Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks

The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD.

Association between Maternal and Fetal MTHFR C677T and MTRR A66G Polymorphisms with the Risk of NTDs: A Systematic Review and Meta-Analysis Study

Background: Neural tube defects (NTDs) are classed as multifactorial birth defects of the brain and spinal cord that arise during embryonic development. Although the etiology is not well understood, NTDs are reported to be prevented by maternal folic acid supplementation before and during early pregnancy. This meta-analysis study aimed to assess the association between fetal and maternal methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with the risk of NTDs. Methods: The PubMed, Scopus, and Springer Link databases were searched (from March 2000 to November 2020) for the literature on the association between MTHFR C677T and MTRR A66G polymorphisms with the risk of NTDs. Results: In total, 33 studies were reviewed in the present study, and it was revealed that, unlike MTRR A66G polymorphism, MTHFR C677T was statistically associated with the risk of NTDs in the overall population. The results of subgroup analysis showed that the Indian subcontinent subgroup with maternal MTHFR C677T polymorphism and the European subgroup with fetal MTHFR C677T polymorphism was significantly susceptible to NTDs. Conclusion: The obtained results revealed that, unlike MTRR A66G, maternal and fetal MTHFR C677T polymorphism was significantly associated with NTDs. Subgroup analysis also demonstrated that folic acid deprivation can be considered the main cause of MTHFR C677T polymorphism in some areas.

Subacute Combined Degeneration Associated with Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism

Subacute combined degeneration (SCD) is a metabolic disease caused by deficiency of vitamin B12. Rarely, it could be associated with genetic problem. An old male presented with progressive both hands weakness. Laboratory study showed deficiency of vitamin B12, but the cause was not clear. We performed a genetic study and methylenetetrahydrofolate reductase (MTHFR) C677T homozygous polymorphism with 30% of normal enzyme activity was confirmed. This case suggests SCD may occur in association with a genetic problem with MTHFR C677T polymorphism.

Association of MTHFR rs1801133 and Homocysteine With Legg-Calvé-Perthes Disease in Mexican Patients

Background: Legg-Calvé-Perthes disease (LCPD) is an avascular osteonecrosis of the femoral epiphysis. It is a rare disease of unclear etiology in children. Alterations in coagulation, or the collagen gene have been described and could be associated with its etiology. Therefore, we set out to evaluate the following alterations: COL1A1 (rs1107946, rs2412298), COL2A1 (rs121912891 and rs387106558), MTHFR rs1801133, CBS rs115742905, and PT rs1799963 and their relationship with LCPD.Methods: DNA was obtained and genotyped by real-time PCR with TaqMan probes. It was determined prothrombin and homocysteine (Hcy) by a coagulometric method. The variables were described as mean and standard deviation or percentages, and genotypic and allelic distributions were analyzed using the Student's t-test. In addition, the Hardy-Weinberg equilibrium, and OR.Results: We studied 23 patients with LCPD and 46 controls. We did not find any association of the MTHFR, CBS, PT, COL1A1, and COL2A1 genetic variants with LCPD. However, when adjusting the data with the Hcy values for the MTHFR C677T polymorphism, the C/C genotypes showed an association with the recessive model (p = 0.038) with susceptibility to LCPD.Conclusion: No association was found with the CBS, PT, COL1A1, and COL2A1 genes. Nevertheless, our results suggest a significant link between moderately elevated Hcy levels and the MTHFR C677T polymorphism in a cohort of Mexican children with LCPD.

Familial cases of Mexican patients with Legg-Calvé-Perthes disease

BackgroundLegg-Calvé-Perthes Disease (LCPD) is described as an avascular necrosis of the femoral head. Although its etiology is still not fully understood, evidences suggest heritable thrombotic disorders and other factors may be implicated in its onset and progress. Our objective is to describe, in three enrolled families, the genetic, biochemical and environmental factors that may be associated with the etiology and development of LCPD. MethodsTherefore, we set out to evaluate the following alterations of collagen genes: MTHFR rs1801133, CBS rs115742905, and PT rs1799963 and their relationship with LCPD. Thrombophilia associated markers (FI, FII, FV, FVII, FVIII, FIX, FX, FXI, FXII, FvW, PC, PS, AT, and homocysteine) were evaluated using coagulometry methods. Results: Seven LCPD patients and 14 healthy volunteers were enrolled. Concentrations in hemoglobin (p ≤ 0.0001), fibrinogen (P ≤ 0.0001), homocysteine (p = 0.0414), factor IX activity percentage (p ≤ 0.0001), and protein S (p = 0.0478) showed statistically significant differences. None of the evaluated polymorphisms showed statistically significant differences. However, all patients presented the mutated MTHFR C677T polymorphism in a homozygous (T/T) or heterozygous manner (C/T).ConclusionsOur results show environmental elements from every family and hemostatic disorders may be involved in suffering and developing LCPD. Also, heritable factors could contribute to the onset of the disease. Clearly, environmental, genetic, and prothrombotic factors are involved in this pathology.

Impact of thrombophilia and waist circumference on the risk of venousthromboembolism

Background Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) represents a major health problem. In the general population, the absolute risk of any kind of VTE is 0.1%–0.2% per year, and it increases with age. VTE is an important and preventable cause of morbidity and mortality, with almost a third of survivors experiencing long term effects. Obesity is well-known risk factor of VTE. The extent of the effects of obesity on VTE depends not only on total body fat, but also on the distribution of adipose tissue (e.g., central obesity) and the interplay among risk factors for VTE, such as genetic mutations, and other risk factors. Thrombophilia, venous thromboembolism, obesity, waist circumference Purpose The aim of this study is to investigate the impact of waist circumference on the risk of venous thromboembolism Methodology The study involved 68 patients with VTE (33 females and 34 males, mean age 56.8 years ±15.3) and 84 patients without VTE (38 males and 46 females, 44.4 years±18.6). From 2015 to 2017, data have been collected from records of patients admitted to department of internal medicine. All subjects were recruited to the study during their stay in the hospital. The reasons for hospitalization were: acute event of DVT or PE for the main group, the absence of acute event or history of VTE for the control group. DVT was diagnosed by ultrasonic Doppler examination, and PE was confirmed by intravenous radiocontrast computed tomography. Anthropometric measures were performed with subjects wearing short-sleeved garments and no shoes; waist circumference was measured in centimeters at the umbilical line. For all patients genetic testing for inherited thrombophilia – Factor V Leiden G1691A, Prothrombin G20210A, MTHFR C677T polymorphism, PAI-1 (SERPIN1) 4G/5G polymorphism – was performed by real-time PCR technique. Results Factor V Leiden G1691A increase the risk of VTE in 2.11 (CI: 1.79–2.48), p=0.049, prothrombin G20210A in 3.21 (CI: 1.66–6.211), p=0.049. MTHFR C677T polymorphism, PAI-1 (SERPIN1) 4G/5G polymorphism also increase the risk of VTE, but it was no significant. Study have shown that waist circumference >80 cm increase the risk of VTE in 3.19 (CI: 1.35–7.58), p=0.019. Combination of inherited thrombophilia (Factor V Leiden G1691A, Prothrombin G20210A, MTHFR C677T polymorphism, PAI-1 (SERPIN1) 4G/5G polymorphism) and waist circumference >80 cm increase the risk of VTE in 3.51 (CI: 1.76–7.04), p<0.001. Conclusion Previous results of our work indicate influence of waist circumference >80 cm on the risk of VTE, especially risk of thrombosis is higher in patients with combination inherited thrombophilia and waist circumference >80 cm. FUNDunding Acknowledgement Type of funding sources: None.

Do MTHFR C677T Genetic Polymorphism Influence in the Pathogenesis of Amyotrophic Lateral Sclerosis?

Amyotrophic Lateral Sclerosis (ALS) is a progressive and lethal neurodegenerative disease without a definitive diagnostic test and effective treatment. A plethora of studies suggest that genetic factors play an important role in ALS development, and potentially link folate pathway dysregulation to disease pathogenesis. This study aims to evaluate folate dysregulation due to MTHFR C677T polymorphism and other factors such as sociodemographic and clinical, to better elucidate the involvement of these factors in ALS pathogenesis, and to investigate possible biomarkers for use as disease diagnostics or prognostics. This hospital-based case-control study analyzed 101 patients diagnosed with ALS and 119 considered healthy, with no suspicion or diagnosis of neurodegenerative disease. Blood samples were collected, stored, and underwent DNA extraction. Clinical and sociodemographic data from patients were collected through a questionnaire, as well as consultation of medical records. Genotypic analyses were performed using PCR-RFLP, and statistical analysis of clinical and genotypic data was conducted with SPSS software, version 23. The results show a higher presence of the mutant genotype (p = 0.02) in the case group, and suggest that mutant allele (T) is a risk factor for ALS susceptibility (OR = 1.54; 95% CI = 1.05–2.29; p = 0.03). Mutant genotype (T/T) interacts with both demographics (White p = 0.005 / Brown p = 0,001) and clinical factors (Physical activity p = 0.006) as risk factors for ALS. Also, a significant difference in alcohol consumption (p = 0.001) between the case and control group was observed. Moreover, a statistical trend towards faster disease progression and death was observed for patients with the mutant allele (T) (p = 0.06). Thus, the results of this study suggest that folate deficiency due to MTHFR C677T polymorphism is implicated in ALS through pathogenic mechanisms and interaction with other risk factors, resulting in faster disease progression and early death.

Associations of homocysteine metabolism with the risk of spinal osteoarthritis progression in postmenopausal women

Purpose Although homocysteine accumulation is a reported risk factor for several age-related disorders, little is known on its relationship with osteoarthritis (OA). We therefore investigated for associations of homocysteine and C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR), which is involved in homocysteine clearance, with the development and progression of spinal OA, through a combined cross-sectional and longitudinal cohort study. Methods A total of 1306 Japanese postmenopausal outpatients participating in the Nagano Cohort Study were followed for a 9.7-year mean period. Cross-sectional multiple logistic regression for spinal OA prevalence at registration by serum homocysteine level was performed with adjustment for confounders. In addition to Kaplan–Meier analysis, multivariate Cox regression was employed to examine the independent risk of MTHFR C677T variant for spinal OA progression. Results Multivariate regression analysis revealed a significant association between homocysteine and spinal OA prevalence (odds ratio 1.38; 95% confidence interval [CI] 1.14–1.68). Kaplan–Meier curves showed a gene dosage effect of the T allele in MTHFR C677T polymorphism on the accelerated progression of spinal OA severity (P = 0.003). A statistically significant independent risk of the T allele for spinal OA advancement was validated by Cox regression analysis. Respective adjusted hazard ratios for the CT/TT and TT genotypes were 1.68 (95% CI 1.16–2.42) and 1.67 (95% CI 1.23–2.28). Conclusions Circulating homocysteine and C677T variant in MTHFR are associated with the prevalence rate and ensuing progression, respectively, of spinal OA. These factors may represent potential interventional targets to prevent OA development and improve clinical outcomes.

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism is associated with breast cancer subtype susceptibility in southwestern China

Methylenetetrahydrofolate reductase (MTHFR), a folate-dependent enzyme, is reportedly involved in several cancer types. The MTHFR C677T polymorphism influences many biological processes, including tumorigenesis. However, the association between the MTHFR C677T polymorphism and breast cancer (BC) subtypes is not fully understood. In this study, the MTHFR C677T polymorphism was genotyped in 490 individuals with or without BC from southwestern China. Analysis of the association between the MTHFR C677T polymorphism and BC revealed that there was a significant association between the MTHFR C677T polymorphism and triple-negative breast cancer (TNBC) (OR = 2.83, 95% CI: 1.12–9.51, P = 0.0401). Furthermore, the MTHFR C677T polymorphism can also serve as a protective factor in luminal A breast cancer (OR = 0.57, 95% CI: 0.34–0.94, P = 0.0258). Evaluation of the association between the MTHFR C677T polymorphism and clinical characteristics indicated that people who suffered from hypertension had an increased risk for BC (OR = 2.27; 95% CI: 1.08–4.6; P = 0.0264), especially TNBC (OR = 215.38; 95% CI: 2.45–84430.3; P = 0.0317). Our results suggest that the MTHFR C677T polymorphism is significantly associated with susceptibility to luminal B breast cancer and TNBC.

Association of MTHFR C677T polymorphism with primary open angle glaucoma: a Meta-analysis based on 18 case-control studies

AIM: To systematically understand the genetic association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and primary open angle glaucoma (POAG). METHODS: 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. RESULTS: 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 vs C OR=1.11, 95%CI: 0.88 to 1.39; for TT vs CC OR=1.01, 95%CI: 0.76 to 1.36; for TT+TC vs CC OR=1.15, 95%CI: 0.84 to 1.58 and for TT vs TC+CC OR=1.02, 95%CI: 0.78 to 1.33). However, a significant effect was revealed in the Asian population (for T vs C OR=1.34, 95%CI: 1.12 to 1.59; for TT+TC vs CC OR=1.41, 95%CI: 1.14 to 1.76). CONCLUSION: 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.