Methylenetetrahydrofolate Reductase Gene Polymorphisms Research Articles

C677T methylenetetrahydrofolate reductase polymorphism, folate and homocysteine levels and the risk of colorectal cancer

Aim: Colorectal cancers are common in the world and many factors play a role. MTHFR (methylenetetrahydrofolate reductase) gene polymorphisms cause a predisposition to cancer formation. C677T polymorphism is the most common among these. To evaluate the role of MTHFR polymorphisms in colorectal carcinogenesis, we examined the associations between MTHFR mutations, homocysteine levels, plasma folate levels and colorectal cancer risk.Materials and Methods: During two years period, 101 naive colorectal cancer cases and 95 controls were enrolled to the study and groups were matched for age, sex and smoking. The presence of the mutation was determined by real-time PCR amplification of genomic DNA using Light.Results: Although only 1 of the cancer patients was homozygous mutant Val/Val, this mutation was present in 10.5% of the control group and this difference was statistically significant (p<0.05). We observed a significant increased risk of colorectal cancer (OR, 0.04; 95% CI, 0.005-0.304) among those with low plasma folate levels (≤3 ng/ml) compared to subjects with adequate levels. However, in both case and control groups mean folate levels were high (10.3 and 10.7 ng/ml, respectively). Homocysteine levels were significantly higher in patients with colorectal cancer compared to healthy volunteers (p <0.05).Conclusion: The data in our study suggested that the MTHFR val/val mutation did not cause a predisposition to cancer development. The presence of a polymorphism other than val/val mutation in the MTHFR enzyme suggests that it may be associated with elevated levels of homocysteine and low folate in cancer patients.

Prevalence of methylenetetrahydrofolate reductase gene polymorphisms (C677T, and A1298C) among Saudi children receiving dental treatment.

BACKGROUND: Methylenetetrahydrofolate reductase, the encoded by the MTHFR gene, plays a crucial role in converting the amino acid homocysteine to methionine. Two polymorphisms of the MTHFR gene, C677T and A1298C, reportedly reduce enzyme activity, resulting in hyperhomocysteinemia. Patients with C677T and A1298C polymorphisms may be at higher risk for developing abnormal hyperhomocysteinemia, which has been linked to catastrophic neurological including fatal outcomes.OBJECTIVE: Determine the prevalence of the MTHFR gene variants C677T and A1298C among pediatric dental patients treated at King Abdulaziz University Hospital.DESIGN: Cross-sectional.SETTING: Clinics of pediatric dentistry department.SUBJECTS AND METHODS: Healthy Saudi children 6–12 years old with no known allergies were screened for eligibility between May and December 2019. A single investigator collected saliva samples. The MTHFR C677T and A1298C polymorphisms were analyzed using polymerase chain reaction and restriction fragment length polymorphism.MAIN OUTCOME MEASURE: The prevalence of MTHFR gene variants (C677T and A1298C) among the subjects.SAMPLE SIZE: 138.RESULTS: MTHFR C677T polymorphism was present in 36.2% of the sample and 90.0% of children carrying this allele were heterozygotes. MTHFR A1298C polymorphism was present in 91.3% of the sample and 77.0% of the children carrying this allele were heterozygotes. No linkage disequilibrium between MTHFR C677T and MTHFR A1298C was observed within this sample.CONCLUSIONS: Our study found a high frequency of the MTHFR A1298C genotype, which was substantially more abundant than expected based on a Hardy-Weinberg distribution. Therefore, caution is advised in using N2O in Saudi children as the increased prevalence of this MTHFR allele may increase the incidence of serious adverse effects among these children.LIMITATIONS: Further studies are recommended with a larger sample size from randomly selected hospitals from different regions of Saudi Arabia.CONFLICT OF INTEREST: None.

Study of A1298C MTHFR Gene Polymorphism as a Risk Factor for Neural Tube Defects in the Eastern Algerian Population

Background: As C677T mutation, A1298C mutation in methylene tetrahydrofolate reductase (MTHFR) gene results in a decreased MTHFR activity but to a less extent, it is known as a risk factor of predisposition to human neural tube defects (NTDs), in some populations. Our objective was therefore to study, for the first time in Algerian population, if A1298C polymorphism confers risk for the occurrence of this abnormality. We have examined the distribution of the genotype and the allele frequencies of A1298C mutation, and also their influence on plasma homocysteine (Hcy) concentration. Patients and Methods: We studied this polymorphism in 38 mothers of NTD cases and 67 control individuals of an eastern Algerian population. The mutation was determined by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR/RFLP). Plasma homocysteine concentration was analyzed using an automated chemiluminescence method. Results: No signi?cant association could be observed between allele and genotypes frequencies of A1298C MTHFR gene polymorphism and NTDs risk. However, we could observe that A1298C polymorphism affects homocysteine metabolism in mothers of NTD cases leading to homocysteine concentration values higher in AA genotype and lower in AC/CC genotypes (15.29 ± 11.8 μmol/l vs. 8.63 ± 3.83 μmol/l, p Conclusion: Data indicate that A1298C MTHFR gene polymorphism might be a risk factor by affecting homocysteine metabolism in mothers of Algerian children with NTDs.

MTHFR Gene Polymorphisms and Cardiovascular Risk Factors, Clinical-Imagistic Features and Outcome in Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) as a severe neurological emergency, is represented by variable conditions in its clinic presentation, onset, risk factors, neuroimagistic features and outcome. The genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C was associated with CVST. We aimed to characterize the prevalence of MTHFR gene polymorphisms associated with cardiovascular risk factors in the group of patients with CVST. Also, we studied additional causes associated with CVST including local infections, general infections, obstetric causes (pregnancy, puerperium) and head injury. This is a retrospective study including 114 patients which referred to our hospital between February 2012–February 2020. The protocol included demographic (age, sex), clinical, neuroimagistic features, paraclinic (genetic polymorphism of MTHFR, factor V G1691A—Leiden, prothrombin G20210A, PAI-1 675 4G/5G; Homocysteine level, the lipid profile, blood glucose and Glycohemoglobin HbA1c, high- sensitive C- reactive protein- hsCRP) data, as well as treatment and outcome. The mean age was 37.55 years with a female predominance (65.79%). In the first group of patients with inherited thrombophilia (60 cases; 52.63%) we found genetic mutation includes MTHFR C677T (38.59%) and A1298C (14.03%), factor V G1691A- Leiden (15.78%), prothrombin G20210A (2.63%), PAI-1 675 4G/5G (42.98%), and hyperhomocysteinemia (35.08%). At the second group with other etiology of CVST, except thrombophilia, we included 54 patients (47.36%). The most common sites of thrombosis were the superior sagittal sinus (52.63%). Headache was the most common symptom (91.22%) and seizures were the main clinical presentation (54.38%). The MTHFR polymorphism was significantly correlated with higher total cholesterol (TC) (p = 0.023), low- density lipoprotein cholesterol (LDL) (p = 0.008), homocysteine level (tHcy) (p < 0.001). Inside the first group with MTHFR polymorphism we have found a significant difference between the levels of homocysteine at the patients with MTHFR C677T versus MTHFR A1298C polymorphism (p < 0.001). The high-sensitive C-reactive protein (hsCRP) was increased in both groups of patients, but the level was much higher in the second group (p = 0.046). Mortality rate was of 2.63%. Demographic, clinical and neuroimagistic presentation of CVST in our study was similar with other studies on the matter, with a high frequency of thrombophilia causes. MTHFR gene polymorphisms (C677T and A1298C) are increased in prevalence in CVST. PAI-1 675 4G/5G gene mutation seems to be involved in CVST etiology. Plasma C-reactive protein level and hyperhomocysteinemia should be considered as a prognostic factor in CVST.

Relationship between MTHFR Gene Polymorphisms and Gastrointestinal Tumors Development: Perspective from Eastern Part of Turkey

Background Gastric and esophageal cancers are 2 of the most prevalent cancer types worldwide. Polymorphisms in the genes that code the methylenetetrahydrofolate reductase (MTHFR) enzyme increase the formation of both cancer types. In this study, it was aimed to research the relationship between the existence of MTHFR C677T and A1298C polymorphisms in patients with gastric and esophageal cancer and the lifespans of patients. Methods and Materials This prospective study was performed at Van Yuzuncu Yil University. Included in the study were 30 patients with esophageal tumors, 70 patients with gastric tumors, and 61 healthy volunteers. From each of the patients, 5 mL of blood was drawn. DNA was isolated via kits with spin-column technology. Results It was concluded that the risk of developing gastric cancer was 4.13 times higher in individuals who had the AC genotype of the A1298C polymorphism when compared to those who had the AA genotype, while the risk was 2.91 times higher in individuals who had the CC genotype when compared to those who had the AA genotype (P = 0.001, P = 0.027). Carriers of the AC genotype of the A1298C polymorphism had 2.89 times higher risk of developing esophageal cancer when compared to those who had the AA genotype (P = 0.033). It was determined that individuals who had the 1298 CC genotype were not at higher risk of developing esophageal cancer when compared to those with the AA genotype (P = 0.863). It was concluded that individuals who had the TT genotype of the C677T polymorphism were not at higher risk of developing gastric and esophageal cancers when compared to those who had the 677CC genotype (P > 0.05). There was no difference in terms of the life spans of the patients with regards to the genotypes (P > 0.05). Conclusion The results showed that the A1298C polymorphism on the MTHFR gene can be a risk factor for gastric and esophageal cancer in eastern Turkey. These polymorphisms may have no effect on the life spans of the patients.

Study on Maternal SNPs of MTHFR Gene and HCY Level Related to Congenital Heart Diseases

The aim of this study is to evaluate the relationship between maternal single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) gene with plasma homocysteine (HCY) level and offspring congenital heart diseases (CHDs). 338 mothers with offspring CHDs as case group and 306 mothers of normal children as control group were recruited. Their pregnant histories were interviewed by questionnaire and the MTHFR rsl801133 and rsl801131 were genotyped. The case–control analysis was used to find out the relationship between maternal SNPs of MTHFR gene and offspring CHDs. And the plasma HCY concentration of the mothers of CHDs children was detected. This case–case study was intended to find out the relevance between maternal HCY level and SNPs of MTHFR gene. There were significant differences in the gender of children, occupation of mothers, family history with CHDs, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHDs group and control group (P < 0.05). MTHFR rs1801133 was significantly associated with their offspring CHDs in mothers. The polymorphism of maternal MTHFR rs1801133 increased plasma HCY level, especially the homozygous mutation. Besides the environmental factors, our results suggested that the maternal MTHFR rs1801133 polymorphism might be a risk factor of their offspring CHDs, which may be due to the hyperhomocysteinemia by abnormal metabolism of HCY.

The sex‐specific effect of the apolipoprotein E allele and methylenetetrahydrofolate reductase gene polymorphism on the biochemical, anatomical, and cognitive profiles of patients clinically diagnosed with probable Alzheimer's disease

We aimed to evaluate the sex-specific effect of apolipoprotein E (APOE) alleles and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on the biochemical, anatomical, and cognitive profiles of Alzheimer's disease (AD) patients. The patient (followed-up for at least 2 years) medical records, which comprised of data on plasma homocysteine and folate levels, lipid profile, HbA1c, MTHFR C677T genotype, APOE allele type, mini-mental state examination (MMSE) and clinical dementia rating (CDR) scores, and brain scans, were retrospectively analyzed. Two trained neurologists scored the white matter lesions (Fazekas scale), medial temporal lobe atrophy (MTA), and microbleeds using brain magnetic resonance imaging scans. This study included 574 patients clinically diagnosed with probable AD (average age, 73.2 years; mean MMSE score, 10.05). The effect of sex on all parameters was evaluated. The triglyceride (TG) and homocysteine levels and the MTA and Fazekas scores were higher in female APOE-ε4/ε4 carriers than in women without APOE-ε4. The TG and homocysteine levels were lower in men with the MTHFR CC allele than in those with the MTHFR TT allele. In contrast, MTHFR polymorphism and APOE-ε4 alleles were not significantly correlated with anatomical lesions and rate of decline in the MMSE and CDR scores. We demonstrated the sex-specific effect of the APOE allele and MTHFR polymorphism on the serological and anatomical biomarkers in AD patients. The APOE allele and MTHFR mutations did not directly affect cognitive progression, but differentially affected other biochemical factors, between the sexes. These findings will aid in devising novel preventive and therapeutic strategies.

Association between serum homocysteine levels and methylene-tetrahydrofolate-reductase gene polymorphism in patients with stroke: A study from a tertiary care teaching hospital from Central India

Background: Hyperhomocysteinemia (HHcy) is a well-established risk factor for vascular thrombosis leading to stroke. Homocysteine (Hcy) is mainly synthesized in the methionine cycle, and it is an intermediate during the conversion of methionine to cysteine. HHcy can develop by polymorphism of several enzymes like methylene-tetrahydrofolate-reductase (MTHFR) mutation and due to deficiency of co-factor Vitamins such as B12, B6, and folic acid. This study was planned to see the association between HHcy and MTHFR gene polymorphism in patients with stroke in populations from central India. Methods: Seventy-two patients diagnosed with stroke aged 18 years and above who met the inclusion criteria were selected. Hcy level and MTHFR mutation were identified among patients of stroke. Results: Forty-two patients (58.33%) were diagnosed with acute ischemic stroke as compared to cerebral venous thrombosis (30, 41.66%) from a total of 72 patients. The statistical analysis projected that the HHcy diagnosed among more (45, 62.5.0%) cases with stroke who had aged ≤45 years as compared to cases who had aged >45 years (17, 23.6%). None of our patients tested positive for either CT (Heterozygous) or TT(Homozygous) genotypes. Conclusions: HHcy is not associated with MTHFR gene mutation in our study group, and this possibly is related to the deficiency of co-factors in Hcy metabolism. Young age group stroke patients have higher Hcy levels.

Relationship between granulomatous lobular mastitis and methylene tetrahydrofolate reductase gene polymorphism.

BACKGROUNDVariations in the methylene tetrahydrofolate reductase (MTHFR) gene have been reported as risk factors for numerous conditions, including cardiovascular disease, thrombophilia, stroke, hypertension and pregnancy-related complications. Moreover, it was reported there is an association between breast cancer and mutations in MTHFR-C677T. However, whether there is an association between MTHFR gene polymorphism and granulomatous lobular mastitis or not has been rarely investigated.AIMTo analyze the association between MTHFR gene polymorphism and granulomatous lobular mastitis.METHODSFifty-one patients with granulomatous lobular mastitis admitted to The First Hospital of Kunming were selected as study samples. Their hospitalization time ranged from February 2018 to February 2019. The 51 patients were included in the experimental group, and another 51 women who underwent physical examination at The First Hospital of Kunming in the same period were included in the control group. Deoxyribonucleic acid and MTFR genetic polymorphism testing were performed in each group. The association between MTHFR gene polymorphism and granulomatous lobular mastitis was observed.RESULTSThere were significant differences in genotype frequency and allele frequency of C/C and C/T between the experimental group and the control group (all P < 0.05). However, there was no significant difference in frequency of T/T genotype between the two groups (P > 0.05). In addition, there was no significant difference in genotype frequency and allele frequency of A/A, A/C and C/C between the two groups (P > 0.05).CONCLUSIONMTHFR gene C677T locus polymorphism is closely related to granulomatous lobular mastitis.

Methylenetetrahydrofolate reductase genetic polymorphism and the risk of diabetic nephropathy in type 2 diabetic patients.

Background:As indicated by numerous studies, there exists a relationship between the polymorphism of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to diabetic nephropathy (DN) in various populations; nonetheless, the findings remain inconsistent. Therefore, we carried out a meta-analysis to determine the relationship between the MTHFR gene polymorphism and DN susceptibility.Materials and method:Related studies were identified from PubMed, Cochrane Library, EMBASE, and the China National Knowledge Infrastructure database (time period: from building the library to October 2019). The strength of the association was examined using odds ratios (ORs) with 95% confidence intervals (95% CIs).Results:The findings illustrated that the C677T gene polymorphism was significantly associated with an enhanced susceptibility to DN compared to that with diabetes mellitus in allelic (OR = 1.64, 95% CI = 1.34–2.00, P < .001), dominant (OR = 1.85, 95% CI = 1.40–2.46, P < .001), codominant (heterozygote: OR = 1.67, 95% CI = 1.27–2.21, P < .001; homozygote: OR = 2.55, 95% CI = 1.82–3.57, P < .001), and recessive (OR = 1.89, 95% CI = 1.50–2.38, P < .001) models of the overall population. Moreover, as compared with the healthy controls, a significantly augmented susceptibility to DN was found in all 5 genetic comparison models (allelic: OR = 2.06, 95% CI = 1.58–2.67, P < .001; dominant: OR = 2.52, 95% CI = 1.73–3.69, P < .001; codominant: OR = 3.78, 95% CI = 2.50–5.70, P < .001; recessive: OR = 2.41, 95% CI = 1.96–2.97, P < .001). Furthermore, stratifying data by ethnicity revealed substantially augmented vulnerability to DN in not only Caucasian but also Asian populations.Conclusion:The present study suggests that the C677T polymorphism was associated with an augmented susceptibility to DN.

MTHFR Gene Polymorphisms Prevalence and Cardiovascular Risk Factors Involved in Cardioembolic Stroke Type and Severity

Background: Cardioembolic stroke (CES), generally known as the most severe subtype of ischemic stroke, is related to many factors, including diabetes mellitus (DM), hypertension (HTN), smoking, hyperlipidemia and atrial fibrillation (AF). Genetic mutations of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C have been recently associated with ischemic stroke. The purpose of this study was to analyze the prevalence of MTHFR gene polymorphisms correlated with cardiovascular risk factors in a selected population of patients with CES due to non-valvular AF (NVAF). Methods: This cross-sectional study was performed on 67 consecutive patients with acute cardioembolic stroke admitted to our hospital. The protocol included general physical examination, neurological clinical status and stroke severity evaluation, imagistic evaluation and genetic testing of MTHFR C677T and A1298C polymorphisms. Results: The prevalence of MTHFR polymorphisms in the study population was 38.2% for C677T and 40.3% for A1298C. The C677T mutation was significantly correlated with increased diastolic blood pressure (DBP) values (p = 0.007), higher total cholesterol (TC) (p = 0.003), low-density lipoprotein cholesterol (LDLc) (p = 0.003) and triglycerides (TGL) (p = 0.001), increased high-sensitive C-reactive protein (hsCRP) values (p = 0.015), HbA1c (p = 0.004) and left ventricle ejection fraction (LVEF) (p = 0.047) and lower high-density lipoprotein cholesterol (HDLc) (p < 0.001) compared to patients without this genetic variant. This genetic profile also included significantly higher CHA2DS2VASC (p = 0.029) and HASBLED (Hypertension, Abnormal liver/renal function, Stroke, Bleeding, Labile INR, Elderly age(>65 years), Drug/Alcohol usage history/Medication usage with bleeding predisposition) (p = 0.025) scores. Stroke severity in patients with MTHFR A1298C mutation was significantly increased when applying National Institutes of Health Stroke Scale (NIHSS) (p = 0.006) and modified Rankin scale (mRS) (p = 0.020) scores. The presence of A1298C mutation as a dependent variable was associated with significantly higher TGL values (odds ratio (OR) = 2.983, 95%CI = (1.972, 7.994)). Conclusions: The results obtained in this study demonstrate that MTHFR gene polymorphisms have a high prevalence in an NVAF cardioembolic stroke population. Moreover, an association between C677T mutation and stroke severity was highlighted. The C677T mutation in patients with NVAF was correlated with a higher incidence of cardiovascular comorbidities (hypertension HTN, heart failure (HF), dyslipidemia, type II diabetes mellitus (T2DM) with high HbA1c and increased inflammatory state). The A1298C MTHFR gene mutation was associated with a higher incidence of previous lacunar stroke and stroke recurrence rate, while dyslipidemia was the main cardiovascular comorbidity in this category.

Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms in Georgian Females with Hypothyroidism.

The aim of this study was to investigate the frequency of methylenetetrahydrofolate reductase ( MTHFR) gene polymorphisms in Georgian females with hypothyroidism. Thirty-four patients and 29 healthy individuals were recruited in this study. Polymerase chain reaction-restriction fragment length polymorphism analyses were used for genotyping of MTHFR polymorphisms. The results of this study suggest that the MTHFR C677T variant was significantly associated with hypothyroidism. In addition, in individuals with T allele risk of hypothyroidism significantly increased. Combination of CT/AA genotypes was more prevalent in the hypothyroid patients than in the control group. Thus, C677T polymorphism could be a possible genetic factor contributing to the pathophysiology of hypothyroidism, possibly through hyperhomocysteinemia.

Methylenetetrahydrofolate reductase gene polymorphisms in the risk of polycystic ovary syndrome and ovarian cancer.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) in hormone metabolism pathways might cause metabolic disturbances and contribute to the development of polycystic ovary syndrome (PCOS) and ovarian cancer, but the published studies were inconsistent. The aim of the present study was to evaluate the MTHFR C677T (rs1801133) and A1298C (rs1801131) gene polymorphisms in the risk of PCOS and ovarian cancer by meta-analysis. A comprehensive electronic search was conducted in databases for studies published from 1995 to 2020. The pooled ORs were calculated by Revman 5.2 software. Twenty-nine articles including 45 case–control studies were included. We found that MTHFR C677T polymorphisms were correlated with elevated PCOS risk (TT vs. CT+CC: OR = 1.41, 95%CI = 1.20–1.67; TT+CT vs. CC: OR = 1.54, 95%CI = 1.07–2.22; CT vs. CC+TT: OR = 1.18, 95%CI 1.04–1.33; TT vs. CC: OR = 1.47, 95%CI = 1.03–2.11; T vs. C: OR = 1.25, 95%CI = 1.06–1.47), which were more obvious in Middle Eastern subgroup. MTHFR A1298C polymorphisms were also associated with overall PCOS susceptibility (CC vs. AC+AA: OR = 2.55, 95% CI = 1.61–4.03; CC+AC vs. AA: OR = 1.84, 95%CI = 1.04–3.28; CC vs. AA: OR = 2.66, 95%CI = 1.68–4.22; C vs. A: OR = 1.67, 95%CI = 1.03–2.71), which were mainly reflected in Asian subjects. For ovarian cancer, MTHFR C677T polymorphisms were only related with elevated ovarian cancer risk in Asian population, while no significant association was found for A1298C polymorphisms. This meta-analysis suggested that MTHFR C677T and MTHFR A1298C polymorphisms were correlated with elevated PCOS risk. MTHFR C667T only posed a higher risk for ovarian cancer in Asians instead of other populations, while MTHFR A1298C polymorphisms were not related to ovarian cancer risk. Further studies are needed to validate the conclusion.

Correlations of Methylenetetrahydrofolate Reductase Gene Polymorphism and Genomic DNA Hypomethylation Level with Ankylosing Spondylitis

Objective To investigate the relationship of both DNA methylation level and methylenetrahydrofolate reductase(MTHFR)gene polymorphism with ankylosing spondylitis(AS). Methods Totally 200 Chinese AS patients with HLA-B27(+)and 120 healthy controls were included from Hunan Province.All the cases were diagnosed according to the 1984 modified New York criteria for AS.The DNA methylation was examined by cytosine extension method,while the MTHFR gene C677T polymorphism was analyzed by the polymerase chain reaction(PCR)and restriction fragment length polymorphism(RFLP).The plasma homocysteine(Hcy)level was examined by enzyme-linked immunosorbent assay(ELISA),while the red blood folate level was analyzed by the specific immunoassays. Results The ratio of the T/T genotype mutation in the AS group was significantly higher than in the control group(17.0% vs. 5.0%;χ2=9.874, P=0.002).The plasma homocysteine concentration of AS group was(18.71 ± 2.42)μmol/L,which was significantly higher than that in normal control group [(10.97 ± 2.93)μmol/L](t=24.402, P<0.001).The plasma Hcy concentration of the T/T genotype [(21.70±1.80)μmol/L] was significantly higher than that of the C/C genotype[(18.31±1.94)μmol/L](q=12.088, P=0.01)and the C/T genotype [(17.80±2.18)μmol/L](q=6.496, P=0.01)in the AS group.The DNA methylation level of the T/T genotype in AS group was significantly lower than that in normal control group(t=5.655, P<0.001)and also significantly lower than those of the C/C genotype(t=11.514, P<0.001)and the C/T genotype in AS group(t=10.287, P<0.001). Conclusions In the Han population in Hunan Province,the C677T polymorphism of the MTHFR gene is associated with the onset of AS.The T/T mutation at position 677 of the MTHFR gene is an important influencing factor for hyperhcyemia in the AS patients.The T/T mutation at position 677 of the MTHFR gene is associated with genomic DNA hypomethylation.Thus,hypomethylation of DNA may be one of the pathogenic mechanisms of AS.

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.

Effects of MTHFR genetic polymorphism on inflammatory protein osteopontin in RA patients: A gender based study in North Indian population

BackgroundRheumatoid arthritis (RA) is a systemic chronic inflammatory disease that ultimately damages bone and cartilage of joints leading to disability. Genetic polymorphism in methylene tetrahydrofolate reductase (MTHFR) gene has been identified as potential marker of susceptibility or disease severity in RA. Risk of RA is three times higher in women than men. Several cytokines and proteins play significant role in synovitis of RA patients. Osteopontin (OPN) is the pro-inflammatory cytokine reported to be associated with synovitis in RA, as it generates T-helper-1 (TH1)-mediated cellular immune response. ObjectiveTo study the impact of MTHFR gene polymorphism on the serum levels of OPN in RA patients and to investigate the cause of greater disease severity in women than men. Patients and methodsThe study included sixty RA patients (eleven men and forty-nine women) from different regions of Uttar Pradesh, North India. OPN was estimated by using enzyme-linked immunosorbent assay and other serological parameters such as Serum glutamic oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), C-reactive protein (CRP), triglycerides (TGA), cholesterol, uric acid, albumin and total protein were estimated using commercially available kits. MTHFR A1298C and C677T polymorphism was genotyped using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) based assays. Disease activity score and health questionnaire was assessed in all patients. ResultsMean age of patients was 44.53 ± 1.59 in women and 46.27 ± 4.22 in men with greater duration of morning stiffness in women than men. There were differences in TJC, SJC and DAS-28 score between men and women. OPN levels were found significantly higher in women than men. Other serological parameters were insignificantly higher in women than men. Genotypic study revealed that MTHFR genotypes are not associated with serum OPN levels. However, the disease activity scores (DAS-28), total joint count (TJC) and swollen joint count (SJC) were significantly associated with 1298CC genotype. Frequency distribution of MTHFR gene between men and women indicates that 1298CC genotype was more frequent in women than men and hence it might be one of the factors to cause disease severity more in women than men. ConclusionA1298C polymorphism is a predictor to the disease severity in RA patients. Patients with homozygous mutant CC genotype have a higher DAS-28 score along with TJC and SJC. The significantly higher OPN levels in female subjects suggest that disease severity is more in women than men. However, other parameters such as SGOT, SGPT, CRP, TGA, creatinine, uric acid, albumin and total protein were higher in women but the change was insignificant.

Assessment of Methylenetetrahydrofolate Reductase Gene Polymorphism in Diabetic Peripheral Neuropathy

Assessment of Methylenetetrahydrofolate Reductase Gene Polymorphism in Diabetic Peripheral Neuropathy

Methylene Tetrahydrofolate Reductase Gene Polymorphism C677T &amp; Risk of Type two Diabetes Mellitus in Beni-Suef Governorate

Background: Methylene Tetrahydrofolate Reductase (MTHFR) is known to be a regulatory enzyme of homocysteine metabolism. In many ethnic groups point mutations in MTHFR gene are implicated in the pathogenesis of diabetic nephropathy (DN) and other complications of type II diabetes mellitus (T2DM). Aim of the work: The aim of this study was to assess if MTHFR C677T gene polymorphism was one of the risk factors for the development of diabetic nephropathy as well as other complications in type 2 diabetes mellitus patients. Subjects and methods: The MTHFR C6777T polymorphisms were detected in 50 persons by PCR-RFLP. Subjects were divided into 2 groups; 30 patients with type II DM and 20 persons who were non-diabetic healthy controls. Results: The presence of MTHFR 677T allele did not increase the risk of complications in T2DM patients. The presence of mutant genotypes CT and TT did not increase the risk of nephropathy or other complications in the subjects having a C677T mutation. Conclusion: Methylene Tetrahydrofolate Reductase (MTHFR) C677T gene mutation was neither associated with an increased risk of diabetic nephropathy nor other complications of type II diabetes mellitus.

MTHFR gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis based on 16 studies.

Rheumatoid arthritis (RA) is the most common autoimmune rheumatic disease, in which an epigenetic implication in the disease etiopathogenesis has been noted. Here in this meta-analysis, we attempted to investigate the pooled association of methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and susceptibility to RA risk. A systematic search was performed in the main databases, including MEDLINE and Scopus to search for studies assessing the association between MTHFR gene C677T and A1298C polymorphisms and the risk of RA prior to December 2019. In this meta-analysis, 15 studies with 2165 patients and 1751 healthy controls for C677T SNP and 14 studies containing 2021 patients and 1760 healthy controls for A1298C SNP were included. A significant positive association between C677T SNP and RA risk was recognized in the dominant, recessive, and allelic model, but not TT and CT genotypes. The results indicated that the risk of RA in African population was increased under all genotype models while these results were repeated in Asian population just for recessive model, allelic model, and TT genotype. Moreover, the analysis of A1298C SNP demonstrated a significant association in overall population according to only the recessive model and CC genotype. Subgroup analysis according to the genotyping method indicated that RFLP-PCR method could impress the results of association between MTHFR gene A1298C and C677T SNPs and RA risk. The outcome of this meta-analysis indicated that MTHFR gene C677T SNP was much possibly be associated with RA risk.

Effects of methionine synthase and methionine synthase reductase polymorphisms on hypertension susceptibility.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are strongly associated with hypertension incidence, although such association is inconsistent among ethnicities studied. However, effects of polymorphisms of other genes related to folate metabolism besides MTHFR on hypertension susceptibility are not well known yet. The aim of this study was to elucidate whether methionine synthase (MTR) 2756A>G and methionine synthase reductase (MTRR) 66A>G polymorphisms might be associated with risks of hypertension susceptibility in the Korean population. Genotyping of these two polymorphisms was performed for 232 hypertensive patients and 247 unrelated healthy controls using polymerase chain reaction-restriction fragment length polymorphism technique. In the present study, mutations of MTR 2756A>G and MTRR 66A>G polymorphisms were associated with increased and decreased susceptibility to hypertension, respectively. Allele combinations from these two polymorphisms were also related to hypertension prevalence. When polymorphism data were stratified according to clinical components of hypertension, The G allele of MTR 2756A>G polymorphism was significantly associated with an increased risk of hypertension in subjects with BMI < 26.1kg/m2 (P = 0.004), WC < 87.2 in. (P = 0.021), FBG < 95.5mg/dL (P = 0.011), triglyceride < 133.5mg/dL (P = 0.034), and HDL-cholesterol < 52.2mg/dL (P = 0.036). The G allele of MTRR 66A>G polymorphism was significantly associated with a decreased risk of hypertension in subjects with WC ≥ 87.2 in. (P = 0.029), FBG ≥ 95.5mg/dL (P = 0.032) and triglyceride ≥ 133.5mg/dL (P = 0.027). MTR 2756A>G and MTRR 66A>G polymorphisms related to folate metabolism might be genetic markers for risk of hypertension in the Korean population.