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Query Topic: MTHFR

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factor v leiden(250)

Association of thrombophilia prospective detection with hemocompatibility related outcomes in left ventricular assist device patients.
Inherited thrombophilias represent a concerning risk factor due to a proclivity to an aberrant clot formation. However, in patients with left ventricular assist device (LVAD), their impact on bleeding and thrombotic complications remains still poorly understood. The aim of the present study was to evaluate the effect of thrombophilic mutation directed anticoagulation therapy on adverse clinical outcomes in LVAD patients. About 138 consecutive patients indicated for LVAD implant (HeartMate II, Abbott, Plymouth, USA) were prospectively screened for three major thrombophilic mutations: factor II (prothrombin), factor V Leiden, and homozygous methylenetetrahydrofolate reductase (MTHFR). Subsequently, discordant individualized anticoagulation targets of INR 2.5-3.0 in thrombophilia positive and INR 1.8-2.2 in negative patients were established; notably without anti-platelet agents given the center standard of care. Mean age was 50 ± 12.7 years, 83% male. Mean duration of support was 464.5 days (SD 482.9; SEM 41.1) and median of 310 days (IQR 162; 546). Full thrombophilia positive cohort analysis has not revealed any significant impact on event free survival. In contrast, detailed analysis of specific thrombophilias subsets has revealed Factor II prothrombin mutation as a significant predisposition for the pump thrombosis risk (SHR 10.48; Our observations suggest that specific thrombophilias in LVAD patients may pose different intensity predisposition for thrombotic complications. Factor II (prothrombin) positive mutation was identified as significant risk factor associated with the pump thrombosis.
Publication Date: 2021-09-21
Journal: The International journal of artificial organs

5 10-methylenetetrahydrofolate reductase(216)

The effect of A1298c polymorphism of the MTHFR gene on anti-Müllerian hormone levels: experimental and Web-based analysis.
The 5,10-methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, which is expressed in human oocytes and preimplantation. Due to the involvement of MTHFR in female reproduction, we tend to evaluate the influence of MTHFR A1298C polymorphism on ovarian marker reserves such as serum anti-Müllerian hormone (AMH) levels in women after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). A total of 100 women, who underwent ART treatment due to male factor infertility, were recruited into this study. MTHFR A1298C polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, and serum AMH concentrations were measured by an ultrasensitive enzyme-linked immunosorbent assay (ELISA). Women with the CC genotype had higher AMH levels (4.15 ± 1.67 ng/ml), albeit not significant, than carriers with other genotypes after ovarian stimulation. No significant differences existed in terms of miscarriage and live birth rates among different genotype groups. The presence of the C mutant allele of the 1298 polymorphism in the MTHFR gene led to an increasing trend in serum AMH concentrations; however, the numbers of oocytes retrieved decreased in women with mutated genotypes. The influence of the MTHFR C677T polymorphism on embryo quality and pregnancy rate after ART cycles remains unclear.
Publication Date: 2021-08-10
Journal: Journal of clinical laboratory analysis

fragment length polymorphism(184)

Correlation of methylation status in MTHFR promoter region with recurrent pregnancy loss.
DNA methylation is an epigenetic process for modifying transcription factors in various genes. Methylenetetrahydrofolate reductase (MTHFR) stimulates synthesis of methyl radical in the homocysteine cycle and delivers methyl groups needed in DNA methylation. Furthermore, numerous studies have linked gene polymorphisms of this enzyme with a larger risk of recurrent pregnancy loss (RPL), yet scarce information is available concerning the association between epigenetic deviations in this gene and RPL. Hypermethylation at precise DNA sequences can function as biomarkers for a diversity of diseases. We aimed by this study to evaluate the methylation status of the promoter region of MTHFR gene in women with RPL compared to healthy fertile women. It is a case-control study. Hundred RPL patients and hundred healthy fertile women with no history of RPL as controls were recruited. MTHFR C677T was assessed by polymerase chain reaction-restriction fragment length polymorphism (RFLP). Quantitative evaluation of DNA methylation was performed by high-resolution melt analysis by real-time PCR. The median of percentage of MTHFR promoter methylation in RPL cases was 6.45 [0.74-100] vs. controls was 4.50 [0.60-91.7], P value < 0.001. In the case group, 57 hypermethylated and 43 normo-methylated among RPL patients vs. 40 hypermethylated and 60 normo-methylated among controls, P< 0.005. Frequency of T allele in C677T MTHFR gene among RPL patients was 29% vs. 23% among the control group; C allele vs. T allele: odds ratio (OR) = 1.367 (95% confidence interval (CI) 0.725-2.581). Findings suggested a significant association between hypermethylation of the MTHFR promoter region in RPL patients compared to healthy fertile women.
Publication Date: 2021-03-23
Journal: Journal, genetic engineering & biotechnology

polymerase chain reaction(157)

MTHFR C677T Polymorphism and Serum Homocysteine Level as Risk Factors of Coronary Heart Disease in Patients with Androgenetic Alopecia: A Case Control Study.
Androgenetic alopecia (AGA) is associated with a risk of coronary heart disease (CHD), although the causes underlying this association are not clear. Serum homocysteine (SH) is a known risk factor for CHD, and methylene tetrahydrofolate reductase enzyme (MTHFR) plays a crucial role in the remethylation of homocysteine to methionine. The polymorphism C677T that affects the catalytic domain of the MTHFR protein leads to a high levels of SH. Our hypothesis was that this polymorphism and SH level are risk factors for CHD in patients with AGA. A total of 106 patients with AGA and 100 well-matched healthy controls were enrolled in the study. SH levels were estimated. DNA was extracted and polymerase chain reaction amplification, followed by restriction enzyme digestion for MTHFR (C677T) gene, was conducted. SH levels were significantly higher in the patient group and highest in those with the TT genotype. The mutant T allele was associated with hyperhomocysteinemia and an increased risk of CHD in patients with AGA. AGA is associated with a higher risk of developing CHD due to the associated higher level of SH that, in turn, depends on and is correlated with mutant MTHFR genotypes. Cardiac evaluation and follow-up of patients with AGA is recommended for early detection and treatment of CHD to avoid an overall detrimental course.
Publication Date: 2021-07-01
Journal: The American journal of the medical sciences

mthfr a1298c polymorphism(108)

MTHFR A1298C gene polymorphism on stroke risk: an updated meta-analysis.
Previous studies have shown the effect of MTHFR A1298C gene polymorphism on stroke risk. But the results of published studies remained inconclusive and controversial. So we conducted a meta-analysis to accurately estimate the potential association between MTHFR A1298C gene polymorphism and stroke susceptibility. A systematic literature search on Embase, Pubmed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) and WanFang electronic database identified 40 articles including 5725 cases and 8655 controls. Strength of association was evaluated by pooled odds ratio (OR), 95% confidence interval (CI) and p value. Funnel plots and Begger's regression test were applied for testing the publication bias. Statistical analysis of all data was performed by Stata 12.0. The meta-analysis results indicated a significant relationship between MTHFR gene A1298C polymorphisms and stoke risk under the C allelic genetic model (OR = 1.19, 95%CI = 1.07-1.32, p = 0.001), dominant genetic model (OR = 1.19, 95%CI = 1.06-1.33, p = 0.004) and recessive genetic model (OR = 1.43, 95%CI =1.15-1.77, p = 0.001). In subgroup analysis, we discovered obvious correlation in three genetic model of Asian, stroke type, adult by ethnicity, population, stroke type, source of control and case size. Additionally, in studies of control from hospital and case size equal 100, obvious correlation was also found in the three genetic model. Our meta-analysis results indicated that there was evidence to support the correlation between MTHFR A1298C polymorphism and stroke susceptibility, especially in adults and ischemic stroke.
Publication Date: 2021-09-27
Journal: Genes and environment : the official journal of the Japanese Environmental Mutagen Society

mthfr c677t genotype(104)

The prevalence, relative risk factors and MTHFR C677T genotype of H type hypertension of the elderly hypertensives in Shanghai, China: a cross-section study : Prevalence of H type hypertension.
H type hypertension is defined as homocysteine (Hcy) ≥ 10 μmol/L in combination with primary hypertension. Studies demonstrated that the existence of hyperhomocysteine (HHcy) in hypertensive exacerbates the poor outcome of cardiocerebral incidents. This study was to investigate the current epidemic situation of H type hypertension and determine the risk factors in order to find intervention targets for H type hypertensives. We conducted a cross-sectional study using cluster sampling design in Shanghai, China from July 2019 and April 2020. 23,652 patients with primary hypertension were enrolled in this study. Their medical information was recorded, and the level of Hcy concentrations and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms were detected. In total, 22,731 of 23,652 patients were recorded. The mean age was 68.9 ± 8.6 y and 43% were men. 80.0% of the enrolled patients had H type hypertension. The frequency of allele T was 40.9%, and the proportions of the CC, CT, and TT genotypes were 36.1%, 46.0%, and 17.9%, respectively. Compared with the TT genotype, the plasma Hcy concentration levels were lower in patients with the CC/CT genotype (18.96 ± 13.48 μmol/L vs. 13.62 ± 5.20/14.28 ± 5.36, F = 75.04, p < 0.01). The risk for H type hypertension was higher in elderly people. Men had ~ 5.55-fold odds of H type hypertension compared with women. Patients with CT genotype and TT genotype had ~ 1.36- and ~ 2.76-fold odds of H type hypertension compared with those with CC genotype, respectively. Smoking and diabetes were not significantly associated with H type hypertension. The prevalence of H type hypertension in patients with primary hypertension was 80.0%, which was higher than the 75% found in prior report in China. Age, gender, and MTHFR C677T polymorphisms rather than smoking and diabetes were independently associated with H type hypertension.
Publication Date: 2021-08-06
Journal: BMC cardiovascular disorders

mthfr c677t polymorphism(102)

Association of MTHFR C677T polymorphism with primary open angle glaucoma: a Meta-analysis based on 18 case-control studies.
To systematically understand the genetic association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and primary open angle glaucoma (POAG). A comprehensive literature search in Google Scholar, PubMed, Science Citation Index, Foreign Medical Literature Retrieval Service, Chinese National Knowledge Infrastructure and Wanfang Databases was performed to collect all eligible studies up to August 2019. Study selection, data abstraction and study quality evaluation were performed by two independent investigators. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association. Eighteen case-control studies including 2156 cases and 2201 controls were identified. There was no significant difference in the terms of MTHFR C677T polymorphism and POAG in the Caucasian population (for T Based on 18 eligible studies, we provide a correlation between MTHFR C677T polymorphism and POAG among the Asians subgroup indicating that the T allele or TT +TC genotype may play a critical role in POAG development in Asians.
Publication Date: 2021-06-22
Journal: International journal of ophthalmology

95 ci(476)

Folate metabolism modifies chromosomal damage induced by 1,3-butadiene: results from a match-up study in China and in vitro experiments.
To explore the role of folate metabolism in 1,3-Butadiene (BD)'s genotoxicity, we conducted a match-up study in BD-exposed workers in China to analyze the associations between the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and the chromosomal damage induced by BD exposure, and culture-based experiments in TK-6 cells to examine the global DNA methylation levels and chromosomal damage when exposed both to BD's genotoxic metabolite, 1,2:3,4-diepoxybutane (DEB), and MTHFR's direct catalytic product, 5-methyltetrahydrofolate (5-MTHF). Cytokinesis block micronucleus assay (CBMN) was used to examine the chromosomal damage induced by BD or DEB. Poisson regression models were produced to quantify the relationship of chromosomal damage and genetic polymorphisms in the BD-exposed workers. Global DNA methylation levels in TK6 cells were examined using DNA Methylation Quantification Kit. We found that BD-exposed workers carrying MTHFR C677T CC (2.00 ± 2.00‰) (FR = 0.36, 95%CI: 0.20-0.67, P < 0.01) or MTHFR C677T CT (2.87 ± 1.98‰) (FR = 0.49, 95%CI: 0.32-0.77, P < 0.01) genotypes had significantly lower nuclear bud (NBUD) frequencies than those carrying genotype MTHFR 677 TT (5.33 ± 2.60‰), respectively. The results in TK6 cells showed that there was a significant increment in frequencies of micronucleus (MN), nucleoplasmic bridge (NPB) and nuclear bud (NBUD) with exposure to DEB at each 5-MTHF dose (ANOVA, P < 0.01). Additionally, there was a significant decrease in frequencies of MN, NPB and NBUD in DEB-exposed cultures with increasing concentration of 5-MTHF (ANOVA, P < 0.05). The levels of global DNA methylation were significantly decreased by DEB treatment in a dose-dependent manner within each 5-MTHF concentration in TK-6 cells (ANOVA, P < 0.01), and were significantly increased by 5-MTHF supplementation within each DEB concentration (ANOVA, P < 0.01). We reported that folate metabolism could modify the association between BD exposure and chromosomal damage, and such effect may be partially mediated by DNA hypomethylation, and 5-MTHF supplementation could rescue it.
Publication Date: 2021-10-11
Journal: Genes and environment : the official journal of the Japanese Environmental Mutagen Society

gene polymorphisms(313)

Correlation between MTHFR gene polymorphism and homocysteine levels for prognosis in patients with pregnancy-induced hypertension.
This research was designed to probe into the correlation between MTHFR gene polymorphisms and homocysteine levels in regard to the prognosis of pregnancy-induced hypertension. A total of 180 patients with pregnancy-induced hypertension who were admitted in the gynecology and obstetrics department of our hospital were collected as the observation group, and 180 normal pregnant women were selected as the control group. The homocysteine (Hcy) level, polymorphism expression of methylenetetrahydrofolate reductase (MTHFR) gene C677T locus and A1298C locus and the correlation between the different gene loci, Hcy level and pregnancy outcome were observed. The Hcy level in the observation group was 18.1±6.2 (100 mmol/L) which was higher than that in the control group (8.6±3.9 mmol/L) (P<0.001). The C677T polymorphism of the MTHFR gene, and the proportion of CC in the observation group was lower than that in the control group, while that of CT and TT in the observation group was significantly higher (P<0.001). The T allele in the observation group was higher than that in the control group, while the C allele was lower than that in the control group (P<0.001). Hcy of TT type in pregnancy-induced hypertension group was higher than that in CC and CT groups (P<0.05). The incidence of adverse pregnancy outcomes in pregnancy-induced hypertension patients was obviously higher than that in normal control group (P<0.01). The incidence of TT type adverse pregnancy outcomes in MTHFR gene C677T polymorphism in patients with gestational hypertension was significantly higher than that in CC and TC groups (P<0.01). The Hcy level in pregnancy-induced hypertension patients and the proportion of CT and TT in the MTHFR gene C677T locus rose; having the TT-type increased the incidence of abnormal pregnancy, which may be related to the increase of Hcy level.
Publication Date: 2021-08-12
Journal: American journal of translational research

risk factors(259)

Association of increased C-Reactive Protein and hypocomplementemia with risk factors for thrombosis in women who have susceptibility for poor gestational outcome; importance of preconceptional counseling.
This study aimed to investigate the association of increased C-Reactive Protein (CRP) and hypocomplementemia with risk factors for thrombosis such as Factor V Leiden (FVLP) and Prothrombin G20210A polymorphisms (PP), increased Activated Protein C Resistance (APCR) and decreased anti-thrombin III (ATIII) activity in women who have metabolic (MTHFR polymorphisms) and immunological risk factors (autoimmune antibody positivity, autoimmune disorders, and chronic inflammatory diseases). All patients (n= 197) were evaluated in terms of risk factors for thrombosis including FVLP, PP, increased APCR, and decreased ATIII activity as well as CRP and complement (C) 3 and C4 levels within a framework of preconceptional care program. Patients with high CRP levels together with hypocomplementemia were included to the study group (n= 13), while women with normal levels of CRP, C3, and C4 were accepted as controls (n= 184). Decreased ATIII activity was found to be statistically more frequent in the study group compared to controls (p= 0.036). There were no significant differences between the study and control groups in terms of the presence of FVLP, PP and increased APCR (p= 0.386, p= 0.462, p= 0.625, respectively). Decreased ATIII activity should be the concern of preconceptional and antenatal care programs in risky patients with increased CRP levels and hypocomplementemia in order to prevent placental inflammation related gestational complications.
Publication Date: 2021-07-20
Journal: Human antibodies

significant association(249)

The methylenetetrahydrofolate reductase 1298 A>C polymorphism is associated with an increased risk of inflammatory bowel disease: evidence from a meta-analysis.
The association between genetic variants in methylenetetrahydrofolate reductase (MTHFR) and risk for inflammatory bowel disease (IBD) has been widely studied. However, the results are equivocal. In this meta-analysis, we aimed to determine the association between MTHFR polymorphisms and susceptibility to IBD. We retrieved studies from the PubMed, Web of Science, Ovid, and China National Knowledge Infrastructure databases. Data were analyzed using STATA software; odds ratios (OR) and confidence intervals (CI) were calculated using fixed or random effects models. A marginally significant association of the MTHFR 677 C > T polymorphism and patients' IBD risk was observed in the overall analysis (OR = 1.11, 95% CI, 1.01-1.23), but not in the analysis of high-quality studies. However, for the MTHFR 1298 A > C polymorphism, a significant association was found between the MTHFR 1298 AC/CC genotypes and IBD risk in the overall analysis (OR = 1.26, 95% CI, 1.10-1.44), in the high-quality studies (OR = 1.20, 95% CI, 1.02-1.41), and in patients with ulcerative colitis (OR = 1.28, 95% CI, 1.10-1.48). Evidence from this meta-analysis indicates that the MTHFR 1298 A > C polymorphism may be responsible for susceptibility to IBD and ulcerative colitis.
Publication Date: 2021-09-17
Journal: Expert review of clinical immunology

mthfr 677tt(206)

Methylenetetrahydrofolate reductase C677T gene polymorphism and the association with dyslipidemia in type 2 diabetic Palestinian patients.
Dyslipidemia in diabetes is common and characterized by hypertriglyceridemia with decreased levels of high-density lipoprotein. The objective of this study was to assess the prevalence of MTHFR C677T polymorphism in Palestinian T2DM patients and to investigate the association between this polymorphism and lipid profile in diabetic patients with and without dyslipidemia. A total of 208 T2DM patients including 98 with dyslipidemia and 110 without dyslipidemia were enrolled in this study. The MTHFR C677T genotyping was conducted by PCR-RFLP followed by agarose gel electrophoresis. There were no significant differences in either the genotype distribution or allele frequency in T2DM patients with or without dyslipidemia (37.8% CC, 54% CT, 8.2% TT vs. 48.2% CC, 41.8% CT, 11% TT; p = 0.209). However, among the dyslipidemic group, the TT carriers have a higher HDL level (46.8 ± 17.8) compared to (CC+CT) carriers (34.68 + 11.9) (p = 0.01). In the group without dyslipidemia, there was a significant elevation in diastolic blood pressure (DBP) among the CC carriers (83.6 ± 10.6) compared to those who carried at least one mutant allele (CT+TT) (78.1 ± 11.1) (p = 0.009). The study shows that in our Palestinian population the MTHFR 677TT genotype lowers DBP significantly in patients without dyslipidemia and is related to increased level of HDL in diabetic dyslipidemia patients.
Publication Date: 2021-09-10
Journal: Journal of clinical laboratory analysis

95 confidence(203)

Traditional risk factors and combined genetic markers of recurrent ischemic stroke in adults.
The involvement of traditional risk factors and combined genetic markers of recurrent arterial ischemic stroke (AIS) in adults remains unclear. This study aims to determine significant clinical and genetic factors of AIS recurrence, and to investigate the combined effect of genotypes on the occurrence of a second cerebral ischemic attack. We investigated a cohort study of AIS patients (18-50 years old) followed in the neurology department over 5 years. Traditional and genetic risk factors were carried through a multivariable logistic regression model. We used a Cox proportional hazard model for identifying predictors of recurrence. Two hundred and seventy patients were enrolled in our study. The risk of AIS recurrence was 36.2% within 5 years. The potential risk of recurrence of AIS increased with traditional and genetic risk factors such as hypertension, diabetes mellitus, heart failure, and family history of cerebrovascular diseases. This risk increased with increasing number of genetic factors. The hazard ratio (HR) was 0.66 (95% confidence interval [CI] 0.97-2.67) for the subject with one genetic factor, 1.61 (95% CI 0.97-2.25) for combined methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and 2.57 (95% CI 1.32-4.99) for combined factor V Leiden (FVL) and MTHFR polymorphisms (677 or 1298). The HR for the three polymorphisms combined was 6.04 (95% CI 2.40-15.16). Our findings suggest that cumulative effect of both traditional and common genetic risk factors was associated with recurrence of ischemic stroke. We demonstrated for the first time that a combined genotype FVL/MTHFR profile increase the risk of a second cerebral ischemic attack.
Publication Date: 2021-07-10
Journal: Journal of thrombosis and haemostasis : JTH

present study(190)

Association of MTHFR C677T variant genotype with serum folate and Vit B12 in Iranian patients with colorectal cancer or adenomatous polyps.
The incidence of colorectal cancer (CRC) has increased during recent years in Iran and other developing countries. Clinical studies suggest that essential folate dietary intake and moderate deficiency of methylenetetrahydrofolate reductase (MTHFR) may protect and reduce the risk of CRC. The present study aimed to investigate the clinical significance of C677T polymorphism within the MTHFR gene and its correlation with the serum folate and Vit B Blood samples were taken from 1017 Iranian individuals (517 cases and 500 controls) who were referred for colonoscopy. TaqMan probe assay was performed for C677T MTHFR polymorphism. Sera were fractionated from the blood samples of 43 patients and controls and folate and Vit B In the current study, we found the frequency of three different genotypes of MTHFR polymorphism in the Iranian population i.e., CC, CT, and TT, to be 51.31, 26.73, 21.96 and 61, 32.2, 6.8 in case and control groups, respectively. The homozygote genotype of MTHFR rs1801133 polymorphism is associated with an increased risk of CRC by 3.68, 1.42, and 3.74-fold in codominant, dominant, and recessive models respectively (p value < 0.01). Our study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups (p value > 0.05). This study revealed that there was no significant difference between the amount of folate and Vit B
Publication Date: 2021-10-15
Journal: BMC medical genomics

folic acid(187)

Individualized Supplement of Folic Acid Based on the Gene Polymorphisms of MTHER/MTRR Reduced the Incidence of Adverse Pregnancy Outcomes and Newborn Defects.
The association between conventional folic acid supplement (FAS) in pregnancy and the occurrence of adverse pregnancy outcomes, newborn defects has been proven. However, recent researches have reported a weakened association. Based on the different maternal metabolism capability of folic acid, it's beneficial for clinicians to provide pregnant women with different doses of FAS, that's individualized FAS. A total of 2,677 pregnant women in Dazu, Chongqing, China were recruited in this cohort study. 1,539 women volunteered to receive individualized FAS, in which FAS dose increased with the risk level of maternal genotype? specify MTHFR and MTRR (write in full then abbreviate bracket open and close) while 1,138 women received conventional FAS with unified FAS dose. Additionally, 1,964 pregnant women without FAS were retrospectively analyzed as the control. Finally, the incidence of adverse pregnancy outcomes and newborn defects were recorded. Based on the genotype of MTHFR and MTRR, women were identified as five risk levels of folic acid metabolism. The distributions of genotype and risk levels were not significantly different between FAS-individualized supplement group and FAS-unified supplement group. However, compared with control or FAS-unified supplement group, the incidence of spontaneous abortion, prolonged pregnancy, premature labor, fetal macrosomia and congenital heart disease were significantly decreased in FAS-individualized supplement group. In subgroup analysis, individualized FAS significantly improved pregnancy outcomes for women between 20-40 years old and inhibited the occurrence of newborn defects in both women of the first gestation and women of ≥2 gestations. The application of individualized FAS based on gene polymorphisms was more effective in preventing adverse outcomes in the mother and child.
Publication Date: 2021-08-17
Journal: Nigerian journal of clinical practice

tt genotype(181)

Association of homocysteine with IVF/ICSI outcomes stratified by MTHFR C677T polymorphisms: a prospective cohort study.
What is the association between homocysteine (Hcy) and IVF/intracytoplasmic sperm injection (ICSI) outcomes, stratified by methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms? This prospective cohort study recruited 1011 infertile women undergoing IVF/ICSI treatment for the first time at the International Peace Maternity and Child Health Hospital between June 2015 and March 2018. The concentration of total serum Hcy was significantly negatively associated with clinical pregnancy and implantation rate. When adjusted for maternal and paternal age and educational level, maternal body mass index, and FSH and oestradiol concentrations, logistic regression analysis showed that women with higher Hcy had a higher risk of unsuccessful pregnancy. After stratification by MTHFR C677T polymorphisms and adjustment for confounding factors, a higher risk of unsuccessful pregnancy and a significantly lower implantation rate only existed in women with higher Hcy concentration in the MTHFR C677T TT genotype. There was no significant association between Hcy concentrations and other ovarian stimulation outcomes (oocytes retrieved, metaphase II stage oocytes, fertilization rate, cleavage rate, high-quality embryo rate) or neonatal outcomes (preterm birth, gestational age at delivery, Caesarean section, birthweight, small for gestational age, large for gestational age or birth defects). Hcy is highly negatively associated with clinical pregnancy and implantation rate during the first IVF/ICSI cycle, especially in women carrying the MTHFR C677T TT genotype. Other factors with impacts on reproductive outcomes, such as stage of embryo transferred, other factors involved in folate metabolism, preimplantation genetic testing, etc., should be taken into account in further research.
Publication Date: 2021-05-22
Journal: Reproductive biomedicine online

methionine synthase(168)

Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density.
Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine β-synthase (CBS). We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength. We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength.  These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
Publication Date: 2021-05-09
Journal: The American journal of clinical nutrition

homocysteine levels(159)

MTHFR gene polymorphism and homocysteine levels in spontaneous abortion of pregnant women.
This research explored the expression of MTHFR gene polymorphism and homocysteine (Hcy) in spontaneous abortions in pregnant women. Eighty-two spontaneous abortion patients treated in our hospital were selected prospectively, and 82 age-matched healthy and normal delivery women were included. The peripheral venous blood of the two groups was obtained, and the differences between MTHFR gene polymorphism and Hcy levels were analyzed. The Hcy levels in spontaneous abortion patients were higher than those in the healthy control group (P<0.05). In the common mutation (C677T) of MTHFR gene polymorphism, the distribution of MTHFRC677T (TT, CC, CT) genotyping of both groups was different, but the Hcy levels in the observation group were higher than those in the normal control group (P<0.05). In addition, logistic analysis manifested that the the Hcy levels were higher than normal and MTHFRC677T (TT) mutant was an independent risk factor for spontaneous abortion of pregnant women. MTHFRC677T (TT) is associated with the occurrence of hyperhomocysteinemia, and its high expression often indicates that the risk of spontaneous abortion is greatly increased, which may provide a new research direction for maternal health.
Publication Date: 2021-07-27
Journal: American journal of translational research

1298a c(145)

Single-nucleotide polymorphisms of methylenetetrahydrofolate reductase gene in a South Indian cohort with nonsyndromic cleft lip with or without palate.
Clefts of the lip, with or without cleft palate and cleft palate only, collectively called as orofacial clefts (OFCs) are one of the most common congenital malformations with varying degrees of penetrance and phenotype expressions. The aim of this study was to investigate the association between methylenetetrahydrofolate reductase (MTHFR) cytosine-to-thymine (c. 677 C>T), adenine-to-cytosine (c.1298 A>C) single- nucleotide polymorphisms (SNPs) and South Indian patients with the nonsyndromic cleft lip with or without palate (NSCL ± P). A cohort consisting of 25 cases of NSCL ± P and 18 controls from a South Indian cohort were included in this case-control study. Genetic analysis of c.677C>T and c.1298A C polymorphisms in the MTHFR gene was carried out using Sanger sequencing and analyzed from chromatogram profiles. Data interpretation was done using statistical software MedCalc Statistical Software version 16.2 and the Statistical Package for the Social Sciences (SPSS version 22.0). DNA sequence analysis of the MTHFR gene revealed c. 677C>T and c. 1298A>C polymorphisms in 16% and 76% of NSCL ± P cases, respectively. Heterozygous variant in MTHFR c. 1298A>C polymorphism was found to be a significant risk factor ( NSCL ± P is one of the most common and challenging congenital malformations with complex etiological basis. Common risk factors such as MTHFR SNPs, namely c.677C>T and c.1298A>C, are subjected to variations in terms of ethnic group, geographic region and micro/macro-environmental factors. Overall, our study has explored part of South Indian ethnic population and revealed a different and unique distribution of mutations in this sample population.
Publication Date: 2021-05-11
Journal: Journal of oral and maxillofacial pathology : JOMFP

vitamin b12(131)

Homocysteine, vitamin B status and MTHFR polymorphisms in Italian infertile women.
The purpose of this study was to evaluate the vitamin B status related to the homocysteine pathway and the prevalence of polymorphisms of the MTHFR gene in infertile women programming homologous or heterologous ART. We investigated 393 consecutive Caucasian women, referred to the Internal Medicine Clinic at the Center for Assisted Reproductive Technology, in order to be framed for their vascular risk before starting homologous or heterologous (oocyte donation) procedures. Total homocysteine, Vitamin B12, folate and vitamin B6 were measured. The women were divided into quartiles of serum concentration of folate, vitamin B12 and vitamin B6. The C677T and A1298C polymorphisms of the MTHFR gene were genotyped by an electronic microchip technology. Sixty-one women (15.5%) had hyperhomocysteinemia, 22.9% had reduced levels of vitamin B12, 4.1% had reduced levels of serum folate and 0.1% had a deficiency of vitamin B6. Women in the highest quartile of vitamin B12 and folates had lower homocysteine ​​levels than women in the first and second quartiles (p < 0.0001). The homozygosity for MTHFR C677T polymorphism was detected in 33.3% (131), and heterozygosity for MTHFR C677T polymorphism in 45.3% (178) of women. We observed a significant association between hyperhomocysteinemia and 677T allele, but not 1298C, of the MTHFR polymorphisms (p = 0.04). We found inadequate vitamin B status related to the homocysteine ​​pathway in women planning Assisted Reproductive Technology. Moreover, interesting association was found regarding hyperhomocysteinemia in women carrying T allele of the C677T MTHFR polymorphism. A specific supplementation with 5-MTHF and adequate vitamin B12 concentrations before Assisted Reproductive Technology warrant serious consideration, in particular in women carrying T allele of the C677T MTHFR polymorphism.
Publication Date: 2021-06-25
Journal: European journal of obstetrics, gynecology, and reproductive biology

polymorphisms snps(114)

Association analysis of maternal MTHFR gene polymorphisms and the occurrence of congenital heart disease in offspring.
Although many studies showed that the risk of congenital heart disease (CHD) was closely related to genetic factors, the exact pathogenesis is still unknown. Our study aimed to comprehensively assess the association of single nucleotide polymorphisms (SNPs) of maternal MTHFR gene with risk of CHD and its three subtypes in offspring. A case-control study involving 569 mothers of CHD cases and 652 health controls was conducted. Thirteen SNPs were detected and analyzed. Our study showed that genetic polymorphisms of maternal MTHFR gene at rs4846052 and rs1801131 were significantly associated with risk of CHD in the homozygote comparisons (TT vs. CC at rs4846052: OR = 7.62 [95%CI 2.95-19.65]; GG vs. TT at rs1801131: OR = 5.18 [95%CI 2.77-9.71]). And six haplotypes of G-C (involving rs4846048 and rs2274976), A-C (involving rs1801133 and rs4846052), G-T (involving rs1801133 and rs4846052), G-T-G (involving rs2066470, rs3737964 and rs535107), A-C-G (involving rs2066470, rs3737964 and rs535107) and G-C-G (involving rs2066470, rs3737964 and rs535107) were identified to be significantly associated with risk of CHD. Additionally, we observed that a two-locus model involving rs2066470 and rs1801131 as well as a three-locus model involving rs227497, rs1801133 and rs1801131 were significantly associated with risk of CHD in the gene-gene interaction analyses. For three subtypes including atrial septal defect, ventricular septal defect and patent ductus arteriosus, similar results were observed. Our study indicated genetic polymorphisms of maternal MTHFR gene were significantly associated with risk of fetal CHD in the Chinese population. Additionally, there were significantly interactions among different SNPs on risk of CHD. However, how these SNPs affect the development of fetal heart remains unknown, and more studies in different ethnic populations and with a larger sample are required to confirm these findings.
Publication Date: 2021-06-16
Journal: BMC cardiovascular disorders

reductase mtrr(110)

Association of three missense mutations in the homocysteine-related MTHFR and MTRR gene with risk of polycystic ovary syndrome in Southern Chinese women.
The etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear. In humans, the level of homocysteine is mainly affected by two enzymes: methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR). While the activity of these two enzymes is mainly affected by three missense mutations, namely C677T (MTHFR), A1298C (MTHFR), and A66G (MTRR). This study aims to examine the association between the three missense mutations and PCOS and investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. A case-control study was designed, comprising 150 people with PCOS and 300 controls. Logistic regression analysis was used to assess the association between the three missense mutations and PCOS. Linear regression analysis was used to assess the association between the three missense mutations and the homocysteine level. Mediation analysis was used to investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. Following adjustments and multiple rounds of testing, MTHFR A1298C was found to be significantly associated with PCOS in a dose-dependent manner (compared to AA, OR = 2.142 for AC & OR = 3.755 for CC; P < 0.001). MTRR A66G was nominally associated with PCOS. Mutations in MTHFR A1298C and MTRR A66G were significantly associated with the homocysteine level. Mediation analysis suggested the effect of MTHFR A1298C on PCOS was mediated by homocysteine. MTHFR A1298C and MTRR A66G were associated with PCOS, and MTHFR A1298C might affect the risk of PCOS by influencing the homocysteine level.
Publication Date: 2021-01-08
Journal: Reproductive biology and endocrinology : RB&E

c677t mutation(109)

Combined Effect of MTHFR C677T and PAI-1 4G/5G Polymorphisms on the Risk of Venous Thromboembolism in Chinese Lung Cancer Patients.
Venous thromboembolism (VTE) is a common and potentially fatal complication in cancer patients. Although several genetic risk factors related to thrombophilia have been identified, their contributions for the occurrence of VTE in cancer patients have conflicting results. The aim of this study was to evaluated the gene polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor-1 (PAI-1) 4G/5G in lung cancer patients, with and without VTE, and the combined effect on the risk of VTE. 92 lung cancer patients diagnosed with VTE (VTE group) and 122 lung cancer patients without VTE (non-VTE group) were enrolled in the study. The gene polymorphisms were analyzed by the method of polymerase chain reaction-restriction fragment length polymorphism. Gene mutation of factor V Leiden was not detected both in non-VTE group and VTE group. The frequency of MTHFR C677T homozygous mutation in VTE group was 25.00%, higher than that in the non-VTE group without statistical difference. It was found that the PAI-1 4G4G genotype is associated with a higher risk of VTE (OR: 2.62, 95%CI: 1.19-5.75). Interestingly, the interaction between MTHFR C677T and PAI-1 4G/5G polymorphisms showed that the coexistence of the 2 homozygous mutation could further increase the risk of VTE. In conclusion, PAI-1 4G/5G polymorphism may be an increased risk factor for VTE among lung cancer patients in Chinese population. The homozygous MTHFR C677T mutation may be not a risk factor for VTE but increases the risk, accompanied with PAI-1 4G5G genotype.
Publication Date: 2021-07-31
Journal: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis

prothrombin g20210a(105)

The association between thrombophilic genes alterations and poor ovarian response in infertile women: a retrospective case-control study.
This research aimed to retrospectively investigate the possible association between poor ovarian stimulation and selected thrombophilia markers in Iranian women with infertility. For this study 100 Iranian infertile women, with a history of at least three Assisted Reproduction Technology (ART) failures (50 with a poor ovarian response and 50 with a normal response), referred to Royan Institute were selected. Targeted genetic variation evaluation for Factor V G1691A, F II Prothrombin G20210A, MTHFR C677T, MTHFR A1298C was performed by PCR-RFLP followed by Sanger Sequencing. The association between these variants and the ovarian response was examined. The results showed an association between Factor V G1691A mutation and poor ovarian response. The heterozygosity rate of the FVL was significantly different between poor responders compared with the normal response group (
Publication Date: 2021-05-04
Journal: Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology

gene mthfr(103)

Epigenetic Modification in Methylene Tetrahydrofolate Reductase (MTHFR) Gene of Women with Pre-eclampsia.
Genetic and epigenetic factors play significant roles in the aetio-pathogenesis of pre-eclampsia (PE). The effects may vary across racial and geographical boundaries. The role of epigenetic modification in pre-eclampsia was studied among African populations in Lagos, Nigeria. This study aimed to determine the pattern of Methylene tetrahydrofolate reductase gene (MTHFR) CpG island methylation in pre-eclampsia, and evaluate associated covariates. This study was an observational, cross-sectional, study conducted at the Lagos University Teaching Hospital and the Lagos State Island Maternity Hospital. A total of 400 pregnant women consisting of 200 pregnant women diagnosed with pre-eclampsia (study group) and 200 pregnant normotensive and apparently healthy women (control group) were recruited for the study. Demographic and clinical histories were obtained through questionnaires. The DNA Methylation status of the CpG Island in promoter region of the MTHFR gene was assessed using bisulphite conversion and methylation specific PCR method. The biochemical parameters measured in the study were: red cell folate, vitamin B12, plasma homocysteine (Hcy) and methylene tetrahydrofolate reductase enzyme level. Homozygous MTHFR CpG island hypomethylation pattern was significantly associated with pre-eclampsia ( Epigenetic modification plays significant role in the pathogenesis of pre-eclampsia.
Publication Date: 2021-04-06
Journal: Journal of obstetrics and gynaecology of India

control group(101)

[Association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of sporadic colorectal cancer].
Colorectal cancer (CRC) is a major global public health problem. Folate metabolism is involved in DNA synthesis, repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Common MTHFR C677T polymorphism was correlated to CRC. This case-control study was conducted to analyze the association between this polymorphism and the risk of sporadic CRC in a Moroccan population. The study involved 76 patients with sporadic colorectal cancer confirmed histologically and 182 patients (control group) without a history of cancer. Deoxyribonucleic acid (DNA) was isolated from peripheral blood and genotypes were determined using PCR-RFLP. The risk of association was estimated using odds ratio (OR) with 95% confidence interval. Genotype frequency of MTHFR in patients and in the control group was CC 34.1%, CT 56.6%, TT 9.21%, CC 51.6%, CT 42.8% and TT 6% respectively. CT genotype and its combination with TT genotype and allele T were associated with an increased risk of CRC and with an OR of 2.02 (with 95% confidence interval [CI]: 1.14-3.58, p = 0.01), 2.05 (95 % CI: 1.18-3.58, p= 0.01) and 1.61 (95% CI: 1.07-2.40, p=0.02). Homozygous TT weren´t a protection factor in our study, with an OR of 2.30 (95% CI: 0.81-6.52, p = 0.11). There was a statistically significant association between the MTHFR C677T variant and the risk of occurrence of sporadic colorectal cancer in the studied population.
Publication Date: 2021-06-15
Journal: The Pan African medical journal

gene c677t(99)

Roles of 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphisms in First-Episode, Drug-Naive Adult Patients With Depression.
5,10-Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is considered as a predisposition and promising genetic candidate to major depressive disorder (MDD), as it is associated with impaired one-carbon cycles, which may be involved in the pathogenesis of depression. Cortical thickness (CT) and subcortical structure volumes have been extensively studied in MDD and have been proposed as one of the phenotypes for MDD. We intend to discuss the association between CT, subcortical structure volume, and
Publication Date: 2020-12-29
Journal: Frontiers in psychiatry

homocysteine hcy(92)

A study of hyperhomocysteinemia in cerebral venous sinus thrombosis.
Vegetarianism may result in low vitamin B12 and acquired hyperhomocysteinemia leading to thrombotic conditions such as cerebral venous sinus thrombosis (CVST). The clinico-radiological presentation and outcome of patients with hyperhomocysteinemia may be different from those without, but there is a paucity of information. This study was undertaken to find out the relationship of homocysteine (Hcy) with vitamin B12, folic acid and methyltetrahydrofolate reductase (MTHFR) mutation in the patients with CVST, and compare clinico-radiological severity and outcome of patients with and without hyperhomocysteinemia. Ninety-six CVST patients in whom Hcy level was measured, were included, and their risk factors and neurological, magnetic resonance (MR) imaging and MR venography findings were noted. They were evaluated for prothrombotic conditions including Hcy, vitamin B12, folic acid and MTHFR 677C→T mutation. Three month outcome was categorized as death, poor and good. Seventy three per cent patients had risk factors; hyperhomocysteinemia in 52.1 per cent, protein S deficiency in 47.8 per cent, protein C deficiency in 19.4 per cent, MTHFR 677C→T mutation in 30.7 per cent, antinuclear antibody 11 per cent, and Factor V Leiden mutation in two per cent each. Thirty two per cent patients with hyperhomocysteinemia had no other thrombotic cause, and 22 per cent of them had either vitamin B12 and or folic acid deficiency only. The patients with hyperhomocysteinemia more frequently had vitamin B12 deficiency (70 vs. 13%), MTHFR 677C→T mutation (47.5 vs. 9.1%) and superior sagittal sinus thrombosis (78 vs. 56.5%) than normal Hcy group. The clinico-radiological severity and outcome were similar. Hyperhomocysteinemia was an important correctable risk factor of CVST in patients from northern India, and majority of them had either low vitamin B12 level or MTHFR mutation.
Publication Date: 2021-06-20
Journal: The Indian journal of medical research

c677t a1298c(76)

MTHFR (C677T, A1298C), FV Leiden polymorphisms, and the prothrombin G20210A mutation in arterial ischemic stroke among young tunisian adults.
Arterial ischemic stroke (AIS) in young adults is less common in older adults, but the underlying pathogenesis and risk factors are more multi-faceted. The role of inherited thrombophilia such as 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, (C677T and A1298C), factor V of Leiden (FVL) polymorphism, and the prothrombin G20210A mutations remains unclear. This study aims to evaluate the role of prothrombin genetic factor in AIS among young adults in Tunisia and to assess the synergistic effect between thrombogenic mutations in the pathogenesis of AIS. In this case-control study, blood samples were collected from patients and healthy controls, all matched for age and gender. The difference between them is evaluated by using the chi-square test. The odds ratio (OR) was carried out to evaluate the associations between each polymorphism and AIS risk using a binary logistic regression model. Values were considered statistically significant when p < 0.05. Patients carrying simultaneously the MTHFR polymorphisms (677T and 1298C) have a higher risk to develop AIS compared to controls. The heterozygous variants FVL increased the risk of AIS only when it is associated with MTHFR C677T or MTHFR A1298C polymorphisms. In conclusion, our study confirmed the involvement of MTHFR polymorphisms as AIS's important risk factors. The existence of FVL polymorphism or prothrombin G20210A mutation alone doesn't correlate with the occurrence of stroke. We assume that the presence of both MTHFR and FVL polymorphisms has a synergistic effect and increased the risk of the AIS.
Publication Date: 2021-01-06
Journal: Metabolic brain disease

tt vs(76)

The association between 5, 10 - methylenetetrahydrofolate reductase and the risk of unexplained recurrent pregnancy loss in China: A Meta-analysis.
To analyze the correlation between gene polymorphisms of 5,10- methylenetetrahydrofolate reductase (MTHFR) and risk of unexplained recurrent pregnancy loss (URPL) in Chinese women. Eligible studies were searched in Pubmed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Established inclusion criteria were used to screening articles, subsequently evaluate the quality of the included studies, Stata 16.0 PM and RevMan 5.3 software were conducted for meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was determined to assess the relationship between MTHFR and risk of URPL in Chinese women. For MTHFR C677T, fifty studies were included, involving 6677 URPL cases and 8111 controls. The overall results showed that MTHFR C677T was significantly correlated with URPL risk, especially in the homozygous model (TT vs CC; OR 3.06; 95% CI 2.56-3.66). For MTHFR A1298C, twenty-first studies were included, involving 3439 URPL cases and 3155 controls. The results showed that MTHFR A1298C was also significantly correlated with URPL risk in recessive (CC vs AC + AA; OR 1.55; 95% CI 1.25-1.93) and homozygous (CC vs AA; OR 1.53; 95% CI 1.22-1.91) models. In addition, sub-group results showed that no significant difference between north and south China populations in the MTHFR gene polymorphisms and URPL risk. Of note, the patients carrying MTHFR C677T and MTHFR A1298C joint mutants had no synergistic effect (OR 2.71; 95% CI 0.84-8.70) on the occurrence of URPL compared with the wild-type homozygous genotype (MTHFR 677CC/ MTHFR 1298AA). Studies included in this meta-analysis suggested that MTHFR 677T allele and 677TT genotype and MTHFR 1298CC genotype were both associated with URPL; testing MTHFR C677T gene polymorphism was a more appropriate target compared with other mutations in the prediction of URPL.
Publication Date: 2021-04-29
Journal: Medicine

mthfr mtr(66)

Folate metabolizing gene polymorphisms and genetic vulnerability to preterm birth in Korean women.
The folate metabolism that converts homocysteine to methionine is closely related to the accumulation of homocysteine. Increased homocysteine levels lead to an impaired antithrombotic function of the vascular endothelium and uterine-placental circulation, resulting in abnormal pregnancy outcomes. Previous studies have reported that gene polymorphisms in folate metabolism are associated with the development of preterm birth (PTB) in various populations. we performed a case-control study to evaluate the association between five polymorphisms in folate metabolic genes (MTHFR, MTR, MTRR, TCN2) and PTB. In this study, a total of 254 subjects were analyzed (111 patients with PTB and 143 women at ≥ 38 weeks of gestation). Genotype and allele frequency differences between patients and control groups and the Hardy-Weinberg equilibrium were assessed using a Chi-square test. For evaluation indicators, odds ratios (ORs) of 95% confidence intervals (CI) were estimated. In addition, we analyzed the combined genotype frequencies of SNPs of folate-metabolizing genes to measure gene-gene interactions for PTB. Our results showed that the MTR rs1805087 GG (p = 0.031), and TCN2 rs1801198 CG genotype (OR 0.53, 95% CI 0.288-0.980, p = 0.042) were significantly associated with PTB. The MTHFR rs4846049 AA showed a marginal trend toward significance (OR 0.15, 95% CI 0.018-1.205, p = 0.041). In particular, the combined genotypes, including MTHFR rs1537514 CC-MTRR rs1801394 GG, MTHFR rs1537514 CC-TCN2 rs1801198 CG, and MTR rs1805087 AA-TCN2 rs1801198 CG, have significant interactions with PTB (OR 0.49, 95% CI 0.248-0.992, p < 0.05). The polymorphisms of folate metabolic genes may have a genetic association with the development of PTB in Korean women. A larger sample set and functional studies are required to further elucidate our findings.
Publication Date: 2021-05-25
Journal: Genes & genomics

vs cc(62)

Association Between MTHFR C677T Polymorphism and Susceptibility to Autism Spectrum Disorders: A Meta-Analysis in Chinese Han Population.
Prior studies have examined the influence of MTHFR C677T on autism susceptibility, however, there are no consensus conclusions and specific analyses of a Chinese population. This meta-analysis included a false-positive report probability (FPRP) test to comprehensively evaluate the association of MTHFR C677T polymorphism with autism susceptibility among a Chinese Han population. A large-scale literature retrieval was conducted using various databases including PubMed, Embase, Wan Fang, and the Chinese National Knowledge Infrastructure (CNKI) up to July 31, 2020, with a total of 2,258 cases and 2,073 controls included. The strength of correlation was assessed by odds ratios (ORs) and 95% confidence intervals (95% CIs). MTHFR C677T showed a significant correlation with increased ASD susceptibility under all genetic models (T vs. C, OR = 1.89, 95% CI 1.28 to 2.79; TT vs. CC: OR = 2.44, 95% CI 1.43 to 4.15; CT vs. CC, OR = 1.73; 95% CI 1.19 to 2.51; CT + TT vs. CC: OR = 2.03, 95% CI 1.31 to 3.15; TT vs. CT + CC, OR = 1.95, 95% CI 1.21 to 3.13). Stratification analysis by region also revealed a consistent association in the Northern Han subgroup, but not in the Southern Han subgroup. Pooled minor allele frequency (MAF) of 30 studies were 45% in Northern Han and 39% in Southern Han. To avoid a possible "false positive report," we further investigated the significant associations observed in the present meta-analysis using the FPRP test, which consolidated the results. In conclusion, MTHFR C677T polymorphism is associated with the increased risk of autism in China, especially in Northern Han. For those mothers and children who are generally susceptible to autism, prenatal folate and vitamin B12 may reduce the risk that children suffer from autism, especially in Northern Han populations. In the future, more well-designed studies with a larger sample size are expected.
Publication Date: 2021-03-30
Journal: Frontiers in pediatrics

polymorphism pcr-rflp(60)

Analysis OF C677T polymorphism in methylene tetrahydrofolate reductase (MTHFR) gene as a risk factor for congenital talipes equino varus (CTEV).
Clubfoot is a common congenital foot deformity. Low folate status in mothers has been associated with CTEV. Folate metabolism might be affected by Methylene Tetrahydrofolate Reductase (MTHFR) gene polymorphism. The present study was aimed to investigate MTHFR C677T polymorphism and its association with CTEV. This is a Case-mother-Dyad study with 30 pairs of cases and controls. Single Nucleotide Polymorphism (SNP) analysis of the MTHFR gene was done in this hospital-based study by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). In this study, we observed less relative risk of CTEV in presence of C allele as compared to T allele in children, with Relative Risk- 0.6281 and likelihood ratio of 0.5714. While analysing the correlation of genotype variation in cases (CC = 8(26.66%) and CT = 22(73.33%)) with there biological mother (CC = 13(43.33%) and CT = 17(56.66%)), no significant correlation (p = 0.3110) was found between cases and their biological mother genotype. Among the enrolled cases, there was a significant association of increased CTEV risk with 677T variant allele of MTHFR gene. Also, maternal MTHFR genotype was not found to influence CTEV risk of offspring.
Publication Date: 2021-03-16
Journal: Journal of clinical orthopaedics and trauma

mthfr 1298a(59)

MTHFR 1298A>C Substitution is a Strong Candidate for Analysis in Recurrent Pregnancy Loss: Evidence from 14,289 Subjects.
We undertook meta-analyses on MTHFR 1298A>C substitution for critically evaluating its association with recurrent pregnancy loss (RPL). MTHFR genotype data for 5888 cases and 8401 controls from 39 studies were pooled to perform this meta-analyses. Genotype data were screened, scrutinized, pooled, analysed and subjected to sensitivity analysis to carefully evaluate the association between MTHFR 1298A>C and recurrent pregnancy loss. Genetic associations were sought using dominant, recessive and co-dominant models of genetic testing with odds ratio and 95% Confidence interval (CI) as the effect measures. Further analyses were undertaken by classifying the studies into Caucasian and East Asian sub-groups. Genetic heterogeneity was tested before pooling the data across studies. For assessing publication bias, Egger's intercept test was undertaken. We found a significant association of 1298A>C substitution with increased risk of RPL in the dominant (P=0.000; OR = 1.58; 95% CI =1.25-1.99) as well as recessive (P=0.000; OR = 1.66; 95% CI =1.25-2.20) models. In sub-group analysis, we observed a significant association of the polymorphism with RPL in the Caucasian populations using dominant (P=0.000; OR = 1.98; 95% CI =1.42-2.76) and recessive (P=0.000; OR = 2.20; 95% CI =1.49-3.24) models. However, this substitution showed no association with RPL in the East Asian populations (P=0.149; OR = 1.187; 95% CI =0.94-1.50). MTHFR 1298A>C substitution shows association with the risk of recurrent pregnancy loss. The association is in a population-specific manner with the substitution being a strong risk factor only in the Caucasian populations.
Publication Date: 2021-03-21
Journal: Reproductive sciences (Thousand Oaks, Calif.)

dominant model(55)

Association between MTHFR polymorphisms (MTHFR C677T, MTHFR A1298C) and recurrent implantation failure: a systematic review and meta-analysis.
To investigate whether polymorphism of MTHFR C677T or MTHFR A1298C is associated with recurrent implantation failure (RIF). This is a systematic review and meta-analysis. Pubmed, EMBASE, and CNKI (China national Knowledge Infrastructure) were searched for case-control studies that evaluated the associations between MTHFR polymorphisms (MTHFR C677T and MTHFR A1298C) and RIF. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were reported to evaluate the strength of association. Data were synthesized using the random-effect model. Nine case-control studies consisted of 1812 women were included in the quantitative meta-analyses (754 were RIF patients, 1058 were control participants). The synthesized results showed that polymorphism of MTHFR C677T (allele model: OR 1.23, 95% CI 0.99-1.53; dominant model: OR 1.24, 95% CI 0.99-1.54; recessive model: OR 1.31, 95% CI 0.78-2.12; homozygotic model: OR 1.39, 95% CI 0.84-2.28; heterozygotic model: OR 1.14, 95% CI 0.90-1.45) or MTHFR A1298C (allele model: OR 1.11, 95% CI 0.78-1.59; dominant model: OR 0.91, 95% CI 0.65-1.26; recessive model: OR 2.04, 95% CI 0.90-4.64; homozygotic model: OR 1.86, 95% CI 0.79-4.38; heterozygotic model: OR 0.77, 95% CI 0.59-0.99) was not significantly associated with RIF. Significant association of MTHFR polymorphisms (including MTHFR C677T and MTHFR A1298C) and RIF could not be confirmed.
Publication Date: 2020-11-01
Journal: Archives of gynecology and obstetrics

cc ct(48)

Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women.
Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL,
Publication Date: 2021-05-01
Journal: Nutrients

χ 2(15)

CT genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is protector factor of major depressive disorder in the Tunisian population: a case control study.
Major depressive disorder (MDD) is a common psychiatric disorder with considerable mortality. Death from unnatural causes, largely suicidal or quasi-suicidal, has a particularly high risk for the functional disorders, especially depression and schizophrenia. One of the prospective risk factors for this disease is hyperhomocysteinemia and folate deficiency. The methylenetetrahydrofolate reductase (MTHFR) gene encodes for a 5-methylenetetrahydrofolate reductase involved in folate metabolism and neurotransmitter synthesis. The aim of this research is to study the association between the C677T polymorphism of MTHFR gene and depression in Tunisian population, to explore their relationship with clinical and therapeutic characteristics of this disease. And it may lead to discover a novel marker to identify a patient with a higher risk of development of depressive disorder to be. This marker can be used for better therapeutic management and prevent disease installation. Our study included 208 depressive patients, 187 controls aged between 44.1 ± 13.5 and 38.9 ± 13.2 years, respectively. MTHFR gene polymorphisms were determined by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). No significant difference was detected in the distribution of the genotype frequencies of MTHFR C677T polymorphisms (χ (2) = 5.443, df = 2, p = 0.066) between patients and controls. But when we study the risk of these genotypes, CT genotype is significantly more frequent in controls compared to patients, it may be a protection from depression (OR = 0.655, CI 95 % = 0.432-0.995, p = 0.047, OR* = 0.638, CI 95 %* = 0.415-0.983, p* = 0.04, before and after adjustment). Women, TT Genotype can increase four times the risk to be depressive. Addictive behavior seems to be associated with CT genotype and there was no significant association between clinical and therapeutic characteristics and this polymorphism. This paper is the first study to prove that CT genotype of MTHFR C677T polymorphism may protect from depression and TT genotype seems to be associated with women's depression. Further studies are required with other polymorphisms and biochemical factors that must be investigated to clarify the implication of MTHFR C677T polymorphism in the pathophysiology of depression.
Publication Date: 2016-08-02
Journal: Annals of general psychiatry


Effects of Ocufolin on retinal microvasculature in patients with mild non-proliferative diabetic retinopathy carrying polymorphisms of the MTHFR gene.
To evaluate effects of Ocufolin on retinal microvasculature in mild non-proliferative diabetic retinopathy patients who carried methylenetetrahydrofolate reductase (MTHFR) polymorphisms (DR+MTHFRP). This 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. BCVA 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. A 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.
Publication Date: 2021-09-16
Journal: BMJ open diabetes research & care


Early-Onset Schizophrenia: A Special Phenotype of the Disease Characterized by Increased MTHFR Polymorphisms and Aggravating Symptoms.
Patients with early-onset schizophrenia usually exhibit more severe symptoms, revealing a potentially distinctive disease phenotype. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate conversion and methylation modification associated with the disease. We aimed to investigate the potential effects of In 177 patients with schizophrenia, Higher levels of symptom severity and Aggravating symptoms, increased
Publication Date: 2021-08-12
Journal: Neuropsychiatric disease and treatment


Methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF) polymorphisms in Brazilian patients with Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
The folate pathway is involved in hepatic carcinogenesis and angiogenesis. Polymorphisms in genes related to such processes, including methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF)] may play an important role in the development of hepatocellular carcinoma (HCC). The objective of this study was to evaluate MTHFR and VEGF polymorphisms in Brazilian patients with hepatitis C virus (HCV)-related HCC. A total of 119 patients diagnosed with confirmed HCC and HCV were included in the study. SNP genotyping assays were performed using real-time PCR. VEGFA (rs2010963, rs3025039, and rs833061) and MTHFRC677T (rs1801133, rs1801131) polymorphisms were evaluated. The C alleles of MTHFR (rs1801131) and VEGF (rs2010963) were associated with protection against the development of multinodular HCC, while the T allele of MTHFR (rs1801133) was associated with a higher risk of multinodular presentation [p=0.04 OR 1.835 CI (1.022-3.297)]. Multivariate analysis revealed that the GG/GC genotypes of VEGF rs2010963 were independently associated with multinodular tumors at diagnosis (p=0.013; OR 4.78 CI (1.38-16.67)]. Our results suggest that these polymorphisms may increase the risk of rapid tumor progression in patients with HCV infection. This subgroup of patients with HCC and who present polymorphism is more likely to be diagnosed with multinodular disease and not be amenable to receiving curative treatments. These data must be validated in larger cohorts, and the screening intervals can be customized based on genetic history.
Publication Date: 2021-10-14
Journal: Clinics (Sao Paulo, Brazil)


The combination of methylenehydrofolate reductase C677T polymorphism screening and gastrointestinal tumor markers detection may be an early screening method for gastrointestinal cancer related to helicobacter pylori infection.
Methyltetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, and its single nucleotide polymorphism (SNP) site C677T may be associated with gastrointestinal cancer. However, the relationship between MTHFR C677T polymorphism and gastrointestinal tumor markers carcinoma embryonic antigen (CEA), carbohydrate antigen 199 (CA199) and carbohydrate antigen 724 (CA724) in
Publication Date: 2021-09-16
Journal: Genes & diseases


MTHFR Knockdown Assists Cell Defense against Folate Depletion Induced Chromosome Segregation and Uracil Misincorporation in DNA.
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
Publication Date: 2021-09-11
Journal: International journal of molecular sciences


Association of MTHFR and TYMS gene polymorphisms with the susceptibility to HCC in Egyptian HCV cirrhotic patients.
Identification of host genetic factors influencing the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection may help to refine patients' selection to benefit from specific preventative measures and/or adapted screening policies. Thus, this study aimed to investigate the association of MTHFR c.677C > T and c.1298A > C in addition to TYMS 3'-UTR 6-bp ins/del polymorphisms with the susceptibility to HCV-related HCC in an Egyptian population. Polymerase chain reaction-restriction fragment length polymorphism was performed to genotype the polymorphisms in 194 HCV-infected patients subdivided into liver cirrhotic (LC, n = 104) and HCC (n = 90) patients as well as 100 healthy subjects. In healthy controls, the MTHFR c.677C > T polymorphism under the homozygous and recessive models (p = 0.005) and the c.1298A > C polymorphism under all the tested genetic models (p-values range from < 0.001 to 0.007) were associated with an increased risk of HCC. In LC patients, the MTHFR c.677C > T polymorphism under the homozygous, dominant, and recessive models (p-values range from 0.001 to 0.007), as well as MTHFR c.1298A > C under the homozygous model only (p = 0.014), increased the susceptibility to HCC. The C/C and T/C haplotypes of MTHFR c.677C > T and MTHFR c.1298A > C polymorphisms were contributed to an increased risk of healthy subjects to develop HCC (p-values range from < 0.001 to 0.015), while only the T/C haplotype was associated with the progression of HCC in LC patients (p = 0.001). In conclusion, MTHFR c.677C > T and c.1298A > C in addition to their haplotypes may contribute to the development of HCV-related HCC in an Egyptian population. These findings may aid in the early diagnosis and management of HCC.
Publication Date: 2021-07-24
Journal: Clinical and experimental medicine


Shifting landscapes of human MTHFR missense-variant effects.
Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.
Publication Date: 2021-07-03
Journal: American journal of human genetics


Epigenetics of Male Infertility: The Role of DNA Methylation.
In recent years, a number of studies focused on the role of epigenetics, including DNA methylation, in spermatogenesis and male infertility. We aimed to provide an overview of the knowledge concerning the gene and genome methylation and its regulation during spermatogenesis, specifically in the context of male infertility etiopathogenesis. Overall, the findings support the hypothesis that sperm DNA methylation is associated with sperm alterations and infertility. Several genes have been found to be differentially methylated in relation to impaired spermatogenesis and/or reproductive dysfunction. Particularly, DNA methylation defects of MEST and H19 within imprinted genes and MTHFR within non-imprinted genes have been repeatedly linked with male infertility. A deep knowledge of sperm DNA methylation status in association with reduced reproductive potential could improve the development of novel diagnostic tools for this disease. Further studies are needed to better elucidate the mechanisms affecting methylation in sperm and their impact on male infertility.
Publication Date: 2021-08-10
Journal: Frontiers in cell and developmental biology


Single Nucleotide Polymorphisms in
Characterization of allelic variants is relevant to demonstrate associations among genetic background and susceptibility to develop cardiovascular diseases, which are the main cause of death in Chile. Association of APOB, APOE, and MTHFR polymorphisms with higher lipid levels and the risk of developing hypertension and cardiovascular diseases have been described. Thus, the aim of this study was to assess genotype distribution and relative allelic frequency of ApoB rs693, ApoE rs7412, ApoE rs429358, MTHFR rs1801131, and MTHFR rs1801133 allelic variants and their effects on lipid profile in young healthy men and women from Northern Chile. A group of 193 healthy subjects were enrolled for this study. Genotyping of rs693 (
Publication Date: 2021-10-08
Journal: Frontiers in genetics


Homozygous methylentetrahydrofolate reductase C667T genotype anticipates age at venous thromboembolism by one decade.
The aim of the study was to compare age at first venous thromboembolism (VTE), plasma homocysteine and activated partial thromboplastin time ratio (aPTTr) amongst unprovoked VTE patients with the methylentetrahydrofolate reductase (MTHFR) C667T genotypes, and to identify predictors of age at first VTE, of plasma homocysteine and of the aPTTr; to evaluate whether heterozygous or homozygous prothrombin (PT) G20210A mutation lowered the age at first VTE when associated with MTHFR TT. Retrospective cohort study on 259 MTHFR TT, 76 MTHFR TC and 64 MTHFR CC participants with unprovoked VTE; each participant contributed age, sex, age at VTE, history of dyslipidaemia, hypertension, smoking, homocysteine (measured by enzyme immunoassay) and aPTTr (measured by standard coagulation assay). Age at first VTE was lower in MTHFR TT than MTHFR TC and CC (41 ± 14 vs. 50 ± 16 vs. 51 ± 12 years, respectively, P < 0.0001); plasma homocysteine was higher in MTHFR TT than in the other groups (22 ± 21 vs. 12 ± 11.6 vs. 10 ± 3.3 μmol/l, respectively, P = 0.0005) whilst aPTTr was not different. MTHFR TT independently predicted age at first VTE (P = 0.001), plasma homocysteine (P < 0.0001) alongside sex (P = 0.0007), age and smoking (P = 0.03 for both). Compound MTHFR TT with PT GA or AA had no lowering effect on age at first VTE compared with MTHFR TT alone (41 ± 13 vs. 41 ± 14 years). Plasma homocysteine inversely related to aPTTr in the MTHFR TT group (P = 0.003). MTHFR TT anticipates age at first VTE by an average of 10 years compared with MTHFR TC and CC genotypes.
Publication Date: 2021-08-17
Journal: Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis


C677T and A1298C MTHFR gene polymorphisms and response to fluoropyrimidine-based chemotherapy in Mestizo patients with metastatic colorectal cancer.
To assess the association between C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and response to first-line fluoropyrimidine-based chemotherapy for metastatic colorectal adenocarcinoma. A total of 68 patients were prospectively followed up in San Juan de Dios Hospital (San José, Costa Rica) from January 2019 to November 2020. Patients received first-line therapy with capecitabine or 5-fluorouracil in combination with oxaliplatin or irinotecan. Germline and somatic DNA was extracted from blood samples and paraffin-embedded tissue, respectively. Overall response rate (partial response + complete response) was assessed according to RECIST 1.1 criteria. Cox regression models were performed to identify the effect of MTHFR C677T and A1298C SNPs on progression-free survival (PFS) and overall survival (OS) (NCT registration number: 03852290). Patients harboring one or both T alleles of the MTHFR C677T SNP had better overall response than homozygous wild-type individuals [odds ratio (OR): 3.21; 95% confidence interval (CI), 1.05-9.81; P = 0.03]. No association was found between the MTHFR A1298C genotypes and overall response (OR: 0.75; 95% CI, 0.26-2.20; P = 0.60). Patients with the MTHFR 677 TT and CT genotypes had longer PFS than CC individuals (hazard ratio: 0.53; 95% CI, 0.28-0.98; P = 0.045), even after adjustment for confounders (hazard ratio: 0.50; 95% CI, 0.25-0.98; P = 0.04). We found no association between the MTHFR A1298C SNP and PFS (hazard ratio: 1.35; 95% CI, 0.72-2.55; P = 0.34). None of the SNPs was associated with OS. Patients carrying at least one mutant allele of the MTHFR C677T SNP had a better overall response and longer PFS than wild-type homozygous patients.
Publication Date: 2021-06-12
Journal: Pharmacogenetics and genomics


Minor allele of rs55763075 located in MTHFR is associated with the risk of cognitive impairment after anesthesia via modulating miR-34b.
This study aimed to investigate the association between cognitive impairment after general anesthesia and rs55763075 polymorphisms. We enrolled and grouped patients undergoing general anesthesia according to their genotypes of rs55763075 polymorphism. Mini-Mental State Examination (MMSE) scoring was performed to evaluate the cognitive status of patients. Quantitative real-time PCR was carried out to analyze the expression of methylenetetrahydrofolate reductase (MTHFR) mRNA and miR-34b while Western blot was performed to evaluate the expression of MTHFR protein. Furthermore, we studied the effect of rs55763075 polymorphism on the expression of MEHFR via luciferase assay. Accordingly, we found that the MMSE score in GG/GA groups was significantly higher than that in AA group. And a significant reduction of MTHFR mRNA expression was observed in the serum and peripheral blood mononuclear cells (PBMCs) of patients carrying AA genotype compared with the patients carrying GG/GA genotypes. Moreover, the MTHFR expression was much lower in the cultured AA-genotyped cells transfected with miR-34b. Luciferase assay results also showed that miR-34b transfection reduced luciferase activity in the cells carrying A allele but not in cells carrying G allele. In summary, the data of this study showed that minor allele (A) of rs55763075 polymorphisms in the 3'-untranslated region of MTHFR mRNA generated a potential binding site for miR-34b, which led to reduced level of folic acid in the patients carrying the AA genotype. Furthermore, we found that the MMSE score of AA-genotyped patients was lower than that of patients carrying GG/GA genotypes.
Publication Date: 2021-05-29
Journal: Scientific reports


Maternal Folic Acid Intake and Methylation Status of Genes Associated with Ventricular Septal Defects in Children: Case-Control Study.
DNA methylation is the best epigenetic mechanism for explaining the interactions between nutrients and genes involved in intrauterine growth and development programming. A possible contributor of methylation abnormalities to congenital heart disease is the folate methylation regulatory pathway; however, the mechanisms and methylation patterns of VSD-associated genes are not fully understood. To determine if maternal dietary intake of folic acid (FA) is related to the methylation status (MS) of VSD-associated genes (AXIN1, MTHFR, TBX1, and TBX20). Prospective case-control study; 48 mothers and their children were evaluated. The mothers' dietary variables were collected through a food frequency questionnaire focusing on FA and the consumption of supplements with FA. The MS of promoters of genes was determined in the children. The intake of FA supplements was significantly higher in the control mothers. In terms of maternal folic acid consumption, significant differences were found in the first trimester of pregnancy. Significant differences were observed in the MS of MTHFR and AXIN1 genes in VSD and control children. A correlation between maternal FA supplementation and MS of AXIN1 and TBX20 genes was found in control and VSD children, respectively. A lower MS of AXIN1 genes and a higher MS of TBX20 genes is associated with FA maternal supplementation.
Publication Date: 2021-07-03
Journal: Nutrients


Stroke in Young Military Men With Heterozygous for MTHFR Gene Mutation or Factor V Leiden Gene Mutation Associated With Patent Foramen Ovale: Report of Two Cases and Therapeutic Strategy.
We report two cases of Brazilian patients (a 22-year-old male and a 48-year-old male) with ischemic stroke, whose arterial vascular study and echocardiographic investigation did not reveal any steno-occlusive arterial disease or typical cardioembolic finding, such as atrial fibrillation or myocardial dysfunction. A transcranial Doppler ultrasound and a transesophageal echocardiogram showed a patent foramen ovale (PFO), and the laboratory screening for coagulation abnormalities showed heterozygosity for MTHFR C677T and A1298C in one of the patients and heterozygosity for factor V Leiden gene mutations in the other patient. The significance of the association of PFO with Methylenetetrahydrofolate (MTHFR) C677T and A1298C variants or factor V Leiden mutation is discussed as a possible cause of ischemic stroke through paradoxical embolism from a venous source. There is a high prevalence of these two mentioned conditions in the general population, so we discuss two cases in which indication for anticoagulant therapy or percutaneous closure of PFO prevails.
Publication Date: 2021-05-17
Journal: Military medicine


Association of laboratory parameters and genetic polymorphisms with ischemic stroke in Chinese Han population.
Numerous genetic polymorphisms and clinical laboratory parameters are associated with ischemic stroke (IS). However, the results of such studies have frequently been inconsistent. The aim of the present study was to evaluate associations between clinical laboratory parameters with genetic polymorphisms that influence the risk of IS in a Chinese Han population. Clinical laboratory parameters were measured by an automatic biochemical analyzer. Genotype and allele frequencies of the polymorphisms angiotensin-converting enzyme (ACE) D/I, methylene tetrahydrofolate reductase (MTHFR) C677T and β-fibrinogen (β-Fg) A/G, 455/148T/C were characterized by restriction fragment length polymorphism-PCR. Furthermore, the gene polymorphisms plasminogen activator inhibitor (PAI)-1-4G/5G and apolipoprotein E (ApoE) ε2,3,4 were characterized by allele-specific PCR. The associations of genotype and allele frequencies of the six risk genes in different groups with clinical laboratory parameters were analyzed by chi-square tests. The distribution maps of the polymorphisms of the six genes and clinical laboratory parameters were compared between a control group of 336 healthy individuals and 762 patients with IS. Certain laboratory parameters were associated with ACE I/D, β-Fg-455 A/G and PAI-1 4G/5G. The D allele of ACE I/D was associated with high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C). Furthermore, high levels of fasting blood glucose, triglyceride and LDL-C were risk factors for IS. There were significant differences in the genotype frequencies of ACE I/D, β-Fg-455 A/G and β-Fg-148 T/C between the IS and the control group. In conclusion, clinical laboratory parameters were associated with the risk of polymorphisms of IS-related genes. The present results support the determination of a range of control values of clinical laboratory parameters for common genotypes in patients with diabetes and hyperlipidemia as a strategy for the early prevention of IS.
Publication Date: 2021-04-02
Journal: Experimental and therapeutic medicine


Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia.
To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680, -675, -556, -464, -317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants.
Publication Date: 2019-12-02
Journal: Journal of B.U.ON. : official journal of the Balkan Union of Oncology


Homocysteinemia is Associated with the Presence of Microbleeds in Cognitively Impaired Patients.
Homocysteine is possibly associated with cerebral small vessel diseases such as leukoaraiosis, silent brain infarction and cerebral microbleeds, which are in turn associated with cognitive dysfunction. We aimed to examine the relationships between cerebral microbleeds (CMBs) and plasma total homocysteine (tHcy) level, methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cognitive function. A total of 819 patients with memory disturbance who visited a dementia clinic consecutively were included in this study. We retrospectively collected demographic, clinical and laboratory data including tHcy level, MTHFR C677T polymorphism and Mini-Mental State Examination (MMSE). All patients underwent brain MRI including fluid attenuated inversion recovery (FLAIR) image and T2*-weighed gradient-echo (GRE) image. Logistic regression analysis was performed to test the association between risk factors and the presence of microbleeds. One hundred and sixty-one (19.7%) patients had CMBs, of whom 88 (54.7%) had CMBs in the lobar region. CMBs were more common in older hypertensive male patients with hyperhomocysteinemia. In multivariable analysis, plasma tHcy remained an independent predictor of the presence of CMBs after adjusting other confounders (OR: 1.035, 95% CI: 1.009-1.062, p = 0.009). Higher plasma tHcy level was also associated with number of CMBs, TT MTHFR genotype, and lower MMSE scores. Elevated plasma tHcy level is related to high prevalence of CMBs and cognitive dysfunction. Lowering plasma tHcy could be helpful in cognitively impaired patients who have CMBs or the MTHFR TT genotype.
Publication Date: 2020-09-30
Journal: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association