Alzheimer\'s disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer\'s disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer\'s disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer\'s disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04-1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23-3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer\'s disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer\'s disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer\'s disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer\'s disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is essential for the metabolism of folic acid and homocysteine. The MTHFR C677T polymorphism is associated with several disorders. Our study aims to explore the geographical distributions of the MTHFR C677T polymorphism of women in China and how migration affected the polymorphism in Suzhou.
METHODS: A total of 7188 women of reproductive age were recruited in Suzhou of the study. Subjects were classified according to their native places after data extraction. MTHFR C677T gene polymorphisms were detected by quantitative PCR with genomic DNA isolated from blood samples.
RESULTS: The frequencies of the 677T allele and 677TT genotype were higher in northern China than that in southern China and decreased in geographical gradients from north to south. The frequencies were considerably higher in the migrant population than that in the indigenous population of Suzhou. The migrant population have gradually changed the prevalence in Suzhou.
CONCLUSIONS: Our study suggested that the prevalence of MTHFR C677T polymorphisms among women varied across different geographical regions in Chinese Han populations. The 677T allele frequencies of the northern populations were significantly higher than those of the southern populations. The migrant population gradually changed the prevalence of the MTHFR C677T polymorphism in Suzhou.

Although para-aminosalicylic acid (PAS) has been used to treat tuberculosis for decades, mechanisms of resistance to this drug in Mycobacterium tuberculosis (M. tuberculosis) clinical isolates have not been thoroughly investigated. Previously, we found that decreased methylenetetrahydrofolate reductase (MTHFR) activity of Rv2172c led to increased sensitivity to antifolates in M. tuberculosis. In this study, we collected the genome-sequencing data of 173 PAS-resistant and 803 PAS-sensitive clinical isolates and analyzed rv2172c mutations in those 976 isolates. The results showed that two mutations (T120P and M172V) on rv2172c could be identified in a certain proportion (6.36%) of PAS-resistant isolates. The results of AlphaFold2 prediction indicated that the T120P or M172V mutation might affect the enzymatic activity of Rv2172c by influencing nicotinamide adenine dinucleotide (NADH) binding, and this was verified by subsequent biochemical analysis, demonstrating the role of residues Thr120 and Met172 on NADH binding and enzymatic activity of Rv2172c. In addition, the effect of rv2172c T120P or M172V mutation on methionine production and PAS resistance was determined in M. tuberculosis. The results showed that both T120P and M172V mutations caused increased intracellular methionine concentrations and high level PAS resistance. In summary, we discovered new molecular markers and also a novel mechanism of PAS resistance in M. tuberculosis clinical isolates and broadened the understanding of the NADH-dependent MTHFR catalytic mechanism of Rv2172c in M. tuberculosis, which will facilitate the molecular diagnosis of PAS resistance and also the development of new drugs targeting Rv2172c.

The methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) are three regulatory enzymes in the folic acid (FA) cycle play a critical role in the balance of methionine and homocysteine. MTHFR and MTRR gene polymorphisms affect the biochemical activities of enzymes, impairing the remethylation of homocysteine to methionine. In 1972, severe MTHFR deficiency resulting in homocystinuria was first reported, suggesting MTHFR involvement in the disease. MTHFR C677T polymorphism can independently increase the risk of high homocysteine (HHcy) in plasma. Elevation of homocysteine levels could increase the risk of microvascular damage, thrombosis, heart disease, etc. Vascular complications were regarded as a leading major cause of diabetes mortality, and disability increases individual health and economic burden. Diabetes mellitus (DM) is a chronic inflammatory disease, and conventional medications do not provide a complete cure for diabetes. It was essential to identify other risk factors for the intervention and prevention of diabetes. MTHFR gene polymorphism is an emerging risk factor in diabetes. Recent studies have shown that polymorphisms of the MTHFR gene play a significant role in the pathophysiology of diabetes, including inflammation and insulin resistance. This review summarizes the association between MTHER gene polymorphism and diabetes.

BACKGROUND: Preeclampsia (PE) poses a substantial risk to prenatal and maternal health. Folic acid (FA) and methylenetetrahydrofolate reductase (MTHFR) play roles in DNA methylation and genomic integrity maintenance, with MTHFR polymorphisms potentially impacting PE occurrence. Human microRNA 149 (miR-149) remains underexplored in PE despite its involvement in folate metabolism. This study seeks to evaluate serum miR-149 levels with the MTHFR C677T polymorphism for diagnosing PE.
METHODS: Seventy females aged 28-40 gestational weeks were divided into control and Preeclampsia groups. Serum miR-149 and MTHFR gene levels were evaluated using real-time PCR.
RESULTS: Preeclamptic patients showed significantly lower serum miR-149 levels than healthy controls (P ≤ 0.01). PE cases showed a higher frequency of the TT genotype and T allele of the C677T polymorphism (OR = 0.181, 2.882, respectively), implicating them as genetic risk factors. The CT genotype also increased PE risk (OR = 0.26), while no significant difference was observed in the CC genotype.
CONCLUSIONS: Merging miR-149 and MTHFR polymorphism assessment improves discrimination between healthy and PE groups, offering valuable insights into PE pathogenesis and potential diagnostic strategies.

BACKGROUND: Major depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters.
METHODS: We analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants\' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment\'s association with depression.
RESULTS: At SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH, and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction.
CONCLUSIONS: CTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders.
CONCLUSIONS: The first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma.

UNASSIGNED: To assess age at 1st central retinal vein occlusion (CRVO) in carriers ≤ 45 years old of the methylenetetrahydrofolate reductase (MTHFR) C667T genotype compared to heterozygous and wild type, and to identify predictors of age at CRVO.
UNASSIGNED: Retrospective cohort study consisting of 18 MTHFR TT, 23 MTHFR TC and 28 MTHFR CC participants; information regarding age, sex, age at CRVO, history of dyslipidaemia, hypertension, smoking and plasma HC measured by immunoassay were collected.
UNASSIGNED: Age at CRVO was lower in MTHFR TT than MTHFR TC and CC (32 ± 6 vs 38 ± 5 vs 37 ± 6 years, respectively, p = 0.005); plasma HC was higher in MTHFR TT than in the other genotypes [14.4 (10.8, 19.6) vs 10.4 ((8.6,12.5) vs 8.5 ((7.5,9.8) μmol/l, p = 0.0002). Smoking (cigarettes/day) independently predicted age at CRVO (p = 0.039) and plasma HC (p = 0.005); smoking status (yes/no) predicted ischemic CRVO (p = 0.01) that was more common in the MTHFR TT group (p = 0.006).
UNASSIGNED: Carriers of the MTHFR TT genotype ≤ 45 years old develop their 1st CRVO on average 5 years earlier than the MTHFR CC genotype; smoking contributes to the prematurity and severity of CRVO in MTHFR TT carriers.

METHODS: Disturbances in one-carbon metabolism contribute to nonalcoholic fatty liver disease (NAFLD) which encompasses steatosis, steatohepatitis, fibrosis, and cirrhosis. The goal is to examine impact of folate deficiency and the Mthfr677C >T variant on NAFLD.
RESULTS: This study uses the new Mthfr677C >T mouse model for the human MTHFR677C >T variant. Mthfr677CC and Mthfr677TT mice were fed control diet (CD) or folate-deficient (FD) diets for 4 months. FD and Mthfr677TT alter choline/methyl metabolites in liver and/or plasma (decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio, methyltetrahydrofolate, and betaine; increased homocysteine [Hcy]). FD, with contribution from Mthfr677TT, provokes fibrosis in males. Studies of normal livers reveal alterations in plasma markers and gene expression that suggest an underlying predisposition to fibrosis induced by FD and/or Mthfr677TT in males. These changes are absent or reverse in females, consistent with the sex disparity of fibrosis. Sex-based differences in methylation potential, betaine, sphingomyelin, and trimethylamine-N-oxide (TMAO) levels may prevent fibrogenesis in females. In contrast, Mthfr677TT alters choline metabolism, dysregulates expression of lipid metabolism genes, and promotes steatosis in females.
CONCLUSIONS: This study suggests that folate deficiency predisposes males to fibrosis, which is exacerbated by Mthfr677TT, whereas Mthfr677TT predisposes females to steatosis, and reveal novel contributory mechanisms for these NAFLD-related disorders.

Background: Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to examine the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5-FU)/leucovorin (LV) in the locally advanced setting. Patients and methods: This case-control study included 119 healthy controls and 97 patients with locally advanced rectal cancer (LARC). For MTHFR genotyping, restriction fragment length polymorphism analysis (PCR-RFLP) was employed. Results: In silico analysis highlighted that SNPs C677T and A1298T correlate with MTHFR gene expression, and that gene expression profile correlates with cancer risk and stage. Using dominant and recessive models, it was found that the MTHFR 677CC vs. 677CT+677TT have increased risk of cancer development (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.30-3.95, p = 0.002) as well as 677CC+677CT compared to 677TT (OR: 4.18, 95% CI: 1.16-14.99, p = 0.014). MTHFR 1298AA also shown increased risk for cancer development compared to 1298AC+1298CC (OR:2.0, 95% CI: 1.20-3.59, p = 0.035) Statistical analysis of combined genotypes highlighted the protective role of CT/AC combined genotype (OR: 3.15 95% CI: 1.576-6.279, p = 0.002) while the CC/AA genotype showed an increased risk for rectal cancer development (OR: 2.499, 95% CI: 1.246-5.081, p = 0.016) The carriers of the 677C/1298A haplotype had the highest risk for developing rectal cancer (OR: 1.74; 95% CI: 1.198-2.530, p = 0.002) while the 677T/1298C haplotype seems to provide a protective effect. (OR: 0.44; 95%CI 0.248-0.795, p = 0.003). No significant association with response to chemoradiotherapy was found. Conclusion: Our data point to MTHFR 667C allele and 1298A alleles as low-penetrance risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan, as various population-based factors might also be significant our findings can be used for future meta-analyses and the construction of genetic cancer risk prediction panels.

BACKGROUND: The impact of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation on the relationship between plasma homocysteine (Hcy) levels and stroke has been extensively studied and documented in previous study. However, it remains unclear whether the MTHFR C677T mutation can affect the response to Hcy lowering treatment in stroke patients with hyperhomocysteinemia (HHcy). Understanding the impact of genetic factors on treatment response can help optimize personalized treatment strategies for stroke patients with HHcy. We aimed to investigate the potential association between the MTHFR C677T gene polymorphisms and the effectiveness of Hcy lowering treatment using vitamin therapy in stroke patients with HHcy.
METHODS: The MTHFR C677T genotype polymorphisms were identified using polymerase chain reaction-restriction fragment length polymorphism, and the distribution of three genotypes in the MTHFR C677T gene locus was compared. The treatment effects of Hcy lowering agents were compared among patients with different genotypes.
RESULTS: Among the 320 stroke patients enrolled in the study, 258 (80.6%) were diagnosed with HHcy. Of these, 162 patients (Effective Group) responded well to the clinical Hcy lowering treatment, while 96 patients (Invalid Group) failed to achieve sufficient response even after taking combination supplements of folic acid, Vitamin B6, and methylcobalamin for one month. Significant differences were observed in terms of age (p < 0.001), hypertension (p = 0.034), dyslipidemia (p = 0.022), hyperuricemia (p = 0.013) and genotype distribution of MTHFR C677T gene polymorphism (p < 0.001) between the Invalid group and the Effective group. The multivariate regression analysis revealed that the T allele (odd rations [OR], 1.327; 95% confidence interval [CI], 1.114-1.580; p = 0.0015) was independently associated with an insufficient Hcy lowering treatment effect. Additionally, the TT genotype was independently associated with insufficient response in both the codominant model (OR, 1.645; 95% CI, 1.093-2.476; p = 0.017) and the recessive model (TT versus CC + CT; OR, 1.529; 95% CI, 1.145-2.042; p = 0.004). However, no relationship was observed between CT + TT genotypes and poor treatment effect in the dominate model.
CONCLUSIONS: Our findings suggested that the TT genotype and T allele of MTHFR C677T polymorphism were independently associated with an insufficient Hcy lowering treatment effect in stroke patients with HHcy.