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Background: Cleft lip with or without cleft palate (CL/P) is the most common congenital anomaly found in Indonesia. CL/P is caused by hereditary (genetic) and environmental factors. Environmental factors can result in methylation in the promoter of the methylenetetrahydrofolate reductase (MTHFR) gene, affecting its expression. Methylation takes place at the CpG site found at chromosome 1, coordinates 11,805,406-11,806,509. Pyrosequencing technology can detect the percentage methylation of a gene quickly, simply, and accurately. Purpose: The aim of the study is to optimize detection of methylation of the MTHFR gene using the pyrosequencing method. Methods: Methods used in this study were DNA extraction from blood, DNA bisulfite conversion, polymerase chain reaction (PCR), and methylation detection using CpG pyrosequencing assay. Samples were taken from 20 CL/P patients (C) and 44 normal patients (N). Results: The pyrosequencing method was successful in detecting methylation at three MTHFR gene sites at coordinates 11,805,507-11,805,529. The methylation level at the third site was higher in group C than in group N, while at the first and second positions, group C had a lower methylation level than group N. In general, the percentage of methylation for both groups was low or hypomethylated (less than 5%). Conclusion: The pyrosequencing method can be used to determine methylation levels in the MTHFR gene with the results presented as percentages (quantitative data). Hypomethylation occurs in groups C and N at the coordinates 11,805,507-11,805,529 of the MTHFR gene promoter. [ABSTRACT FROM AUTHOR]

Background: Bortezomib results in peripheral neuropathy (PN) in approximately 50% of patients, during multiple myeloma (MM) treatment, a complication known as Bortezomib-induced peripheral neuropathy (BIPN). The drug response varies among individuals. Genetic factor may play an important role in BIPN. Methods: A nextgeneration sequencing (NGS) panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy. mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR (RT-qPCR). Serum homocysteine (Hcy) levels were detected in 40 samples by chemiluminescent microparticle immunoassay (CMIA). Results: Compared with the non-BIPN group (n = 89), a total of 8 significantly associated single nucleotide polymorphisms (SNPs) were identified in the BIPN group (n = 115): MTHFR (rs1801131, rs1801133, rs17421511), EPHX1 (rs1051740), MME (rs2016848), ALDH1A1 (rs6151031), HTR7 (rs1935349) and CYP2A6 (rs8192720). The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment (NP group) was lower than that of newly diagnosed patients without peripheral neuritis after treatment (NnP group) (1.70 ± 0.77 vs. 2.81 ± 0.97, p = 0.009). Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group (11.66 ± 1.79 μmol/L vs. 8.52 ± 3.29 μmol/L, p = 0.016) and healthy controls (11.66 ± 1.79 μmol/L vs. 8.55 ± 2.13 μmol/L, p ≤ 0.001). Conclusion: CYP2A6, EPHX1, MTHFR, ALDH1A1, HTR7, MME and BIPN are linked in Chinese MM patients. BIPN is more likely to occur in patients with lower MTHFR mRNA expression, which might result in higher serum Hcy levels. [ABSTRACT FROM AUTHOR]

Folic acid supplementation has been shown to provide benefits in preventing neural tube defects and other birth defects, as well as reducing adverse pregnancy outcomes. This study aimed to examine the impact of various folic acid supplementation methods on pregnancy. TaqMan-MGB technology was used to detect polymorphisms in the folate metabolism-related genes, MTHFR C677T and A1298C. Blood-related biochemical indicators, including HCY levels and history of adverse pregnancy, were examined in relation to different exposure factors (MTHFR gene polymorphism, HCY levels, and adverse pregnancy history) and their impact on pregnancy outcomes. Various forms of folic acid intervention were implemented in a population with an adverse pregnancy history and high HCY levels to analyze the effects of reducing HCY levels and improving pregnancy outcomes. Exposure factors, such as adverse pregnancy history, HCY, and medium-to-high risk of gene metabolism, were closely associated with pregnancy outcomes. Interestingly, methylfolate efficiently reduced the serum HCY levels. More importantly, the methylfolate group exhibited a significantly lower incidence of adverse pregnancies than the synthetic folic acid group. In this study, the risk factors, including adverse pregnancy history, HCY, and medium-to-high risk of gene metabolism, were confirmed to lead to the poorer pregnancy outcomes in our cohort. 5-methyltetrahydrofolate may be an effective approach for decreasing the incidence of adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

This article discusses a case where the Taqman system, commonly used for genotyping, failed to accurately identify a specific genetic mutation. The study found that a rare mutation at the MTHFR 679 locus resulted in the failure of genotyping for a different mutation. The authors highlight the importance of adaptability and alternative approaches in genetic testing. They also explore the relationship between this mutation and enzyme activity and susceptibility to recurrent spontaneous abortion. The article provides valuable information on a specific genetic variant and its clinical significance, making it a useful resource for those researching genetics and its connection to specific health conditions. [Extracted from the article]

Orofacial clefts (OFCs) are the second most common birth defect worldwide. The etiology of OFCs involves complex interactions between genetics and environment. Advances in genomic technologies have identified gene variants associated with OFCs. This study aimed to investigate whether selected SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes influence the occurrence of non-syndromic OFCs in the Polish population. The study included 209 individuals with non-syndromic OFCs and 418 healthy controls. Saliva and umbilical cord blood samples were collected for DNA extraction. Four SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes were genotyped using real-time PCR-based TaqMan assays. Statistical analysis was performed using logistic regression to assess the association between SNPs and OFCs. A significant association was found between the rs7078 CC polymorphism and OFCs (OR = 3.22, CI 1.68–6.17, p < 0.001). No significant associations were identified for the rs1081131, rs13041247, and rs3769817 polymorphisms. The research indicates that the rs7078 polymorphism significantly influences the occurrence of orofacial cleft palate in the Polish population, whereas the rs3769817, rs1801131, and rs13041247 SNPs do not show such a correlation. [ABSTRACT FROM AUTHOR]

Aim: Remethylation disorders such as 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency reduce the remethylation of homocysteine to methionine. The resulting hyperhomocysteinemia can lead to serious neurological consequences and multisystem toxicity. The role of MTHFR genotypes has not been investigated in patients with Rett Syndrome (RTT). In this study, we sought to assess the impact of co-occurring MTHFR genotypes on symptom profiles in RTT. Method: Using pharmacogenomic (PGx) testing, the MTHFR genetic polymorphisms rs1801133 (c.665C>T mutation) and rs1801131 (c.1286A>C mutation) were determined in 65 patients (18.7 years ± 12.1 [mean ± standard deviation]) with RTT as part of routine clinical care within the Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, a National and Specialist Child and Adolescent Mental Health Service (CAMHS) in the UK. The clinical severity of patients was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI). Results: The clinical severity symptom distribution varied between the homozygous and heterozygous MTHFR rs1801133 and rs1801131 genotypes. Those with the homozygous genotype had a narrower spread of severity scores across several domains (language and communication, ambulation, hand-use and eye contact clinical domains). Patients with the homozygous genotype had statistically significantly greater CGI-Severity scores than individuals with a non-homozygous MTHFR genotype (Z = −2.44, p = 0.015). When comparing the ratings of moderately impaired (4), markedly impaired (5), severely impaired (6) and extremely impaired (7), individuals with the homozygous MTHFR genotype were more impaired than those with the non-homozygous MTHFR genotype (Z = −2.06, p = 0.039). There was no statistically significant difference in the number of prescribed anti-epileptic drugs between the genotypes. Conclusions: Our findings show that in those with a pathogenic RTT genetic variant, co-occurring homozygotic MTHFR rs1801133 and rs1801131 polymorphisms may act as associative genetic modifiers of clinical severity in a subset of patients. Profiling of rs1801133 and rs1801131 in RTT may therefore be useful, especially for high-risk patients who may be at the most risk from symptom deterioration. [ABSTRACT FROM AUTHOR]

• The novelty is that MTHFR genotype may modulate the response to betaine intake. • Betaine concentrations increase more in TT/CT compared to CC. • Betaine supplementation decreases serum homocysteine concentration. • Betaine does not affect amino acid profile in healthy, athletic males. • The effect of betaine was not dose dependent. Betaine supplementation is used by athletes, but its mechanism of action is still not fully understood. We hypothesized that betaine supplementation would increase betaine concentration and alter amino acid profiles in relation to MTHFR genotype and dose in physically active males. The study followed a randomized placebo-controlled cross-over design. Blood samples were collected before and after each supplementation period. Serum was analyzed for amino acid profile, homocysteine, betaine, choline, and trimethylamine N-oxide (TMAO) concentrations. For the washout analysis, only participants starting with betaine were included (n = 20). Statistical analysis revealed no differences in the amino acid profile after betaine supplementation. However, betaine concentration significantly increased after betaine supplementation (from 4.89 ± 1.59 µg/mL to 17.31 ± 9.21 µg/mL, P <.001), with a greater increase observed in MTHFR (C677T, rs180113) T-allele carriers compared to CC (P =.027). Betaine supplementation caused a decrease in homocysteine concentration (from 17.04 ± 4.13 µmol/L to 15.44 ± 3.48 µmol/L, P =.00005) and a non-significant increase in TMAO concentrations (from 0.27 ± 0.20 µg/ml to 0.44 ± 0.70 µg/ml, P =.053), but had no effect on choline concentrations. Serum betaine concentrations were not significantly different after the 21-day washout from the baseline values (baseline: 4.93 ± 1.87 µg/mL and after washout: 4.70 ± 1.70 µg/mL, P = 1.000). In conclusion, betaine supplementation increased betaine and decreased homocysteine concentrations, but did not affect the amino acid profile or choline concentrations in healthy active males. Betaine concentrations may be dependent on MTHFR genotype. This was a randomized cross-over study of betaine supplementation in healthy athletic males. We showed that the increase in serum betaine concentrations was dependent on MTHFR genotype. Specifically, T-allele carriers experienced greater increase in betaine concentrations than CC homozygotes. Homocysteine concentration decreased with betaine supplementation. Abbreviations: BET, betaine; Hcy, homocysteine; MTHFR, methylenetatrahydrofolate; PL, placebo; WO, washout. [Display omitted] [ABSTRACT FROM AUTHOR]

Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022–0.553)] and TG [OR (95% CI) 0.106 (0.021–0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023–0.507)] together predict responders compared to the TT genotype. The Ars1801133Grs1801131 haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208–0.723)], while the Grs1801133Trs1801131 haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965–4.064)]. In the final multivariate analysis, GG/TGrs1801131 genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TTrs1801131 genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics. [ABSTRACT FROM AUTHOR]

Methylenetetrahydrofolate reductase (MTHFR) is key to the metabolism of folic acid, with loss of function mutations resulting in elevated homocysteine levels, a known risk factor for cardiovascular disease. Psoriasis patients may demonstrate hyperhomocysteinemia. To assess for the association between psoriasis and MTHFR C677T and A1298C polymorphisms. A systematic literature search was conducted in MEDLINE, Embase, Cochrane CENTRAL, and Web of Science. Case reports, case–control, cohort, and cross-sectional studies with full-text availability in English were considered. Meta-analysis was conducted with pooled ORs calculated via the random effects model (I2 > 50%). Of 917 records identified, 10 studies were selected for review of 1965 psoriasis patients and 2030 controls. Meta-analysis demonstrated that for MTHFR C677T, there were positive associations between psoriasis and the allele contrast model (C vs T, pooled OR = 1.69, 95% CI = 1.10–2.59), the additive model (CC vs TT, pooled OR = 2.44, 95% CI = 1.06–5.60), the dominant model (CC vs CT + TT, pooled OR = 1.77, 95% CI = 1.06–2.98), and the recessive model (CC + CT vs TT, pooled OR = 2.08, 95% CI = 1.05–4.13). For MTHFR A1298C, there were positive associations between psoriasis and the allele contrast model (A vs C, pooled OR = 3.57, 95% CI = 1.19–10.68), the dominant model (AA vs AC + CC, pooled OR = 4.44, 95% CI = 1.12–17.66), and the overdominant model (AC vs AA + CC, pooled OR = 0.26, 95% CI = 0.07–0.91). There may be a link between the C677T and A1298C polymorphisms with psoriasis diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022–0.553)] and TG [OR (95% CI) 0.106 (0.021–0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023–0.507)] together predict responders compared to the TT genotype. The Ars1801133Grs1801131 haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208–0.723)], while the Grs1801133Trs1801131 haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965–4.064)]. In the final multivariate analysis, GG/TGrs1801131 genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TTrs1801131 genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics.

Sarcopenia is associated with progressive generalized skeletal muscle weakness, persistent decline in muscle strength, function, and quality of life in the elderly population. The presence of sarcopenia worsens the prognosis of older patients. In this regard, the study of the etiology and pathogenesis of sarcopenia, the identification of early markers for the diagnosis of this disease are relevant areas today. Myokines are secreted by skeletal muscle and play a important role in the regulation of muscle mass and function, metabolic homeostasis. Myokine synthesis disruption may contribute to the development of sarcopenia. In addition, we can see the polymorphism association of various genes with the development of the disease. This review brings together current knowledge about myokines and genetic factors as potential biomarkers for the early diagnosis of sarcopenia.

Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.

Abstract 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.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of unknown cause. Alterations in one-carbon metabolism have impact in the pathophysiology by genetic susceptibility to MS and increased the risk of MS. The aim of this study was to investigate the contribution of the gene polymorphism on Methylenetetrahydrofolate Reductase (MTHFR), Methionine Synthase Reductase (MTRR), Methionine Synthase (MTR) enzymes and of the essential factors (homocysteine, Hcy; cysteine, Cys; and vitamin B12, VitB12) in folate metabolism. Eligible MS patients (n = 147) and health controls (n = 127) were participated. The gene polymorphisms were analyzed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and the levels of plasma Hcy, Cys and VitB12 were measured by Enzyme Linked Immunuabsorbent Assay (ELISA). Our results showed that the levels of Hcy and VitB12 were lower and the levels of Cys were higher in MS compared to controls. The observation of high Cys values in all 3 gene polymorphisms suggests that the transsulfiration pathway of Hcy is directed towards Cys formation since the methionine synthesis pathway does not work. We could not find any association with all gene polymorphisms with the risk of MS. The T allele of MTHFR C677T and G allele of MTR A2756G are risk factors for serum Cys level on MS. As for MTR A2756G, serum vitB12 was observed in MS patients with G allele. [ABSTRACT FROM AUTHOR]

Purpose: Colorectal cancer (CRC) is one of the most common malignancies, with a high incidence and mortality worldwide. Methylated Septin 9 (mSEPT9) has been used clinically as an auxiliary tool for CRC screening. The aim of the present study was to investigate the association of the methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism with the risk of CRC and the methylation status of Septin 9 in CRC. Methods: Information of 540 patients with a confirmed diagnosis of CRC and with a physical examination were utilized to assess the association of the MTHFR rs1801133 polymorphism with CRC and the methylation of SEPT9. MTHFR rs1801133 polymorphism was genotyped using polymerase chain reaction (PCR). The commercial Septin 9 Gene Methylation(mSEPT9) Detection Kit was used for plasma SEPT9 methylation analysis. Results: Among 540 patients, 61.48% were men and the median age was 54.47 ± 13.14. 65.37% of all colorectal tumors developed in the rectum. 195 patients had negative mSEPT9 methylation, while 345 had positive results. 87 individuals with stage I, 90 with stage II, 287 with stage III, and 76 with stage IV colorectal cancer were included in the sample. The results demonstrated that the positivity rate and degree of methylation of mSEPT9 were remarkably higher in patients with more advanced TNM stages than in those with less advanced stages. The frequencies of the MTHFR rs1801133 CC genotype and allele C carriers in patients with CRC were significantly higher than those in healthy individuals (P = 0.006 and P = 0.001, respectively). The positivity rate of the mSEPT9 assay was significantly higher among the MTHFR rs1801133 TT genotype and allele T carriers than among the CC and allele C carriers respectively. The MTHFR rs1801133 TT genotype and allele T carriers were positively associated with the methylation of SEPT9 (OR = 3.320, 95% CI 1.485–7.424, P = 0.003 and OR = 1.783, 95% CI 1.056–3.010, P = 0.030, respectively). Conclusion: In conclusion, individuals harboring the MTHFR rs1801133 CC genotype had a higher risk of CRC and the MTHFR rs1801133 TT carriers were more susceptible to Septin 9 gene methylation. [ABSTRACT FROM AUTHOR]

Exploring the link between genetic polymorphisms in folate metabolism genes (MTHFR, MTR, and MTRR) and cardiovascular disease (CVD), this study evaluates the effect of B vitamin supplements (methylfolate, pyridoxal-5′-phosphate, and methylcobalamin) on homocysteine and lipid levels, potentially guiding personalized CVD risk management. In a randomized, double-blind, placebo-controlled trial, 54 patients aged 40–75 with elevated homocysteine and moderate LDL-C levels were divided based on MTHFR, MTR, and MTRR genetic polymorphisms. Over six months, they received either a combination of methylfolate, P5P, and methylcobalamin, or a placebo. At the 6 months follow-up, the treatment group demonstrated a significant reduction in homocysteine levels by 30.0% (95% CI: −39.7% to −20.3%) and LDL-C by 7.5% (95% CI: −10.3% to −4.7%), compared to the placebo (p < 0.01 for all). In the subgroup analysis, Homozygous Minor Allele Carriers showed a more significant reduction in homocysteine levels (48.3%, 95% CI: −62.3% to −34.3%, p < 0.01) compared to mixed allele carriers (18.6%, 95% CI: −25.6% to −11.6%, p < 0.01), with a notable intergroup difference (29.7%, 95% CI: −50.7% to −8.7%, p < 0.01). LDL-C levels decreased by 11.8% in homozygous carriers (95% CI: −15.8% to −7.8%, p < 0.01) and 4.8% in mixed allele carriers (95% CI: −6.8% to −2.8%, p < 0.01), with a significant between-group difference (7.0%, 95% CI: −13.0% to −1.0%, p < 0.01). Methylfolate, P5P, and methylcobalamin supplementation tailored to genetic profiles effectively reduced homocysteine and LDL-C levels in patients with specific MTHFR, MTR, and MTRR polymorphisms, particularly with homozygous minor allele polymorphisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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)]. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction: One of the primary obstacles faced by individuals with advanced colorectal cancer (CRC) is the potential development of acquired chemoresistance as the disease advances. Studies have indicated a direct association between elevated levels of miR-92a-3p and the progression, metastasis, and chemoresistance observed in CRC. We proposed that miR-92a-3p impairs FOLFOX (fluorouracil/oxaliplatin) chemotherapy response by upregulating the expression of chemoresistance biomarker genes through the activation of ß-catenin and epithelial-mesenchymal transition (EMT). These FOLFOX biomarker genes include the pyrimidine biosynthesis pathway genes dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and the genes encoding the DNA repair complexes subunits ERCC1 and ERCC2, and XRCC1. Methods: To assess this, we transfected SW480 and SW620 colon cancer cell lines with miR-92a-3p mimics and then quantified the expression of DPYD, TYMS, MTHFR, ERCC1, ERCC2, and XRCC1, the expression of EMT markers and transcription factors, and activation of ß-catenin. Results and discussion: Our results reveal that miR-92a-3p does not affect the expression of DPYD, TYMS, MTHFR, and ERCC1. Furthermore, even though miR-92a-3p affects ERCC2, XRCC1, E-cadherin, and ß-catenin mRNA levels, it has no influence on their protein expression. Conclusion: We found that miR-92a-3p does not upregulate the expression of proteins of DNA-repair pathways and other genes involved in FOLFOX chemotherapy resistance. [ABSTRACT FROM AUTHOR]

Introduction and Objective. The significance of MTHFR gene polymorphisms in the course of pregnancy has not been definitively resolved. Variants c.665C>T and c.1286A>C in the MTHFR gene leads to increased concentration of homocysteine. The aim of the study was to evaluate homocysteine serum concentrations in Polish women with recurrent pregnancy loss, depending on the presence of the MTHFR gene variants c.665C>T and c.1286A>C in the MTHFR gene. Materials and Method. 137 women with recurrent miscarriages, normal karyotype and normal molecular tests results for the variants c.1691G>A of F5 gene and c.97*G>A of F2 gene were qualified for the study. The relationship between the presence of the MTHFR gene polymorphisms c.665C>T and c.1286A>C in gene MTHFR and homocysteine serum concentration was stadied. Results. There were no significant differences found in homocysteine levels in the study group of women with recurrent miscarriages. There were no differences in homocysteine concentration in patients with MTHFR gene c.655C>T polymorphism (heterozygous nor homozygous), compared to patients without the MTHFR gene polymorphism (CC wild type). Similarly, no differences were noted between patients with AA-wild type and patients with the MTHFR variant c.1286A>C (heterozygous nor homozygous). There was no also correlation between homocysteine concentration and women's age, regardless of the patients' group (control vs. study groups). Conclusions. The c.655C>T and c.1286A>C variants of the MTHFR remain without significant impact on homocysteine concentration in Polish women with recurrent pregnancy loss. [ABSTRACT FROM AUTHOR]

Abstract Background Thrombophilia is characterised by an abnormality of blood coagulation that increases thrombosis. Homocystinuria encompasses a group of disorders marked by increased levels of homocysteine and other amino acids detectable in the bloodstream and urine. Conversely, homocystinuria due to methylenetetrahydrofolatereductase (MTHFR) deficiency, a rarer disorder, stems from impaired folate metabolism due to deficient MTHFR enzyme. Case presentation A 16-year-old boy presented with walking difficulties, headaches, and thrombotic events, thrombophilia workup led to a diagnosis of homocystinuria due to a novel mutation in MTHFR gene. Anticoagulant therapy was initiated which showed clinical improvement, but financial constraints hindered follow-up. Conclusions This case highlights the complexities of diagnosing and treating paediatric thrombophilia, particularly in resource-limited settings. Notably, the identified homozygous autosomal recessive (AR) missense variation in the MTHFR gene (Exon 4—c582C>G) represents a novel mutation, suggesting the ongoing significance of genetic research in elucidating the underlying mechanisms of thrombotic disorders.

Abstract Background Adiponectin 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. Methods Ninety-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. Results Compared to healthy controls, pLN patients exhibited significantly greater serum leptin (11.3 vs. 18.2 ng/mL, 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). Conclusion Serum 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.

Abstract Background Considering the various manifestations of coronavirus disease 2019 and its imperative importance in terms of the right clinical approach and early management, we sought to present a hemicentral retinal vein occlusion case, with a history of heterozygosity of methylenetetrahydrofolate reductase (MTHFR) genes and potential for clotting complications as a late manifestation of coronavirus disease 2019, and provide a brief review of reported retinal vein occlusion cases in patients with coronavirus disease 2019. Case presentation A 35-year-old Iranian patient presented with a visual impairment in the left eye 4 months after recovering from coronavirus disease 2019. He reported a mild blurring of vision in the same eye a few days after admission due to coronavirus disease 2019. The ophthalmic evaluation was compatible with hemicentral retinal vein occlusion. Systemic and laboratory workups were negative except for borderline protein C activity, homocysteine levels, and heterozygosity of MTHFR genes. The patient was scheduled to receive three monthly intravitreal antivascular endothelial growth factor injections. Conclusion We present a case of inferior hemicentral retinal vein occlusion case with an MTHFR mutation with sequential loss of vision 4 months after coronavirus disease 2019 to make clinicians aware of the possibility of late ocular coronavirus disease 2019 manifestations.

Background: This study aimed to detect two genetic polymorphisms, correlate each genotype of polymorphism with biomarker serum levels, and identify which genetic variation could increase susceptibility or be associated with the severity and mortality of Covid-19 infection by examining the following genetic polymorphisms: rs1801133 MTHFR, and rs1799889 SERPINE-1 (PAI-1). Methods: In this study, a total of 102 patients with COVID-19 (mean age 52.66±18.82) and 92 apparently healthy controls (mean age 37.88±14.19) were included. The single nucleotide polymorphisms (SNPs) in MTHFR (rs1801133) and SERPIN1 (rs1799889) were analyzed using ARMS-PCR and sequencing techniques. The levels of homocysteine (Hcy) and plasminogen activator inhibitor 1 (PAI-1) proteins were quantified using an ELISA. Results: Our findings suggest that MTHFR rs1801133 CT and TT genotypes are associated with increased COVID-19 risk and mortality. CT genotype is linked to higher susceptibility (OR = 1.56, p = 0.0009), and both CT and TT genotypes are linked to more severe illness (OR = 1.66, p = 0.018 and OR = 4.10, p

Background: Diabetic retinopathy (DR) is expanding to epidemic levels globally due to the progressing prevalence of diabetes mellitus (DM). In this study, the association between factor V Leiden (FVL), MTHFRC677T, and FXIIIVal34Leu polymorphisms and diabetic retinopathy was investigated in Eastern Iran. Methods: This case-control study enlisted the participation of 300 people (diabetic patients=100, diabetic retinopathy patients=100, healthy controls=100), and polymorphisms were examined by Tetra primer ARMS-PCR. Results: The frequency of FVL (p=0.294) and FXIIIVal34Leu (P=0.349) polymorphism showed no significant results between the genotype frequency in the mentioned groups. In contrast, MTHFRC677T SNP was significantly different in diabetic patients and controls (P=0.008). The MTHFRC677T polymorphism was found to be connected with increased systolic blood pressure in patients who had the TT genotype (130.96±11.92mm/Hg; P=0.011). Conclusion: Our study recommended that the MTHFRC677T polymorphism may offer to DR development. Studies with larger sample sizes and a wider spectrum of populations are authorized to verify this finding.

Background: Adiponectin 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. Methods: Ninety-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. Results: Compared 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). Conclusion: Serum 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. [ABSTRACT FROM AUTHOR]

• Variation on CβS , MTHFR and ACE1 genes are associated with leiomyoma onset. • Genetic variation on NOS3 is associated with a lower leiomyoma uterus volume. • Epistatic interaction between NOS3 and ACE1 genes modulate leiomyoma onset. • Genetics of the systemic vascular system can play a role in the onset of leiomyoma. The link between the systemic vasculature system and tumor biology is here investigated by studying the contribution of CβS (844ins68), MTHFR (677C > T), NOS3 (4a/4b), CYBA (C242T), and ACE1 (I/D) genes to leiomyoma onset, uterus and leiomyoma volumes. DNA samples from 130 women with leiomyomas and 527 from healthy women were genotyped by PCR or PCR-RFLP. Qui-square (χ2) or Fisher's exact test were used to test associations. All the mentioned tests were performed in IBM® SPSS® Statistics Version 28. Statistical significance was defined as a p-value < 0.05. Results revealed that CβS (in the codominant and allelic models, p = 0.044 and, p = 0.015, OR = 1.791 [1.114–2.879], respectively), MTHFR (in the codominant, allelic and dominant models, p = 0.009, p = 0.002, OR = 0.585 [0.416–0.824] and p = 0.003, OR = 0.527 [0.346–0.802], respectively) and ACE1 (dominant model, p = 0.045, OR = 0.639 [0.411–0.992]) genes are associated with leiomyoma onset. NOS3 4a4a genotype is associated with a lower uterus volume (p = 0.004). This study also uncovers intriguing epistatic interactions among some genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the CC genotype (MTHFR) and (+/+) (CβS; p = 0.003), 4b4b (NOS3; p = 0.006 , OR = 2.050 [1.223–3.439]) or DD (ACE1 ; p < 0.001, OR = 2.362 [1.438–3.880]) were shown to be associated with the disease, while 4a presence (NOS3) in epistasis with I presence (ACE1), increased the effect protection having just the I allele presence (p = 0.029, OR = 0.446 [0.214–0.930]). We conclude that variation in genes related to the systemic vascular system can play a role in the onset and development of leiomyoma. [ABSTRACT FROM AUTHOR]

Neutrophil-lymphocyte (NLR), platelet-lymphocyte (PLR), eosinophil-lymphocyte (ELR), and monocyte-lymphocyte (MLR) ratios are systemic inflammatory markers related to myocardial infarction. The aim of this study is to investigate the association of Src homology 2-B adapter protein 3 (SH2B3) C784 T and methylenetetrahydrofolate reductase (MTHFR) C677 T polymorphisms (SNP) with systemic inflammatory markers and the severity of coronary artery disease (CAD) in 150 ST-elevation myocardial infarction (STEMI) patients. Single nucleotide polymorphisms were genotyped using the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method. The inflammatory markers were calculated. An interventional cardiologist blinded to other data assessed the SYNTAX (SX) Score. Eosinophil and platelet counts were significantly higher in SH2B3 variants than in the wild type. Additionally, SH2B3 variants had significantly higher ELR than the wild type (.12 ±.19 vs.25 ±.34, p =.018). NLR, PLR, ELR, and MLR were considerably higher in MTHFR variants than in the wild type (p <.05). The SX score was significantly higher in both SH2B3 C784 T (21.24 ± 8.90 vs 15.29 ± 9.40, p =.00) and MTHFR C677 T (20.34 ± 10.21 vs 16.08 ± 8.39, p =.00) variants when compared with wild type. In conclusion, these polymorphisms are associated with several markers of systemic inflammation as well as the severity of CAD. [ABSTRACT FROM AUTHOR]

Background: The folate metabolism pathway plays an integral part in DNA synthesis, methylation, and repair. Methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) are both enzymes that are involved in this pathway, and the single nucleotide polymorphisms (SNPs) in genes coding for them have modulatory effects on DNA expression. This study aimed to investigate the relationship between MTHFR C677T (rs1801133) and MTHFD1 G1958A (rs2236225) polymorphisms and the risk of developing breast cancer in Georgian women. Methods: A case-control study was performed examining the MTHFR C677T and MTHFD1 G1958A SNP in breast cancer–confirmed cases and healthy matched controls. Real time-polymerase chain reaction (PCR) was used to genotype SNPs. The case individuals' pathology reports were obtained following surgeries for cancer characteristic data. Statistical analysis was performed to investigate the significance of the acquired data. Results: Statistical analysis of MTHFR C677T SNP revealed that the CT genotype increased the risk of breast cancer by 2.17 folds in the over-dominant model. Statistical analysis of MTHFD1 G1958A SNP showed that the GA genotype increased the risk of breast cancer by 4.12 folds in the codominant model and 2.41 folds in the over-dominant model. No statistically significant link was found between genotypes and lymph node status, however, patients with the CT genotype had higher percentages of proliferative activity. Conclusions: Breast cancer seems to have a statistically significant association with the CT genotype in MTHFR C677T and the GA genotype in MTHFD1 G1958A in Georgian women. [ABSTRACT FROM AUTHOR]

Background: Considering the various manifestations of coronavirus disease 2019 and its imperative importance in terms of the right clinical approach and early management, we sought to present a hemicentral retinal vein occlusion case, with a history of heterozygosity of methylenetetrahydrofolate reductase (MTHFR) genes and potential for clotting complications as a late manifestation of coronavirus disease 2019, and provide a brief review of reported retinal vein occlusion cases in patients with coronavirus disease 2019. Case presentation: A 35-year-old Iranian patient presented with a visual impairment in the left eye 4 months after recovering from coronavirus disease 2019. He reported a mild blurring of vision in the same eye a few days after admission due to coronavirus disease 2019. The ophthalmic evaluation was compatible with hemicentral retinal vein occlusion. Systemic and laboratory workups were negative except for borderline protein C activity, homocysteine levels, and heterozygosity of MTHFR genes. The patient was scheduled to receive three monthly intravitreal antivascular endothelial growth factor injections. Conclusion: We present a case of inferior hemicentral retinal vein occlusion case with an MTHFR mutation with sequential loss of vision 4 months after coronavirus disease 2019 to make clinicians aware of the possibility of late ocular coronavirus disease 2019 manifestations. [ABSTRACT FROM AUTHOR]

Background: The association between MTHFR gene polymorphisms (C677T and A1298C) and prostate cancer risk remains controversial. Methods: Two independent researchers searched the PubMed, Embase, Cochrane and Web of Science databases for all papers published up to 12/19/2023 and used various genetic models to evaluate the relationship between MTHFR polymorphisms and prostate cancer risk. Results: The meta-analysis included 26 case-control studies with a total of 12,455 cases and 13,900 controls with the C677T polymorphism and 6,396 cases and 8,913 controls with the A1298C polymorphism. Overall, no significant association was found between the MTHFR gene polymorphisms and prostate cancer risk. However, the C677T polymorphism was associated with reduced prostate cancer risk in the Asian population (T allele vs. C allele: OR = 0.759, 95% CI 0.669-0.861, p < 0.001; TT + CT vs. CC: OR = 0.720, 95% CI 0.638-0.812, p < 0.001; TT vs. CC + CT: OR = 0.719, 95% CI 0.617-0.838, p < 0.001; TT vs. CC: OR = 0.620, 95% CI 0.522-0.737, p < 0.001); however, the A1298C polymorphism was associated with an increased risk in the mixed race group from the United States (CC + AC vs. AA: OR = 1.464, 95% CI 1.052-2.037, p = 0.024; AC vs. AA: OR = 1.615, 95% CI 1.037-2.514, p = 0.034). Conclusion: The meta-analysis suggested that MTHFR gene polymorphisms (C677T and A1298C) may have different effects on prostate cancer risk in specific populations. [ABSTRACT FROM AUTHOR]

This article explores the complex relationship between genetics and cognition, specifically examining the impact of genetic variants, particularly single nucleotide polymorphisms (SNPs), on cognitive functions and the development of neuropsychiatric disorders. Focusing on neurotransmitter regulation within the prefrontal cortex's dopaminergic circuits, this study emphasizes the role of genes like COMT, PRODH, and DRD in shaping executive functions and influencing conditions such as ADHD and schizophrenia. Additionally, it explores the significance of genetic factors in neurodevelopmental disorders, emphasizing the need for early identification to guide appropriate therapeutic interventions. This article also investigates polymorphisms in the transsulfuration pathway, revealing their association with cognitive impairment diseases. Computational analyses, including machine learning algorithms, are highlighted for their potential in predicting symptom severity in ADHD based on genetic variations. In conclusion, this article underscores the intricate interplay of genetic and environmental factors in shaping cognitive outcomes, providing valuable insights for tailored treatments and a more comprehensive understanding of neuropsychiatric conditions. [ABSTRACT FROM AUTHOR]

Polymorphisms in genes coding folate-metabolising enzymes might alter the pharmacokinetics and sensitivity for methotrexate "MTX". The aim of the study aimed to investigate the influence of MTHFR C677T, DHFR19 Ins/del, GGH −401 C > T, and MTR A2756G polymorphisms on MTX toxicity and pharmacokinetics in Egyptian patients with Acute lymphoblastic leukaemia (ALL) or Non-Hodgkin lymphoma (NHL). Fifty adult Egyptian patients with ALL and NHL, treated with high dose MTX, were prospectively enrolled in the study. Clinical and biochemical data was collected objectively from medical records after each cycle of MTX. Plasma concentrations of MTX were measured after 72 h of initiation of infusion. Genotyping was done with a PCR-ARMS and PCR-RFLP assays. The MTHFR C677T T variants significantly increased the risk of leukopoenia, whereas the genotype MTHFR 677 C > T TT significantly associated with lymphocytopenia, thrombocytopenia, and anaemia. The genotype GGH-401 TT was significantly correlated with anaemia. Plasma MTX level was significantly higher in patients with MTR A2756G G variants. MTHFR polymorphism played the main role in MTX toxicities. The pharmacokinetics of MTX was affected by MTR polymorphism. GGH mutation was mainly concerned with anaemia. Pharmacogenetic testing are recommended to optimise MTX therapy. [ABSTRACT FROM AUTHOR]

The placenta provides nutrients to the fetus, and it has protective effects against harmful substances. Unhealthy maternal diets and toxic agents might increase free radical (FR) production. Elevated FR levels are associated with a high risk of oxidative stress, which may cause DNA damage. DNA might be oxidized in the placenta, occasionally affecting its methylation profile due to 8-hidroxy-2′-deoxyguanosine formation. This study assessed 130 mothers and their children. The maternal's nutritional patterns were determined using the Food Frequency Questionnaire. Information on smoking and alcohol consumption was collected during the medical examination. Data on placental DNA were obtained to determine the MTHFR 677C/T genotype and the proportion of placental DNA methylation (pDNAm). Consumption of vitamins and folic acid was above 85%. The pDNAm was found to be correlated with gestational age and coffee intake. Mothers with a smoking history had a low pDNAm. Placentas with the TT genotype had a higher but not significant pDNAm. In the placentas with the CC/CT genotype, the pDNAm was positively associated with carbohydrate and biotin intake. However, the TT genotype was negatively associated with folate and vegetable intake. The pDNAm was positively associated with coffee intake, but not with macro-, and micronutrient intake. However, it was negatively associated with cigarette smoking. The placentas with the CC/CT genotype had a lower pDNAm than those with the TT genotype. In the placentas with the CC/CT or TT genotype, methylation was positively, and negatively associated with micro- or macronutrients, respectively. • Maternal coffee intake was associated with changes in the DNA methylation pattern of the placenta. • Maternal smoking in early gestation was associated with decreased placental DNA methylation. • The placental TT genotype of the MTHFR gene and maternal nutrition (folic acid and vegetables) was correlated with changes in the methylation pattern of the placenta. [ABSTRACT FROM AUTHOR]

Background: This study aimed to detect two genetic polymorphisms, correlate each genotype of polymorphism with biomarker serum levels, and identify which genetic variation could increase susceptibility or be associated with the severity and mortality of Covid-19 infection by examining the following genetic polymorphisms: rs1801133 MTHFR, and rs1799889 SERPINE-1 (PAI-1). Methods: In this study, a total of 102 patients with COVID-19 (mean age 52.66±18.82) and 92 apparently healthy controls (mean age 37.88±14.19) were included. The single nucleotide polymorphisms (SNPs) in MTHFR (rs1801133) and SERPIN1 (rs1799889) were analyzed using ARMS-PCR and sequencing techniques. The levels of homocysteine (Hcy) and plasminogen activator inhibitor 1 (PAI-1) proteins were quantified using an ELISA. Results: Our findings suggest that MTHFR rs1801133 CT and TT genotypes are associated with increased COVID-19 risk and mortality. CT genotype is linked to higher susceptibility (OR = 1.56, p = 0.0009), and both CT and TT genotypes are linked to more severe illness (OR = 1.66, p = 0.018 and OR = 4.10, p < 0.001, respectively). PAI-1 rs1799889 4G/5G genotype correlates with COVID-19 risk and severity (OR = 2, p = 0.03 and OR = 2.7, p =0.04, respectively). In a subgroup, CT/TT genotypes have elevated Hcy levels compared to CC genotype (p = 0.00016). Also, 4G/5G and 5G/5G genotypes have lower PAI-1 levels than 4G/4G genotype. Conclusion: A significant association was found between gene variations in MTHFR and SERPINE1 genes and COVID-19 infection susceptibility and severity. [ABSTRACT FROM AUTHOR]

The impacts of patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) I148M‐rs738409, methylenetetrahydrofolate reductase (MTHFR) Ala222Val‐rs1801133, and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys‐rs671 on the outcomes of Taiwanese patients with steatotic liver disease (SLD) have remained elusive. An 8‐year prospective cohort study of patients with (n = 546) and without (n = 580) SLD (controls) was undertaken in a Taiwanese tertiary care center. The 546 SLD patients comprised 306 (56.0%) men and 240 (44.0%) women with mean ages of 53.3 and 56.4 years, respectively. Compared with the controls, SLD patients had an increased frequency of the PNPLA3 I148M‐rs738409 GG genotype (25.5 vs. 5.9%, p = 0.001). Among the SLD patients, 236 (43.1%) suffered cardiovascular events, 52 (9.5%) showed extrahepatic cancers, 13 (2.38%) experienced hepatic events, including hepatocellular carcinoma (n = 3, 0.5%) and liver cirrhosis (n = 8, 1.47%), and none died. The Fibrosis‐4 (FIB‐4) scores were associated with extrahepatic cancer (hazard ratio [HR] 1.325; 95% confidence interval [CI], 1.038–1.691) and cirrhosis development (HR 1.532; 95% CI, 1.055–2.224), and the PNPLA3 I148M‐rs738409 G allele (β = 0.158, 95% CI, 0.054–0.325) was associated with the FIB‐4 score. Stratified analyses showed that the impact of the FIB‐4 score on extrahepatic cancer development was evident only in SLD patients with the PNPLA3 I148M‐rs738409 GG genotype (HR 1.543; 95% CI, 1.195–1.993) and not in patients with the GC or CC genotype. Moreover, the ALDH2 Glu504Lys‐rs671 G allele had a dose‐dependent effect on alcoholism, and the MTHFR and ALDH2 genotypes were not significantly associated with SLD patient outcomes. In conclusion, special vigilance should be exercised for emerging extrahepatic cancer in SLD patients with the PNPLA3 I148M‐rs738409 GG genotype and high FIB‐4 scores. [ABSTRACT FROM AUTHOR]

Lower bone mineral density (BMD) constitutes a common issue in inflammatory bowel disease (IBD). Studies often explore the association between BMD and folic acid level. The presented study aimed to evaluate the impact of MTHFR gene polymorphism and folic acid levels on BMD in patients with IBDs: Crohn's disease (CD) and ulcerative colitis (UC). The study group comprised IBD patients and a healthy control group. BMD, T-score, and Z-score of the lumbar spine (L1-L4) and femoral neck (FN) were assessed using dual-energy X-ray absorptiometry. Folic acid level was determined using direct chemiluminescence, and the MTHFR 677C > T (rs1801133) and 1298A > C (rs1801131) genotyping were performed by HRMA. Our study found no significant differences in the folic acid levels between the groups. Patients with CD and UC presented a lower BMD, T-score, and Z-score of the FN and L1-L4 than the CG. UC patients who were homozygotes AA in loci c.1298A>C presented lower than controls lumbar spine L1-L4 BMD and T-score values. Regarding MTHFR 677 polymorphism, we found that IBD patients carrying CC genotype demonstrated lower than controls femoral neck Z-score, lumbar spine L1-L4 BMD, T-score and Z-score. MTHFR polymorphisms were found to have no impact on folic acid concentrations. IBD patients presented a higher risk of low BMD than the healthy controls, regardless of MTHFR 677 and 1298 genotypes. However, MTHFR polymorphism may influence on bone in IBD patients. Nevertheless, it appears essential to conduct further studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The gene known as methylenetetrahydrofolate reductase (MTHFR) is control of the production and methylation of deoxynucleic acids. Male infertility has been linked to the MTHFR polymorphism (C677T). Objective: a current study on male infertility was carried out to ascertain whether the MTHFR polymorphism (C677T) is connected to male infertility. The study included 30 male infertility patients aged between (26-58) years and 20 individual healthy control groups. The studied ages were distributed into three groups. The major group was (26 -- 36) years, and the percentage was (40%). The second group was (37 -- 47) years, and the rate was (26.67 %); the third group was (48 -- 58) years, with a percentage (of 33.33%). The last group is the most prevalent among the three groups. Method: DNA was isolated, and Restriction Fragment Length Polymorphism -- Polymerase Chain Reaction (RFLP-PCR) was done by using specific primers to the MTHFR gene. Results: the results indicated to the presence of mutations in 15 out of 30 patients after using restriction enzymes Hinf. Statistical analysis showed a correlation between male infertility and the emergence of MTHFR C677T gene mutation paralleled through the control group. Conclusion: When we compared the patient's group and the healthy group, we established there is a correlation between MTHFR C677T gene polymorphism and the incidence of male infertility in our study population. [ABSTRACT FROM AUTHOR]

Neuropathy is the most prevalent microvascular complication in type 2 diabetes mellitus (T2DM). Metformin consumption is associated with higher neuropathy risk. The Methylenetetrahydrofolate reductase (MTHFR) enzyme has confirmed its role in neuropathy. Metformin and MTHFR may decrease folate and induce hyper-homocysteine. The MTHFR gene variant, C677T, commonly found in exons, was studied for its connection to neuropathy risk in newly diagnosed T2DM patients initiating metformin treatment. This cross-sectional study recruited 103 patients. The neuropathy risk was examined according to medical judgement through Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) criteria. Genotyping C677T was performed using PCR-RFLP. This study revealed that only one patient had a homozygote mutant, with over 50% of patients were detected with allele mutants. There were no statistical differences in patient characteristics between CC and CT genotypes (p>0.05). The association between C677T and neuropathy risk was not significant statistically, either in the genotype model (p=0.97), allele model (p=0.82), and dominant model (p=0.91). Even after adjusting for several confounding factors, no significant association was observed. In conclusion, C677T in our population did not influence neuropathy risk. More specific criteria and laboratory parameters indicated neuropathy should be examined in future studies. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) is defined as a fetal failure to reach the genetic potential for intrauterine growth. IUGR complicates up to 10% of pregnancies, representing a primary cause of morbidity and mortality. Hereditary thrombophilia has been detected in about 65% of pregnancies and because of the association with IUGR, preeclampsia, uteroplacental apoplexy, recurrent miscarriage and fetal intrauterine death, prenatal testing is recommended. Our study included a number of 122 patients without pre-existing pregnancy pathology (study group) who were compared with a control group that included 122 patients with normal birth weight fetuses. Patients were evaluated at about 6-7 weeks postnatally when we tried to correlate the intrauterine growth restriction with the profile of hereditary thrombophilia (determination of factor II gene mutations, factor V Leiden, MTHFR gene, PAI gene, factor XIII mutation, antithrombin III, protein C, protein S). The results of the study showed the presence of hereditary thrombophilia in 82 cases (67.2%) in the study group and in 21 cases (17.21%) in the control group. Among the genetic analyses performed we found a predominance of PAI-1 gene as well as a positive association with intrauterine growth restriction in case of concomitant presence of factor V Leiden and PAI-1 gene or MTHFR gene. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is expanding to epidemic levels globally due to the progressing prevalence of diabetes mellitus (DM). In this study, the association between factor V Leiden (FVL), MTHFRC677T, and FXIIIVal34Leu polymorphisms and diabetic retinopathy was investigated in Eastern Iran. Methods: This case-control study enlisted the participation of 300 people (diabetic patients=100, diabetic retinopathy patients=100, healthy controls=100), and polymorphisms were examined by Tetra primer ARMS-PCR. Results: The frequency of FVL (p=0.294) and FXIIIVal34Leu (P=0.349) polymorphism showed no significant results between the genotype frequency in the mentioned groups. In contrast, MTHFRC677T SNP was significantly different in diabetic patients and controls (P=0.008). The MTHFRC677T polymorphism was found to be connected with increased systolic blood pressure in patients who had the TT genotype (130.96±11.92mm/Hg; P=0.011). Conclusion: Our study recommended that the MTHFRC677T polymorphism may offer to DR development. Studies with larger sample sizes and a wider spectrum of populations are authorized to verify this finding. [ABSTRACT FROM AUTHOR]

[Abstract]: Objective: This study aimed to investigate the relationship between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and early neurological deterioration (END) in patients with acute ischemic stroke (AIS) and any possible interactions between specific MTHFR alleles and traditional risk factors among a Han Chinese cohort. Methods: 434 AIS patients were consecutively recruited between January 2017 and June 2019, including 129 END and 305 non-END cases. A candidate gene association study design was used to analyze the association between MTHFR gene polymorphism and END risk. The polymerase chain reaction-restriction fragment length polymorphism (RFLP) method was employed to genotype the MTHFR C677T polymorphism. The interactional analyses were performed using the multifactor dimensionality reduction test. Results: Hyperglycemia (odds ratio [OR]: 2.410, 95 % confidence interval [CI]: 1.436–4.046, p = 0.001), neurological function impairment (NIHSS score >5) (OR: 2.158, 95%CI: 1.337–3.484, p = 0.002) on admission, and hyperhomocysteinemia (HHcy) (OR: 2.570, 95%CI: 1.229–5.376, p = 0.012) were independently associated with END. The TT genotype (OR: 1.710, 95%CI: 1.021–2.863, p = 0.043) and T allele (OR: 1.710, 95%CI: 1.021–2.863, p = 0.043) of this C677T polymorphism were associated with susceptibility to END, and the TT genotype was more common in the subjects with HHcy (OR: 2.525, 95%CI: 1.111–5.739, P = 0.023). In addition, we also found interactions for END risk between the C677T polymorphism and traditional risk factors for END, including: hyperglycemia on admission, drinking, and moderate to severe neurological deficits (OR 1.237, 95 % CI 0.227–6.734), although the results were not statistically significant (p = 0.806). Conclusions: Our results show a possible association between MTHFR C677T polymorphism and gene–environment interactions with END susceptibility in a Han Chinese cohort.

Introduction: One of the primary obstacles faced by individuals with advanced colorectal cancer (CRC) is the potential development of acquired chemoresistance as the disease advances. Studies have indicated a direct association between elevated levels of miR-92a-3p and the progression, metastasis, and chemoresistance observed in CRC. We proposed that miR-92a-3p impairs FOLFOX (fluorouracil/oxaliplatin) chemotherapy response by upregulating the expression of chemoresistance biomarker genes through the activation of β-catenin and epithelial-mesenchymal transition (EMT). These FOLFOX biomarker genes include the pyrimidine biosynthesis pathway genes dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and the genes encoding the DNA repair complexes subunits ERCC1 and ERCC2, and XRCC1.Methods: To assess this, we transfected SW480 and SW620 colon cancer cell lines with miR-92a-3p mimics and then quantified the expression of DPYD, TYMS, MTHFR, ERCC1, ERCC2, and XRCC1, the expression of EMT markers and transcription factors, and activation of β-catenin.Results and discussion: Our results reveal that miR-92a-3p does not affect the expression of DPYD, TYMS, MTHFR, and ERCC1. Furthermore, even though miR-92a-3p affects ERCC2, XRCC1, E-cadherin, and β-catenin mRNA levels, it has no influence on their protein expression.Conclusion: We found that miR-92a-3p does not upregulate the expression of proteins of DNA-repair pathways and other genes involved in FOLFOX chemotherapy resistance.

Background: Thrombophilia is characterised by an abnormality of blood coagulation that increases thrombosis. Homocystinuria encompasses a group of disorders marked by increased levels of homocysteine and other amino acids detectable in the bloodstream and urine. Conversely, homocystinuria due to methylenetetrahydrofolatereductase (MTHFR) deficiency, a rarer disorder, stems from impaired folate metabolism due to deficient MTHFR enzyme. Case presentation: A 16-year-old boy presented with walking difficulties, headaches, and thrombotic events, thrombophilia workup led to a diagnosis of homocystinuria due to a novel mutation in MTHFR gene. Anticoagulant therapy was initiated which showed clinical improvement, but financial constraints hindered follow-up. Conclusions: This case highlights the complexities of diagnosing and treating paediatric thrombophilia, particularly in resource-limited settings. Notably, the identified homozygous autosomal recessive (AR) missense variation in the MTHFR gene (Exon 4—c582C>G) represents a novel mutation, suggesting the ongoing significance of genetic research in elucidating the underlying mechanisms of thrombotic disorders. [ABSTRACT FROM AUTHOR]

Abstract Objective Seizures are a common clinical presentation in patients with glioma and substantially impact patients' quality of life. Hyperhomocysteinemia is defined as abnormally high serum levels of homocysteine (Hcy) and is reportedly linked to susceptibility to various nervous system diseases. However, it remains unclear whether and how hyperhomocysteinemia and its associated genetic polymorphisms promote seizures in glioma patients. Methods We retrospectively reviewed all medical data from 127 patients with malignant gliomas, who underwent initial tumor resection by our team between July 2019 and June 2021 and had preoperative measurements of serum Hcy levels. According to whether they had at least one seizure before surgery, they were divided into the seizure and nonseizure groups. We also detected polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and measured intratumoral Hcy levels in these patients. Results Hyperhomocysteinemia was a susceptibility factor for preoperative seizures in glioma patients according to both univariate analyses (P

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Womens Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.