Methylenetetrahydrofolate Reductase Polymorphisms Research Articles

5,10-methylenetetrahydrofolate reductase C677T gene polymorphism as a risk factor for premature coronary artery disease in patients with type 2 diabetes mellitus

BackgroundAfrica, like the rest of the world, is experiencing an increasing prevalence of diabetes mellitus. Diabetes increases the risk for coronary artery disease (CAD) by fourfold compared to people without diabetes. C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were reported by many studies as risk factors for CAD among patients with type 2 diabetes mellitus (T2DM). Early detection of modifiable risk factors for CAD is an important aspect of management of diabetes. This is the only study in Sudan which investigates the association between MTHFR genotypes and plasma homocysteine levels, and their role in premature CAD (PCAD) among patients with T2DM.MethodsThis study is a comparative study. We enrolled 226 Sudanese patients with T2DM, age range 25-60 years, recruited from Alshaab and Omdurman teaching hospitals in Khartoum State. 113 patients had CAD confirmed by angiography and electrocardiography (ECG) and 113 had no evidence of CAD. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), using Hinf1 restriction enzyme, were used to determine MTHFR genotypes. Plasma homocysteine levels were determined by enzymatic assay on the Hitachi Cobas Integra® 400 plus. Data was analyzed using statistical package for Social Sciences (SPSS) 23, using Mann-Whtney U test, general linear model, Chi-square test and logistic regression analysis.ResultsThe frequencies of TT, CT, and CC genotypes were 16,40 and 44% among T2DM patients with PCAD. In T2DM patients without PCAD, the frequencies of TT, CT, and CC genotypes were 00,19 and 83%. The T allele showed strong association with PCAD among T2DM patients, p <0.001, odds ratio (OR) 6.2, 95% CI (3.4-11.6). Patients with PCAD showed higher plasma homocysteine levels than patients without PCAD (13.5 µmol/L versus 10 µmol/L, p < 0.001). The T allele had significant effect on homocysteine level, (p <0.001). Plasma homocysteine levels were higher in individuals with TT genotype than those with CT or CC genotypes in patients with PCAD (16.2 + 5.3, 14.3 + 5.7 and 12.9 + 5.02 µmol/L, p=0.017). Homocysteine levels showed a significant association with CAD, p<0.001, OR 3.2, 95% CI (1.9—5.5).ConclusionsOur study suggests that C677T polymorphism of MTHFR gene and hyperhomocysteinemia are risk factors for PCAD in Sudanese population with T2DM.

The Relationship between Homocysteine Levels, MTHFR C677T and A1298C Polymorphism, and Pregnancy Outcomes in Georgian Women with Polycystic Ovary Syndrome: A Case-Control Study.

Over the past decade, numerous studies have been conducted to determine the role of homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in the pathogenesis of polycystic ovary syndrome (PCOS), yet the results are inconsistent. The aim of the current study was to determine the association between homocysteine levels (Hcy), MTHFR) C677T and A1298C polymorphisms, and pregnancy outcomes in Georgian women with PCOS. This case-control study included 177 female participants, of which 96 women were diagnosed with PCOS, and 81 age-matched women were without PCOS. Participants were divided into four groups; group I: 59 PCOS patients with history of recurrent pregnancy loss (RPL), group II: 37 PCOS patients with live birth in history and without RPL, group III: 39 women with RPL, without PCOS, group IV: controls, 42 women with live birth in history, without RPL and PCOS. These groups were compared based on their serum Hcy and the presence of two common single nucleotide polymorphisms (SNPs) in the MTHFR) gene: C677T and A1298C. The mean Hcy, frequency of hyperhomocysteinemia (Hhcy) and the prevalence of C677T and A1298C polymorphisms in MTHFR) gene in PCOS patients were significantly higher than those without PCOS (P<0.05). Group I (PCOS with RPL) showed significantly elevated Hcy (13.7 ± 2.7) compared to group II (10.3 ± 2.6), group III (11.5 ± 2.3), and group IV (7.3 ± 2.2), P<0.001. In group I, the frequencies of the C677T-CT, A1298CAC genotypes, and the compound heterozygous of C677T-CT/A1298C-AC were significantly higher than in the other groups (P<0.05). The prevalence of MTHFR) A1298C (CC) was significantly higher in group II (PCOS patients with live birth) than in other comparison groups (P<0.05). The study reveals a significant correlation between hyperhomocysteinemia, MTHFR) polymorphisms (C677T and A1298C), and PCOS, impacting pregnancy outcomes.

Evaluating the Association Between Methylenetetrahydrofolate Reductase (Rs1801131 and Rs1801133) Gene Polymorphisms and Severity of Coronary Lesions in Patients With STEMI and NSTEMI: A Retrospective Cross-Sectional Study.

Mounting evidence have implicated that rs1801131 and rs1801133, located in the Methylenetetrahydrofolate reductase (MTHFR) gene, may emerge as novel biomarkers for coronary artery disease (CAD). The Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score is also an appropriate predictor for revascularization strategy in patients with complex CAD. The aim of this study is to investigate the correlation between rs1801131 and rs1801133 with the severity of coronary lesions in patients with ST‑Elevation Myocardial Infarction (STEMI) and Non‑ST‑Elevation Myocardial Infarction (NSTEMI) based on the SYNTAX score. This retrospective cross-sectional study included 96 patients diagnosed with STEMI and NSTEMI from Razi University Hospital between April and September 2019. Ninety-six patients were diagnosed with STEMI (N = 43) and NSTEMI (N = 53) were recruited from South Khorasan, Iran. The angiographical characteristics of CAD were defined by the SYNTAX score. Genomic DNA was isolated from peripheral blood and genotyped for rs1801131 and rs1801133 using the TaqMan real-time PCR method. The results of the one-way analysis of variance indicated that there is no association between rs1801131 and rs1801133 with the severity of coronary lesions in patients with STEMI (p = 0.44) and NSTEMI (p = 0.91). However, the two-way analysis of variance comparison and post-hoc test demonstrated that rs1801133 in the presence of rs1801131 is correlated with the SYNTAX score in NSTEMI (p = 0.03) and total patients (p = 0.03). In conclusion, our study reveals a significant association between the MTHFR polymorphism rs1801133 and CAD severity, particularly in NSTEMI patients. While rs1801131 showed no correlation, rs1801133 may serve as a valuable genetic biomarker for assessing CAD severity. Further research with larger populations is needed to confirm these findings.

Exploring the interplay: aspirin therapy, genetic polymorphisms, and homocysteine levels in cardiovascular disease patients

Cardiovascular disease (CVD) is a significant worldwide health threat expected to cause 23.6 million deaths annually by 2030. Homocysteine is an amino acid that is generated during the breakdown of methionine. Elevated levels of homocysteine are recognised as a standalone risk factor for cardiovascular disease, such as coronary artery disease and stroke. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) play essential roles in regulating homocysteine levels and maintaining cardiovascular health. The C677T (rs1801133) mutation of the MTHFR gene is closely linked to coronary artery disease due to decreased enzyme activity while the A2756G mutation (rs1805087) in the MS gene disrupts the remethylation process and is linked to elevated homocysteine levels and a higher risk of cardiovascular disease. Aspirin is a key treatment for cardiovascular disease by preventing platelet activation and aggregation, reducing the likelihood of blood clot formation. In addition, aspirin usage seems to be connected to homocysteine levels in persons dealing with CVD. The precise interplay between aspirin therapy, genetic polymorphisms, and their collective impact on homocysteine levels in CVD patients remains unclear. Therefore, this investigation aims to explore the effects of genetic polymorphisms (MTHFR and MS genes) and aspirin therapy on homocysteine levels in CVD patients from two hospitals in Selangor, Malaysia. Blood samples from 52 patients were collected and analysed, with homocysteine levels quantified using LCMS-QQQ, aspirin abundance determined through LCMS-QTOF, and genetic polymorphisms of MTHFR and MS genes identified using RT-PCR. Interestingly, individuals with CVD exhibiting elevated homocysteine levels did not show the mutant genotype for neither MTHFR nor MS genes. Furthermore, the potential influence of aspirin therapy emerged as a plausible explanation for the observed lower homocysteine levels in these patients. Other variables than genetic predisposition may play a role in causing elevated homocysteine levels in people with CVD. Our findings suggest that aspirin therapy may have a potential impact on reducing homocysteine levels in these patients. However, more research is needed to understand the underlying mechanisms.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with major depressive disorder in the Saudi patients attending Erada complex for mental health and Erada services - Jeddah, Saudi Arabia.

Background: Major Depressive Disorder (MDD) is a prevalent and debilitating mental disorder that has been linked to hyperhomocysteinemia and folate deficiency. These conditions are influenced by the methylenetetrahydrofolate reductase (MTHFR) gene, which plays a crucial role in converting homocysteine to methionine and is essential for folate metabolism and neurotransmitter synthesis, including serotonin. Study aim: This study explored the association between MTHFR C677T and A1298C polymorphisms among Saudi MDD patients attending the Erada Complex for Mental Health and Erada Services outpatient clinic in Jeddah, Saudi Arabia. Methods: The study involved 87 MDD patients and 87 control subjects. Saliva samples were collected, and genomic DNA was extracted. Polymerase chain reaction-restriction fragment length polymorphism was used to detect MTHFR gene polymorphisms. Results: A significant difference was observed in the distribution of genotype frequencies for MTHFR C677T and A1298C polymorphisms between MDD patients and controls in the Saudi cohort (C677T: P = 0.001; A1298C: P = 0.01) Risk analysis indicated that individuals with the mutant TT genotype of the C677T polymorphism (Odd Ratio (OR) = 6.80, CI 95% = 1.47???31.36, P = 0.01) and the mutant CC genotype of the A1298C polymorphism (OR = 2.64, CI 95% = 1.36???5.13, P = 0.004) are more common in MDD patients, suggesting a higher risk for depression. Gender-specific analyses showed that the MTHFR C677T TT genotype significantly increases the risk of MDD in males compared to females. Conclusion: These findings underscore the significant impact of genetic factors, particularly the association of MTHFR polymorphisms with MDD. The results highlight the importance of personalized treatment approaches considering individual genetic profiles.

MTHFR Gene Polymorphisms and DNA Methylation in Idiopathic Spontaneous Preterm Birth

Background and Objectives: Preterm birth (PTB) is a complex condition with various contributing factors, including genetic and epigenetic influences such as DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in DNA methylation and the remethylation of homocysteine. This study aimed to investigate the association between maternal MTHFR C677T and A1298C polymorphisms, LINE-1 DNA methylation levels, and the risk of idiopathic spontaneous preterm birth (SPTB) in Caucasian women from Croatia and Slovenia. Materials and Methods: A total of 50 women with SPTB (&lt;34 weeks of gestation) and 50 control women were included in the study. MTHFR polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and LINE-1 DNA methylation levels were quantified using the MethyLight method. Results: The study found no significant differences in MTHFR C677T and A1298C polymorphisms’ genotype or allele frequencies between women with SPTB and controls. Additionally, no statistical significance of LINE-1 DNA methylation was found between the genotypes of the MTHFR polymorphisms analyzed. Conclusions: The study suggests no conclusive association between MTHFR C677T and A1298C polymorphisms, LINE-1 DNA methylation, and SPTB in Croatian and Slovenian women. Considering prior evidence connecting MTHFR polymorphisms, hyperhomocysteinemia, and PTB, the lack of homocysteine measurements and unassessed impact of folate or vitamin B supplementation limit the conclusions.

Associations between maternal MTHFR polymorphisms and embryological outcomes in Korean patients with infertility undergoing IVF/ICSI cycles

Objective Methylenetetrahydrofolatereductase (MTHFR) is important for folate metabolism, which is involved in DNA synthesis and cell growth. However, the relationship between Maternal MTHFR polymorphisms and outcomes in assisted reproduction remains controversial. This is the first study to explore the effect of MTHFR polymorphisms on the embryological outcomes in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles in Korean patients with infertility. Materials and methods This retrospective cohort study included 173 women who underwent MTHFR genotyping between July, 2021 and June, 2022. The embryologic outcomes of 301 IVF/ICSI cycles were compared between groups according to MTHFR polymorphisms using ANOVA and Chi-square test. Results Oocyte maturation rates were 80.0%, 75.0%, and 71.4% for MTHFR 677CC, 677CT, and 677TT, respectively. Cleaved embryo formation and transplantable embryo rates were comparable across various maternal MTHFR 677 genotypes. Good-quality embryo (GQE) rate was higher for MTHFR 677CT than those for 677CC and 677TT (40.0% vs. 29.4%, p = 0.001 and 40.0% vs. 33.3%, p = 0.025, respectively). When analyzing the combined MTHFR genotypes, the oocyte maturation rate was significantly lower in 677TT than in 677CC 1298AA/677CC 1298AC and 677CC 1298CC/677CT 1298AA/677CT 1298AC (71.4% vs. 76.7%, p = 0.012 and 71.4% vs. 75.7%, p = 0.029, respectively). The MTHFR 677CC/1298CC, 677CT/1298AA, and 677CT/1298AC genotypes had the highest GQE rates. Conclusions MTHFR 677TT genotype, which had the lowest enzymatic activity, had the lowest oocyte maturation rate. The combined MTHFR 677CC/1298CC, 677CT/1298AA, and 677CT/1298AC genotypes with intermediate enzyme activities had higher GQE rates. However, no differences were observed in the transplantable embryo rate between MTHFR genotypes.

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.

Study of the Association between MTHFR Polymorphism (rs1801133) and the Outcome of Methotrexate Treatment in Rheumatoid Arthritis Patient

Abstract Background Rheumatoid arthritis is a chronic systemic autoimmune disease that causes loss of joint function and significantly reduces the quality of life. Methotrexate is one of the disease- modifying anti-rheumatic drugs that can influence treatment efficacy and toxicity. Methotrexate is used as an anchor drug for the treatment of rheumatoid arthritis and there may be differences in drug action between genotypes. Aim of the Work The present study was aimed to evaluate the impact of methylenetetrahydrofolate reductase (MTHFR) gene C677T (rs1801133) polymorphism on the clinical outcome of methotrexate treatment as regards treatment efficacy or toxicity in Egyptian rheumatoid arthritis patients. Subjects and Methods This study conducted on 45 patients diagnosed with rheumatoid arthritis receiving methotrexate as a first line of treatment. Subjects were classified into two groups; group I (responders, n = 25) and group II (non-Responders, n = 20) according to clinical response to methotrexate by using disease activity score (DAS28). Complete blood count, erythrocyte sedimentation rate, liver function, renal function, C- reactive protein, cyclic citrullinated peptide antibody and rheumatoid factor were done for all patients. Determination of methylenetetrahydrofolate reductase gene C677T (rs1801133) polymorphism was carried out using Real-time polymerase chain reaction. Results The present study did not confirm the presence of a significant association between the genotypic frequencies of the methylenetetrahydrofolate reductase gene C677T (rs1801133) polymorphism among the responders and the non-responders group in patients with rheumatoid arthritis. In addition, the methylenetetrahydrofolate reductase gene C677T (rs1801133) polymorphism did not show significant difference between disease complications among the responders and the non-responders groups. On the other hand, our findings suggested that a statistically significant difference was found between two groups of patients regarding disease activity score (DAS 28). Conclusion The current study revealed that there is no significant association between the genotypic frequencies of the methylenetetrahydrofolate reductase gene C677T (rs1801133) polymorphism among the responders and the non-responders groups of patients with rheumatoid arthritis. Moreover, the methylenetetrahydrofolate reductase gene C677T (rs1801133) polymorphism did not show significant difference between disease complications among the responders and the non-responders groups in patients with rheumatoid arthritis.

Association of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism with Osteosarcoma in a Mexican Population.

The methylenetetrahydrofolate reductase (MTHFR) gene 677C➔T polymorphism is capable of altering folate metabolism and can modify certain neoplasia risk. Reports have suggested that folate can have an influence on bone development and so it is of interest to know if the MTHFR 677C➔T polymorphism is associated with the malignant transformation process of this tissue. The polymorphism was determined in 55 patients with osteosarcoma and in 180 healthy individuals. Compared with C/T+C/C genotypes, a 3.7-fold reduction in osteosarcoma probability is possible with the T/T genotype (OR 0.27, CI 95% 0.07-0.82). Undoubtedly, further studies, utilizing large samples and carried out on different populations, are necessary to confirm these results.

Polymorphism of Folate Metabolism Genes among Ethnic Kazakh Women with Preeclampsia in Kazakhstan: A Descriptive Study.

Preeclampsia is a severe multifactorial complication of pregnancy. Studies found associations between folate metabolism genes' polymorphisms and preeclampsia. However, investigations in this field are limited among Asian populations. Thus, the study's aim was to evaluate the prevalence of methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) genes' polymorphisms among ethnic Kazakh women with preeclampsia. This was a retrospective study involving 4246 patients' data for the period of 2018-2022. Identification of MTR, MTRR, and MTHFR genes' polymorphism was performed via PR-PCR. Peripheral blood samples were obtained for the analyses. In total, 4246 patients' data of Kazakh ethnicity with preeclampsia at >20 weeks gestational age who had undergone an investigation to identify polymorphisms of the folate metabolism pathway genes for the period of 5 years were included in this study. The most common and prevalent mutation was the MTRR A66G polymorphism: 24.5% of all tested patients with preeclampsia had the MTRR A66G polymorphism. It was highest among the 35-39 age group participants. The second most prevalent was the MTHFR C677T polymorphism: 9% of women with preeclampsia had the MTHFR C677T mutation. It was highest among women aged 30-34. There was a rare association of the MTR A2756G mutation with preeclampsia among the study participants. The identified levels of MTRR A66G and MTHFR C677T polymorphisms among the study participants suggest the importance of evaluating MTRR and MTHFR polymorphisms in women with preeclampsia. The role of the MTR A2756G polymorphism in the development of preeclampsia needs to be further investigated.

Cerebral venous sinus thrombosis and SCN1A, a novel association?

Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke. Acquired and inherited prothrombotic conditions are the most common risk factors for CVST. Sometimes, an etiology is not found. Wide utilization of next generation sequencing technologies in clinical practice may lead to identification of risk factors other than those classically associated with CVST. This retrospective clinical-laboratory observational study has a reference patient who presented with CVST as an adolescent. Work up for prothrombotic conditions showed high homocysteine level secondary to homozygosity for a common polymorphism, c.677C > T in the methylenetetrahydrofolate reductase (MTHFR) gene. His older unaffected brother has a similar MTHFR genotype and high homocysteine. The whole exome sequencing revealed a likely pathogenic variant in the sodium voltage gated channel, alpha subunit 1(SCN1A) gene. CVST is a multifactorial disease. Prothrombotic conditions are the most common risk factors for CVST. High homocysteine due to the common MTHFR polymorphisms was previously attributed to various thrombotic conditions including CVST. Although high homocysteine due to MTHFR polymorphism may be a contributing factor, additional risk factors such as blood flow abnormalities during SCN1A related seizures may be needed for thrombosis.

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.

Association of methylenetetrahydrofolate reductase A1298C mutation with normal homocysteine level: A rare cause of cerebral venous sinus thrombosis in an infant

Abstract Inherited causes of cavernous venous sinus thrombosis (CVST) leading to stroke in infancy are rare. Methylenetetrahydrofolate reductase (MTHFR) gene mutation is one such cause. Polymorphism of MTHFR, an essential enzyme in Vitamin B12 metabolism, leads to an increase in homocysteine levels. This is a prothrombotic state and, therefore, causes pediatric stroke. Children with a mutation of the MTHFR gene have elevated homocysteine levels. The index case of MTHFR polymorphism with CVST leading to stoke had a normal homocysteine level. The association of MTHFR A1298C mutation with CVST can be confirmed only after further studies, as the role of heterozygous A1298C mutation in prothrombotic state is conflicting.

Associations of methylene tetrahydrofolate reductase (MTHFR) polymorphism with hepatocellular carcinoma in Egyptian population

Liver serves as a hub for key metabolic pathways such as folate cycle that provides one-carbon units for a network of metabolic reactions. Methylenetetrahydrofolate reductase (MTHFR) is a rate limiting enzyme in folate metabolism and thus it is vital for DNA methylation, synthesis and repair [1]. The objective of this study was to evaluate an eventual association between MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) and the susceptibility to hepatocellular carcinoma (HCC) in Egyptian population.Blood samples from patients and controls from Mansoura university hospital were used after signed consent and approval from Medical ethical committee. The two genetic loci were designed for amplification and genotyped by using PCR–RFLP.Our results clarify that, the most important predictors for HCC are T/T genotype of variant C677T and C/C genotype of variant (A1298C) with odds ratio 3.28 and 2.99 respectively. Also, MTHFR variant C677T genotype C/C or T/T combined with MTHFR variant A1298C genotype C/C were associated with an increased risk of HCC, with the OR, 2.6 and 7 respectively. CT genotype of MTHFR variant C677T showed significant difference between HCC grades and C allele of variant C677T showed significant difference in BCLC stages of HCC.Our data indicates that, the two variants (C677T and A1298C) constitute a risk factor for the development of HCC and this could be attributed to the low activities of the enzyme MTHFR that disturb one carbon metabolism and subsequently, DNA synthesis, repair and methylation, thus cellular redox state, growth, and proliferation.

Assessing the possible association between MTHFR (rs1801133) and GPx-1 (rs1050450) polymorphisms with the risk of type 2 diabetes, diabetic neuropathy, and diabetic retinopathy.

Oxidative stress in chronic hyperglycemia could injure the tissues and onset of diabetes-related complications like retinopathy and neuropathy. This study investigates the association between methylenetetrahydrofolate reductase (MTHFR) and glutathione peroxidase (GPx) genetic variants with these complications. In this case-control study, 400 individuals, including 100 healthy subjects and 300 patients with type 2 diabetes mellitus (T2DM) in three subgroups: with retinopathy(n = 100), with neuropathy(n = 100), and without complication (n = 100) from West Iran, were studied. MTHFR (rs1801133) and GPx-1 (rs1050450) variants were identified by the PCR-RFLP method. The plasma levels of GPx activity, glutathione, malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidative stress (TOS) were measured by chemical methods. Higher BMI, TOS and MDA levels were observed in patients with neuropathy compared to other patients and controls. Diabetic patients with neuropathy had lower levels of glutathione (7.8 ± 4.5; P < 0.001), GPx activity (39.5 ± 8.5; P < 0.001), and TAC (703.1 ± 129.1; P = 0.0001) in comparison with other groups. The patients without complication and retinopathic patients had higher plasma levels of glutathione (12.2 ± 2.4; p = 0.02) and TAC (793.4 ± 124.6; P < 0.001), respectively. MTHFR TT genotype significantly correlated with lower levels of TOS (3.5 ± 1.1; P < 0.001) and OSI (0.0050 ± 0.001; P < 0.001). Subjects with the GPx-1 TT genotype had higher levels of MDA (6.8 ± 2.5; P = 0.02) and lower levels of TOS (3.7 ± 1.6; P < 0.001), which is statistically significant. TT genotype of MTHFR was associated with 3.9 fold (95% CI 1.04-4.76; P = 0.0436) increased risk of neuropathy. Also, GPx-1 CT genotype increased the risk of retinopathy [OR = 2.7 (95% CI = 1.38-5.44; P = 0.0039)]. The MTHFR TT genotype increased the risk of neuropathy in diabetic patients significantly. The GPx-1 CT genotype is related to increased retinopathy risk among diabetic patients. Both MTHFR and Gpx-1 TT genotypes were associated with higher BMI levels.

Skin disorders in women with poor obstetric history: MTHFR polymorphisms and importance of preconceptional counseling

Objectives This study focused on the link between skin disorders and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Methods Study cases were taken from a pre-conceptional care program where patients with poor obstetric history were evaluated in terms of systemic disorders including skin diseases. This retrospective cohort (n = 472) consisted of 110 (23.3%) and 362 (76.7%) women with or without skin disorders, respectively. For ease of analysis, the history of skin diseases was classified into seven categories: (1) acne/rosacea/other acneiform disorders; (2) fungal disease; (3) pruritis/xerosis; (4) psoriasis vulgaris; (5) acrochordons and other benign skin growths; (6) urticaria/dermatitis; and (7) viral diseases. Results In this retrospective cohort of 472 women, we explored the impact of MTHFR A1298C and C677T polymorphisms on skin disorders. Despite similar allelic frequencies, our findings revealed a statistically significant association between the presence of MTHFR polymorphisms and skin disorders (p = .027). Subgroup analysis indicated significantly higher rates of MTHFR polymorphisms in patients with psoriasis vulgaris (p = .033) and acrochordons (p = .030), highlighting their potential relevance in specific skin disorder subtypes. Conclusions The increased prevalence of psoriasis and acrochordons among women with MTHFR deficiency underscores the complex relationship between genetic factors and dermatological health. Our findings emphasized the critical role of MTHFR polymorphisms not only in poor obstetric history but also as significant contributors to skin disorders. This dual association highlights the importance of comprehensive preconception counseling, especially customized for women affected by skin disorders.

Prevalence of MTHFR Polymorphisms in Patients With Hypermobile Ehlers-Danlos Syndrome and Hypermobile Spectrum Disorders in a US Hypermobility Clinic.

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are characterized by joint hypermobility, joint subluxations and dislocations, hyperextensible skin, and chronic and progressive multiorgan comorbidities. Diagnosing hEDS and HSD is difficult because of variable phenotypes and unknown genetic etiology. In our clinic, we observed many patients with hEDS and HSD with a high serum level of unmetabolized folate, which suggests that hypermobility may be linked to methylenetetrahydrofolate reductase (MTHFR)-mediated folate metabolism. The present study aims to examine the prevalence of MTHFR polymorphisms, C677T and A1298C, among patients with hEDS and HSD. Clinical and demographic information of patients visiting our hypermobility clinic from January 2023 to July 2023 were retrospectively reviewed. Continuous variables were reported as mean ± SD and range, whereas categorical variables were reported as total count and percentage. Among 157 patients, 93% of patients were female patients, 52.2% were diagnosed with hEDS, and 47.8% were diagnosed with HSD. Interestingly, 85% of the patients had MTHFR C677T and/or A1298C polymorphisms in heterozygous or homozygous state. MTHFR 677CT/TT genotype was present in 52.9% of cases, and 49.7% of patients had 1298AC/CC genotype. In addition,14% of patients with hypermobility exhibited MTHFR 677TT genotype, 10.2% showed 1298CC genotype, and 17.2% displayed combined heterozygosity, collectively representing 41.4% hypermobile patients with two copies of MTHFR variant alleles. There is a high prevalence of MTHFR polymorphisms among patients with hypermobility, which supports the hypothesis that hypermobility may be dependent on folate status.

Effect of L-Methylfolate Supplementation on Sleep for Patients with Reduced Methylenetetrahydrofolate Reductase Activity

Introduction Clinicians have limited options outside controlled substances to address sleep disturbance, which left untreated can negatively affect patient outcomes in cardiovascular health, mental health, immunologic function, and more. For some, genetic factors may influence sleep disturbances. L-methylfolate, the active form of folate, plays a critical role in regulation of monoamine neurotransmitters known to have significant impact on sleep regulation: dopamine, serotonin, norepinephrine. Single nucleotide polymorphisms of the enzyme methylene-tetrahydrofolate-reductase are common and can impact monoamine production. The goal of this study was to evaluate effects of L-methylfolate supplementation on sleep in a cohort with reduced methylene tetrahydrofolate reductase (MTHFR) activity. Methods A retrospective cohort of patients being treated with L-methylfolate in a concierge medical clinic setting was studied. Patients presenting with sleep complaints were evaluated using the Patient-Reported Outcomes Measurement Information System at baseline. Patients with known MTHFR polymorphisms at either C667T and/or A1298C were recommended 5 mg of L-methylfolate daily and were reevaluated at 2 wks, at 4 wks, and at 8 wks of supplementation. Statistical comparisons were made utilizing ANOVA and T-test comparisons. Results Ten were included in the final cohort: six male and four female, average age 43 ± 16 years. Beginning at wk 2, average sleep disturbance improved significantly by −6.94 points (p = 0.005) and by 8 wks, all patients had improvement with a −14.34 change in disturbance from baseline (p = 0.001). Conclusion Improvement in sleep disturbance was seen in both low and intermediate function phenotypes. L-methylfolate may be useful for improving sleep in patients with MTHFR polymorphism.

Exploring the interplay of MTHFR and FGG polymorphisms with serum levels of adiponectin and leptin in pediatric lupus nephritis: a pilot study

BackgroundAdiponectin and leptin are pivotal in the regulation of metabolism. Pediatric lupus nephritis (pLN), a manifestation of childhood systemic lupus erythematosus (SLE) affecting the kidneys, is associated with impaired adipokine levels, suggesting a role in pLN pathogenesis. The aim of this study was to explore the potential relationship between specific single-nucleotide polymorphisms (SNPs)—methylenetetrahydrofolate reductase (MTHFR) rs1801131 and fibrinogen gamma chain (FGG) rs2066865—and the serum levels of leptin and adiponectin in patients with pLN.MethodsNinety-eight pLN patients and one hundred controls were enrolled in the study. Serum leptin and adiponectin levels were measured using ELISA. DNA extraction and real-time PCR genotyping were performed for MTHFR rs1801131 and FGG rs2066865 SNPs.ResultsCompared to healthy controls, pLN patients exhibited significantly greater serum leptin (11.3 vs. 18.2 ng/mL, p < 0.001) and adiponectin (18.2 vs. 2.7 ug/mL, p < 0.001). Adiponectin levels were positively correlated with proteinuria (p < 0.05), while leptin levels positively correlated with proteinuria, SLE disease activity index-2000 (SLEDAI-2K), and cyclophosphamide usage (all p < 0.05). There was no significant association between MTHFR rs1801131 or FGG rs2066865 SNPs and pLN in either codominant or allelic models (all p > 0.05). However, the AG genotype of FGG gene rs2066865 SNP was significantly associated with high leptin levels (> 15 ng/mL) (p = 0.01).ConclusionSerum adiponectin and leptin levels are associated with pathological manifestations of pLN. High leptin levels are associated with the AG genotype of FGG rs2066865 SNP in pLN patients, suggesting direct involvement in disease progression and potential utility as a disease biomarker.