Methylenetetrahydrofolate Reductase 677C Research Articles

Study of the relationships of polymorphisms of the folate cycle genes with the levels of homocysteine and folic acid as risk factors of cardiovascular disorders in the post-covid period

Enzymes of the folate cycle participate in the process of remethylation of homocysteine (HC) to methionine, where folates are coenzymes for methyl transfer. The aim of the work was to identify the interrelationships of gene polymorphisms of associations between folate cycle enzyme gene polymorphisms and cardiometabolic risk factors such as increased serum homocysteine levels and folic acid deficiency in patients in the post-covid period. In 51 patients who suffered from COVID-19, a general clinical and laboratory examination, and assessment of serum homocysteine and folic acid concentrations by immunoenzymatic method was carried out. Polymorphisms of the genes: methylenetetrahydrofolate reductase (677C>T and 1298A>C), methionine synthase-reductase (66A>G) and methionine synthase (2756A>G) were determined by real time polymerase chain reaction. For each of the named polymorphisms, the examined patients were divided into 3 groups according to the nucleotide alleles in the corresponding position: 1) homozygous dominant, 2) heterozygous and 3) homozygous recessive. For the methylenetetrahydro­folatereductase gene at position 677, serum levels of homocysteine and folate did not differ between the groups 1 and 2 with genotypes 677 C/C (n=26) and 677C/T (n=21), (p>0.05); in group 3, the recessive genotype 677 T/T was found in only 4 people (8%), that did not allow comparison of indices. The distribution of patients into 3 groups according to the genotype of the same gene at position 1298 revealed that the recessive 1298 C/C mutation in group 3 (n=9) associated with an increased homocysteine level (19.56±1.89 μmol/l), versus 10.68±0.76 (p=0.012) and 11.63±1.25 μmol/l (p=0.013) in groups 1 and 2, with no difference in folate levels between groups. Group 3 differed by a higher degree of obesity, a higher frequency of hypertension disease and chronic heart failure (in 85% of patients in group 3, against 41 and 50% in groups 1 and 2), a higher number of platelets, a longer duration of hospitalization due to COVID-19, a higher level of D-dimer. The study of groups of patients, divided depending on the genotype of methioninesynthase reductase at position 66, showed that carriers of the recessive homozygous 66 G/G mutation (group 3, n=15) had increased serum homocysteine level (16.56±1.64 μmol/l) in comparison with individuals of group 1 (n=17) 66 A/A (10.28±1.17 μmol/l; p=0.004) and group 2 (n=19) 66 A/G (11.32±1.17 μmol/l, p=0.013). In group 3, a longer duration of hospitalization due to COVID-19 was noted (17.15±1.65 vs. 11.88±0.97 days, p=0.008), higher frequency of hypertension (67% vs. 35%) and heart failure (67% against 29%) compared to group 1. The use of a molecular genetic approach made it possible to establish that the presence of recessive mutations of the folate cycle genes is associated with a potential predisposition to hyperhomocysteinemia, thrombophilia, severe forms of cardiometabolic complications and coronavirus disease.

Combined Exposure to Folate and Lead during Pregnancy and Autistic-Like Behaviors among Canadian Children from the MIREC Pregnancy and Birth Cohort.

Folic acid (FA) supplementation may attenuate the associations between gestational exposure to certain chemicals and autism or autistic-like behaviors, but to our knowledge, this has not been assessed for lead. We examined whether the relationship between gestational blood-lead levels (BLLs) and autistic-like behaviors was modified by gestational plasma total folate concentrations, FA supplementation, and maternal methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype. We used data from the Maternal-Infant Research on Environmental Chemicals study (2008-2011), a Canadian pregnancy and birth cohort study. Childhood autistic-like behaviors were documented in 601 children 3-4 y of age with the Social Responsiveness Scale-2 (SRS-2), where higher scores denote more autistic-like behaviors. We measured BLLs and plasma total folate concentrations during the first and third trimesters of pregnancy. We also estimated gestational FA supplementation via surveys and genotyped the maternal MTHFR 677C>T single nucleotide polymorphism (SNP). We estimated the confounder-adjusted associations between -transformed BLLs and SRS-2 scores by two indicators of folate exposure and maternal MTHFR 677C>T genotype using linear regression. Third-trimester BLLs were associated with increased SRS-2 scores [; 95% confidence interval (CI): 1.1, 5.5] among participants with low ( percentile), third-trimester, plasma total folate concentrations, but BLL-SRS-2 associations were null (; 95% CI: , 0.5) among those in the middle category ( and percentiles) (p-interaction ). FA supplementation also attenuated these associations. Both folate indicators modified first-trimester BLL-SRS-2 associations, but to a lesser extent. Third-trimester BLL-SRS-2 associations were slightly stronger among participants who were homozygous for the T (minor) allele of the MTHFR 677C>T SNP (; 95% CI: , 3.1) than those without the T allele (; 95% CI: , 0.7), but the difference was not statistically significant (). Folate may modify the associations between gestational lead exposure and childhood autistic-like behaviors, suggesting that it mitigates the neurotoxic effects of prenatal lead exposure. https://doi.org/10.1289/EHP14479.

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms and five related serum molecular levels in 2587 patients: Associated differentially with adverse pregnancy.

The aim of the study is to investigate the relationship between Methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) polymorphisms, 5 serum related molecular levels and the risk of adverse pregnancies in different genders. Patients aged from 22 to 38 with a history of adverse pregnancy treated in our genetic eugenics clinic of Henan Provincial People's Hospital are selected. The controls aged from 20 to 34 undergoing eugenics examinations in our genetic eugenics clinic that had no history of adverse pregnancy and at least one healthy child are selected. Sanger sequencing and Chemiluminescence Microparticle Immuno Assay (CMIA) are used for detecting the mutations of MTHFR and MTRR and the 5 serum molecular serum levels. In the female group, MTHFR 677C > T is associated with Recurrent spontaneous abortion (RSA) (P = 0.0017), Chromosomal abnormality (CA) (P = 0.0053), Cleft lip and palate (CLP) (P = 0.0326) and Brain dysplasia (BD) (P = 0.0072); MTHFR 1298A > C is associated with Infertility (P = 0.0026) and BD (P = 0.0382); MTRR 66A > G is associated with CLP (P = 0.0131). In the male group, MTHFR 677C > T is associated with RSA (P = 0.0003), Infertility (P = 0.0013), CA (P = 0.0027) and BD (P = 0.0293). In the female group, the genotype of MTHFR 677C > T is associated with RSA (P = 0.0017), CA (P = 0.0014) and BD (P = 0.0021); MTHFR 1298A > C is associated with Infertility (P = 0.0081) and MTRR 66A > G is associated with Infertility (P = 0.0309). In the male group, the genotype of MTHFR 677C > T is associated with RSA (P = 0.0008), Infertility (P = 0.0096) and CA (P = 0.0165) and MTRR 66A > G is associated with Infertility (P = 0.0158) and congenital heart disease (CHD) (P = 0.0218). In the male group, there is statistically significant difference of the serum Homocysteine (Hcy) levels (P < 0.0001) between adverse pregnancy group and controls.In the female group,there is statistically significant difference of the serum vitamin D levels (P = 0.0015) between adverse pregnancy group and controls. Polymorphic variants in MTHFR and MTRR, serum Folic acid (FA), Hcy and B12 levels in the male group and vitamin D levels in the female group are associated differentially with adverse pregnancy.

Association of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism with Osteosarcoma in a Mexican Population.

The methylenetetrahydrofolate reductase (MTHFR) gene 677C➔T polymorphism is capable of altering folate metabolism and can modify certain neoplasia risk. Reports have suggested that folate can have an influence on bone development and so it is of interest to know if the MTHFR 677C➔T polymorphism is associated with the malignant transformation process of this tissue. The polymorphism was determined in 55 patients with osteosarcoma and in 180 healthy individuals. Compared with C/T+C/C genotypes, a 3.7-fold reduction in osteosarcoma probability is possible with the T/T genotype (OR 0.27, CI 95% 0.07-0.82). Undoubtedly, further studies, utilizing large samples and carried out on different populations, are necessary to confirm these results.

Association of maternal genetic polymorphisms with fetal growth restriction syndrome in Russian pregnant women from Rostov region

BackgroundFetal growth restriction (FGR) is one of the main syndromes causing fetal morbidity and mortality. It was known to be associated with different factors including maternal, fetal, and environmental. However, the effect of genetic factors in FGR is not totally understood. Recently, researchers have focused on investigating genetic variants as possible markers of FGR. This especially concerns maternal genetic polymorphisms since they could serve as prenatal prognostic biomarkers. Accordingly, we aimed to study the association of several polymorphisms affecting vital processes of pregnancy with FGR in pregnant women. Targeted polymorphisms include methylenetetrahydrofolate reductase (MTHFR) 677C > T; methionine synthase reductase (MTRR) 66A > G; methionine synthase (MTR) 2756A > G; angiotensinogen (AGT) 704 T > C; and vascular endothelial growth factor A (VEGFA) 634C > G. In addition, this study examined SNP–SNP interactions, linkage disequilibrium (LD), and haplotypes association for these polymorphisms in the studied population.ResultsAccording to our data, MTRR 66(GG) carriers had increased FGR risk (OR = 3.18, 95% CI 1.31–7.72) while (AG) genotype was associated with lower FGR risk (OR = 0.37, 95% CI 0.17–0.84). AGT 704T > C also showed significant association with FGR with allele (T) as a risk factor. SNP–SNP interactions analysis revealed antagonistic relationship between these two polymorphisms and haplotypes association confirmed this finding. High LD possibility was shown between MTHFR 677C > T and MTR 2756A > G (D′ = 0.999) located on chromosome 1.ConclusionWe suggest MTRR 66A > G and AGT 704T > C as associated with FGR susceptibility with antagonistic interaction. Result will help to expand our understanding of FGR as a multifactorial syndrome and improve prenatal prognosis using maternal genetic biomarkers, but further studies in different populations are needed to confirm findings.

Src homology 2-B adapter protein 3 C784T and Methylenetetrahydrofolate reductase C677T Polymorphisms and Inflammation Markers in ST-segment Elevation Myocardial Infarction Patients.

Neutrophil-lymphocyte (NLR), platelet-lymphocyte (PLR), eosinophil-lymphocyte (ELR), and monocyte-lymphocyte (MLR) ratios are systemic inflammatory markers related to myocardial infarction. The aim of this study is to investigate the association of Src homology 2-B adapter protein 3 (SH2B3) C784T and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms (SNP) with systemic inflammatory markers and the severity of coronary artery disease (CAD) in 150 ST-elevation myocardial infarction (STEMI) patients. Single nucleotide polymorphisms were genotyped using the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method. The inflammatory markers were calculated. An interventional cardiologist blinded to other data assessed the SYNTAX (SX) Score. Eosinophil and platelet counts were significantly higher in SH2B3 variants than in the wild type. Additionally, SH2B3 variants had significantly higher ELR than the wild type (.12 ± .19 vs .25 ± .34, p = .018). NLR, PLR, ELR, and MLR were considerably higher in MTHFR variants than in the wild type (p < .05). The SX score was significantly higher in both SH2B3 C784T (21.24 ± 8.90 vs 15.29 ± 9.40, p = .00) and MTHFR C677T (20.34 ± 10.21 vs 16.08 ± 8.39, p = .00) variants when compared with wild type. In conclusion, these polymorphisms are associated with several markers of systemic inflammation as well as the severity of CAD.

Genetic Determinants of Cardiovascular Disease: The Endothelial Nitric Oxide Synthase 3 (eNOS3), Krüppel-Like Factor-14 (KLF-14), Methylenetetrahydrofolate Reductase (MTHFR), MiRNAs27a and Their Association with the Predisposition and Susceptibility to Coronary Artery Disease.

Amplification Refractory Mutation System (ARMS) PCR was used to detect MTHFR, KLF-14, miRNA-27a and eNOS3 genotyping in CAD patients and healthy controls. About 125 CAD cases and 125 controls were enrolled in this study and statistical associations were calculated including p-value, risk ratio (RR), and odds ratio (OD). There were statistically significant differences (p &lt; 0.05) in genotype distributions of MTHFR 677 C&gt;T, KLF-14 rs972283 G&gt;A, miRNAs27a rs895819 A&gt;G and eNOS3 rs1799983 G&gt;T between CAD patients and controls. In addition, our results indicated that the MTHFR-TT genotype was associated with increased CAD susceptibility with an OR 2.75 (95%) and p &lt; 0.049, and the KLF14-AA genotype was also associated with increased CAD susceptibility with an OR of 2.24 (95%) and p &lt; 0.024. Moreover, the miRNAs27a-GG genotype protects from CAD risk with an OR = 0.31 (0.016), p = 0.016. Our results also indicated that eNOS3 -GT genotype is associated with CAD susceptibility with an OR = 2.65, and p &lt; 0.0003. The MTHFR 677C&gt;T, KLF14 rs972283 G&gt;A, miRNAs27a A&gt;G, and eNOS3 rs1799983 G&gt;T genotypes were associated with CAD susceptibility (p &lt; 0.05). These findings require verification in future large-scale population based studies before these loci are used for the prediction and identification of individuals at risk to CAD. Weight control, physical activity, and smoking cessation are very influential recommendations given by clinicians to the at risk individuals to reduce or delay the development of CAD.

Association of MTHFR 677C>T polymorphism with breast cancer risk: A case-control study and meta-analysis.

Breast cancer is a complex, multifactorial disease that arises as a result of interactions between multiple genes and environmental factors. Methylenetetrahydrofolate reductase (MTHFR) is a low susceptibility gene, involved in folate metabolism. It assists in conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate which further leads to DNA methylation. 5,10-methylenetetrahydrofolate assists in conversion of uracil to thymine and purine synthesis for DNA synthesis. MTHFR 677C>T polymorphism alters the activity of MTHFR enzyme potentially effecting DNA repair and synthesis, hence a potential risk for cancer like breast cancer. Hence, the present study was conducted to evaluate association of MTHFR 677C>T polymorphism and breast cancer in Punjabi population. Moreover, a meta-analysis was conducted to address the same. A total of 247 breast cancer patients and 247 controls were selected from Punjabi population for analysis using PCR-RFLP method. For meta-analysis, 67 studies were selected, and allele contrast, homozygous, heterozygous, dominant, and recessive models were used to evaluate the association between MTHFR 677C>T and breast cancer. The frequencies of CC, CT, and TT genotype were 68.4% versus 74.5%, 28.7% versus 23.5%, and 2.9% versus 2.0% in patients and controls, respectively. There was no significant difference found. In meta-analysis, significant association was found in overall and Asian population while no significant association was found in Caucasians. MTHFR 677C>T polymorphism is not a risk factor for breast cancer in Punjabi population. Inconsistency with the meta-analysis can be due to ethnic diversity.

Reduced Steroid Synthesis in the Follicular Fluid of MTHFR 677TT Mutation Carriers: Effects of Increased Folic Acid Administration.

Objective To compare steroid profiles in the follicular fluid (FF) from women homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation and wildtype controls and to correlate it with the folic acid administration scheme applied at the time of oocyte retrieval. Design Retrospective single center study. Subjects and Methods Infertile patients treated by using assisted reproductive techniques were genotyped routinely for the MTHFR 677C>T mutation. In 2006 they had received folic acid supplementation doses of 400 µg daily per os. This group was designated Group-400 (n = 10). From 2008 onwards, all of our infertility patients received a daily dose of 800 µg folic acid per os. Women from this group were designated Group-800 (n = 28). FF were collected and a panel of steroid hormones (estradiol, estrone, estriol, cortisol, progesterone, 17-OH progesterone, testosterone, androstenedione, aldosterone, DHEA, and DHEA-S) was measured by isotope dilution liquid chromatography-tandem mass spectrometry employing atmospheric pressure photo ionization (APPI). Results In Group-400, the FF hormone profile confirmed a significant reduction of estradiol in homozygous 677TT carriers (0.52 ± 0.08-fold, exact p = 0.032) and for the first time also revealed significantly reduced estriol concentrations in these individuals (0.54 ± 0.05-fold, p = 0.016), as compared to wildtype controls. In Group-800, no significant differences were found for concentrations of any of the steroid hormones between homozygous 677TT carriers and wildtype controls. Conclusions The current findings support and extend previous reports on reduced concentrations of specific steroid hormones in follicular fluids of homozygous MTHFR 677C>T mutation carriers. The restoration of the FF hormone profile by elevated-dose folic acid supplementation might impact performing ART in infertile women with the MTHFR 677TT-genotype. Further adequately powered studies are necessary to verify our finding and to demonstrate the clinical effect of enhanced folic supplementation on ovarian function.

Methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in breast cancer: A Filipino preliminary case-control study

Single nucleotide polymorphisms (SNP) present in folate metabolic enzymes, such as methylenetetrahydrofolate reductase (MTHFR), affect DNA synthesis and methylation processes that can lead to cancer development. Several studies suggest that MTHFR SNP is associated with breast cancer risk, particularly among Asian populations. Thus, this study determined the association of MTHFR 677C>T SNP with breast cancer risk in selected Filipino population. DNA samples from breast cancer cases (n = 100) and clinically healthy controls (n = 100) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The differences in MTHFR genotype and allele frequencies were evaluated by computing for the odds ratio (OR) with a 95 % confidence interval (CI). The CT genotype (OR: 0.775, 95 % CI: 0.35–1.71, p = 0.53), T allele (OR: 0.703, 95 % CI: 0.34–1.48, p = 0.35), and presence of at least one T allele (ORCT+TT: 0.729, 95 % CI: 0.33–1.60, p = 0.43) were not associated with breast cancer risk. Based on the SNP interaction with other risk factors, no significant difference (p > 0.05) was observed for the tumor characteristics, menarche age, and menopause age. Interestingly, a decreased risk (OR: 0.342, 95 % CI: 0.14–0.84, p = 0.019) was observed for the CC genotype in individuals who consumed dietary fibers. Meanwhile, there was an increased risk for passive smokers with the CC genotype (OR: 6.31, 95 % CI: 2.68–14.9, p < 0.001). Overall, the MTHFR 677C>T was not significantly associated with breast cancer risk in a selected Filipino population. Since this study involved a relatively small number of participants, increasing the number of samples is recommended for a more conclusive test of association of MTHFR 677C>T with breast cancer risk in Filipinos.

Association of MTHFR 677C>T polymorphism with pregnancy outcomes in IVF/ICSI-ET recipients with adequate synthetic folic acid supplementation.

Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphism rs1801133 (677C>T) will decrease the utilization of folate. Folate deficiency and its resulting homocysteine (HCY) accumulation can impair female fertility. Folic acid (FA) supplementation is necessary in pregnant women who are undergoing in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) - embryo transfer (ET), and especially in women with MTHFR rs1801133 C-to-T mutations. At present, affordable and accessible synthetic FA is mainly used. However, some studies have suggested that 5-methylenetetrahydrofolate (5-MTHF), a type of active FA, may be more suitable for women with the MTHFR 677C>T polymorphism, since it is safer and more effective. This retrospective study aimed to evaluate whether the MTHFR rs1801133 gene polymorphism is related to the pregnancy outcomes of IVF/ICSI-ET recipients after sufficient supplementation with FA instead of 5-MTHF. Data on 692 women undergoing IVF/ICSI-ET and taking adequate FA were collected. Participant characteristics were compared using the Kruskal-Wallis test and Pearson chi-square test. Logistic regressions were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI), after adjusting for age, BMI, method of fertilization, method of embryo transfer and number of embryos transferred. An additive model (T/T vs. C/C), dominant model (C/T + T/T vs. C/C), and recessive model (T/T vs. C/T + C/C) were evaluated. Analysis revealed that MTHFR rs1801133 in IVF/ICSI-ET women with adequate FA supplementation was not associated with the pregnancy rate but with age (OR = 0.91, 95% CI = 0.88, 0.94, P < 0.001) and BMI (OR = 0.95, 95% CI = 0.90, 0.997, P = 0.037). In 349 clinically pregnant women, no association of the MTHFR 677C>T with pregnancy outcomes was found in the additive model, dominant model, or recessive model. Of the 273 women with positive pregnancy outcomes, 34 had a preterm delivery. MTHFR 677C>T was not associated with a preterm delivery after adjusting for age and BMI. The current results indicated that MTHFR polymorphism rs1801133 was not related to the pregnancy rate or pregnancy outcomes of women undergoing IVF/ICSI-ET with adequate synthetic FA supplementation, suggesting that simple supplementation with less expensive and readily available FA, rather than expensive 5-MTHF, appeared to be appropriate.

Metabolic Analysis of Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms (MTHFR 677C

Neural tube defects (NTDs)are among the most prevalent and debilitating birth defects with their causes are still unknown, despite mounting evidence that genetic and/or environmental factors may play a role. We aimed to analyze two single nucleotide polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene, serum folate and vitamin B12 status among a cohort of Egyptian children with NTDs and their mothers. A case-control study has been conducted on 50 Egyptian children with various types of NTDs and their mothers. They were comparable with 50 unrelated healthy, age and sex matched children and their mothers (50) selected as controls. Pediatric and neurosurgical assessments were performed to the included cases. Serum folate and vitamin B12 were measured using ELISA kits. MTHFR 677C<T (rs1801133) and MTHFR1298A<C (rs1801131) were analyzed by restriction fragment length polymorphism using polymerase chain reaction. Lumbosacral meningomyelocele was the most frequent NTDs (50%). Significantly lower serum folate and vitamin B12 among cases and case mothers compared to the control and control mothers (p<0.05 for all). Significantly higher frequencies of both heterozygous mutant (CT) and homozygous mutant (TT) genotypes, and mutant T allele of MTHFR 677C<T among case mothers compared to control mothers (p<0.05 for all), with lack of significant differences of this SNP between pediatric groups. Mutant homozygous (AA) genotype and mutant A allele of MTHFR 1298A<C among control mothers were significantly frequent compared to case mothers (p<0.05 for both), with OR 6.081 and 7.071, [95%CI were 3.071-11.287 and 3.296-15.172, respectively]. Significantly frequent wild homozygous (CC) genotype and normal C allele of MTHFR 1298A<C among children with NTDs compared to the controls (p<0.05 for both), with OR 0.231 and 0.754, [95%CI were 0.095-0.561and 0.432-1.317, respectively].Low serum folate and B12 are frequently common among children with NTDs and their mothers. MTHFR 677C<T in mothers could be considered as genetic risk factors for development of NTDs in their children, while MTHFR1298A<C could be protective genetic factor against NTDs development.

THYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISMS AND SUSCEPTIBILITY TO ESOPHAGEAL CANCER: A CASE-CONTROL STUDY.

ABSTRACTBACKGROUND:The enzyme methylenetetrahydrofolate reductase is engaged in DNA synthesis through folate metabolism. Inhibiting the activity of this enzyme increases the susceptibility to mutations, and damage and aberrant DNA methylation, which alters the gene expression of tumor suppressors and proto-oncogenes, potential risk factors for esophageal cancer.AIMS:This study aimed to investigate the association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and susceptibility to esophageal cancer, by assessing the distribution of genotypes and haplotypes between cases and controls, as well as to investigate the association of polymorphisms with clinical and epidemiological characteristics and survival.METHODS:A total of 109 esophageal cancer patients who underwent esophagectomy were evaluated, while 102 subjects constitute the control group. Genomic DNA was isolated from the peripheral blood buffy coat followed by amplification by polymerase chain reaction and real-time analysis. Logistic regression was used to assess associations between polymorphisms and the risk of developing esophageal cancer.RESULTS:There was no association for methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and haplotypes, with esophageal cancer susceptibility. Esophageal cancer patients carrying methylenetetrahydrofolate reductase 677TT polymorphism had higher risk of death from the disease. For polymorphic homozygote TT genotype, the risk of death significantly increased compared to wild-type genotype methylenetetrahydrofolate reductase 677CC (reference) cases (p=0.045; RR=2.22, 95%CI 1.02–4.83).CONCLUSIONS:There was no association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and esophageal cancer susceptibility risk. Polymorphic homozygote genotype methylenetetrahydrofolate reductase 677TT was associated with higher risk of death after surgical treatment for esophageal cancer.

Associations of Genetic Variants of Methylenetetrahydrofolate Reductase and Serum Folate Levels with Metabolic Parameters in Patients with Schizophrenia.

The one-carbon metabolism pathway is a suitable candidate for studying the genetic and epigenetic factors contributing to metabolic abnormalities in patients with schizophrenia. We recruited 232 patients with schizophrenia and analyzed their serum folate, vitamin B12, and homocysteine levels and metabolic parameters to investigate the associations of genetic variants of methylenetetrahydrofolate reductase (MTHFR) and folate levels with metabolic parameters. MTHFR C677T and MTHFR A1298C were genotyped. Results showed that MTHFR 677T allele carriers had lower levels of total cholesterol and low-density lipoprotein cholesterol than those with the 677CC genotype. Metabolic parameters did not differ between MTHFR 1298C and 1298AA carriers. Patients with a low folate level had a lower high-density lipoprotein cholesterol level than those with a normal folate level, but the effect disappeared after adjustment for age, sex, and types of antipsychotics used. We found significant interactions between MTHFR A1298C and the folate level status (low vs. normal) in terms of body mass index and waist circumference. In conclusion, genetic variants in one-carbon metabolism might play a role in antipsychotic-induced metabolic abnormalities. Prospective studies on drug-naïve, first-episode patients with schizophrenia are warranted to identify key regions of DNA methylation changes accounting for antipsychotic-induced metabolic abnormalities.

Association of MTHFR 677C>T and 1298A>C genetic polymorphisms with colorectal cancer: Genotype and haplotype analysis in a Southeast Iranian population

BackgroundThe methylenetetrahydrofolate reductase (MTHFR) gene is involved in DNA methylation, synthesis and repair, which influences the risk of cancers. Many studies have demonstrated that the MTHFR rs1801133 and rs1801131 polymorphisms are linked with the risks of colorectal cancer (CRC). However, no study has probed the relationship between these polymorphisms and CRC risk in southeast Iranian population. Therefore, the aim of this study was to investigate the association of these two polymorphisms with CRC risk in a case-control investigation. MethodsA total of 200 confirmed CRC patients and 200 healthy controls (matched to sex and age) were recruited from the Southeast of Iran between 2014 and 2019. Genomic DNA was extracted and genotyped for the polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism method. The relationship between the polymorphism and CRC risk was evaluated by logistical regression analysis. ResultsMTHFR 667C>T polymorphism was significantly associated with a lower risk of CRC (TT vs CC: p-value = 0.021; CT vs CC: p-value = 0.047; CT+TT vs CC: p-value = 0.017). The T-allele was associated with decreased risk for CRC (p-value = 0.012). However, we did not observe any association of 1298A>C with CRC. Furthermore, stratified analysis showed that MTHFR 667C>T polymorphism was correlated with tumor location in CRC patients. The frequency of T-A haplotype was significantly higher in the healthy controls compared to CRC patients (p-value = 0.021). ConclusionIn conclusion, the T-allele of MTHFR 667C>T polymorphism was related to decreased susceptibility to CRC in this Iranian population. Moreover, the CT-AA and TT-AA combined genotypes and T-A haplotype of MTHFR 667C>T and 1298A>C polymorphisms were associated with decreased risk of CRC.

EFFECT OF 5-METHYLTETRAHYDROFOLATE IN INFERTILE PATIENTS WITH METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) 677TT MUTATION UNDERGOING IVF

This study was performed to investigate the effect of 5-methyltetrahydrofolate (5-MTHF) on IVF outcome and uterine artery (UA) blood flow in infertile women with homozygous TT mutation of methylenetetrahydrofolate reductase (MTHFR) 677C>T undergoing IVF-ET treatment.

COVID-19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence.

BackgroundHomocysteine assessment has been proposed as a potential predictive biomarker for the severity of COVID‐19 infection. The purpose of this review was to analyze the correlation between the prevalence of MTHFR C677 T gene polymorphism and COVID‐19 incidence and mortality worldwide.MethodsData regarding MTHFR C677 T gene mutation were obtained from the interrogation of the Genome Aggregation Database (genomAD), which is publicly available from the web“https://gnomad.broadinstitute.org.” COVID‐19 cases, including prevalence and mortality, were obtained from“https://www.worldometers.info/coronavirus” 27 August 2020.ResultsThere is a clear trend toward the worldwide prevalence of MTHFR 677 T and COVID‐19 incidence and mortality. The prevalence of MTHFR 677 T allele in the Latino population, and the incidence and mortality for COVID‐19 was higher for this ethnic group than that reported for most other populations globally. Statistical analysis showed a relatively strong correlation between C677 T and death from coronavirus.ConclusionsGenetic polymorphism of MTHFR C677 T may modulate the incidence and severity of COVID‐19 pandemic infection.

Association of MTHFR C677T Polymorphism With Antipsychotic-Induced Change of Weight and Metabolism Index.

Although antipsychotic medication contributed to the improvement of psychotic symptoms and reduced relapse, it induced weight gain and metabolic syndrome during antipsychotic medication treatment, which was seriously concerning. To investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene C677T (rs1801133) polymorphism with antipsychotic-induced weight gain and metabolism parameter change, we employed 1,868 patients with schizophrenia in this study and randomly allocated them to seven antipsychotic medication treatment groups. All patients received antipsychotics monotherapy and were followed up for 6 weeks. Height, body weight, and metabolic parameters of the patients were measured at baseline and at 2, 4, and 6 weeks after antipsychotic treatment. We genotyped blood DNA from patients for MTHFR C677T polymorphisms and performed quantitative analyses using analysis of variance (ANOVA) and the analysis of covariance (ANCOVA) among three genotype groups.We found a predominant association between MTHFR C677T and body weight mass index (BMI) change after 6-week risperidone treatment. After 6-week treatment of risperidone, the BMI change rate (%) of MTHFR C677 carriers was significantly higher than that of MTHFR TT genotype carriers [CC (2.81 ± 6.77)%, CT (3.79 ± 5.22)%, TT (1.42 ± 3.53)%, F = 4.749, P = 0.009]. Some of the abnormal metabolic parameters were found to be associated with the MTHFR 677T, including higher levels of low-density lipoprotein and waist circumference. Validation was performed in an independent cohort, consisting of 252 patients with schizophrenia treated with three atypical antipsychotic drugs. Overall, the MTHFR C677 was associated with high risk of antipsychotic-induced weight gain and metabolism abnormalities.

Impact of the common MTHFR 677C\u2192T polymorphism on blood pressure in adulthood and role of riboflavin in modifying the genetic risk of hypertension: evidence from the JINGO project

BackgroundGenome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension.MethodsObservational data on 6076 adults of 18–102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008–2012 using standardised methods.ResultsThe variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34–6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027).ConclusionsThe MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.

Prevalence of the methylenetetrahydrofolate reductase 677C>T polymorphism in the pregnant women of Yunnan Province, China.

Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene can result in a reduced ability to utilize folic acid. The MTHFR 677C>T polymorphism in particular has been linked to both birth defects and pregnancy-associated diseases. This study aimed to evaluate the prevalence of the MTHFR 677C>T mutation among pregnant women in Yunnan Province so as to collect baseline data that may be utilized to guide folic acid supplementation efforts and to support related disease prevention programs. We retrospectively reviewed 3387 pregnant women from Yunnan Province. The MTHFR 677C>T polymorphism was identified using polymerase chain reaction (PCR) and DNA sequencing. In total, 1350 (39.9%) subjects were homozygous for the C allele (CC), 1540 (45.4%) subjects were heterozygous (CT), and 497 (14.7%) subjects were homozygous for the T allele (TT). The MTHFR 677C>T polymorphism was found to be present within the studied population, with ∼60% of these patients being either heterozygous or homozygous for the mutant allele and with an overall T allele frequency of 0.37. The frequency of the T allele was significantly higher among pregnant women with complications relative to women with healthy pregnancies, particularly among women <30 years old. As such, the maternal MTHFR 677C>T polymorphism may be a genetic risk factor associated with pregnancy complications and may help identify pregnant women at a high risk of such complications.