Methylenetetrahydrofolate Reductase Polymorphisms Research Articles

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.

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.

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.

Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension

ObjectiveTo analyse the relationship between the polymorphisms of the H-type hypertensive methylenetetrahydrofolate reductase (MTHFR) C677T gene and neutrophil gelatinase-associated lipocalin (NGAL) in early kidney injury.MethodA total of 279 hospitalised patients with hypertension were selected and grouped according to their homocysteine (Hcy) level. If their blood Hcy level was ≥ 10 µmol/L they were assigned to the H-type hypertensive group, and if it was < 10 µmol/L they were assigned to the non-H-type hypertensive group. Blood lipid indexes, renal function indexes and blood glucose indexes were collected, and the differences between the two groups were compared. Furthermore, MTHFR C677T genotype distribution and allele frequency and Hcy level of MTHFR C677T genotype were compared, and logistic multiple regression analysis was conducted for the correlation of different genotypes of MTHFR C677T and the early kidney injury marker NGAL.ResultsIn the non-H-type hypertensive group, the levels of Hcy and NGAL, cystatin, blood urea nitrogen, serum creatinine, uric acid, serum β2-microglobulin and urinary microalbumin-to-creatinine ratio increased significantly, and the glomerular filtration rate level decreased significantly, when compared with the H-type hypertensive group, with statistical differences (p < 0.05). The H-type hypertensive group and the non-H-type hypertensive group had significant differences in the CC, CT and TT genotypes and allele frequencies at the MTHFR C677T locus. The MTHFR C677T gene mutation rate of the H-type hypertensive group was significantly higher than that of the non-H-type hypertensive group. The H-type hypertensive group had higher levels of the TT genotype and CT genotype Hcy. There was a statistical difference (p < 0.05).ConclusionMethylenetetrahydrofolate reductase C677T polymorphism is correlated with the Hcy level, and its gene polymorphism will affect the Hcy level. Methylenetetrahydrofolate reductase C677T polymorphism has an interactive effect with NGAL. Screening NGAL and reducing Hcy levels are valuable methods for the prevention and treatment of early renal injury in patients with H-type hypertension and help improve the prognosis of patients and their quality of life.

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.

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.

Relationship between homocysteine, vitamin B9, vitamin B12 levels methylenetetrahydrofolate reductase (C677T, A1298C) polymorphisms, and cryptogenic stroke in Tunisian adults´ patients: a case-control study

Relationship between homocysteine, vitamin B9, vitamin B12 levels methylenetetrahydrofolate reductase (C677T, A1298C) polymorphisms, and cryptogenic stroke in Tunisian adults´ patients: a case-control study

Study of the association of polymorphisms of the folate cycle enzyme gene with the degree of cognitive and affective disorders in patients in the post-covid period

Recently, molecular genetic studies have become widespread, and demonstrated the importance of DNA and histone methylation processes in the epigenetic regulation of gene expression. The aim of this study was to detect the association of polymorphisms of the folate cycle enzyme gene methylenetetrahydrofolate reductase (MTHGFR) with the degree of cognitive and affective disorders and the serum level of homocysteine and folic acid in 41 post-covid patients. Hematological and laboratory indices, serum concentration of C-reactive protein, D-dimer, homocysteine and folic acid were determined. MTHGFR polymorphisms for C677T and A1298C mutations were determined by polymerase chain reaction in real time. According to the MTHGFR C677T genotype variant, the examined patients were divided into 3 groups: 1) 21 persons (male/female 10/11) with homozygous CC genotype; 2) 17 ones (male/female 12/5) with heterozygous CT genotype; 3) 3 persons with a recessive homozygous TT genotype (all men). Six months after the end of the acute phase of the coronavirus disease, patients were surveyed using questionnaires to assess the psycho-emotional state: cognitive function, anxiety and depression. No significant difference was found in the average scores of cognitive function, anxiety and depression in patients of group 1 and 2. Individuals of the group 1 C677C, who had an additional recessive homozygous C1298C mutation (group 1a, n=6), were characterized by an elevated level of homocysteine, which showed a high negative correlation with serum folate (r= -0.95). A small group of individuals with the recessive homozygous T677T genotype (group 3, all men) was distinguished by an older age, the presence of cardiovascular diseases, type 2 diabetes (2 cases out of 3), more severe manifestations of COVID-19, which forces us to pay attention to potentially increased risk of complications in such patients and requires further investigation. Correlation relationships between assessments of cognitive function, anxiety, depression and serum levels of homocysteine and folate in patients with different genotypes of MTHGFR C677T were recorded. Therefore, the use of a molecular genetic approach made it possible to pay attention to the possible predisposition to hyperhomocysteinemia in individuals who have a folic acid deficiency, and different combination of alleles of the MTHGFR gene C677T and A1298C.

The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases.

Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in the one-carbon cycle. This enzyme is essential for the metabolism of methionine, folate, and RNA, as well as for the production of proteins, DNA, and RNA. MTHFR catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to its active form, 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Numerous variants of the MTHFR gene have been recognised, among which the C677T variant is the most extensively studied. The C677T polymorphism, which results in the conversion of valine to alanine at codon 222, is associated with reduced activity and an increased thermolability of the enzyme. Impaired MTHFR efficiency is associated with increased levels of homocysteine, which can contribute to increased production of reactive oxygen species and the development of oxidative stress. Homocysteine is acknowledged as an independent risk factor for cardiovascular disease, while chronic inflammation serves as the common underlying factor among these issues. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and an increased risk of cardiovascular disease, hypertension, diabetes, and overweight/obesity. There is substantial evidence supporting this association, although several studies have concluded that the polymorphism cannot be reliably used for prediction. This review examines the latest research on MTHFR polymorphisms and their correlation with cardiovascular disease, obesity, and epigenetic regulation.

The gene polymorphisms of eNOS and MTHFR modulates the development of preeclampsia in Han population

We explored the effects of the endothelial nitric oxide synthase (eNOS) gene −786 T > C and 894 G > T locus polymorphisms and the methylenetetrahydrofolate reductase (MTHFR) gene 1298 A > C and 677 C > T locus polymorphisms on preeclampsia (PE) in pregnant women in Quanzhou area and provide reliable and stable predictors PE. This study included 160 normal pregnant women (normal control group) and 160 women with preeclampsia (PE group). Polymorphisms in eNOS gene and MTHFR were analyzed by the polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) technique. eNOS 894 G > T locus and MTHFR 1298 A > C locus had no significant difference between the two groups. In the PE patients, eNOS −786 T allele (OR: 2.07, p = 0.03) and MTHFR 677 C allele (OR: 1.83, p = 0.04) had significantly lower frequency. The nitric oxide (NO) level in patients with eNOS −786 C C was significantly lower than that in those with −786 TT. The homocysteine (Hcy) level in patients with MTHFR 677 TT was significantly higher than that in those with 677 C C. In conclusion, the frequency of the eNOS −786 C C genotype and MTHFR 677 TT genotype are higher in women with PE, which cause lower NO level and higher Hcy level.

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.