Methylenetetrahydrofolate Reductase Gene Polymorphisms Research Articles

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in Turkish postmenopausal women with osteoporosis

Osteoporosis is a common age-related skeletal disease, characterized by changes in the microarchitectural structure of bone tissue and decreased bone mass, especially affecting postmenopausal women. Genetic and environmental factors affecting bone metabolism play a role in the development of osteoporosis. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene lead to impaired function or inactivation of this enzyme. A decrease in MTHFR enzyme activity and an increase in homocysteine levels affect bone metabolism. In this study, we aimed to investigate the relationship between C677T and A1298C polymorphisms and osteoporosis in Turkish postmenopausal women. DNA samples were extracted from 200 volunteers. The PCR-RFLP technique was used to identify the MTHFR gene polymorphisms C677T and A1298C. The statistical significance of the analysis’s results was assessed. C677T genotype and allele frequency distributions were not statistically different between postmenopausal osteoporosis and healthy control groups (p = 0.249, p = 0.754), while A1298C genotype and allele frequency distributions were found to be statistically significant (p = 0.002, p = 0.013). The results of our study showed that the A1298C polymorphism may be a genetic factor associated with osteoporosis in this specific population. However, the C677T polymorphism did not show a significant connection. To gain a more comprehensive understanding of the genetic basis of osteoporosis, future research with larger sample sizes and the consideration of additional genetic and environmental factors is essential. Additionally, it is crucial to account for ethnic disparities, gene-gene interactions, and gene-environment interplays. These insights can inform the development of personalized preventive and therapeutic strategies for individuals at risk of osteoporosis in diverse populations.

Genetic association and computational analysis of MTHFR gene polymorphisms rs1801131 and rs1801133 with breast cancer in the Bangladeshi population

Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating one-carbon metabolism. Polymorphisms within the MTHFR gene have been found to increase the risk of breast cancer in different populations. In this study, we evaluated the association of polymorphisms of the MTHFR gene (rs1801133 and rs1801131) with the risk of breast cancer in the Bangladeshi population. This case‒control study included 202 breast cancer patients and 104 healthy controls. After the organic extraction of DNA, genotyping was performed via the PCR-RFLP method. Sanger sequencing was performed to validate the RFLP data. Statistical analyses were performed to evaluate the associations of the polymorphisms. Different computational tools were used to predict the structural and functional consequences of the SNPs. Our study revealed that the MTHFR gene polymorphism rs1801131 is associated with an increased risk of developing breast cancer (p < 0.001, OR = 3.85, 95% CI = 2.06–7.25 for the AC genotype and p < 0.001, OR = 7.82, 95% CI = 2.69–22.05 for the CC genotype). An association was also observed in the dominant model (AC + CC) (p < 0.001, OR = 4.19, 95% CI = 2.28–7.78). For rs1801131, premenopausal status was significantly associated with breast cancer risk (p < 0.001). For rs1801133, no significant association was found with breast cancer risk (p > 0.05, OR = 1.57, 95% CI = 0.90–2.74 for the CT genotype; p > 0.05, OR = 1.35, 95% CI = 0.36–4.92 for the TT genotype). Computational analyses predicted rs1801131 to be tolerated and rs1801133 to be deleterious. Structural analyses demonstrated no significant changes in protein structure but revealed alterations in neighboring interactions according to both bond distances and angles. In conclusion, rs1801131 but not rs1801133 is significantly associated with breast cancer risk in the Bangladeshi population. Moreover, in silico analyses demonstrated changes in the interaction pattern of polymorphic residues with adjacent amino acids.

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

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

Exploring the correlation between homocysteine, red blood cell folate and MTHFRC677T genotypes with female infertility.

Aim: To investigate the association between serum homocysteine (HCY) levels, red blood cell folate (RCF) levels, methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and infertility.Materials & methods: Serum HCY and RCF levels and C677T polymorphism of MTHFR gene were analyzed in 149 infertile patients and 223 women of normal reproductive age with healthy childbirth history.Results: The HCY level of MTHFR C677T TT genotype infertility patients was higher than that of women of normal reproductive age, while the RCF level was not significantly different between the two groups.Conclusion: Serum HCY levels increased in infertility patients, and the MTHFR C677T TT genotype in childbearing-aged women are associated with a higher risk of infertility. The results showed that HCY level and MTHFR C677T genotype were closely related to infertility.

MTHFR polymorphisms and vitamin B12 deficiency: correlation between mthfr polymorphisms and clinical and laboratory findings.

Vitamin B12 deficiency is a common condition that causes a variety of disorders ranging from the development of megaloblastic anemia to the building up of neurological damage. Historically one of the leading causes of B12 deficiency appears to be secondary to malabsorption in part caused by the development of atrophic gastritis in pernicious anemia. More recently B12 deficiency could also depend on dietary restrictions. Cobalamin deficiency also appears to be closely related to folate metabolism, causing a reduction in methionine synthase activity. This results in the accumulation of 5-methyltetrahydrofolate (5-MTHF) and defective DNA synthesis. It has been hypothesized that reduced activity of the enzyme methylene-tetrahydrofolate reductase (MTHFR) could reduce the production of 5-MTHF, thereby shifting folate metabolism to thymidylate synthesis and promoting proper DNA synthesis. Our aim was to investigate the role of the C677T and A1298C MTHFR gene polymorphisms, which are associated with reduced enzyme activity, in predisposing to the development of anemia, neurological symptoms, and atrophic gastritis in a population of 105 consecutive Italian patients with cobalamin deficiency. We found statistically significant correlations between the degree of anemia and thrombocytopenia and the C677T MTHFR polymorphism, while hemoglobin levels alone significantly correlated with A1298C polymorphism, contradicting the potential protective role of these polymorphisms. Furthermore, in patients with atrophic gastritis, we found an association between the absence of parietal cell antibodies and the presence of the C677T polymorphism in homozygosity. Our results suggest a role for MTHFR enzyme activity in the severity of hematologic manifestations of vitamin B12 deficiency and as an independent mechanism of predisposition to the development of atrophic gastritis.

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms in andrology-a narrative review.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism and one-carbon metabolism. MTHFR gene polymorphism affects enzyme activity. MTHFR gene polymorphism is closely related to many human diseases, such as cardiocerebrovascular diseases, diabetes, neural tube defects (NTDs), tumors, and so on. In the field of Andrology, MTHFR gene polymorphism may be associated with male infertility and erectile dysfunction (ED), and there is a possibility of treating male infertility and ED by supplementing with folic acid. However, its exact pathophysiologic mechanism is not fully understood. We sought to obtain a robust understanding of the interactions between MTHFR gene polymorphism, oxidative stress, DNA methylation, hyperhomocysteinemia (HHcy), male infertility, and ED. We performed a non-systematic literature review using the PubMed database to identify articles specifically related to MTHFR, male infertility and ED. Our literature review on MTHFR gene polymorphism in male infertility patients indicates a significant association between C677T gene polymorphism and male infertility. There is limited literature on the correlation between ED and MTHFR gene polymorphism, and there are two different conclusions, related and unrelated. More clinical data are needed to clarify the conclusion. There is a possibility of using folic acid supplementation to treat male infertility and ED, especially for patients with thymine-thymine (TT) genotype. Future research is necessary to further understand the relationship between MTHFR gene polymorphism and male infertility and ED. Our literature review on MTHFR gene polymorphism in male infertility patients indicates a significant association between C677T gene polymorphism and male infertility. Folic acid supplementation can improve sperm quality. The correlation between MTHFR gene polymorphisms and ED is questionable and needs to be confirmed by more clinical data. MTHFR gene polymorphisms are associated with homocysteine (Hcy) levels, which affects vascular endothelial function and may be related to the development of vascular ED (VED). Folic acid supplementation improves International Index for Erectile Function (IIEF) questionnaire scores in ED patients in whom phosphodiesterase 5 inhibitor (PDE5i) alone is ineffective.

Non-syndromic Cleft Lip and Palate Patients of the North Indian Population and the Association of Methylenetetrahydrofolate Reductase Gene.

Cleft lip and palate (CLP) is a common congenital anomaly characterized by incomplete fusion of the lip and/or palate during embryonic development. The etiology of CLP is multifactorial, involving genetics and different environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene has been proposed as a candidate gene associated with CLP due to its involvement in folate metabolism and DNA methylation processes. However, the association between MTHFR gene variants and CLP in non-syndromic patients in the North Indian population remains unclear. This research aimed to see the association between MTHFR gene polymorphisms in non-syndromic patients withCLP in the North Indian population. A case-control observational design comprised 50 CLP patients (cases) and 50 healthy individuals without CLP (controls).Blood samples were collected from patients visiting two hospitals. Genomic DNA was extracted from collected peripheral blood samples, and the genotyping of MTHFR gene polymorphisms (specifically, C677T) was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The allelic and genotypic frequencies of MTHFR gene variants were compared between cases and controls using appropriate statistical tests. This research revealed a significant association between MTHFR gene polymorphismand CLP in the North Indian population. The odds for the genotypes reach statistical significance, suggesting that the MTHFR gene variantmay play a major role in this population's susceptibility to non-syndromic CLP. This study provides evidence for a linkage between the MTHFR gene C677T polymorphism and an increased risk of CLP in non-syndromic patients in the North Indian population. These findings do support the involvement of MTHFR gene variants in the etiology of CLP. In the future, more research is warranted to elucidate the underlying mechanisms linking MTHFR gene variants to CLP and to explore potential gene-environment interactions in this context.

Exploring the Nexus: A Systematic Review on the Interplay of the Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T Genotype, Hyperhomocysteinemia, and Spontaneous Cervical/Vertebral Artery Dissection in Young Adults.

Ischemic strokes (IS)in young adults often evade early detection, resulting in delayed diagnosis until complications arise. Cervical/vertebral artery dissection, a significant contributor to these strokes, presents with symptoms such as migraine with aura, severe headache, and neck pain, commonly overlooked due to their nonspecific nature. This review investigates early indicators of artery dissections, emphasizing their importance in diagnosis and exploring the correlation between methylenetetrahydrofolate reductase (MTHFR) gene C677Tgenotype polymorphism, hyperhomocysteinemia (HHCY), and IS in young adults. This systematic review encompasses a thorough analysis of 11 papers, including four observational studies, three case reports, three narrative reviews, and one experimental study, involving 4,840 patients aged 18-45 years. Findings reveal HHCY as a significant contributor to vascular damage and tissue ischemia leading to IS. The MTHFR gene C677Tgenotype polymorphism is closely associated with HHCY, often contributing to underdiagnosed strokes in young adults. Cervical/vertebral artery dissection may manifest as initial symptoms of neck pain or headache, remaining undiagnosed until imaging is conducted. Importantly, the review suggests that MTHFR gene polymorphism can be mitigated through simple supplementation with vitamin B12 and folates, serving as a valuable tool for primary prevention. Additionally, betaine, a methyl donor, was explored in severe MTHFR gene polymorphism cases resistant to conventional supplementation. In conclusion, recognizing the significance of early signs and symptoms, along with a high clinical suspicion, is crucial for preventing catastrophic outcomes, mortality, and morbidity associated with IS in young adults lacking traditional risk factors. The MTHFR gene C677Tgenotype polymorphism, a potential genetic cause, can be easily managed with simple measures but is often overlooked or underdiagnosed.

Association of Methylenetetrahydrofolate Reductase Gene Polymorphism C677T with Oocyte Number and Embryo Quality in Iraqi Infertile Women Undergoing Intracytoplasmic Sperm Injection

Background: Methylenetetrahydrofolate reductase (MTHFR) C677T is a single nucleotide polymorphism (SNP) that affects the production of 5-methyltetrahydrofolate (5-MTHF), the active folate that enables the recycling of homocysteine (Hcy) to methionine. Objective: to investigate the association between the MTHFR (C677T) polymorphism and the outcomes of intracytoplasmic sperm injection (ICSI). Methods: A prospective cohort study included 85 infertile women undergoing ICSI treatment at the High Institute of Infertility Diagnosis and Assisted Reproductive Technologies in Baghdad, Iraq. The study period extended from January 2022 to September 2023. The MTHFR C677T polymorphism genotyping was evaluated in these patients, and they were classified into three groups according to genotyping results: normal (CC), heterozygote mutated (CT), and mutated homozygote (TT). In addition, we conducted a comparative analysis of oocyte, embryo and pregnancy rates among these three groups. Results: In comparison to the CT and TT genotypes, the total number of oocytes, total embryos, mature oocytes, good-quality embryos, and pregnancy rate were all found to be significantly higher (p&lt;0.05) in the CC genotype. Compared to the CC group, the proportion of immature oocytes and poor-quality embryos was significantly higher in the TT and CT groups (p&lt;0.05). The rate of fertilization was comparable among the study groups. Conclusions: The maternal MTHFR C677T polymorphism is linked to oocyte number, maturity, total embryo, embryo quality, and pregnancy in ICSI. In light of this, MTHFR polymorphism in our community offers useful data regarding the success of ICSI.

Association of MTHFR gene polymorphisms with non-Hodgkin lymphoma risk: Evidence from 31 articles.

Background: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, particularly C677T and A1298C, have been implicated in various cancers, including non-Hodgkin lymphoma (NHL); however, their association with NHL risk remains inconclusive. Methods: We conducted an updated meta-analysis to assess the relationship between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk. Relevant studies were identified through systematic literature searches in multiple databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Results: The meta-analysis included 32 studies (8222 cases vs. 12956 controls) for MTHFR C677T and 26 studies (6930 cases vs. 11611 controls) for the A1298C polymorphism. Our meta-analysis revealed no significant associations between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk. However, subgroup analysis stratified by ethnicity and NHL subtype yielded interesting findings for the C677T polymorphism. Specifically, in the subgroup analysis of Caucasians, the C677T polymorphism was significantly associated with NHL risk (heterozygous: OR=1.16, 95% CI=1.02-1.32; allele comparison: OR=1.07, 95% CI=1.01-1.13). Furthermore, in the analysis stratified by NHL subtype, the C677T polymorphism was significantly associated with increased follicular lymphoma (FL) risk (homozygous: OR=1.25, 95% CI=1.02-1.53; recessive: OR=1.28, 95% CI=1.06-1.56). False-positive result possibility (FPRP) analysis verified that the association of the MTHFR C677T polymorphism with NHL risk for Caucasians and FL subtypes was a true positive and deserves attention. We also determined that the C677T polymorphism is an expression quantitative trait locus (eQTL) since it is associated with MTHFR gene expression. Conclusion: There was no overall association between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk, but stratified analyses revealed significant associations in specific subgroups. While meta-analyses inherently build upon existing studies, our work distinguishes itself by incorporating recent data, applying rigorous analytical techniques, and providing more evidence of the MTHFR C677T polymorphism as an eQTL.

Methylenetetrahydrofolate reductase gene polymorphisms, lipid profiles, and basic renal functional markers as risk for myocardial infarction: A case-control study and haplotype analysis

Myocardial infarction (MI) is a serious cardiovascular disease and the primary cause of mortality, with a complex etiopathology. Identifying the genetic basis of myocardial infarction (MI) is essential for developing personalized medical treatments. This study examined the possible association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and MI. In the study, 120 patients with MI and 120 age-and-sex-matched controls were genotyped for C677T and A1298C MTHFR polymorphisms by the allele-specific or amplification refractory mutation systempolymerase chain reaction (ARMS-PCR). In the case of the C677T polymorphism, the T/T and C/T genotypes were associated with a significantly increased risk of MI under the dominant genetic model (odds ratio (OR)=2.060; P=0.006). Although there was no significant association between the A1298C variant and MI, this polymorphism was linked to a higher level of creatinine in MI patients (P&lt;0.002). A similar association was observed for the C677T polymorphism (P=0.003). An A-T haplotype represented an increased risk for MI (OR=1.630; P=0.014), whereas the A-C haplotype had a protective role (R=0.517; P=0.002). These findings indicate that C677T MTHFR polymorphism is strongly associated with and increased risk of MI, making it a potential genetic risk factor and a possible predictor of MI.

Exploring the sophistications of unexplained recurrent pregnancy loss: A case-control study.

Unexplained recurrent pregnancy loss (URPL) is a significant obstetric challenge affecting maternal health and well-being. Genetic factors, including mutations in the methylenetetrahydrofolate reductase (MTHFR) gene and elevated homocysteine levels, are increasingly recognized as contributors to URPL, though their precise roles remain complex. This study aimed to comprehensively explore these factors. This study examines the links between MTHFR gene polymorphisms (C677T and A1298C), plasma homocysteine levels, and URPL. It also aims to create a predictive model for URPL based on these factors. A case-control study with Vietnamese women who had at least one pregnancy between January 2017 and June 2020, recruited from Medlatec Hospital and Hanoi Medical University. Participants included URPL cases (n = 128) and controls (n = 126). Participants were selected based on specific criteria. Main analyses identified the optimal multivariable logistic regression model for predicting URPL using Bayesian Model Averaging, with the optimal model chosen based on the highest Area Under the Curve (AUC) and posterior probability. A nomogram for clinical risk prediction was developed based on parameters from the optimal model. URPL cases exhibited significantly higher plasma homocysteine levels (11.73 ± 6.08 µmol/L) compared to controls (7.64 ± 1.78 µmol/L), correlating with increased URPL risk (OR: 1.64, 95% confidence interval (CI): 1.41-1.96; p < 0.001). The MTHFR C677T variant showed strong associations with URPL, particularly the CT genotype (OR: 6.07, 95% CI: 3.00-12.93; p < 0.001) and TT genotype (OR: 14.62, 95% CI: 2.85-114.77; p = 0.003). Similarly, the A1298C variant demonstrated elevated URPL risk with the AC genotype (OR: 2.73, 95% CI: 1.34-5.78; p = 0.007) and CC genotype (OR: 12.43, 95% CI: 3.17-64.22; p = 0.001). This study provides insights into the complex interplay of MTHFR gene mutations, elevated homocysteine levels, and URPL. Genetic testing and biomarker assessment may play a crucial role in customizing risk assessment and management strategies for women at risk of URPL.

MTHFR Gene C677T Polymorphism (rs1801133) and Susceptibility to Colorectal Polyps in an Azerbaijani Population.

Understanding the relationships between the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, colorectal polyps, and CRC risk can aid in advancing personalized medicine approaches in CRC prevention. The aim of the current study is to identify the association of C677T polymorphism of the MTHFR gene with the risk of colorectal polyps in the Azerbaijani population. This study included 125 patients with colon polyps and 155 healthy individuals as a control group. DNA was extracted from venous blood samples obtained from patients and healthy individuals, and the results were analyzed through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and agarose gel electrophoresis. Wild-type, heterozygote, and homozygous mutant were revealed within 69 (55.2%), 49 (39.2%), and 7 (5.6%) patients and within 100 (64.5%), 45 (29%), and 10 (6.5%) healthy controls, respectively. However, no significant statistical associations were observed between CT and TT genotypes, dominant (CC vs. CT + TT) and recessive (CC + CT vs. TT) models, and the mutant T allele and disease risk. There were also no significant differences between patients and controls regarding age, sex, smoking and alcohol use. Our research did not reveal any significant association between the MTHFR C677T polymorphism and susceptibility to colorectal polyps in the Azerbaijan population.

A Genetic Association Study of MTHFR C677T Polymorphism with Risk of Metabolic Syndrome: A Systematic Review and Meta-Analysis

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a crucial role as a methyl-group donor in demethylation of homocysteine. The aim of this systematic review and meta-analysis was to study the relationship between MTHFR gene polymorphism and metabolic syndrome (MS). We used search engines and databases such as Science Direct, Google Scholar, Embase, Cochrane Library, and PubMed to identify eligible studies up to 2018. The articles were studied based on keywords including MTHFR, mutation, variant, and polymorphism in combination with MS. Data was analyzed using Comprehensive Meta-Analysis version 2.2.064 software. After extracting the data from seven articles, the total number of subjects was 1280 in the patient group and 1374 in the control group. The odds ratio was estimated to be 1.078 for the allele model of T vs. C (95% confidence interval [CI]: 1.626-0.715), 1.157 for the allele model of CC vs. CT (95% CI: 0.829-1.615), 1.020 for the allele model of CT + TT vs. CC (95% CI: 1.611-0.646) and 0.799 for the allele model of TT vs. CC + CT (95% CI: 1.185-0.539). As well, the results showed no statistically significant correlation between polymorphism genotypes of the MTHFR gene and MS (P&lt;0.05). In general, this study showed that the presence of C677T polymorphism in the MTHFR gene has no effect on the incidence of MS. [GMJ.2019;8:e1472]

Association between COVID-19 Infection or Vaccination Outcomes and Methylenetetrahydrofolate Reductase Gene Polymorphism: A Systematic Review of the Literature.

Thrombosis is a detrimental sequala of COVID-19 infection; thus, prophylactic anti-coagulant therapy has been deemed mandatory in treatment unless serious contraindications are present. Susceptibility to thromboembolic events in COVID-19, or following COVID-19 vaccination, is likely attributable to an interplay of factors, including a patient's baseline clinical status and comorbidities, alongside genetic risk factors. In Europe, 8-20% of the population are homozygous for the MTHFR (methylene tetrahydrofolate reductase) variant, which compromises folate metabolism and elevates homocysteine levels. While heightened homocysteine levels are considered a risk factor for thromboembolic events, the precise clinical significance remains a contentious issue. However, recent research suggests elevated homocysteine levels may predict the course and severity of COVID-19 infection. Given the lack of reliable biomarkers predictive of COVID-19 thrombotic risk existing in practice, and the accessibility of MTHFR screening, we established two main outcomes for this study: (1) to determine the association between hereditary MTHFR mutations and COVID-19 severity and thromboembolic events and (2) to determine the link between MTHFR variants and adverse thrombotic events following COVID-19 vaccination. The review was conducted in accordance with PRISMA guidelines. Medline, Scopus, and Web of Science databases were searched from pandemic inception (11 March 2020) to 30 October 2023. Eligibility criteria were applied, and data extraction performed. From 63 citations identified, a total of 14 articles met the full inclusion criteria (8 of which were cross-sectional or observational studies, and 6 were case studies or reports). Among the eight observational and cross-sectional studies evaluating the relationship between MTHFR variants (C667T; A1298C) and thromboembolic events in COVID-19 infection, four studies established a connection (n = 2200), while the remaining four studies failed to demonstrate any significant association (n = 38). This systematic review demonstrated a possible association between the MTHFR gene variants and COVID-19 severity, thromboembolic events, and adverse events following vaccination. However, the paucity of robust data precluded any firm conclusions being drawn. Further prospective trials are required to determine the connection between the MTHFR gene variant and COVID-19 infection and vaccination outcomes.

Methylenetetrahydrofolate Reductase Gene Polymorphism as a Risk Factor for Coronary Artery Disease

Methylenetetrahydrofolate Reductase Gene Polymorphism as a Risk Factor for Coronary Artery Disease

MTHFR gene polymorphisms and susceptibility to myocardial infarction: Evidence from meta-analysis and trial sequential analysis

BackgroundThis meta-analysis aimed to provide a comprehensive assessment of the association between Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, specifically C677T and A1298C, and the susceptibility to myocardial infarction (MI). MethodsA systematic literature search was conducted in MEDLINE, Web of Science, and Scopus until April 2023 to identify studies investigating the relationship between MTHFR gene polymorphisms (C677T and A1298C) and the risk of MI. ResultsThe analysis included 66 studies involving 16,860 cases and 20,403 controls for the C677T polymorphism and 18 studies comprising 3162 cases and 3632 controls for the A1298C polymorphism. Significant associations were observed between the C677T polymorphism and MI risk in various genetic models: dominant (OR = 1.16, 95 % CI = 1.06–1.28, P = 0.008), recessive (OR = 1.20, 95 % CI = 1.12–1.28, P < 0.001), allelic (OR = 1.13, 95 % CI = 1.06–1.21, P < 0.001), TT vs. CC (OR = 1.19, 95 % CI = 1.05–1.36, P < 0.001), and CT vs. CC (OR = 1.11, 95 % CI = 1.02–1.21, P = 0.01). Furthermore, an overall analysis indicated a marginally significant association between the A1298C polymorphism and MI risk in the recessive model (OR = 1.27, 95 % CI = 1.06–1.51, P = 0.008), allelic model (OR = 1.18, 95 % CI = 1.01–1.39, P = 0.03), and CC vs. AA model (OR = 1.22, 95 % CI = 1.01–1.47, P = 0.04). Meta-regression analysis revealed that none of the potential factors contributed to the observed heterogeneity. ConclusionsThis meta-analysis revealed an association between MTHFR gene C677T and A1298C polymorphisms and the risk of MI.

Association of epistatic effects of MTHFR, ACE, APOB, and APOE gene polymorphisms with the risk of myocardial infarction and unstable angina in Egyptian patients

Despite remarkable discoveries in the genetic susceptibility of coronary artery disease (CAD), a large part of heritability awaits identification. Epistasis or gene‐gene interaction has a profound influence on CAD and might contribute to its missed genetic variability; however, this impact was largely unexplored. Here, we appraised the associations of gene-gene interactions and haplotypes of five polymorphisms, namely methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, angiotensin converting enzyme (ACE) insertion/deletion (I/D), apolipoprotein B (APOB) R3500Q, and apolipoprotein E (APOE) ε4 with the risk of myocardial infarction (MI) and unstable angina (UA). Gene-environment interactions with traditional risk factors and clinical data were also scrutinized. This study recruited 100 MI, 50 UA patients, and 100 apparently healthy controls. Logistic regression models were employed in association analyses. We remarked that the single locus effect of individual polymorphisms was relatively weak; however, a magnified effect of their combination via gene-gene interaction may predict MI risk after adjustment for multiple comparisons. Only MTHFR C677T, ACE I/D, and APOB R5300Q were associated with the risk of UA, and the ACE I/D-R3500Q interaction posed a decreased UA risk. APOB R3500Q was in strong linkage disequilibrium with MTHFR C677T, ACE I/D, and APE ε4 polymorphisms. The TCDGε3, CADGε4, and TADGε4-C677T-A1298C-ACE I/D-R3500Q-APOE haplotypes were associated with escalating MI risk, while the CDG or CIG-C677T-ACE I/D-R3500Q haplotype was highly protective against UA risk compared to controls. Interestingly, the CADGε4 and CAIGε3 haplotypes were strongly associated with the presence of diabetes and hypertension, respectively in MI patients; both haplotypes stratified patients according to the ECHO results. In UA, the CDG haplotype was negatively associated with the presence of diabetes or dilated heart. Conclusively, our results advocate that a stronger combined effect of polymorphisms in MTHFR, ACE, APOB, and APOE genes via gene-gene and gene-environment interactions might help in risk stratification of MI and UA patients.

Association Between MTHFR Gene Polymorphism (A1298c) C&gt;A and Sensitivity to Cervical Cancer: A Meta-Analysis

We have investigated the association between methylenetetrahydrofolate reductase A1298C polymorphism and cervical cancer. A comprehensive search was conducted in Wanfang, China HowNet and PubMed databases to retrieve Chinese and English literature from the construction of the database to December 2019. Stata software was utilized to conduct the analysis of the five genetic models, while the odds ratio and 95% confidence interval were employed to assess the correlation. 12 pertinent publications were included with 3839 subjects (1546 patients and 2293 healthy control). There were no significant associations between A1298C and cervical cancer risk under recessive model, dominant model, allele model, co-dominant model. In the sub-analysis by ethnic groups, a significant association between A1298C and cervical cancer risk under recessive model in Asia. It is suggested a potential association between methylenetetrahydrofolate reductase gene polymorphism A1298C and an elevated susceptibility to cervical cancer in the Asian population, specifically under the recessive model.

Relationship between MTHFR gene polymorphism and risk of thrombosis in postoperative patients with colorectal cancer.

An association between the methylenetetrahydrofolate reductase (MTHFR) C667T genotype and the risk of colorectal cancer, as well as a link between MTHFR gene polymorphism and thrombosis, have been revealed. However, the connection between MTHFR gene polymorphism and the risk of thrombosis in patients with colorectal cancer has remained to be fully elucidated. The present study investigated the link between MTHFR gene polymorphism and basic clinical data, postoperative D-dimer (DDi), postoperative thromboelastogram and postoperative thrombosis in 591 patients who underwent surgery for colorectal cancer. Postoperative DDi, thromboelastogram and postoperative thrombosis were not significantly different among patients with colorectal cancer and different MTHFR genotypes. While the results were 'negative', the present study may help physicians understand that it is not necessary to detect MTHFR polymorphism for therapeutic purposes. Regarding the danger of venous thrombosis, more focus should be placed on the standardized procedural enforcement system for deep vein thrombosis prevention for patients undergoing pelvic and abdominal surgery.