Journal articles on the topic 'MTHFR'
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1
Thompson, Henry R., Gayle M. Jones, and Michael R. Narkewicz. "Ontogeny of hepatic enzymes involved in serine- and folate-dependent one-carbon metabolism in rabbits." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 5 (May 1, 2001): G873—G878. http://dx.doi.org/10.1152/ajpgi.2001.280.5.g873.
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Serine occupies a central position in folate-dependent, one-carbon metabolism through 5,10-methylenetetrahydrofolate (MTHF) and 5-formyltetrahydrofolate (FTHF). We characterized the ontogeny of the specific activity of key enzymes involved in serine, 5,10-MTHF, and 5-FTHF metabolism: methenyltetrahydrofolate synthetase (MTHFS), MTHF reductase (MTHFR), the glycine cleavage system (GCS), methionine synthase (MS), and serine hydroxymethyltransferase (SHMT) in rabbit liver, placenta, brain, and kidney. In liver, MTHFS activity is low in the fetus (0.36 ± 0.07 nmol · min−1 · mg protein−1), peaks at 3 wk (1.48 ± 0.50 nmol · min−1 · mg protein−1), and then decreases to adult levels (1.13 ± 0.32 nmol · min−1 · mg protein−1). MTHFR activity is highest early in gestation (24.9 ± 2.4 nmol · h−1 · mg protein−1) and declines rapidly by birth (4.7 ± 1.3 nmol · h−1 · mg protein−1). MS is highest during fetal life and declines after birth. Cytosolic SHMT activity does not vary during development, but mitochondrial SHMT peaks at 23 days. GCS activity is high in the fetus and the neonate, declining after weaning. In placenta and brain, all activities are low throughout gestation. Cytosolic and mitochondrial SHMT activities are low in kidney and rise after weaning, whereas MTHFS is low throughout development. These data suggest that the liver is the primary site of activity for these enzymes. Throughout development, there are multiple potential sources for production of 5,10-MTHF, but early in gestation high MTHFR activity and low MTHFS activity could reduce 5,10-MTHF availability.
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Elsadig Babiker, Nihad. "Detection of Mthfr (C667t) and Mthfd (G1958a) Polymorphisms Among Sudanese Women with The Recurrent Miscarriages." Archives of Gynaecology and Women Health 1, no. 1 (February 6, 2023): 01–04. http://dx.doi.org/10.58489/2836-497x/006.
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Background Recurrent pregnancy loss affects 1 to 5% of women trying to conceive, I t has a significant impact at individual and social level. Methodology case-control study conducted at the research laboratory of the national center of neurological sciences, Khartoum, Sudan. All patients attending Ibrahim Malik teaching hospital and diagnosed with recurrent spontaneous abortion were included as case and healthy women at reproductive age were included as controls. The DNA was isolated by standard phenol chloroform extraction method, The PCR was done by using commercial thermal cycler machine with specific protocol. PCR products were sent for sequencing to Macro gene Europe Laboratory. Results 494 bp of MTHFR(C677T) and 174 bp of MTHFD (rs2236225) (G19581A) alleles were detected after PCR. The PCR result of MTHFR(C677T) shows; 40 (90%) forMTHFR (C677T) allele was positive in the cases and only12 (24 %) were positive for the control group. For MTHFD (G19581A) allele 42 (95%) were positive in the case group and 14 (28%) were positive in the control. When compared between case and control there was highly significant differences. The sequencing results for MTHFR C677; single Base Exchange was found C>T in the case groups, when used the mutation taster software the mutation was predicted. For MTHFD (G1958A) in the case group tow single Base Exchange were found T>A and G>A, the mutation taster software was predicted T>A mutation. Conclusion According to this result the MTHF polymorphisms might become one of the main causes of unexplained diagnosis women with recurrent spontaneous abortion
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Cole, Leslie, Alina Cernasev, Katie Webb, Santosh Kumar, and A. Shaun Rowe. "A Study of the MTHFR Gene Prevalence in a Rural Tennessee Opioid Use Disorder Treatment Center Population." International Journal of Environmental Research and Public Health 19, no. 6 (March 10, 2022): 3255. http://dx.doi.org/10.3390/ijerph19063255.
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Background: Opioid Use Disorder (OUD) has been linked to dopamine and the neurological reward centers. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the production of many neurotransmitters such as dopamine. As such, MTHFR variants that lead to decreased production of neurotransmitters may play a role in OUD. However, lacunae exist for characterizing the prevalence of the MTHFR mutations in an OUD population. The objective of this study was to determine prevalence of the MTHFR gene mutations in a rural Tennessean population with OUD. Methods: This study was a retrospective cohort of individuals with OUD that evaluated the prevalence of MTHFR variants. Patients were categorized as normal, homozygous C677T, heterozygous C677T, homozygous A1298C, or heterozygous A1298C. The primary outcome was a qualitative comparison of the prevalence of each of the MTHFR variants in our cohort to the publicly reported MTHR polymorphism prevalence. Secondary outcomes include race and ethnicity differences as well as stimulant use differences for each of the variants. Results: A total of 232 patients undergoing care for opioid use disorder were included in the study. Of those included, 30 patients had a normal MTHFR allele and 202 had a variant MTHFR allele. Overall, the prevalence of any MTHFR variant was 87.1% (95% CI 82.6–91.4%). When comparing those with a normal MTHFR allele to those with any MTHFR variant, there was no difference in age, sex, race and ethnicity, or stimulant use. Conclusion: The overall prevalence of MTHFR variants in patients with opioid use disorders is high.
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Karagur, Ege, Mustafa Alay, Aydin Demiray, Nedim Karagenc, Onur Tokgün, Taner Durak, and Hakan Akca. "The impact of hereditary thrombophilias in recurrent pregnancy loss." Genetika 54, no. 3 (2022): 1399–410. http://dx.doi.org/10.2298/gensr2203399k.
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Introduction: Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy loss which occurs before the 20th weeks of pregnancies for the last menstrual period. Hereditary cause of thrombophilic gene mutations and polymorphism may play an essential role in RPLs. Material and Method: 291 women with a history of two or more consecutive abortions as a study group and 61 women without the history of miscarriages as a control group were included in a study. In this study we analysed the effects of Factor II Prothrombin mutation ,FV Leiden mutation, MTHFR C677T, MTHFT A1298C, PAI-1, ?-fibrinogen, Factor XIIIA (V34L) and Glycoprotein IIIa (L33P) polymorphisms on RPL by using pyrosequencing. Chi-square and multiple regression analysis were used for statistical analysis. Results: FII prothrombin mutation, FV Leiden mutation, MTHFR C677T, MTHFR A1298C, PAI1 and Beta fibrinogen were found statistically significant in the chi-square test. Heterozygous FV G1691A (OR:8.092, CI: 1.280-51.165), homozygous MTHFR A1298C (OR:17.621, CI: 3.644 - 85.203), Heterozygous MTHFR C677T (OR: 2.921 CI: 0.811-10.515), Homozygous MTHFR C677T (OR: 3.619 CI: 1.647-7.954), heterozygous MTHFR A1298C (OR: 5.989, CI: 2.574-13.934), homozygous PAI1 (OR: 8.756, CI: 2.805 -27.334), heterozygous PAI1 ( OR: 7.114, CI: 3.145- 16.096) homozygous FibrinogenG455A (4.085, CI: 1.438-11.610) were found statistically significant in logistic regression analysis for RPL(p<0.05). Discussion: This study indicated that there is a significant association between thrombophilias and RPL. Therefore, it is important to detect thrombophilic mutations in RPL.
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Marosi, Krisztina, Annamária Ágota, Veronika Végh, József Gábor Joó, Zoltán Langmár, Ildikó †Kriszbacher, and Zsolt B. Nagy. "The role of homocysteine and methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase polymorphisms in the development of cardiovascular diseases and hypertension." Orvosi Hetilap 153, no. 12 (March 2012): 445–53. http://dx.doi.org/10.1556/oh.2012.29326.
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Cardiovascular diseases (CVDs) are the leading causes of death in the developed countries. Elevated homocysteine level is as an independent risk factor of CVDs. The C677T and A1298C variants of methylenetetrahydrofolate reductase gene (MTHFR) have been shown to influence folate and homocysteine metabolisms. However, the relationship between MTHFR polymorphisms and hyperhomocysteinemia has not been well established yet. The gene variants were also reported to be associated with CVDs. In addition, the C677T polymorphisms may play a role in the development of hypertension. Recent research evidence has suggested that MTHFR variants might be independently linked to CVDs and hypertension, because of the involvement of the MTHFR enzyme product (5-methyl-tetrahydrofolate /5-MTHF) in the regulation of endothelial functions. Further research is required to investigate the association between gene polymorphisms of folate-metabolizing enzymes and CVDs, and to identify the possible role of the relevant gene variants in the molecular pathogenesis of hyperhomocysteinemia. Orv. Hetil., 2012, 153, 445–453.
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Liu, Zhiping, Hong Jiang, Justin H. Townsend, and Jianhua Wang. "Effects of Ocufolin on retinal microvasculature in patients with mild non-proliferative diabetic retinopathy carrying polymorphisms of the MTHFR gene." BMJ Open Diabetes Research & Care 9, no. 1 (September 2021): e002327. http://dx.doi.org/10.1136/bmjdrc-2021-002327.
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IntroductionTo evaluate effects of Ocufolin on retinal microvasculature in mild non-proliferative diabetic retinopathy patients who carried methylenetetrahydrofolate reductase (MTHFR) polymorphisms (DR+MTHFRP).Research design and methodsThis is a prospective cohort study. Eight DR+MTHFRP (administrated Ocufolin for 6 months) and 15 normal controls (NCs) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal vessel density (VD) and microstructure were evaluated by optical coherence tomography angiography.ResultsBCVA and vascular indices of DR+MTHFRP at baseline were worse than those of NC and improved. Compared with baseline, DR+MTHFRP had significantly improved BCVA during follow-up period (p<0.05). VD of superficial vascular plexus was increased at 4 months (p=0.012), while VD of retinal vascular network did not change (p>0.05). Carriers of A1298C and C677T showed statistically significant increase in VD at all layers by 6 months, while carriers of C677T alone showed no significant change and carriers of A1298C alone showed decreased density from 4 months to 6 months. Microstructure did not change during the follow-up period.ConclusionA 6-month intake of Ocufolin is capable of reversing structural changes of microangiopathy in mild non-proliferative DR+MTHFRP. This suggests a novel way to address these impairments prior to catastrophic vision loss.
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Lu, Mong-Liang, Wei-Chi Ku, Nailis Syifa, Shu-Chin Hu, Chia-Te Chou, Yi-Hsio Wu, Po-Hsiu Kuo, Chun-Hsin Chen, Wei J. Chen, and Tzu-Hua Wu. "Developing a Sensitive Platform to Measure 5-Methyltetrahydrofolate in Subjects with MTHFR and PON1 Gene Polymorphisms." Nutrients 14, no. 16 (August 13, 2022): 3320. http://dx.doi.org/10.3390/nu14163320.
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Inadequate levels of 5-methyltetrahydrofolate (5-MTHF) and the T variant of MTHFR C677T have been suggested to be associated with an increased risk of developing mental illness, whereas the PON1 SNP variant provides a protective role. However, reports validating the methodology for plasma 5-MTHF levels in schizophrenia patients are limited. A sensitive LC–MS/MS system using an amide column and calibration curve was determined by dialyzed human plasma, and applied to schizophrenia patients and healthy controls in Taiwan, and the differences between the subgroups were discussed. This analysis system meets regulation criteria, and the lower limit of quantification for 5-MTHF levels was 4 nM from 200 μL plasma, within 7 min. The mean plasma 5-MTHF levels in schizophrenia patients (n = 34; 11.70 ± 10.37 nM) were lower than those in the healthy controls (n = 42; 22.67 ± 11.12 nM) significantly (p < 0.01). 5-MTHF concentrations were significantly lower in male carriers than in female carriers (18.30 ± 10.37 nM vs. 24.83 ± 11.01 nM, p < 0.05), especially in subjects who were MTHFR CT/PON1 Q allele carriers. In conclusion, this quantitative system, which employed sensitive and simple processing methods, was successfully applied, and identified that schizophrenic patients had significantly lower levels of 5-MTHF. Lower plasma 5-MTHF concentrations were observed in male subjects.
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Tsaousidou, Maria M. K. T., Fotis F. I. G. Girtovitis, Afroditi A. K. Boutou, Elefteria E. P. Pithara, and Pantelis M. E. P. Makris. "Appliance of the DNA-Micro Array Technique for the Identification of Patients with Thrombophilic Diathesis. I-Comparison to the Classic PCR Analysis." Blood 104, no. 11 (November 16, 2004): 4049. http://dx.doi.org/10.1182/blood.v104.11.4049.4049.
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Abstract Introduction: DNA Micro array have the ability to test a large number of samples for a large number of mutations on the same time, something practically impossible with the traditional hybridization methods. The goal of this study is to compare the ability of DNA micro array application to recognize genetic predisposition to thrombosis, with the one of RLF-PCR. Material: DNA samples from 37 subjects (24 male with mean age 41.9 and 13 female with mean age 38.8) were studied both with micro arrays and PCR analysis. All of these subjects had a history of either recurrent thrombosis or thrombosis at unusual sites (e.g. retina’s central vein thrombosis). Method: The thrombo-check microarray contains the following mutations and polymorphisms: Factor V Leiden (FV G1691A), FII G20210A (prothrombin mutation), FV Cambridge (FV G1091C), MTHFR C677T, MTHFR A1298C, CBS 844ins68, Plasminogen Activator Inhibitor (PAI 1 4G/5G). The thrombo-check microarray can distinguish between the normal sequence, as well as heterozygosity and homozygosity for the mutated sequence. To ensure the result is correct specific probes are included on the microarray to control for the RLF-PCR reaction, the hybridization reaction and the silver staining procedure. In addition, the correct functioning of the entire reaction can be checked using an external control DNA. Results: As long as FVL and FII are concerned, in 35 out of 37 patients (pts) both methods gave similar results. However, the results of DNA analysis were different for the other two patients. The first one was found to be, using the micro array DNA method, a double heterozygous carrier of both FVL and FII mutations, while RLF-PCR did not relieve any such genetic defects. The other patient was found to be, using the RLF-PCR a homozygous carrier for the prothrombin mutation, while micro array also revealed heterozygous mutation of FV Leiden. Moreover, the micro array method detected totally 1 patient with FVC, 4 pts homozygous for MTHFR1, 6 pts homozygous for PAI and 4 pts homozygous for MTHFR2 mutation. Further more, micro array detected the co-existence of FVL and homozygocity in a) FII mutation (2 pts), b) PAI mutation (1patient) and c) MTHFR2 (2pts). Finally, 1 patient with FII was found to be also homozygous for MTHFR1 mutation.
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Simonian, Rebecca, Emanuela Pannia, Rola Hammoud, Xiucheng Cui, Ruslan Kubant, Brandi Wasek, Terry Bottiglieri, James Dowling, Ramil Noche, and G. Harvey Anderson. "Methylenetetrahydrofolate Reductase Deficiency Reduces Brain Microglia in Zebrafish During Embryonic Development and Is Not Corrected by Folic Acid." Current Developments in Nutrition 5, Supplement_2 (June 2021): 925. http://dx.doi.org/10.1093/cdn/nzab049_038.
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Abstract Objectives Neuronal development and function is dependent on the interaction between the central nervous system and immune system. Microglia are resident macrophages of the brain critical for regulating neuronal activity during embryonic development. 5-methyltetrahydrofolate (5MTHF), the bioactive folate form, is essential for fetal brain development and immune function. Common variants in methylenetetrahydrofolate reductase (MTHFR), required for conversion of folic acid (FA) to 5-MTHF, limits its production. High dose FA supplementation is recommended but high FA may have the converse effect of reducing MTHFR activity. The objective of this study was to determine the effects of mthfr deficiency and its interaction with FA during embryonic development on microglia in a zebrafish model. Methods The mthfr gene in zebrafish was disrupted using two CRISPR mutagenesis methods. A set of 4 guide RNAs (gRNAs) + cas9 protein or cas9 alone (control) were injected to assay F0 zebrafish, or 2 gRNAs + cas9 mRNA were used to induce a germline mutation. To visualize macrophages at 4 days post fertilization (dpf) in live zebrafish, the transgenic mpeg1: mcherry line was used. In a subset of embryos, FA was added at 0, 50, 75, or 100- μM from 0–4dpf. At 4dpf, live neutral red staining for microglia was performed and the number in the optic tectum was quantified. 5MTHF, s-adenosylmethionine (SAM) and s-adenosylhomocysteine (SAH) were assayed in whole zebrafish at 5dpf. Results In vivo imaging revealed a reduction in macrophage number (∼30%, P < 0.001) in the head region of mthfr disrupted zebrafish, but not in the periphery. mthfr zebrafish also had less microglia compared to controls (15%, P < 0.001). These changes were associated with lower 5MTHF (90%, P < 0.0001) and SAM: SAH (∼50%, P < 0.001) at 5dpf indicative of lower methylation potential. Exposure with FA did not correct the phenotype and at 100µM FA, control zebrafish also showed a decrease in microglia similar to mthfr zebrafish, confirming inhibitory effects of the high FA dose. Conclusions mthfr deficiency reduces microglia in zebrafish but supplementation with FA does not prevent and may exacerbate the negative effects. The 5MTHF form of folate may be a better alternative to FA for brain health in patients with underlying genetic conditions. Funding Sources Supported by CIHR-INMD.
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Devlin, Angela M., Erland Arning, Teodoro Bottiglieri, Frank M. Faraci, Rima Rozen, and Steven R. Lentz. "Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice." Blood 103, no. 7 (April 1, 2004): 2624–29. http://dx.doi.org/10.1182/blood-2003-09-3078.
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Abstract Deficiency of methylenetetrahydrofolate reductase (MTHFR) predisposes to hyperhomocysteinemia and vascular disease. We tested the hypothesis that heterozygous disruption of the Mthfr gene sensitizes mice to diet-induced hyperhomocysteinemia and endothelial dysfunction. Mthfr+/- and Mthfr+/+ mice were fed 1 of 4 diets: control, high methionine (HM), low folate (LF), or high methionine/low folate (HM/LF). Plasma total homocysteine (tHcy) was higher with the LF and HM/LF diets than the control (P < .01) or HM (P < .05) diets, and Mthfr+/- mice had higher tHcy than Mthfr+/+ mice (P < .05). With the control diet, the S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) ratio was lower in the liver and brain of Mthfr+/- mice than Mthfr+/+ mice (P < .05). SAM/SAH ratios decreased further in Mthfr+/+ or Mthfr+/- mice fed LF or LF/HM diets (P < .05). In cerebral arterioles, endothelium-dependent dilation to 1 or 10 μM acetylcholine was markedly and selectively impaired with the HM/LF diet compared with the control diet for both Mthfr+/+ (maximum dilation 5% ± 2% versus 21% ± 4%; P < .01) and Mthfr+/- (6% ± 2% versus 21% ± 3%; P < .01) mice. These findings demonstrate that the Mthfr+/- genotype sensitizes mice to diet-induced hyperhomocysteinemia and that hyperhomocysteinemia alters tissue methylation capacity and impairs endothelial function in cerebral microvessels.
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Soydan, Ender A., Pervin Topcuoglu, Muhit Ozcan, Onder Arslan, Gunhan Gurman, Meral Beksac, Mutlu Arat, and Osman Ilhan. "The Impact of Methylenetetrahydrofolate Reductase C677T Gene Polymorphism on Engraftment after Allogeneic Hematopoetic Cell Transplantation." Blood 106, no. 11 (November 16, 2005): 5318. http://dx.doi.org/10.1182/blood.v106.11.5318.5318.
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Abstract Methotrexate (MTX) is an antifolate agent used to prevent graft versus host disease (GVHD) in allogeneic hemapoietic cell transplantation (AHCT). The effectiveness of MTX is largely attributable to its role of MTHR and its gene polymorphism is a common (10–12% homozygote and 40% heterozygote) variation in the population. It was shown by Ulrich et al that C677T polymorphism leads to variations in toxicities. Depending on to this finding, we investigated whether methylenetetrahyrofolate reductase (MTHFR) C677T gene polymorphism has any affect on engraftment kinetics of patients undergoing AHCT. We retrospectively analyzed our cohort of 82 allogeneic stem cell recipients whose MTHFR gene polymorphism of C677T region was analyzed by RQ-PCR for the pretransplant evaluation of hereditary thrombophilia. The patient’s median age was 31 (range, 14–50) years, with a M/F: 50/32 and diagnosis; 35 AML, 26 CML, 12 ALL and 9 other. Nearly all the patients received ablative conditioning regimen (BU-CY) or CY-TBI. All the patients received CSA and short term MTX for GVHD prophylaxis. Stem cell source was bone marrow (BM) in 23 and peripheral blood (PB) in 59. MTHFR gene polymorphism was detected in 32 (39%) of all patients, whose 90% were heterozygote (MTHFR HeZ). When we compared the engraftment kinetics, granulocyte engraftment was found to be late in MTHFR HeZ group (neutrophil 1000 median 19 vs 17 d; p=0.01) but no difference in platelet engraftment. In order to eliminate the effect of stem cell source on engraftment kinetics we have done the same analysis for BM and PB group separately. We have observed that MTHFR gene polymorphism had a prominent effect on BM recipients, as both neutrophil 500 and 1000 and also platelet engraftments were affected (granulocyte 500 median 21 vs 15 p=0.005; granulocyte 1000 median 22.5 vs 17 p=0.0001 and plt 20 median 27 vs 21 p=0.03) significantly. On the contrary, there was no difference in the PB group. There was no difference in acute GVHD incidence. Our knowledge on epigenetic data will help us on tailoring the chemotherapy regimen for conditioning and GvHD prophylaxis in transplant recipients. Our data on a limited patient size suggests that the presence of MTHFR HeZ may have an impact on allo HCT recipients’ engraftment kinetics while using MTX for GVHD prophylaxis and BM as stem cell source.
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Xie, Xiong-wei, Mao-ren Wang, and Yong-lian Zhang. "Methylenetetrahydrofolate reductase polymorphism and capecitabine-induced toxicity in patients with gastric cancer." Tropical Journal of Pharmaceutical Research 19, no. 1 (April 9, 2020): 195–99. http://dx.doi.org/10.4314/tjpr.v19i1.28.
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Purpose: To evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) polymorphism on toxicity in gastric cancer (GC) patients treated with capecitabine.
Methods: One hundred and twenty-six GC patients were treated with capecitabine in the study. DNA from GC patients was genotyped for MTHFR A1298C using direct sequencing. Toxicity evaluations were graded. Clinical response was assessed.
Results: In 87.3 % of the patients, capecitabine toxicity was observed. As for MTHFR A1298C polymorphism, 55.6 % patients who exhibited it were associated with reduced MTHFR activity. MTHFR A1298C was associated with capecitabine-related toxicity (p = 0.008); in addition, MTHFR A1298C was significantly associated with gastrointestinal toxicity (p = 0.026), but not with other types of toxicity.
Conclusion: The findings suggest that MTHFR A1298C may be useful for predicting toxicity in GC patients receiving capecitabine treatment, especially gastrointestinal toxicity.
Keywords: MTHFR, Polymorphism, Gastric cancer, Toxicity
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Stangler Herodež, Š., B. Zagradišnik, A. Erjavec Škerget, A. Zagorac, I. Takač, V. Vlaisavljević, L. Lokar, and N. Kokalj Vokač. "MTHFR C677T and A1298C Genotypes and Haplotypes in Slovenian Couples with Unexplained Infertility Problems and in Embryonic Tissues from Spontaneous Abortions." Balkan Journal of Medical Genetics 16, no. 1 (June 1, 2013): 31–39. http://dx.doi.org/10.2478/bjmg-2013-0015.
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Abstract The objective of this study was to analyze the methylenetetrahydrofolate reductases (MTHFRs) C677T and A1298C genotype distributions in couples with unexplained fertility problems (UFP) and healthy controls, and to analyze the genotype and haplotype distribution in spontaneously aborted embryonic tissues (SAET) using allele specific polymerase chain reaction (PCR) in 200 probands with UFP, 353 samples of SAET and 222 healthy controls. The analysis revealed a significant overall representation of the 677T allele in male probands from couples with UFP (p = 0.036). The combined genotype distribution for both MTHFR polymorphisms was also significantly altered (χ2 21.73, p <0.001) although female probands made no contribution (c2 1.33, p = 0.72). The overall representation of the 677T allele was more pronounced in SAET (0.5 vs. 0.351 in controls, p <0.001) regardless of the karyotype status (aneuploidy vs. normal karyotype). In addition, the frequencies of the CA and CC haplotypes were significantly lower than in the control group (p = 0.021 and p = 0.001, respectively), whereas the frequency of the TC haplotype was significantly higher than in controls (p <0.0001). The presented findings indicate that only male probands contribute to the association of MTHFR mutations with fertility problems in grown adults and demonstrate a high prevalence of mutated MTHFR genotypes in SAET.
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He, Wei, Minzhi Lu, Guoqing Li, Zhigang Sun, Dinghua Liu, and Lujun Gu. "Methylene Tetrahydrofolate Reductase (MTHFR) rs868014 Polymorphism Regulated by miR-1203 Associates with Risk and Short Term Outcome of Ischemic Stroke." Cellular Physiology and Biochemistry 41, no. 2 (2017): 701–10. http://dx.doi.org/10.1159/000458429.
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Background/Aims: Genetic polymorphisms of methylene tetrahydrofolate reductase (MTHFR) were associated with ischemic stroke risk. This study analyzed MTHFR polymorphisms at the 3'-untranslated region for association with risk and outcome of ischemic stroke in a Chinese Han population. Methods: 500 patients and 600 healthy volunteers were enrolled for MTHFR rs868014 genotyping identified bioinformatically. The binding of miR-1203 to MTHFR rs868014 was determined by luciferase assay, MTHFR expression was assessed using qRT-PCR, and plasma homocysteine levels were assayed by ELISA. Results: Cigarette smoking, alcohol consumption, diabetes, hypertension (all P <0.001), low levels of serum high-density lipoprotein-C (P = 0.01), and high levels of serum low-density lipoprotein-C (P = 0.005) were associated with an increased risk of developing ischemic stroke. BMI and total serum cholesterol concentration was not associated with ischemic stroke. MTHFR rs868014 TC and CC genotypes were significantly associated with increased risk of ischemic stroke compared with the TT genotype (OR: 1.52; 95% CI: 1.01-3.39 for TC genotype, while OR: 1.99; 95% CI: 1.29-3.88 for CC genotype). Furthermore, the MTHFR rs868014 SNP was associated with a poor short-term ischemic stroke outcome. qRT-PCR confirmed that MTHFR rs868014 TC or CC genotypes could facilitate miR-1203 binding leading to low MTHFR levels in cells. In addition, patients carrying the MTHFR rs868014 TC or CC genotypes were associated with accumulation of serum tHcy and a poor ischemic stroke outcome. Linkage disequilibrium analysis indicated that the newly identified SNP rs868014 was strongly linked with the MTHFR A1298C polymorphism. Conclusion: This study demonstrates that the MTHFR rs868014 SNP is associated with increased risk in developing ischemic stroke, miR-1203 binding, low MTHFR levels in cells, and poor shot term outcome of patients.
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Siraj, Abdul K., Rong Bu, Mona Ibrahim, Maha Al-Rasheed, Shahab Uddin, Adnan Ezzat, and Khawla Al-Kuraya. "Genetic Polymorphisms of Methylenetetrahydrofolate Reductase Genes and Diffuse Large B-Cell Lymphoma Risk in Middle Eastern Population." Blood 108, no. 11 (November 16, 2006): 4609. http://dx.doi.org/10.1182/blood.v108.11.4609.4609.
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Abstract Diffuse large B-Cell Lymphoma (DLBCL) is one of the most common non-Hodgkin lymphoma types and increased incidence has also been reported during the past 30 years. Methylenetetrahydrofolate (MTHFR) balances the pool of folate coenzymes in one carbon metabolism of DNA synthesis and methylation, both are implicated in carcinogenesis of many types of cancer including lymphoma. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate caner predisposing factor. These genetic differences are highly race specific and have never been screened in the Saudi DLBCL patients. We conducted hospital-based case control study in the Saudi DLBCL patients. To evaluate the MTHFR C677T and A1298C functional polymorphisms in the MTHFR gene and their association with Saudi DLBCL risk. A hospital based case control study was conducted on a Saudi population- which is known for their genetic homogeneity and high consanguinity- consisting of 187 histologically confirmed DLBCL cases and 513 Saudi controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping. Data showed that Saudi individuals carrying MTHFR 1298 CC genotype (p<0.001) and genotypes carrying MTHFR 1298C allele (p= 0.012) had 4.23 and 1.73-fold higher risk of developing DLBCL, respectively. Additionally, combined genotype CCCC (MTHFR 677CC+ MTHFR 1298CC) among intermediate MTHFR activity group was associated with 3.489 fold and CTCC (MTHFR 677 CT + 1298CC) among low MTHFR activity group was related to 9.515 fold higher risk, compared with full MTHFR enzyme activity. Our findings suggest that polymorphisms of MTHFR enzyme genes support for the important role of folate metabolism in lymphomagenesis and may be associated with the individual susceptibility to develop DLBCL in Saudi Arabian population. Table 1 Distribution of MTHFR polymorphisms in healthy population and lymphoma patients. Polymorphism Genotype Control group Lymphoma patients p -Methylenetetrahydrofolate reductase (MTHFR) MTHFR C677T CC 372 (72.8%) 109 (68.1%) CT 126 (24.7%) 45 (28.1%) 0.346 1.219 TT 13 (2.5%) 6 (3.8%) 0.404 1.575 CT+TT 139 (27.2%) 51 (31.9%) 0.269 1.252 MTHFR A1298C AA 239 (46.8%) 38 (33.6%) AC 220 (43.1%) 40 (35.4%) 0.625 1.144 CC 52 (10.2%) 35 (31%) <0.001 4.233 AC+CC 272 (53.2%) 75 (66.4%) 0.012 1.734 Table 2 Distribution of combined C677T and A1298C MTHFR genotypes in case and control group. Genotype Control Case p OR ND=Not detected Full Activity group CCAA 157 (30.8%) 22 (27.8%) Intermediate Activity group CCAC 169 (33.2%) 28 (35.4%) 0.649 1.182 CCCC 45 (8.8%) 22 (27.8%) <0.001 3.489 CTAA 69 (13.6%) 13 (16.5%) 0.439 1.345 TOTAL 283 63 0.104 1.589 Low Activity Group CTAC 50 (9.8%) 5 (6.3%) 0.634 0.714 CTCC 6 (1.2%) 8 (10.1%) <0.001 9.515 TTAA 12 (2.4%) 1 (1.3%) 1 0.595 TTAC 0 2 (2.5%) 0.017 ND TTCC 1 (0.2%) - - - TOTAL 69 16 0.189 1.655 Intermediate + Low 352 (69.1%) 79 0.073 1.602
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Li, Zhen, Ji Zhang, Wei Zou, Qi Xu, Siyuan Li, Jie Wu, Li Zhu, et al. "The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism is associated with breast cancer subtype susceptibility in southwestern China." PLOS ONE 16, no. 7 (July 9, 2021): e0254267. http://dx.doi.org/10.1371/journal.pone.0254267.
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Methylenetetrahydrofolate reductase (MTHFR), a folate-dependent enzyme, is reportedly involved in several cancer types. The MTHFR C677T polymorphism influences many biological processes, including tumorigenesis. However, the association between the MTHFR C677T polymorphism and breast cancer (BC) subtypes is not fully understood. In this study, the MTHFR C677T polymorphism was genotyped in 490 individuals with or without BC from southwestern China. Analysis of the association between the MTHFR C677T polymorphism and BC revealed that there was a significant association between the MTHFR C677T polymorphism and triple-negative breast cancer (TNBC) (OR = 2.83, 95% CI: 1.12–9.51, P = 0.0401). Furthermore, the MTHFR C677T polymorphism can also serve as a protective factor in luminal A breast cancer (OR = 0.57, 95% CI: 0.34–0.94, P = 0.0258). Evaluation of the association between the MTHFR C677T polymorphism and clinical characteristics indicated that people who suffered from hypertension had an increased risk for BC (OR = 2.27; 95% CI: 1.08–4.6; P = 0.0264), especially TNBC (OR = 215.38; 95% CI: 2.45–84430.3; P = 0.0317). Our results suggest that the MTHFR C677T polymorphism is significantly associated with susceptibility to luminal B breast cancer and TNBC.
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SCHWAHN, Bernd C., Maurice D. LARYEA, Zhoutao CHEN, Stepan MELNYK, Igor POGRIBNY, Timothy GARROW, S. Jill JAMES, and Rima ROZEN. "Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency." Biochemical Journal 382, no. 3 (September 7, 2004): 831–40. http://dx.doi.org/10.1042/bj20030822.
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MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr−/− mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr−/− mice from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr−/− mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr−/− pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.
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Lazic, Jelena, Nikola Kotur, Nada Krstovski, Lidija Dokmanovic, Branka Zukic, Jelica Predojevic-Samardzic, Maja Zivotic, et al. "Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia." Archives of Biological Sciences 69, no. 2 (2017): 239–46. http://dx.doi.org/10.2298/abs160325091l.
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Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C>T and MTHFR c.1298A>C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCRRFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C>T and MTHFR c.1298A>C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A>C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C>T and MTHFR c.1298A>C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C>T nor MTHFR c.1298A>C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.
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Clark, Daniel F., Rachael Schmelz, Nicole Rogers, Nuri E. Smith, and Kimberly R. Shorter. "Acute high folic acid treatment in SH-SY5Y cells with and without MTHFR function leads to gene expression changes in epigenetic modifying enzymes, changes in epigenetic marks, and changes in dendritic spine densities." PLOS ONE 16, no. 1 (January 7, 2021): e0245005. http://dx.doi.org/10.1371/journal.pone.0245005.
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Epigenetics are known to be involved in various disorders, including neurobiological disorders like autism. Dietary factors such as folic acid can affect epigenetic marks using methylenetetrahydrofolate reductase (MTHFR) to metabolize folic acid to a one-carbon methyl group. As MTHFR mutations are frequent, it is curious as to whether excess folic acid, with or without functioning MTHFR, could affect gene expression, epigenetics, and neuromorphology. Here, we investigated gene expression and activity of epigenetic modifying enzymes, genome-wide DNA methylation, histone 3 modifications, and dendritic spine densities in SH-SY5Y cells with or without a knockdown of MTHFR and with or without an excess of folic acid. We found alterations to gene expression of epigenetic modifying enzymes, including those associated with disorders like autism. Grouping the epigenetic modifying enzymes by function indicated that gene expression was widely affected for genes that code for enzymes affecting DNA methylation, histone acetylation, histone methylation, histone phosphorylation, and histone ubiquitination when excess folic acid treatment occurred with or without the knockdown of MTHFR. MTHFR was significantly reduced upon excess folic acid treatment whether MTHFR was knocked-down or not. Further, methyl-CpG binding protein 2 expression was significantly decreased with excess folic acid treatment with and without proper MTHFR expression. Global DNA methylation decreased due to the knockdown alone while global hydroxymethylated DNA increased due to the knockdown alone. TET2 expression significantly increased with the MTHFR knockdown alone. Excess folic acid alone induced a decrease in TET3 expression. Excess folic acid induced an increase in dendritic spines without the MTHFR knockdown, but folic acid induced a decrease in dendritic spines when MTHFR was knocked-down. The knockdown alone also increased the dendritic spines significantly. Histone 3 acetylation at lysine 18 was significantly increased when excess folic acid was applied to cells with the MTHFR knockdown, as was histone 3 phosphorylation at serine 10. Broadly, our results indicate that excess folic acid, even with functioning MTHFR, could have detrimental effects on cells.
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FÖDINGER, MANUELA, HEIDI BUCHMAYER, GOTFRIED HEINZ, MENELAOS PAPAGIANNOPOULOS, JOSEF KLETZMAYR, SUSANNE RASOUL-ROCKENSCHAUB, WALTER H. HÖRL, and GERE SUNDER-PLASSMANN. "Effect of MTHFR 1298A→C and MTHFR 677C→T Genotypes on Total Homocysteine, Folate, and Vitamin B12 Plasma Concentrations in Kdiney Graft Recipients." Journal of the American Society of Nephrology 11, no. 10 (October 2000): 1918–25. http://dx.doi.org/10.1681/asn.v11101918.
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Abstract. The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C on total homocysteine (tHcy), folate and vitamin B12 levels was investigated in 733 kidney graft recipients. The six major genotype combinations were used as grouping variables, and age, gender, BMI, serum creatinine, and creatinine clearance and ln-folate, ln-vitamin B12, or logarithmus naturalis tHcy (ln-tHcy) were used as covariates in three ANCOVA and multiple stepwise linear regression models. Hyperhomocysteinemia was present in 49.7% of the patients. The allele frequency of MTHFR 677T and 1298C was 0.319 and 0.326. MTHFR genotype and all other variables were significant predictors of ln-tHcy (higher tHcy plasma levels for MTHFR 677TT/1298AA versus all other five genotype groups: P < 0.05). BMI, creatinine clearance, ln-tHcy, and MTHFR genotype influenced ln-folate (lower folate levels for MTHFR 677TT/1298AA versus all other genotype groups: P < 0.05). Creatinine clearance and ln-tHcy were the only predictors of ln-vitamin B12 levels. In a prespecified subgroup analysis (n = 496), the MTHFR genotype also influenced tHcy levels and compound heterozygous patients had significantly lower folate levels as compared with MTHFR 677CC/1298AA and 677CC/1298CC. This study shows that the MTHFR 677TT/1298AA and 677CT/1298AC genotypes are significant predictors of tHcy and folate plasma levels.
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Zhang, Yong-lian, and Xiong-wei Xie. "Methylenetetrahydrofolate reductase C677T polymorphism and toxicity to 5-FU-based chemotherapy in colorectal cancer." Tropical Journal of Pharmaceutical Research 19, no. 1 (April 9, 2020): 209–13. http://dx.doi.org/10.4314/tjpr.v19i1.30.
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Purpose: To investigate the toxicity of methylenetetrahydrofolate reductase (MTHFR) polymorphism in colorectal cancer patients treated with 5-fluorouracil (5-FU).Methods: A total of 105 patients with colorectal cancer who underwent 5-FU therapy were included in this study. MTHFR C677T polymorphisms were determined using direct sequencing. Physical examination and the results of blood and urine tests were used to evaluate the toxicities, including gastrointestinal toxicity, hematopoietic toxicity, hair-skin toxicity and hand-foot syndrome.Results: In 90.5 % of all patients, 5-FU toxicity was observed. With regard to MTHFR C677T mutation, 45.7 % heterozygote mutants and 19.0 % homozygote mutants were observed. MTHFR C677T polymorphism was statistically related to 5-FU toxicity (p = 0.000). In addition, MTHFR C677T mutation was closely related to hematopoietic toxicity (p = 0.005).Conclusion: MTHFR C677T can be used for the prediction of 5-FU toxicity, and can also predict hematopoietic toxicity in patients with colorectal cancer.
Keywords: MTHFR genes, Polymorphism, Colorectal cancer, Biomarker, Toxicity
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Chan, Donovan, Duncan W. Cushnie, Oana R. Neaga, Andrea K. Lawrance, Rima Rozen, and Jacquetta M. Trasler. "Strain-Specific Defects in Testicular Development and Sperm Epigenetic Patterns in 5,10-Methylenetetrahydrofolate Reductase-Deficient Mice." Endocrinology 151, no. 7 (May 5, 2010): 3363–73. http://dx.doi.org/10.1210/en.2009-1340.
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Methylenetetrahydrofolate reductase (MTHFR) is a crucial folate pathway enzyme that contributes to the maintenance of cellular pools of S-adenosylmethionine, the universal methyl donor for several reactions including DNA methylation. Whereas Mthfr−/− BALB/c mice show growth retardation, developmental delay, and spermatogenic defects and infertility, C57BL/6 mice appear to have a less severe phenotype. In the present study, we investigated the effects of MTHFR deficiency on early germ cell development in both strains and assessed whether MTHFR deficiency results in DNA methylation abnormalities in sperm. The reproductive phenotype associated with MTHFR deficiency differed strikingly between the two strains, with BALB/c mice showing an early postnatal loss of germ cell number and proliferation that was not evident in the C57BL/6 mice. As a result, the BALB/c MTHFR-deficient mice were infertile, whereas the C57BL/6 mice had decreased sperm numbers and altered testicular histology but showed normal fertility. Imprinted genes and sequences that normally become methylated during spermatogenesis were unaffected by MTHFR deficiency in C57BL/6 mice. In contrast, a genome-wide restriction landmark genomic scanning approach revealed a number of sites of hypo- and hypermethylation in the sperm of this mouse strain. These results showing strain-specific defects in MTHFR-deficient mice may help to explain population differences in infertility among men with common MTHFR polymorphisms.
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Nguyễn, Thu Hằng, Thị Trang Nguyễn, Huy Thịnh Trần, Thị Huyền Vũ, Minh Tuấn Nguyễn, Thị Tình Phan, Hoàng Linh Dương, and Thị Minh Lê. "KHẢO SÁT MỘT SỐ ĐA HÌNH GEN (MTHFR, MTR, MTRR) Ở PHỤ NỮ CÓ TIỀN SỬ SẢY THAI." Tạp chí Sinh lý học Việt Nam 25, no. 4 (June 13, 2022): 23–29. http://dx.doi.org/10.54928/vjop.v25i4.35.
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Mục tiêu: Khảo sát các đa hình gen: MTHFR (C677T và A1298C), MTR (A2756G), MTRR (A66G) trên những phụ nữ có tiền sử sảy thai. Đối tượng nghiên cứu và phương pháp: nghiên cứu mô tả cắt ngang trên 100 mẫu máu của bệnh nhân có tiền sử sảy thai được làm xét nghiệm đa hình gen MTHFR C677T và A1298C, MTR (A2756G), MTRR (A66G) bằng kỹ thuật Realtime – PCR trong mẫu DNA tách chiết từ máu ngoại vi tại Trung tâm tư vấn Di truyền, Bệnh viện Đại học Y Hà Nội. Kết quả: Tỷ lệ kiểu gen dị hợp tử và đồng hợp tử mang alen đột biến gen MTHFR C677T, MTHFR A1298C, MTR A2756G và MTRR A66G lần lượt là 41%, 45%, 22% và 40%. Tổ hợp MTHFR (A1298C) và MTRR (A66G) biểu hiện tương tác bổ trợ với mức độ tương tác cao; tổ hợp giữa MTHFR (A1298C) và MTRR (A66G) với MTHFR (C677T) hoặc MTR (A2756G) thể hiện mức độ tương tác trung bình. Nguy cơ sẩy thai tái diễn tăng lên khi người phụ nữ mang phối hợp những kiểu gen đa hình này. Kết luận: Tổ hợp MTHFR (A1298C) và MTRR (A66G) biểu hiện tương tác bổ trợ với mức độ tương tác cao làm tăng nguy cơ sẩy thai tái diễn khi phụ nữ mang phối hợp kiểu đa hình này; tổ hợp giữa MTHFR (A1298C) và MTRR (A66G) với MTHFR (C677T) hoặc MTR (A2756G) thể hiện mức độ tương tác trung bình.
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He, Yan, Zhengbao Zhu, Daoxia Guo, Huan Zhang, Xiaowei Zheng, Nimei Zeng, Qiu Zhang, et al. "The U-shaped Relationship Between Serum Methylene Tetrahydrofolate Reductase and Large-artery Atherosclerotic Stroke." Current Neurovascular Research 16, no. 1 (May 13, 2019): 82–88. http://dx.doi.org/10.2174/1567202616666190207161818.
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Background: Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with ischemic stroke. However, the association between serum MTHFR level and ischemic stroke has not yet been studied. We aimed to examine the association between them in patients with large-artery atherosclerotic stroke and community-based healthy controls. Methods: This study includes three hundred ninety-five patients with large-artery atherosclerotic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and 395 age- and sex-matched healthy controls from Chinese communities. Serum MTHFR concentrations were examined and some conventional risk factors of stroke were collected. The association between serum MTHFR and large-artery atherosclerotic stroke was evaluated. Results: A U-shaped association of serum MTHFR level with large-artery atherosclerotic stroke was observed (p for nonlinearity =0.008). After multivariate adjustment, the odds ratios (95% confidence intervals) of large-artery atherosclerotic stroke associated with the first, second, fourth, and fifth quintiles of MTHFR were 5.62 (1.10-28.87), 2.13 (0.51-8.99), 1.08 (0.21-5.56), and 2.31 (0.57-9.34), respectively, compared with the third quintiles of MTHFR. Adding MTHFR quintiles to a model containing conventional risk factors improved the predictive power for large-artery atherosclerotic stroke (continuous net reclassification improvement=63.78%, p<0.001; categorical net reclassification improvement=2.54%, p=0.012). Conclusion: There is a significant U-shaped relationship between serum MTHFR levels and largeartery atherosclerotic stroke. Our findings raise the possibility that serum MTHFR may have a potential role in the pathogenesis of large-artery atherosclerotic stroke.
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Bagher, Amina M., Alexander P. Young, Thikryat Neamatallah, Reham M. Al-Amoudi, Sara M. Bagher, and Eileen M. Denovan-Wright. "Prevalence of methylenetetrahydrofolate reductase gene polymorphisms (C677T, and A1298C) among Saudi children receiving dental treatment." Annals of Saudi Medicine 41, no. 1 (January 2021): 1–7. http://dx.doi.org/10.5144/0256-4947.2021.1.
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BACKGROUND: Methylenetetrahydrofolate reductase, the encoded by the MTHFR gene, plays a crucial role in converting the amino acid homocysteine to methionine. Two polymorphisms of the MTHFR gene, C677T and A1298C, reportedly reduce enzyme activity, resulting in hyperhomocysteinemia. Patients with C677T and A1298C polymorphisms may be at higher risk for developing abnormal hyperhomocysteinemia, which has been linked to catastrophic neurological including fatal outcomes. OBJECTIVE: Determine the prevalence of the MTHFR gene variants C677T and A1298C among pediatric dental patients treated at King Abdulaziz University Hospital. DESIGN: Cross-sectional. SETTING: Clinics of pediatric dentistry department. SUBJECTS AND METHODS: Healthy Saudi children 6–12 years old with no known allergies were screened for eligibility between May and December 2019. A single investigator collected saliva samples. The MTHFR C677T and A1298C polymorphisms were analyzed using polymerase chain reaction and restriction fragment length polymorphism. MAIN OUTCOME MEASURE: The prevalence of MTHFR gene variants (C677T and A1298C) among the subjects. SAMPLE SIZE: 138. RESULTS: MTHFR C677T polymorphism was present in 36.2% of the sample and 90.0% of children carrying this allele were heterozygotes. MTHFR A1298C polymorphism was present in 91.3% of the sample and 77.0% of the children carrying this allele were heterozygotes. No linkage disequilibrium between MTHFR C677T and MTHFR A1298C was observed within this sample. CONCLUSIONS: Our study found a high frequency of the MTHFR A1298C genotype, which was substantially more abundant than expected based on a Hardy-Weinberg distribution. Therefore, caution is advised in using N 2 O in Saudi children as the increased prevalence of this MTHFR allele may increase the incidence of serious adverse effects among these children. LIMITATIONS: Further studies are recommended with a larger sample size from randomly selected hospitals from different regions of Saudi Arabia. CONFLICT OF INTEREST: None.
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Gupta, Akriti, Shubhangi Sharma, Saikrishna Lakkakula, and Lakkakula VKS Bhaskar. "Association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C polymorphisms and the risk of diabetic nephropathy; a meta-analysis." Journal of Renal Injury Prevention 8, no. 3 (June 18, 2019): 175–84. http://dx.doi.org/10.15171/jrip.2019.33.
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Methylenetetrahydrofolate reductase (MTHFR) is involved in the homocysteine metabolism. Two common variants of MTHFR gene (677C>T and 1298A>C), have been reported to reduce the MTHFR enzyme activity and leading to plasma hyperhomocysteinemia. There are a number of recent case-control studies that investigated the association between the MTHFR polymorphism and diabetic nephropathy (DN), albeit with inconsistent results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of MTHFR with susceptibility to DN. A literature search was conducted on PubMed, Embase and Google scholar from inception till March 18, 2019. For MTHFR 677C>T analysis, a total of 23 studies including DM controls (3095 cases and 3187 DM controls) and 12 studies including non-DM controls (1590 cases and 2052 nonDM controls) were taken. For MTHFR 1298A>C analysis, a total of 7 studies using DM controls (959 cases and 1209 DM controls) and 3 studies using non-DM controls (400 cases and 802 nonDM controls) were taken. Meta-analysis showed that mutant genotypes of the 677C>T (OR: 1.58; 95%CI: 1.16-2.14) and 1298A>C (OR: 1.38; 95%CI: 1.16-1.65) polymorphisms in the MTHFR gene were associated with increased risk of DN (diabetic kidney disease). MTHFR 677C>T and 1298A>C polymorphisms revealed significant heterogeneity between studies. Further, there was no evidence for publication bias for these polymorphisms. In conclusion, this meta-analysis provides strong evidence that MTHFR 677C>T and 1298A>C polymorphisms may be associated with increased risks of DN. However, further studies are still needed to accurately determine whether MTHFR genetic polymorphisms are associated with susceptibility to DN.
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Jadavji, Nafisa M., Lauren K. Murray, Joshua T. Emmerson, Chris A. Rudyk, Shawn Hayley, and Patrice D. Smith. "Paraquat Exposure Increases Oxidative Stress Within the Dorsal Striatum of Male Mice With a Genetic Deficiency in One-carbon Metabolism." Toxicological Sciences 169, no. 1 (February 6, 2019): 25–33. http://dx.doi.org/10.1093/toxsci/kfz034.
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Abstract Paraquat is an herbicide that is commonly used worldwide. Exposure to paraquat results in Parkinson’s disease (PD)-like symptoms including dopaminergic cell loss. Nutrition has also been linked in the pathogenesis of PD, such as reduced levels of folic acid, a B-vitamin, and component of one-carbon metabolism. Within one-carbon metabolism, methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. A polymorphism in MTHFR (677 C&→T) has been reported in 5%–15% of North American and European human populations. The MTHFR polymorphism is also prevalent in PD patients. The goal of this study was to investigate the impact of paraquat-induced PD-like pathology in the context of reduced levels of MTHFR. Three-month-old male Mthfr+/− mice, which model the MTHFR polymorphism observed in humans, were administered intraperitoneal injections of paraquat (10 mg/kg) or saline 6 times over 3 weeks. At the end of paraquat treatment, motor and memory function were assessed followed by collection of brain tissue for biochemical analysis. Mthfr+/– mice treated with paraquat showed impaired motor function. There was increased microglial activation within the substantia nigra (SN) of Mthfr+/− mice treated with paraquat. Additionally, all Mthfr+/− mice that were treated with paraquat showed increased oxidative stress within the dorsal striatum, but not the SN. The present results show that paraquat exposure increases PD-like pathology in mice deficient in one-carbon metabolism.
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Shen, Yaqing, Zhujun Wang, Fen Zhou, and Runming Jin. "The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia." Open Life Sciences 16, no. 1 (January 1, 2021): 1203–12. http://dx.doi.org/10.1515/biol-2021-0121.
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Abstract MTHFR is a crucial enzyme in folate metabolism. This study aimed to determine the relationship between MTHFR genetic polymorphism and elimination and toxicities of methotrexate (MTX). To do that, the study enrolled 145 patients diagnosed with acute lymphoblastic leukemia, who received chemotherapy following the Chinese Children’s Cancer Group Acute Lymphoblastic Leukemia (CCCG-ALL)-2015 protocol (clinical trial number: ChiCTR-IPR-14005706). We analyzed the effects of MTHFR C677T and A1298C polymorphisms on MTX elimination and toxicities. Patients with the MTHFR C677T TT genotype could tolerate a significantly higher MTX dose than those with the CC/CT genotype. However, patients with C677T TT genotypes had an increased risk of hypokalemia (1.369 to CC and 1.409 to CT types). The MTX infusion rate in patients with the MTHFR A1298C AC genotype was slightly lower than that in those with CC or AA genotypes. Patients with the A1298C AA genotype had a 1.405-fold higher risk of hepatotoxicity than those with the AC genotype (P > 0.05). There was no significant difference between the prevalence of other toxicities among MTHFR C677T or A1298C genotypes (P > 0.05). Neither MTHFR C677T nor A1298C polymorphisms were significantly associated with delayed MTX clearance. To conclude, MTHFR polymorphisms were not good predictors of MTX-related toxicities.
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Coppedè, Stoccoro, Tannorella, Gallo, Nicolì, and Migliore. "Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels." International Journal of Molecular Sciences 20, no. 15 (July 31, 2019): 3754. http://dx.doi.org/10.3390/ijms20153754.
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Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation.
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Bisht, Shilpa, Bhavna Chawla, and Rima Dada. "Oxidative Stress and Polymorphism in MTHFR SNPs (677 and 1298) in Paternal Sperm DNA is Associated with an Increased Risk of Retinoblastoma in Their Children: A Case–Control Study." Journal of Pediatric Genetics 07, no. 03 (July 11, 2018): 103–13. http://dx.doi.org/10.1055/s-0038-1667037.
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AbstractSperm DNA is considered as the most vulnerable to oxidative stress-induced damage that also impairs global sperm DNA methylation leading to sperm-associated pathologies. C677T and A1298C polymorphisms of the methylene tetrahydrofolate reductase (MTHFR) gene affect MTHFR enzyme activity. This study was planned as a case–control study to determine the MTHFR gene polymorphisms in the fathers of children affected with sporadic nonfamilial heritable retinoblastoma in an Indian population. MTHFR polymorphisms for single nucleotide polymorphisms 677 and 1298 were also determined in sporadic nonfamilial heritable retinoblastoma patients to estimate the risk for retinoblastoma development and to evaluate the role of MTHFR in retinoblastoma pathogenesis.
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Wu, Ming-Tsung, Wei-Ting Ye, Yi-Cheng Wang, Po-Ming Chen, Jun-You Liu, Chien-Kuo Tai, Feng-Yao Tang, Jian-Rong Li, Chun-Chi Liu, and En-Pei Isabel Chiang. "MTHFR Knockdown Assists Cell Defense against Folate Depletion Induced Chromosome Segregation and Uracil Misincorporation in DNA." International Journal of Molecular Sciences 22, no. 17 (August 30, 2021): 9392. http://dx.doi.org/10.3390/ijms22179392.
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Folate depletion causes chromosomal instability by increasing DNA strand breakage, uracil misincorporation, and defective repair. Folate mediated one-carbon metabolism has been suggested to play a key role in the carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. Methylenetetrahydrofolate reductase (MTHFR) is the enzyme catalyzing the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate that can control folate cofactor distributions and modulate the partitioning of intracellular one-carbon moieties. The association between MTHFR polymorphisms and HCC risk is inconsistent and remains controversial in populational studies. We aimed to establish an in vitro cell model of liver origin to elucidate the interactions between MTHFR function, folate status, and chromosome stability. In the present study, we (1) examined MTHFR expression in HCC patients; (2) established cell models of liver origin with stabilized inhibition of MTHFR using small hairpin RNA delivered by a lentiviral vector, and (3) investigated the impacts of reduced MTHFR and folate status on cell cycle, methyl group homeostasis, nucleotide biosynthesis, and DNA stability, all of which are pathways involved in DNA integrity and repair and are critical in human tumorigenesis. By analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that HCC cancer patients with higher MTHFR had a worse survival rate. The shRNA of MTHFR (shMTHFR) resulted in decreased MTHFR gene expression, MTHFR protein, and enzymatic activity in human hepatoma cell HepG2. shMTHFR tended to decrease intracellular S-adenosylmethionine (SAM) contents but folate depletion similarly decreased SAM in wildtype (WT), negative control (Neg), and shMTHFR cells, indicating that in cells of liver origin, shMTHFR does not exacerbate the methyl group supply in folate depletion. shMTHFR caused cell accumulations in the G2/M, and cell population in the G2/M was inversely correlated with MTHFR gene level (r = −0.81, p < 0.0001), MTHFR protein expression (r = −0.8; p = 0.01), and MTHFR enzyme activity (r = −0.842; p = 0.005). Folate depletion resulted in G2/M cell cycle arrest in WT and Neg but not in shMTHFR cells, indicating that shMTHFR does not exacerbate folate depletion-induced G2/M cell cycle arrest. In addition, shMTHFR promoted the expression and translocation of nuclei thymidine synthetic enzyme complex SHMT1/DHFR/TYMS and assisted folate-dependent de novo nucleotide biosynthesis under folate restriction. Finally, shMTHFR promoted nuclear MLH1/p53 expression under folate deficiency and further reduced micronuclei formation and DNA uracil misincorporation under folate deficiency. In conclusion, shMTHFR in HepG2 induces cell cycle arrest in G2/M that may promote nucleotide supply and assist cell defense against folate depletion-induced chromosome segregation and uracil misincorporation in the DNA. This study provided insight into the significant impact of MTHFR function on chromosome stability of hepatic tissues. Data from the present study may shed light on the potential regulatory mechanism by which MTHFR modulates the risk for hepatic malignancies.
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Goekkurt, Eray, Jan Stoehlmacher, Christian Stueber, Christine Wolschke, Tatjana Zabelina, Thomas Eiermann, Thomas Binder, Simona Iacobelli, Axel R. Zander, and Nicolaus Kröger. "MTHFR-A1298C Polymorphism Is Associated with Veno-Occlusive Disease (VOD) and Liver Toxicity after Busulfan/Cyclophosphamide Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)." Blood 106, no. 11 (November 16, 2005): 2730. http://dx.doi.org/10.1182/blood.v106.11.2730.2730.
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Abstract Purpose: The aim of our study was to evaluate the impact of genomic polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR) and glutathione S-transferases (GST) on liver toxicities seen in patients receiving busulfan and cyclophoshamide conditioning followed by allogeneic HSCT. Background: Polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR) have been shown to potentially influence toxicity (e.g. mucositis) in HSCT. Additionally, many chemotherapeutics that have been linked to veno-occlusive disease (VOD) and liver toxicity (e.g. Busulfan) are metabolised by glutathione S-transferases (GST). Little is known about the impact of gene polymorphisms of MTHFR and various GSTs on VOD and liver toxicity in allogeneic HSCT. Methods: 84 adult patients were enrolled in this retrospective study. The majority of the patients had chronic myelogenous leukemia (CML) in 1st chronic phase (94%). 2 patients suffered from acute myelogenous leukemia (AML-M4), 2 from myelodysplastic syndrome (MDS) and 1 patients from Farber’s disease. DNA was isolated from leucocytes of stem cell recipients collected prior to HSCT. Common gene polymorphisms of glutathione S-transferases (GSTP1-Ile105Val, GSTA1*A/B, GSTM1, GSTT1) and methylene-tetrahydofolate-reductase (MTHFR-C677T, MTHFR-A1298C) were detected by PCR-RFLP. All patients were treated with busulfan/cyclophosphamide as conditioning regimen and received cyclosporine and short-course MTX for GvHD prophylaxis. 67 patients (80%) received additionally anti-thymocyte globulin (ATG). Assessment of liver toxicities was based on appearance of VOD according to the Baltimore criteria, maximum bilirubin levels within 20 days after HSCT and duration of hyperbilirubinaemia > 2 mg/dl. Results: Analyses revealed statistical significant association between the MTHFR-A1298C polymorphism and liver toxicities. There was significant higher incidence of VOD in patients that are homozygous for the C allele (p = 0,04). Independently of VOD, patients carrying the MTHFR-1298CC genotype demonstrated higher median maximum levels of bilirubin with 6.8 mg/dl than MTHFR-1298AC and MTHFR-1298AA patients (3,0 mg/dl and 3,4 mg/dl) (p = 0,004). Furthermore, elevation of bilirubin levels > 2 mg/dl lasted longer in MTHFR-1298CC patients with a median of 14 days compared to 3 and 6 days in patients harbouring the MTHFR-1298AC and MTHFR-1298AA genotype (p = 0,004). Interestingly, the common MTHFR-C677T polymorphism did not reach statistical significance in accordance to liver toxicity in our study population. No significant associations between GSTP1-Ile105Val, GSTA1*A/B, GSTM1 and GSTT1 polymorphisms and liver toxicity were found in this study. Conclusion: Our data suggest that the MTHFR-A1298C polymorphism is associated with VOD and hyperbilirubinaemia in patients treated with busulfan/cyclophosphamide as conditioning regimen followed by allogeneic HSCT. To the best of our knowledge this the first report linking the MTHFR-A1298C polymorphism to liver toxicity in patients receiving allogeneic HSCT.
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Pannia, Emanuela, Rebecca Simonian, Rola Hammoud, Xiucheng Cui, Ruslan Kubant, Brandi Wasek, Terry Bottiglieri, James Dowling, Ramil Noche, and G. Harvey Anderson. "Development of a Zebrafish Model for Studies of the Interaction of Methylenetetrahydrofolate Reductase Deficiency and Dietary Folates on Metabolic Regulation." Current Developments in Nutrition 5, Supplement_2 (June 2021): 947. http://dx.doi.org/10.1093/cdn/nzab050_014.
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Abstract Objectives Methylenetetrahydrofolate reductase (MTHFR) is required for 5-methyltetrahydrofolate (5MTHF) synthesis, and common variants reduces its efficiency and associate with metabolic disorders. High folic acid (FA) intakes, commonly consumed by pregnant women in North America, may further inhibit MTHFR enzyme; programming long-term metabolic dysregulation in offspring. The zebrafish (Danio rerio) is a valuable model for study of embryonic development and high-throughput nutrient × gene interactions. The objective of this study was to characterize a zebrafish model of mthfr deficiency and assess the interaction between mthfr and FA intakes on early-life metabolic dysregulation. Methods Zebrafish were co-injected with a set of 4 guide RNAs (gRNAs) or cas9 protein alone and F0 embryos were assayed for a high-throughput phenotypic screen. Germline F1 knock-out homozygous mutants (mthfr −/−) were made by co-injecting cas9 mRNA with 2 gRNAs targeting the transcriptional start site of the mthfr gene. Embryos were raised up to 5 days post-fertilization (dpf) and folate and 1-carbon metabolites measured by LC-MS/MS. Lipid accumulation was assessed at 5dpf and after feeding a high cholesterol diet (HDC) with cholesteryl-ester (CE)-BoDipy-C12® from 5–15dpf. A subset of embryos were exposed to no (0µM) or high (100µM) FA from 0–5dpf and whole-body lipids measured. Results mthfr disruption in zebrafish reduced (80%) mthfr mRNA and 5MTHF levels (90%) compared to controls (P < 0.0001). They had lower 1-carbon metabolites including betaine, methionine, s-adenosylmethionine, and higher choline, s-adenosylhomocysteine, cystathionine and homocysteine (P < 0.01). As well, neutral lipid accumulation was higher in liver, heart and vasculature at 5 and 15 dpf along with higher CE altered cholesterol transport/metabolism. High FA exposure ameliorated lipid accumulation in mthfr mutants at 5 dpf (P = 0.06), but increased lipids accumulation in controls compared to no exposure (P = 0.03). Conclusions The zebrafish mthfr deficient model exhibits a similar alteration to 1-carbon metabolites as in humans with severe MTHFR deficiency. This zebrafish model has potential for understanding the interaction of mthfr deficiency and dietary folates on metabolism. Funding Sources CIHR-INMD, EP by NSERC-CGS
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Mosnier, Hannah, Erin Kelly, Kamaya Lawrence, Sarah Cruickshank, Sarah Stacey, Adelina McCall, Sunny Dhatt, Erland Arning, Teodoro Bottiglieri, and Nafisa Jadavji. "The Role of One-Carbon Metabolism After Ischemic Stroke in an Aged Mouse Model." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1226. http://dx.doi.org/10.1093/cdn/nzaa057_042.
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Abstract Objectives Nutrition is a modifiable risk factor for stroke, which is one of the leading causes of death and disability world-wide. In humans deficiencies in one-carbon metabolism, including the methyltetrahydrofolate reductase (MTHFR) polymorphism, have been linked to increased risk of stroke. The Mthfr+/− mice mouse model mimics the phenotype of the MTHFR677C – >T polymorphism. In our work using in vitro and in vivo models of ischemic stroke we have observed decreased recovery after stroke through reduced neuronal and astrocyte viability and increased apoptosis in MTHFR-deficient mice. In addition, we have previously shown dietary supplementation of one-carbon metabolites increases neuroplasticity and reduced oxidative stress after ischemic stroke. Using the MTHFR-deficient mouse model, the aim of this study was to investigate the impact of dietary supplementation with one-carbon metabolites on stroke outcome. Methods Male Mthfr+/− and wildtype littermate control mice were aged to 1.5-year-old and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr+/− and wildtype littermate mice were fed a supplemented diet (SD) containing 5-methylTHF, vitamin B12, and choline. Four weeks after PT damage and SD motor function was assessed and brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes. Results Mthfr +/− mice fed a SD after PT did not have an impaired neuroscore compared to CD Mthfr+/− mice. When compared to CD, SD Mthfr+/− mice were able to stay on the accelerating rotarod longer and travelled further, they also used their impaired forepaw more. Total homocysteine levels in plasma and lesion volume were reduced in SD Mthfr+/+ and Mthfr+/− mice. In the brain, within the damage site, there were reduced levels of apoptotic cell death and an increased neuroprotective cellular response in SD treated Mthfr+/− mice. Conclusions This study reveals a critical role for one-carbon supplementation in supporting improvement of function after ischemic stroke. Our data suggests that in stroke affected patients, nutritional supplementation maybe an important component to post-operative care, in addition to pharmacological and rehabilitation therapies. Funding Sources NSERC.
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Trachtman, Joseph N., and Vincent Pagano. "Antifolates and MTHFR." Therapeutic Drug Monitoring 37, no. 6 (December 2015): 697–98. http://dx.doi.org/10.1097/ftd.0000000000000215.
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Bertsch, Johannes, Christian Öppinger, Verena Hess, Julian D. Langer, and Volker Müller. "Heterotrimeric NADH-Oxidizing Methylenetetrahydrofolate Reductase from the Acetogenic Bacterium Acetobacterium woodii." Journal of Bacteriology 197, no. 9 (March 2, 2015): 1681–89. http://dx.doi.org/10.1128/jb.00048-15.
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ABSTRACTThe methylenetetrahydrofolate reductase (MTHFR) of acetogenic bacteria catalyzes the reduction of methylene-THF, which is highly exergonic with NADH as the reductant. Therefore, the enzyme was suggested to be involved in energy conservation by reducing ferredoxin via electron bifurcation, followed by Na+translocation by the Rnf complex. The enzyme was purified fromAcetobacterium woodiiand shown to have an unprecedented subunit composition containing the three subunits RnfC2, MetF, and MetV. The stable complex contained 2 flavin mononucleotides (FMN), 23.5 ± 1.2 Fe and 24.5 ± 1.5 S, which fits well to the predicted six [4Fe4S] clusters in MetV and RnfC2. The enzyme catalyzed NADH:methylviologen and NADH:ferricyanide oxidoreductase activity but also methylene-tetrahydrofolate (THF) reduction with NADH as the reductant. The NADH:methylene-THF reductase activity was high (248 U/mg) and not stimulated by ferredoxin. Furthermore, reduction of ferredoxin, alone or in the presence of methylene-THF and NADH, was never observed. MetF or MetVF was not able to catalyze the methylene-THF-dependent oxidation of NADH, but MetVF could reduce methylene-THF using methyl viologen as the electron donor. The purified MTHFR complex did not catalyze the reverse reaction, the endergonic oxidation of methyl-THF with NAD+as the acceptor, and this reaction could not be driven by reduced ferredoxin. However, addition of protein fractions made the oxidation of methyl-THF to methylene-THF coupled to NAD+reduction possible. Our data demonstrate that the MTHFR ofA. woodiicatalyzes methylene-THF reduction according to the following reaction: NADH + methylene-THF → methyl-THF + NAD+. The differences in the subunit compositions of MTHFRs of bacteria are discussed in the light of their different functions.IMPORTANCEEnergy conservation in the acetogenic bacteriumAcetobacterium woodiiinvolves ferredoxin reduction followed by a chemiosmotic mechanism involving Na+-translocating ferredoxin oxidation and a Na+-dependent F1FoATP synthase. All redox enzymes of the pathway have been characterized except the methylenetetrahydrofolate reductase (MTHFR). Here we report the purification of the MTHFR ofA. woodii, which has an unprecedented heterotrimeric structure. The enzyme reduces methylene-THF with NADH. Ferredoxin did not stimulate the reaction; neither was it oxidized or reduced with NADH. Since the last enzyme with a potential role in energy metabolism ofA. woodiihas now been characterized, we can propose a quantitative bioenergetic scheme for acetogenesis from H2plus CO2in the model acetogenA. woodii.
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Bulloch, Rhodi E., Clare R. Wall, Lesley M. E. McCowan, Rennae S. Taylor, Claire T. Roberts, and John M. D. Thompson. "The Effect of Interactions between Folic Acid Supplementation and One Carbon Metabolism Gene Variants on Small-for-Gestational-Age Births in the Screening for Pregnancy Endpoints (SCOPE) Cohort Study." Nutrients 12, no. 6 (June 4, 2020): 1677. http://dx.doi.org/10.3390/nu12061677.
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Small-for-gestational-age (SGA) is associated with significant perinatal morbidity and mortality. Our aim was to investigate gene-nutrient interactions between maternal one-carbon single nucleotide polymorphisms (SNPs) and folic acid supplement (FAS) use, and their association with SGA. Nulliparous New Zealand women with singleton pregnancy were recruited as part of the Screening for Pregnancy Endpoints prospective cohort study. Data on FAS use was collected via face-to-face interview at 15 weeks’ gestation; participants were followed prospectively and birth outcome data collected within 72 h of delivery. Participants were genotyped for MTHFR 677, MTHFR 1298, MTHFD1 1958, MTR 2756, MTRR 66 and TCN2 776 SNPs. Genotype data for at least one SNP was available for 1873 (93%) of eligible participants. Analysis showed a significant SNP-FAS interaction for MTHFR 1298 (p = 0.020), MTHFR 677 (p = 0.019) and TCN2 776 (p = 0.017) in relation to SGA: MTHFR 1298 CC variant non-FAS users had an increased likelihood [Odds Ratio (OR) = 2.91 (95% Confidence Interval (CI) = 1.52, 5.60] compared with wild-type (MTHFR 1298 AA) FAS users. MTHFR 677 variant allele carrier (MTHFR 677 CT + MTHFR 677 TT) non-FAS users had an increased likelihood [OR = 1.87 (95% CI = 1.21, 2.88)] compared to wild-type (MTHFR 677 CC) FAS users. TCN2 776 variant (TCN2 776 GG) non-FAS users had an increased likelihood [OR = 2.16 (95% CI = 1.26, 3.71)] compared with wild type homozygote + heterozygote (TCN2 776 CC + TCN2 776 CG) FAS users. No significant interactions were observed for MTHFD1 1958, MTR 2756 or MTRR 66 (p > 0.05). We observed an overall pattern of FAS attenuating differences in the likelihood of SGA seen between genotype groups in FAS non-users. Future research should focus on how intake of other one-carbon nutrients might mediate these gene-nutrient interactions.
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Gadiyaram, V. K., M. A. Khan, T. Hogan, R. Altaha, E. Crowell, G. Hobbs, and P. Perrota. "Significance of MTHFR gene mutation with normal homocysteine level in vascular events." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e20520-e20520. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e20520.
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e20520 Background: Hyperhomocysteinemia, due to a combination of genetic and environmental factors, is considered to be a risk factor for vascular disease. Two common variations of the MTHFR gene (C677T and A1298C) result in amino acid substitutions and enhanced thermolability of the enzyme. Individuals with MTHFR gene mutations appear to have raised plasma level of homocysteine which may lead to increased risk of vascular events. However, significance of MTHFR gene mutations with normal homocysteine levels is unknown. Objective: To assess the relation of MTHFR gene mutations with normal homocysteine level and risk of Vascular events (deep venous thrombosis (DVT), pulmonary embolism (PE), Ischemic Heart disease (IHD), cerebrovascular accidents (CVA),recurrent fetal loss). Methods: We reviewed the records of 90 patients referred to our benign hematology clinic for thrombophilia evaluation between 2006 and 2008. All available medical history for risk factors and laboratory test results, obtained from first vascular event through time of consultation, including genetic testing, were reviewed. Anti-cardiolipin antibody, MTHFR genotyping and Protein C and Protein S assays were performed at Warde Medical Laboratory, Ann Arbor, MI. Results: 61 patients with documented vascular events were tested for MTHFR gene mutations. Forty one of these patients also had homocysteine levels available. Thirty-eight of these 41 (92 %) patients had an MTHFR gene mutation with normal homocysteine levels. Eighteen (47%) of these 38 patients had only an MTHFR gene mutation with normal homocysteine level and no other congenital or acquired risk factors for vascular events identified. Conclusions: In our clinic population, many patients with documented vascular events had MTHFR gene polymorphisms with normal homocysteine levels with no other thrombophilia risk factors identified, raising the question of whether MTHFR gene polymorphisms alone, without hyperhomocysteinemia, may somehow contribute to thrombophilia. [Table: see text] No significant financial relationships to disclose.
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Nam, Hee, Yeo-Kyeoung Kim, Il-Kwon Lee, Deok-Hwan Yang, Kyeong-Soo Park, Je-Jung Lee, and Hyeoung-Joon Kim. "Methylenetetrahydrofolate Reductase and Methionine Synthase Polymorphism and Risk of Non-Hodgkin’s Lymphoma." Blood 106, no. 11 (November 16, 2005): 4691. http://dx.doi.org/10.1182/blood.v106.11.4691.4691.
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Abstract Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are key enzymes in folate metabolism, which is essential for DNA methylation and synthesis. It is known that polymorphisms in its genes have been associated with some forms of cancer including lymphoma. Previous studies have shown MTHFR 677TT was associated with decreased risk of non-Hodgkin’s lymphoma(NHL). However, recent two reports have shown MTHFR 677TT was associated with increased risk. To evaluate the association between the MTHFR C677T and MTR A2756G polymorphisms and risk of non-Hodgkin’s lymphoma, large-scale population-based case-control study was conducted in Chonnam University Hwasun Hospital between March 1997 and June 2005. Three hundreds sixty-five patients with histologically comfirmed lymphoma and 1,162 controls were evaluated. Genotyping was done using PCR-RFLP. The cases consisted of 203 diffuse large B-cell lymphomas(DLBCL), 77 T-cell lymphomas, 62 other B-cell lymphomas, and 23 unclassifiable lymphomas. The MTHFR 677CT and 677TT genotypes were inversely associated with NHL and DLBCL, respectively. Using subjects with the MTHFR 677CC as reference group, the odds ratio of MTHFR 677CT and 677TT were (0.70, 95% CI 0.54–0.90) and (0.46, 95% CI 0.32–0.68) for NHL. The association was more evident for DLBCL (OR 0.56, 95% CI 0.40–0.78 for 677CT; OR 0.40, 95% CI 0.24–0.65 for 677TT). Dose-response effect was evident for the MTHFR T-allele (p < 0.01). There was no significant association of MTR A2756G with NHL. These results suggest that the MTHFR polymorphism may play an important role in the pathogenesis of NHL, particularly DLBCL.
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Marques, Manuel, Francisco Alves, Miguel Leitão, Catarina Rodrigues, and Joana Tavares Ferreira. "Methylenetetrahydrofolate reductase polymorphisms as risk factors for retinal venous occlusive disease: A literature review." European Journal of Ophthalmology 31, no. 3 (March 9, 2021): 884–91. http://dx.doi.org/10.1177/11206721211000647.
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The role of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene in retinal vein occlusion (RVO) is a theme of discussion since the first reports of RVO in patients with MTHFR C677T mutation and without classic acquired risk factors for retinal vascular disease. The association between MTHFR polymorphisms and RVO has been studied over the last 20 years producing conflicting results. This review aims to summarize the literature concerning the role MTHFR polymorphisms as risk factors for RVO.
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Liu, Xinye, Lingxu Wang, Hao Chi, Jin Wang, Qian Zheng, Jingye Li, Yong Li, and Dongwei Yang. "The SNP Rs915014 in MTHFR Regulated by MiRNA Associates with Atherosclerosis." Cellular Physiology and Biochemistry 45, no. 3 (2018): 1149–55. http://dx.doi.org/10.1159/000487355.
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Background/Aims: The association between the genetic polymorphisms located in either the exon or untranslated region of MTHFR and the risk of human atherosclerosis has been well-documented. This study analyzed MTHFR polymorphisms at the 3’-untranslated region for association with risk and outcome of atherosclerosis in a Chinese Han population. Methods: The hospital based case-control study was conducted with 500 patients and 600 healthy volunteers as control enrolled. The genotyping was conducted by using Taqman probe. The potential interaction was predicted by multiple bioinformatics analysis. The relative expression of MTHFR was detected by qRT-PCR. Further confirmation was determined by dual-luciferase assay. The plasma homocysteine levels were assayed by ELISA. Results: Cigarette smoking, alcohol consumption, diabetes, hypertension and low levels of serum high-density lipoprotein-C were associated with an increased risk of developing ischemic stroke. MTHFR rs915014 AG and GG genotypes were significantly associated with increased risk of rs915014 compared with the GG genotype. The qRT-PCR confirmed that MTHFR rs915014 AG or GG genotypes could facilitate miR-2861 binding leading to decreased MTHFR levels in cells. In addition, patients carrying the MTHFR rs915014 AG or GG genotypes were associated with accumulation of circulating tHcy volume and a poor atherosclerosis consequence. Conclusions: This study demonstrates that the MTHFR rs915014 is associated with increased risk of atherosclerosis and might be a shot term outcome biomarker for atherosclerosis patients.
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Daugėlaitė, Klaudija, and Danielius Serapinas. "The importance of MTHFR gene mutation detection in patient with recurrent miscarriages." Genetika 47, no. 2 (2015): 609–16. http://dx.doi.org/10.2298/gensr1502609d.
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Homocysteine is an enzyme encoded by MTHFR (methylenetetrahydrofolate reductase) gene located on chromosome 1. Mutations in MTHFR gene may result in the afflicted metabolism of homocysteine and thus might increase the risk of recurrent miscarriages. In some cases, recurrent pregnancy loss could be prevented by prescribing folic acid and B group vitamin supplements. The demand of MTHFR gene sequencing for variations is commonly overlooked by doctors or genetic counsellors. To highlight this problem we present a case study of recurrent miscarriages in a patient with a homozygous c. 655C>T variation in MTHFR gene. Moreover, we discuss the need of molecular genetic testing for MTHFR gene variations in patients with recurrent miscarriages and the treatment of hyperhomocysteinemia.
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Liu, Nan, Xue Sheng Wang, Juan Cheng, Jing Wei Xiao, and Bin Li. "Association between Genetic Polymorphisms of 5,10-Methylenetetrahydrofolate Reductase and Cytokinesis-Block Micronucleus in Peripheral Blood Lymphocyte among 1,3-Butadiene Workers." Applied Mechanics and Materials 273 (January 2013): 478–82. http://dx.doi.org/10.4028/www.scientific.net/amm.273.478.
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Exploring the associations between genetic polymorphisms and susceptibility of chromosomal damage induced by 1,3-butadiene(BD) is of much importance for understanding BD carcinogenesis. In current study, we investigated the effects of MTHFR polymorphisms and MTHFR gene haplotype pairs on chromosome damage detected by the cytokinesis-block micronucleus (CBMN) assay in peripheral blood lymphocytes. The data showed that the frequencies of CBMN among BD-exposed workers were significantly associated with the MTHFR A1298C polymorphism (P=0.04 and P=0.03, respectively) by multivariate analysis of covariance. The foundings also showed that the haplotype pairs in the MTHFR gene were more likely than single SNPs to correlate with the BD-induced chromosome damage among occupational exposed workers. Gene-environment interactions between occupational BD exposure and polymorphisms of MTHFR were also evident. These results indicate that the MTHFR polymorphisms may play a role in sensitivity or genetic susceptibility in genotoxic effects of BD exposure in the occupational exposure population.
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Turkowski, Yana, Syed Razvi, and Abdul Razzaque Ahmed. "Pyoderma gangrenosum-like lesion secondary to methylenetetrahydrofolate reductase mutation: an unusual presentation of a rare disease." BMJ Case Reports 12, no. 4 (April 2019): e228403. http://dx.doi.org/10.1136/bcr-2018-228403.
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Pyoderma gangrenosum (PG)-like ulcerations are a rare clinical manifestation of methylenetetrahydrofolate reductase (MTHFR) mutation. We describe a patient considered to have PG who was treated with long-term high doses of systemic corticosteroids and multiple immunosuppressive agents for several years. In spite of this continuous aggressive therapy, the lesions did not improve but continued to get worse. She developed many significant and catastrophic side effects to them. When referred to our dermatology centre, on investigation, it was discovered that she has an MTHFR mutation. It seemed reasonable to presume that PG-like lesions were related to it. Treatment with a biologically active form of folate—[6S]-5-MTHF—with vitamins B6 and B12 was initiated. It was considered to be beneficial and capable of reducing hyperhomocysteinaemia and endothelial damage consequent from it. Since the institution of this treatment, the patient has begun to show very gradual but slow and incremental improvement.
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Jiang, Huafeng, and Yi Shen. "Methylene tetrahydrofolate reductase (MTHFR) gene rs1801133 C>T polymorphisms and response to 5-FU based chemotherapy in patients with colorectal cancer: a meta-analysis." Pteridines 30, no. 1 (January 1, 2019): 126–32. http://dx.doi.org/10.1515/pteridines-2019-0015.
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Abstract Background: Methylene tetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Single nucleotide polymorphisms (SNP) of MTHF rs1801133 C>T can influence susceptibility to colorectal cancer. However, an association between MTHFR rs1801133 C>T polymorphisms and response to 5-Fluorouracil (5-FU) based chemotherapy in patients with colorectal cancer was not clear. Methods: Studies relevant to MTHFR rs1801133 C>T polymorphisms and response to 5-FU based chemotherapy in patients with colorectal cancer were systematic searched in the electronic databases of PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI). The genotypes of CC, CT, and TT were extracted from each included publication. The genotypes CC, CT, and TT distribution in 5-FU based chemotherapy response and resistance groups were calculated and pooled through random or fixed effect model by the effect size of odds ratio (OR) and 95% confidence interval (95% CI). The publication bias was evaluated through Begg’s funnel plot and Egger’s line regression test. Results: After searching the electronic databases, 16 studies related to MTHFR gene rs1801133 C>T polymorphisms and a response to 5-FU based chemotherapy in patients with colorectal cancer were included in the present meta-analysis. The pooled data showed no statistical difference in tumor response rate between CT+TT and CC groups in the dominant genetic model CT+CC vs CC (OR=1.21, 95% CI: 0.93~1.59, p>0.05) and recessive model TT vs CT+CC (OR=1.37, 95% CI: 0.91~2.06, p>0.05). The grade 3-4 adverse reaction rate between CT+TT and CC groups also had no statistical difference in the dominant genetic model CT+CC vs CC (OR=0.90, 95% CI: 0.76~1.07, p>0.05) and recessive model TT vs CT+CC (OR=1.12, 95% CI: 0.84~1.50, p>0.05). The Begg’s funnel plot and Egger’s line regression test demonstrated no publication bias. Conclusion: The response and adverse reaction of 5-FU based chemotherapy in colorectal patients were not different in terms of MTHFR rs1801133 C>T polymorphisms.
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Mohamed Hefila, Nermeen. "Methylen tetrahydrofolate reductase enzyme gene C677T and A1298C mutations in primigravida with first trimester missed abortion: cross-sectional study." International Journal of Reproduction, Contraception, Obstetrics and Gynecology 10, no. 3 (February 24, 2021): 836. http://dx.doi.org/10.18203/2320-1770.ijrcog20210492.
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Background: This work aimed to correlate between MTHFR C677T and A1298C genes (methylenetetrahydrofolate reductase) mutation and first trimester missed abortion in primigravida to identify pregnant ladies who need anticoagulation therapy to improve pregnancy outcome. The conducted study was a cross-sectional study. Data were collected from females recruited from EL Shatby hospital, Alexandria, Egypt. The present study was done on 40 primigravida females recruited from EL Shatby hospital. Methods: All participating women were primigravida in their first trimester with missed abortion. Blood specimens were collected from all cases involved in the study for DNA extraction and genotype analysis based on PCR and reverse hybridization. The mutations studied are the MTHFR C667T and A1298C genes. Main outcome measures: The MTHFR C667T mutations in our study is not significantly related to abortion in primigravida while MTHFR A1298C mutations prevalence were appeared significantly have a relation to abortion.Results: In the current study, the prevalence of MTHFR A1298C mutations was in 52.5% of cases, with homozygosity in 15 % of cases and heterozygosity in 37.5% of cases. However, the total prevalence of the MTHFR C667T gene mutations was 30% of cases only and all are heterozygous. Four cases were prevalent with combined thrombophilia (MTHFR C677T and A1298C) in the participating cases. Finally, the number of individuals were assessed for each of the gene mutations based on of homozygous or heterozygous. No homozygous cases were detected for MTHFR C667T gene mutation.Conclusions: In this current study, there is an association between miscarriage and thrombophilia.
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Djurovic, Jelena, Oliver Stojkovic, Jelena Todorovic, Kristina Savic, and Gorana Stamenkovic. "Should MTHFR 1298 A>C be tested together with MTHFR 677 C>T polymorphism in women with reproductive challenges?" Genetika 49, no. 2 (2017): 377–86. http://dx.doi.org/10.2298/gensr1702377d.
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Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in the folate metabolism. The polymorphism 677C>T of the MTHFR gene, producing thermolabile enzyme with decreased function, is widely studied and associated with many conditions. Additionally, it has been shown that another polymorphism, 1298A>C, also reduces the activity of this enzyme, although to a lesser extent. The aim of this study is to evaluate the clinical informativeness of testing both MTHFR polymorphisms. Genomic DNA, were extracted from peripheral blood of 180 female patients with pregnancy complications and 183 healthy female controls, and genotyped for MTHFR 677C>T and 1298A>C loci, using TaqMan assays. Our study found similar frequency of alleles and genotypes between two groups. Based on MTHFR 677C>T genotype, 11.7% of patients homozygous for this mutation were under the possible risk. When the position 1298 was included in the testing, 22.8% of the patients were heterozygous for both polymorphisms. Additionally, 8.9% of the patients were homozygous only for the MTHFR 1298 mutation. Although,s there was no differences compared to healthy control (p>0.05), 43% of patients were found to have elevated risk which is about four time highers than results with only MTHFR 677C>T genotyping. After obtaining information for the 677 position, testing for the second polymorphism (1298A>C) should be considered, since we have shown that it dramatically increases the rate of detection of patients who are potentially at risk for MTHFR associated conditions.
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Shane, Barry, Faith Pangilinan, James L. Mills, Ruzong Fan, Tingting Gong, Cheryl D. Cropp, Yoonhee Kim, et al. "The 677C→T variant of MTHFR is the major genetic modifier of biomarkers of folate status in a young, healthy Irish population." American Journal of Clinical Nutrition 108, no. 6 (October 19, 2018): 1334–41. http://dx.doi.org/10.1093/ajcn/nqy209.
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ABSTRACT Background Genetic polymorphisms can explain some of the population- and individual-based variations in nutritional status biomarkers. Objective We sought to screen the entire human genome for common genetic polymorphisms that influence folate-status biomarkers in healthy individuals. Design We carried out candidate gene analyses and genome-wide association scans in 2232 young, healthy Irish subjects to evaluate which common genetic polymorphisms influence red blood cell folate, serum folate, and plasma total homocysteine. Results The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) variant was the major genetic modifier of all 3 folate-related biomarkers in this Irish population and reached genome-wide significance for red blood cell folate (P = 1.37 × 10−17), serum folate (P = 2.82 × 10−11), and plasma total homocysteine (P = 1.26 × 10−19) concentrations. A second polymorphism in the MTHFR gene (rs3753584, P = 1.09 × 10−11) was the only additional MTHFR variant to exhibit any significant independent effect on red blood cell folate. Other MTHFR variants, including the 1298A→C variant (rs1801131), appeared to reach genome-wide significance, but these variants shared linkage disequilibrium with MTHFR 677C→T and were not significant when analyzed in MTHFR 677CC homozygotes. No additional non-MTHFR modifiers of red blood cell or plasma folate were detected. Two additional genome-wide significant modifiers of plasma homocysteine were found in the region of the dipeptidase 1 (DPEP1) gene on chromosome 16 and the Twist neighbor B (TWISTNB) gene on chromosome 7. Conclusions The MTHFR 677C→T variant is the predominant genetic modifier of folate status biomarkers in this healthy Irish population. It is not necessary to determine MTHFR 677C→T genotype to evaluate folate status because its effect is reflected in concentrations of standard folate biomarkers. The MTHFR 1298A→C variant had no independent effect on folate status biomarkers. To our knowledge, this is the first genome-wide association study report on red blood cell folate and the first report of an association between homocysteine and TWISTNB.
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Hashemi, Seyed, Nourollah Ramroodi, Hamed Amiri Fard, Sahar Talebian, Maryam Haghighi Rohani, Mahnaz Rezaei, Mehrangiz Noora, and Saeedeh Salimi. "Common Variations in Prothrombotic Genes and Susceptibility to Ischemic Stroke in Young Patients: A Case-Control Study in Southeast Iran." Medicina 55, no. 2 (February 13, 2019): 47. http://dx.doi.org/10.3390/medicina55020047.
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Background and Objective: Evidence indicates that genetic factors may be involved in the risk of ischemic stroke (IS). The aim of this study was to assess the effect of genetic polymorphisms located in exons or untranslated regions of MTHFR as well as FV genes on ischemic stroke. Materials and Methods: In this case-control study, 106 patients with IS and 157 healthy volunteers (age <50 years) were genotyped for MTHFR C677T, A1298C, C2572A and C4869G, FVL, and prothrombin G20210A polymorphisms. Results: The MTHFR 677CT genotype was more frequent in patients and increased risk of IS with Odds Ratio = 1.9. The MTHFR A1298C and C2572A polymorphisms were not associated with IS in dominant and recessive models. Our findings showed a significant decrease in the MTHFR 4869CG genotype in IS patients, and this variant was associated with a decreased risk of IS in the dominant model. The CAAT haplotype was associated with increased risk, and the GAAC haplotype was associated with decreased risk of IS compared to other haplotypes. There was no relation between FVL G1691A polymorphism and IS risk. Conclusions: The present study showed that the MTHFR 677CT genotype was more frequent and the MTHFR 4869CG genotype was less frequent in young IS patients.
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Panja, Amrita, Abhishek Abhinay, and Antim Akash Pakhira. "Study on the polymorphism of methylenetetrahydrofolate reductase C677T gene as the genetic predisposition of congenital heart disease in North Indian population." Asian Journal of Medical Sciences 13, no. 2 (February 1, 2022): 86–94. http://dx.doi.org/10.3126/ajms.v13i2.40766.
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Background: The etiology of congenital heart disease (CHD) is still not known properly. The variant alleles in the methylenetetrahydrofolate reductase (MTHFR) C677T gene help in elevating the serum homocysteine level which is an independent predisposing factor for generating CHD. Aims and Objectives: The aim of the present study was to analyze the role of polymorphism of MTHFR C677T gene polymorphisms in CHD patients of Varanasi, Uttar Pradesh, North India. Materials and Methods: The present study included 36 unrelated CHD patients along with their parents. At the same time, 40 healthy control samples were included in the study. MTHFR 677 C>T genotype was identified by polymerase chain reaction followed by restriction digestion restriction fragment length polymorphism mechanism. Results: There was a significant difference observed in MTHFR C677T gene polymorphism between the cases and controls (P<0.001). Among the different etiological factors, increased maternal age, family history, and teratogens are the major ones. Maternal MTHFR C677T genotype and periconceptional folate intake have important ascription toward CHD formation. Conclusion: The results designate that MTHFR C677T polymorphism has a substantial association with the development and progression of CHDs. Folate supplementation might be the probable management strategy for reducing the risk of CHDs as maternal MTHFR C677T polymorphism has an important contribution.