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Thrombophilia associated gene polymorphisms: Does use of medication, including anti-coagulants, minerals or folic acid, prevent the miscarriages?
Aslan, I, Ozyigit, S, Paul, LT, Tosun, O, Tulay, P
Journal of reproductive immunology. 2020;:103172
Abstract
OBJECTIVE Recurrent pregnancy loss (RPL) has been associated with thrombophilia. The use of prophylactic treatments against thrombophilia becomes necessary in order to increase the live birth rates in women with RPL. The aim of this study was to genotype thrombophilia associated polymorphisms and investigates the benefit of prophylactic treatment on the clinical pregnancy outcomes of women with specific genotypes of these polymorphisms. MATERIALS AND METHODS A total of 62 women were included in this study. The polymorphisms associated with thrombophilia, including methyltetrahydrofolate reductase (MTHFR) 1298 and 677, Factor V Leiden (FVL) 1691, plasminogen activator inhibitor-1 (PA1-1) G/G and Factor II prothrombin 20,210, were genotyped using the real time PCR. The effect of prophylactic treatment using anti-coagulants of 0.4 mL dose of enoxaparin (3000-6000IU) and 75 mg dose of aspirin, 81 mg dose of aspirin, mineral of 15 mg dose of zinco c or10 mg dose of folic acid, was correlated with the genotypes of polymorphisms. RESULTS AND CONCLUSION The clinical pregnancy outcomes were significantly improved in patients with MTHFR 677CC genotype when treated with zinco c. Furthermore, treatment with 75 mg of aspirin resulted in higher negative pregnancy rates in patients with MTHFR A1298C genotypes. Therefore, the results of this study should be used to re-evaluate the clinical applications in women with miscarriages.
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Effects of folic acid on oligozoospermia with MTHFR polymorphisms in term of seminal parameters, DNA fragmentation, and live birth rate: a double-blind, randomized, placebo-controlled trial.
Huang, WJ, Lu, XL, Li, JT, Zhang, JM
Andrology. 2020;(1):110-116
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Abstract
BACKGROUND It has been reported that paternal folic acid deficiency is correlated with male infertility and increased birth defects in the offspring. However, there are few data concerning the influence of folic acid supplementation on male-factor infertility with MTHFR gene polymorphisms. OBJECTIVES To evaluate whether folic acid supplementation has a beneficial effect on oligozoospermia with MTHFR gene polymorphisms in Chinese infertility population. MATERIALS AND METHODS The infertile men suffering oligozoospermia with MTHFR gene polymorphisms were randomly divided into the folic acid treatment groups receiving folic acid 0.8 mg daily for 3 months and the placebo groups receiving placebo for 3 months. Semen parameters, seminal MDA, and DNA fragmentation were measured. Furthermore, spontaneous pregnancy rate and live birth rate were evaluated. RESULTS Administration of folic acid for 3 months could significantly improve the seminal parameters in patients with MTHFR 677 TT genotype in comparison with that receiving placebo. Moreover, seminal MDA and sperm DNA fragmentation index in patients with MTHFR 677 TT genotype significantly declined at the end of treatment. Spontaneous pregnancy rate and live birth rate tended to be significantly higher in couples in which the men with MTHFR 677 TT genotype receiving folic acid than that receiving placebo. However, folic acid treatment did not exhibit any advantage in MTHFR 677 CT, 1298 AC, 1298 CC, 1793 GA, or combined 677 CT/1298 AC genotype. DISCUSSION The anti-oxidation function of folic acid is one of possible mechanisms invovled in improving seminal parameters and pregnancy outcome. CONCLUSIONS Folic acid supplementation has a beneficial effect on oligozoospermia with MTHFR 677 TT genotype in term of seminal parameters, seminal MDA, sperm DNA fragmentation, and pregnancy outcome.
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A meta-analysis on associations of FTO, MTHFR and TCF7L2 polymorphisms with polycystic ovary syndrome.
Wang, X, Wang, K, Yan, J, Wu, M
Genomics. 2020;(2):1516-1521
Abstract
BACKGROUND We aimed to better clarify the relationship between FTO/MTHFR/TCF7L2 polymorphisms and PCOS in a larger combined population by performing a meta-analysis. METHODS Eligible articles were retrieved from Pubmed, Embase, Web of Science and CNKI. Review Manager Version was used to perform statistical analyses. RESULTS Forty-six studies were included for this meta-analysis. FTO rs9939609 polymorphism was found to be significantly associated with PCOS under dominant, recessive, over-dominant and allele comparisons, MTHFR rs1801131 polymorphism was found to be significantly associated with PCOS under recessive and allele comparisons, and MTHFR rs1801133 polymorphism was also found to be significantly associated with PCOS under dominant, recessive and allele comparisons in general population. In subgroup analyses, we found that positive results were mainly driven by the Asians. CONCLUSIONS Collectively, this meta-analysis proved that FTO rs9939609, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may serve as predisposing factors of PCOS, especially for Asians.
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Association of Homocysteine, Methionine, and MTHFR 677C>T Polymorphism With Rate of Cardiovascular Multimorbidity Development in Older Adults in Sweden.
Calderón-Larrañaga, A, Saadeh, M, Hooshmand, B, Refsum, H, Smith, AD, Marengoni, A, Vetrano, DL
JAMA network open. 2020;(5):e205316
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Abstract
IMPORTANCE Strong evidence links high total serum homocysteine (tHcy) and low methionine (Met) levels with higher risk of ischemic disease, but other cardiovascular (CV) diseases may also be associated with their pleiotropic effects. OBJECTIVES To investigate the association of serum concentrations of tHcy and Met with the rate of CV multimorbidity development in older adults and to explore the role of methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in this association. DESIGN, SETTING, AND PARTICIPANTS The Swedish National Study on Aging and Care in Kungsholmen is a cohort study of randomly selected individuals aged 60 years or older. The present study included data on 1969 individuals with complete information and without CV diseases at baseline, collected from the baseline examination (2001-2004) to the fourth follow-up (2013-2016). Data analysis was conducted from January to May 2019. EXPOSURES Concentrations of tHcy and Met were measured from nonfasting venous blood samples. The Met:tHcy ratio was considered a possible indicator of methylation activity. MTHFR status was dichotomized as any T carriers vs noncarriers. MAIN OUTCOME AND MEASURES The number of CV diseases at each wave was ascertained based on medical interviews and records, laboratory test results, and drug data. Linear mixed models were used to study the association of baseline tHcy and Met levels and the rate of CV multimorbidity development, adjusting for sociodemographic characteristics, CV risk factors, chronic disease burden, and drug use. RESULTS Of 1969 participants, most were women (1261 [64.0%]), with a mean (SD) age of 70.9 (9.8) years; 1703 participants (86.6%) had at least a high school level of education. Baseline measurements of serum tHcy, Met, and the Met:tHcy ratio were associated with the rate of CV disease accumulation (tHcy: β = 0.023 per year; 95% CI, 0.015 to 0.030; P < .001; Met: β = -0.007 per year; 95% CI, -0.013 to -0.001; P = .02; Met:tHcy ratio: β = -0.017 per year; 95% CI, -0.023 to -0.011; P < .001). The association between low Met concentrations and the rate of CV multimorbidity development was restricted to the group with CT/TT alleles of MTHFR (β = 0.023 per year; 95% CI, 0.006 to 0.041; P = .009). Results remained largely significant when individual CV diseases were removed from the total count 1 at a time (eg, ischemic heart disease, tHcy: β = 0.023 per year; 95% CI, 0.013 to 0.027; P < .001; Met: β = -0.006 per year; 95% CI, -0.011 to -0.0003; P = .04; Met:tHcy ratio: β = -0.015 per year; 95% CI, -0.020 to -0.009; P < .001). CONCLUSIONS AND RELEVANCE In this study, high tHcy and low Met levels were associated with faster CV multimorbidity development in older age. The interactive association of Met concentrations and MTHFR polymorphism, together with the association found for the Met:tHcy ratio, point toward the relevance of impaired methylation in the pathogenesis of CV aging.
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Riboflavin supplementation alters global and gene-specific DNA methylation in adults with the MTHFR 677 TT genotype.
Amenyah, SD, McMahon, A, Ward, M, Deane, J, McNulty, H, Hughes, CF, Strain, JJ, Horigan, G, Purvis, J, Walsh, CP, et al
Biochimie. 2020;:17-26
Abstract
DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (-1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.
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Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation.
Rooney, M, Bottiglieri, T, Wasek-Patterson, B, McMahon, A, Hughes, CF, McCann, A, Horigan, G, Strain, JJ, McNulty, H, Ward, M
Biochimie. 2020;:91-99
Abstract
Homozygosity for the C677T polymorphism in MTHFR (TT genotype) is associated with a 24-87% increased risk of hypertension. Blood pressure (BP) lowering was previously reported in adults with the TT genotype, in response to supplementation with the MTHFR cofactor, riboflavin. Whether the BP phenotype associated with the polymorphism is related to perturbed one-carbon metabolism is unknown. This study investigated one-carbon metabolites and their responsiveness to riboflavin in adults with the TT genotype. Plasma samples from adults (n 115) screened for the MTHFR genotype, who previously participated in RCTs to lower BP, were analysed for methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), betaine, choline and cystathionine by liquid chromatography tandem mass spectrometry (LC-MS/MS). The one-carbon metabolite response to riboflavin (1.6 mg/d; n 24) or placebo (n 23) for 16 weeks in adults with the TT genotype was also investigated. Plasma SAM (74.7 ± 21.0 vs 85.2 ± 22.6 nmol/L, P = 0.013) and SAM:SAH ratio (1.66 ± 0.55 vs 1.85 ± 0.51, P = 0.043) were lower and plasma homocysteine was higher (P = 0.043) in TT, compared to CC individuals. In response to riboflavin, SAM (P = 0.008) and cystathionine (P = 0.045) concentrations increased, with no responses in other one-carbon metabolites observed. These findings confirm perturbed one-carbon metabolism in individuals with the MTHFR 677TT genotype, and for the first time demonstrate that SAM, and cystathionine, increase in response to riboflavin supplementation in this genotype group. The genotype-specific, one-carbon metabolite responses to riboflavin intervention observed could offer some insight into the role of this gene-nutrient interaction in blood pressure.
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Assessment of the relationship between methylenetetrahydrofolate reductase polymorphism and acute lymphoblastic leukemia: Evidence from an updated meta-analysis.
Frikha, R
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2020;(7):1598-1610
Abstract
OBJECTIVE The methylenetetrahydrofolate reductase gene C677T polymorphism is closely related to the acute lymphoblastic leukemia. Several case-control studies have investigated this association; however, no conclusions could be drawn. A comprehensive updated meta-analysis is established to explain these contradictions and clarify the overall impact of this variant on the susceptibility to acute lymphoblastic leukemia. METHODS Electronic searches were conducted to select published studies prior to June 2018. Pooled odds ratios and stratification analysis were performed under different genetic comparison models, age, and ethnicity. RESULTS Totally, 66 case-control studies including 9619 acute lymphoblastic leukemia cases and 17,396 controls were selected. Our analyses showed that methylenetetrahydrofolate reductase C677T polymorphism was protective mainly in Asian and European countries, under all genetic models and regardless of age, but leukemogenic in mixed population. CONCLUSION Thus, C677T polymorphism may be a promising acute lymphoblastic leukemia biomarker, but they should be interpreted with caution considering other factors such as folic acid intake, gene-gene and gene-environment interactions.
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Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.
Wiedemann, A, Chery, C, Coelho, D, Flayac, J, Gueguen, N, Desquiret-Dumas, V, Feillet, F, Lavigne, C, Neau, JP, Fowler, B, et al
Journal of human genetics. 2020;(2):91-98
Abstract
Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
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Association of MTHFR gene polymorphisms with pancreatic cancer: meta-analysis of 17 case-control studies.
Nie, F, Yu, M, Zhang, K, Yang, L, Zhang, Q, Liu, S, Liu, M, Shang, M, Zeng, F, Liu, W
International journal of clinical oncology. 2020;(2):312-321
Abstract
BACKGROUND Pancreatic cancer (PC) is a seriously malignant tumor with a low 5-year survival rate. The relationship between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and PC has been reported by several studies. However, the results were controversial. Thus, we conducted a meta-analysis to summarize available data on MTHFR gene and PC. METHODS We searched PubMed, Embase, Web of Science, Wanfang, CNKI databases prior to July 2019. Data were analyzed by RevMan 5.3 and STATA 12.0 software. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of the association. Subgroup analysis, sensitivity analysis and assessment of publication bias were performed in this study. RESULTS Ten articles with 17 reports (10 for C677T, 7 for A1298C) were eligible for inclusion in the meta-analysis (1864 cases and 3165 controls for C677T, and 1488 cases and 1946 controls for A1298C). Our meta-analysis detected that C677T was associated with PC for three genetic models (allele model: OR = 1.24, 95% CI: 1.00-1.53, P = 0.047; recessive model: OR = 1.39, 95% CI: 1.04-1.86, P = 0.027; homozygous model: OR = 1.60, 95% CI: 1.04-2.45, P = 0.034). In the stratified analyses according to ethnicity, source of controls and genotyping method, significant association was observed in genotyping method subgroup. For the A1298C polymorphism, no significant association was observed either in overall analysis or in subgroup analysis under all genetic models. CONCLUSIONS MTHFR gene C677T rather than A1298C polymorphism may be associated with PC. Larger sample size studies should be performed to find the association between MTHFR gene and PC.
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Methylenetetrahydrofolate reductase C677T polymorphism and diabetic retinopathy risk: a meta-analysis of the Chinese population.
Xu, WH, Zhuang, Y, Han, X, Yuan, ZL
The Journal of international medical research. 2020;(1):300060518816834
Abstract
OBJECTIVES This study evaluated associations between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and diabetic retinopathy (DR) susceptibility within the Chinese population. METHODS Five databases (PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure) were used for literature searches of open access articles from inception through April 2017. RESULTS Eight publications were identified involving 600 DR cases, 363 healthy controls, and 646 nondiabetic retinopathy (NDR) controls. There was a positive association between MTHFR C677T polymorphisms and DR risk within the Chinese population (DR with NDR controls: T vs. C, odds ratio (OR): 2.14, 95% confidence interval (CI): 1.55–2.97; TT vs. CC, OR: 4.19, 95% CI: 2.09–8.41; TT + CT vs. CC, OR: 2.83, 95% CI: 1.86–4.40; TT vs. CC + CT, OR: 2.48, 95% CI: 1.52–4.05. DR with healthy controls: T vs. C, OR: 2.48, 95% CI: 1.99–3.09; TT vs. CC, OR: 4.92, 95% CI: 3.18–7.62; TT + CT vs. CC, OR: 3.22, 95% CI: 2.32–4.48; TT vs. CC + CT, OR: 3.11, 95% CI: 1.83–5.28). The association was similar in South China and North China, when stratifying by geographic areas. CONCLUSION MTHFR C677T polymorphisms increase DR risk within the Chinese population.