIONS The meta-analysis suggested that the T allele of the rs1801133 polymorphism is a risk factor for CAD, which is possibly and partly mediated by abnormal lipid levels.