Effect Of Methylenetetrahydrofolate Reductase C677T Polymorphism Research Articles

Effects of MTHFR C677T polymorphism on homocysteine and vitamin D in women with polycystic ovary syndrome

ObjectivesTo evaluate the correlation between serum vitamin D, homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism in women with polycystic ovary syndrome (PCOS).Study designWe retrospectively compared the serum homocysteine and vitamin D levels and the MTHFR C677T polymorphism in 104 PCOS patients and 104 controls. Parameters related to PCOS were statistically analysed. ResultsComparative analysis revealed that women with PCOS had significantly greater serum homocysteine levels (P = 0.002) and lower vitamin D concentrations (P = 0.040) than controls. The distribution frequency of the MTHFR C677T genotype did not significantly differ between the PCOS group and the control group. (P > 0.05). In the PCOS group, the serum level of homocysteine in the TT group was significantly greater than that in the CT (P = 0.003) and CC (P = 0.002) groups and the level of vitamin D in the TT group was significantly less than that in the CC (P < 0.001) and CT (P = 0.172) groups. The results were similar when the PCOS and control groups were divided according to whether they had insulin resistance. Vitamin D levels were significantly negatively correlated with homocysteine levels in all PCOS patients (r = −0.281, P = 0.004), similarly, vitamin D levels were negatively correlated with homocysteine levels in the CC, CT and TT of PCOS patients. According to multivariate analysis, vitamin D concentration was an independent risk factor for hyperhomocysteinaemia (adjusted OR 1.372, 95 % CI: 1.100–1.712). ConclusionsNo significant differences were found in the distributions of MTHFR C677T genotypes between the PCOS and control groups but these genotypes affected the patients’ serum homocysteine and vitamin D concentrations. Women with the TT genotype have significantly lower vitamin D levels and higher homocysteine levels than women with the CC and CT genotypes. However, because of the limitations of this investigation, large-sample, high-quality prospective studies are needed to further verify these results in the future.

Correlation analysis of age and MTHFR C677T polymorphism with sperm motility and sperm DNA integrity.

Several factors, including age and polymorphisms in genes such as MTHFR, affect sperm quality. However, the relationship between MTHFR C677T polymorphism and infertility remains unclear. Hence, the purpose of this study was to investigate the effects of age and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on the forward progressive sperm motility and sperm DNA integrity. For this purpose, a total of 845 men were recruited from the hospital's infertility clinic for semen analysis, sperm DNA integrity testing, and MTHFR C677T genotyping. The participants were grouped by age (<30 years, 30-35 years, >35 years) to determine the relationship between age and the progressive motility of sperms (PR%) and sperm DNA integrity. The effect of MTHFR C677T polymorphism on sperm motility and sperm DNA integrity was also analyzed in all the age groups. Results showed that PR% and DNA fragmentation index (DFI) differed significantly among the groups (P<0.001). The correlation analysis showed that age was positively correlated with DFI and negatively correlated with PR%. DFI correlated negatively with PR% (P <0.01). When the age groups were classified based on the C677T genotype, we observed that PR% and DFI did not differ significantly between different genotypes within the same age range (P>0.05). The conclusion was that age exerted a negative effect on sperm motility and sperm DNA integrity. Age correlated positively with DFI and negatively with PR%. MTHFR C677T polymorphism did not affect forward motile sperm count and sperm DNA integrity. Our observations will be useful for fertility guidance and MTHFR genotype interpretation in the clinic for couples of childbearing age.

Effects of MTHFR C677T polymorphism on vitamin D, homocysteine and natural killer cell cytotoxicity in women with recurrent pregnancy losses.

Is there any relationship between vitamin D [25 (OH) vitamin D], total plasma homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in women with recurrent pregnancy losses (RPL)? Women with MTHFR 677TT (homozygous mutation, TT) genotype have significantly lower vitamin D levels, higher homocysteine and natural killer (NK) cell cytotoxicities than those of women with MTHFR 677CC (wild type, CC) and 677CT (heterozygous mutation, CT) genotypes. Vitamin D insufficiency, MTHFR C677T polymorphism and hyperhomocysteinemia have been reported as risk factors for RPL. However, the relationship between these risk factors is not known in this population. This is a retrospective cross-sectional study, including 837 women with RPL, who were enrolled in Reproductive Medicine and Immunology, Chicago Medical School, between 2012 and 2017. Women with two or more RPL prior to 20 weeks of gestation were included. To investigate whether the MTHFR C677T polymorphism affects the levels of homocysteine and vitamin D as well as immune parameters in women with RPL, biochemical data, such as plasma total homocysteine and serum vitamin D levels, and immune parameters, including NK cell cytotoxicity, were analyzed by MTHFR C677T genotype (CC, CT and TT). The serum level of vitamin D in TT was significantly lower when compared with those of CT (P = 0.001) and CC (P = 0.003), while the level of homocysteine in TT was significantly higher than those in CT (P = 0.01) and CC (P = 0.01). NK cytotoxicity in TT was significantly higher than that of CC (P = 0.04) but not CT (P = 0.09). There was a significant negative correlation between the levels of vitamin D and homocysteine in TT (r = -0.357, P < 0.01). In multivariate analysis, vitamin D insufficiency (<30 ng/ml) was an independent risk factor for hyperhomocysteinemia (adjusted odds ratio 1.89, 95% CI 1.41-2.52). The study was retrospective and included only women with RPL but not healthy fertile controls. In addition, folic acid, vitamin B6 and B12 intake, which could modify the level of homocysteine and vitamin D, were not investigated. Thus, a considerable part of women might have folic acid and vitamin D supplementation and prenatal vitamin pills, and there are probable confounders in this study associated with unrestricted vitamin supplementation. Therefore, the findings should be carefully interpreted and applied to RPL women with MTHFR gene polymorphism. The findings attained in this analysis regarding the MTHFR polymorphism and its relationship with vitamin D, homocysteine and NK cytotoxicity may aid in uncovering the underlying etiology and mechanism for RPL. The study highlights an interplay between nutrition and immune responses in RPL. No external funding was received for this study. None of the authors have any conflict of interest to declare. N/A.

MTHFR C677T polymorphism affects normotensive diastolic blood pressure independently of blood lipids.

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was found to be associated with hypertension. High blood pressure (BP) is a major risk factor for cardiovascular disease, gestational hypertension, and high-risk pregnancy. BP is a complex trait strongly associated with blood lipid parameters. However, studies of the effect of MTHFR C677T polymorphism on BP levels independently of blood lipids are scarce. Our objective was to analyze and quantify the effect of MTHFR C677T polymorphism on normotensive BP independently of blood lipids. MTHFR C677T genotyping was done for 151 Israeli women attending the genetics clinic at Soroka Medical Center. Biochemical (blood lipids) and BP data were extracted from Soroka Medical Center records. BP was regarded as a continuous parameter using analysis of covariance and post hoc Tukey's HSD (honestly significant difference) analysis. The frequencies of genotypes CC, TT, and CT were 41%, 12%, and 47%, respectively. A significant (P < 0.0001) association was found between genotype and diastolic BP (DBP) when adjusted to body mass index and age. Mean DBP was significantly lower for CC than for TT genotypes (71.2 vs. 78.7 mm Hg); however the difference between the heterozygotes (73.9 mm Hg) and the other 2 genotypes was not significant. Cholesterol, LDLcalc (LDLcalculaed), and homocysteine blood levels significantly contributed to the effect of MTHFR C677T polymorphism on the DBP trait. There was also significant association between genotype and folic acid levels. MTHFR C677T polymorphism significantly affects DBP in Israeli women, independently of blood lipids. Each C to T substitution is associated with a mean 3.4-mm Hg increase in DBP.

Association between MTHFR C677T, MTHFR A1298C and MS A2756G polymorphisms and risk of cervical intraepithelial neoplasia II/III and cervical cancer: A meta-analysis

Numerous case-control studies on the association between polymorphisms of key genes involved in methionine remethylation [methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS)] and the susceptibility of cervical intraepithelial neoplasia (CIN) and cervical cancer have provided inconclusive results. The aim of the present meta-analysis was to determine the effects of two MTHFR (C677T and A1298C) and one MS gene polymorphism (A2756G) on the risk of CIN II/III or cervical cancer. Relevant data were retrieved following a systematic search in PubMed, Web of Science, MEDLINE and Wanfang Data up to November 2012. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated from eligible studies by meta-analysis with subgroup analyses stratified by ethnicity. A total of 13 studies with 1,936 cases and 2,858 controls were included in the present meta‑analysis. An increased risk of cervical cancer was found in Asian women with the MTHFR 677T allele (TT vs. CC: OR=1.41, 95% CI=1.07‑1.86, P=0.01; TT vs. CC+CT: OR=1.38, 95% CI=1.08-1.75, P=0.008), while a decreased risk was observed in Caucasian women (TT vs. CC: OR=0.65, 95% CI=0.45-0.93, P=0.02; TT+CT vs. CC: OR=0.7, 95% CI=0.58-0.86, P=0.0005). No effects of MTHFR C677T polymorphism on CIN II/III risk and MTHFR A1298C or MS A2756G polymorphisms on cervical cancer risk were detected. The sensitivity analysis suggested stability of this meta-analysis and no publication bias was detected. The MTHFR 677T allele may enhance the risk of cervical cancer in the Asian female population and play a protective role in Caucasian females. However, limited association is suggested between MTHFR A1298C and MS A2756G polymorphisms with cervical tumorigenesis.

Diet Folate, DNA Methylation and Polymorphisms in Methylenetetrahydrofolate Reductase in Association with the Susceptibility to Gastric Cancer

Methylenetetrahydrofolate reductase (MTHFR) has been reported to be associated with DNA methylation, an epigenetic feature frequently found in gastric cancer. We conducted a case-control study to explore the association of MTHFR C677T polymorphisms with gastric cancer risk and its relation with the DNA methylation of COX-2, MGMT, and hMLH1 genes. Genotyping of P16, MGMT and HMLH1 was determined by methylation-specific PCR after sodium bisulfate modification of DNA, and genotyping of MTHFR C677T was conducted by TaqMan assays using the ABI Prism 7911HT Sequence Detection System. Folate intake was calculated with the aid of a questionnaire. Compared with the MTHFR 677CC genotype, the TT genotype was significantly associated with 2.08 fold risk of gastric cancer when adjusting for potential risk factors. Individuals who had an intake of folate above 310 μg/day showed protective effects against gastric cancer risk. The effect of MTHFR C677T polymorphisms on the risk of gastric cancer was modified by folate intake and methylation status of MGMT (P for interaction <0.05).

Association of MTHFR C677T polymorphism with schizophrenia and its effect on episodic memory and gray matter density in patients

Growing evidence suggests that the methylenetetrahydrofolate reductase (MTHFR) may play a role in the pathogenesis of schizophrenia. Recent studies suggested that the MTHFR 677T, as a risk allele, has an impact on brain activation and memory function in schizophrenia patients. To confirm further the association between this functional polymorphism and schizophrenia, we detected genotypes of MTHFR C677T polymorphism in 1002 schizophrenic patients and 1036 controls of Chinese Han population, by using direct DNA sequencing method. To explore further effects of MTHFR C677T polymorphism on memory and brain function in schizophrenia, 33 schizophrenia patients and 29 healthy participants were selected from above samples to be assessed with MRI scanning and episodic memory (EM) examination. The case-control association study results showed that the MTHFR C677T was associated with schizophrenia (χ2=14.11, P=1.74×10−4, OR=0.79; 95% CI=0.70–0.89). We also found that the MTHFR 677T allele had a load-dependent effect on EM in schizophrenic patients, but not in healthy control participants. Further analysis on gray matter density (GMD) revealed significant diagnostic effects in bilateral frontal cortices, bilateral insula, left medial temporal cortex and bilateral occipital cortices, effects of MTHFR genotype in the right insula, right inferior frontal gyrus, right rolandic opercula, right parahippocampal gyrus and right medial temporal pole, and effects of genotype-diagnosis interaction in the right temporal gyrus. Our findings suggested that the MTHFR 677T allele might have effect on risk of schizophrenia, memory impairment and GMD changes in patients.

Influence of Methylenetetrahydrofolate Reductase C677T Polymorphism on the Risk of Lung Cancer and the Clinical Response to Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer: An Updated Meta-Analysis

PurposeMethylenetetrahydrofolate reductase (MTHFR) has been implicated in lung cancer risk and response to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the results are controversial. We performed meta-analysis to investigate the effect of MTHFR C677T polymorphism on lung cancer risk and response to platinum-based chemotherapy in advanced NSCLC.Materials and MethodsThe databases of PubMed, Ovid, Wanfang and Chinese Biomedicine were searched for eligible studies. Nineteen studies on MTHFR C677T polymorphism and lung cancer risk and three articles on C677T polymorphism and response to platinum-based chemotherapy in advanced NSCLC, were identified.ResultsThe results indicated that the allelic contrast, homozygous contrast and recessive model of the MTHFR C677T polymorphism were associated significantly with increased lung cancer risk. In the subgroup analysis, the C677T polymorphism was significantly correlated with an increased risk of NSCLC, with the exception of the recessive model. The dominant model and the variant T allele showed a significant association with lung cancer susceptibility of ever smokers. Male TT homozygote carriers had a higher susceptibility, but the allelic contrast and homozygote model had a protective effect in females. No relationship was observed for SCLC in any comparison model. In addition, MTHFR 677TT homozygote carriers had a better response to platinum-based chemotherapy in advanced NSCLC in the recessive model.ConclusionThe MTHFR C677T polymorphism might be a genetic marker for lung cancer risk or response to platinum-based chemotherapy in advanced NSCLC. However, our results require further verification.

Association of MTHFR C677T polymorphism with loneliness but not depression in cognitively normal elderly males

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is involved in folate and homocysteine metabolism, and has been associated with geriatric disorders, including dementia and late-life depression. The present work aimed to investigate the effect of MTHFR C677T polymorphism on the presence of depression and loneliness in cognitively normal male subjects. A total of 323 cognitively normal male subjects were included in this study (mean age=80.6; SD=5.3). Depression was assessed by the Geriatric Depression Scale-Short Form (GDS-SF) and loneliness by UCLA loneliness scales. Analysis of variance (ANOVA) was used to test the between MTHFR genotype difference in depression and loneliness. Multiple regression was used to test the effect of MTHFR polymorphism on the loneliness, controlling for age, education, cognitive function, and depression. ANOVA showed a significant between-genotype difference in loneliness scores (P=0.015), and post hoc comparisons showed that subjects with C/C genotype had significantly higher loneliness ratings, compared to those with C/T or T/T genotype. Regression analysis indicated that the effect of MTHFR polymorphism on loneliness was independent of age, education, cognitive function, and depression. Our findings suggest that MTHFR C677T polymorphism may be linked more to loneliness than depression in the cognitively normal elderly males, and may be implicated in the pathophysiology of late-life depression in relation to MTHFR genes.

Methylenetetrahydrofolate reductase C677T polymorphism in patients with Henoch‐Schönlein purpura

Associations between several vascular diseases such as Kawasaki disease, venous and arterial thromboembolism, cardiovascular disease, diabetic nephropathy, focal segmental glomerulosclerosis and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have been reported. This is a clinical study designed to investigate the possible effects of MTHFR C677T polymorphism on the development of Henoch-Schönlein purpura (HSP). Forty-one patients with HSP (25 male/16 female) with a mean age of 7.8 ± 2.9 years were included in the study. The control group consisted of 50 healthy children. MTHFR genotypes were determined by polymerase chain reaction and by Hindf I restriction enzyme analysis and subsequent 3% agarose gel electrophoresis techniques. No significant differences were observed in the distribution of MTHFR genotypes or allele frequencies in the HSP cases versus controls. Plasma homocysteine levels and vitamin B(12) levels were almost comparable in the HSP patients and control group without a significant difference. Folic acid levels were within normal limits in the HSP cases and the control group, HSP patients' levels being significantly higher than the control group. No significant relationship was present with the MTHFR genotype and plasma homocysteine, vitamin B(12) and folic acid levels in HSP patients. No association with MTHFR gene polymorphism and homocysteine plasma levels could be found in patients with HSP. The results of this study indicate that other mechanisms should be operative in the development of HSP.