Methylenetetrahydrofolate Reductase Research Articles

Level of homocysteine and polymorphism of genes involved in folate metabolism in women with polycystic ovary syndrome

Background. Polycystic ovary syndrome (PCOS) is a multifactorial disease in the development of which gene polymorphism plays an important role. In recent years, data on the role of homocysteine (Hcy) in the formation of PCOS have appeared, and hyperhomocysteinemia is even considered one of the main symptoms of this disease. The causes of an impaired Hcy metabolism are varied and mainly depend on the condition of the genes encoding enzymes of the folate cycle. At the same time, available data on the effect of the 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) gene polymorphisms on the development of hyperhomocysteinemia and the risk of PCOS are few and contradictory. The purpose of the study was to investigate the polymorphisms of the main genes encoding enzymes of the folate cycle (MTHFR, MTR, MTRR) and to reveal their relationship with the level of Hcy in PCOS. Material and methods. One hundred and twenty-nine women aged 20–28 years were examined: the main group — 98 patients with PCOS, the control group — 31 healthy women. The serum content of Hcy was evaluated and a molecular genetic study was conducted to identify the MTHFR, MTR, and MTRR genes. Results. Polymorphic variants of genes involved in folate metabolism were found in both patients with PCOS and in healthy women. However, serum concentration of Hcy was significantly higher in PCOS. Analysis of the MTHFR C677T polymorphism gene showed that the presence of the mutant T allele was associated with an increased Hcy level (12.9 ± 0.2 μmol/l) and the risk of PCOS (odds ratio (OR) = 1.19; 95% confidence interval (CI) 0.52–2.71). In the presence of two T alleles, the level of Hcy (14.6 ± 0.3 µmol/L) and the risk of deve­loping PCOS (OR = 7.69; 95% CI 0.98–59.87) increased even further compared to the functionally “normal” C677C genotype. There was also an association between the MTHFR gene polymorphism at locus 1298 and PCOS whose strength depended on the number of pathological C alleles and was mediated by Hcy content, although this mutation was accompanied by a less significant increase in the level of Hcy than the mutation at locus 677. Compared to carriers of the homozygous A1298A genotype, the risk of developing PCOS was 5.7 times higher in patients with one C allele, and 7.3 times higher in the presence of two C alleles. The MTRR A66A and A66G genotypes were associated with a significant increase in the level of Hcy compared to that of the control group and were associated with an increased risk of PCOS. The mutant homozygous G66G genotype was more common in the control group and had no significant effect on Hcy concentration. It is not proved that the MTR gene is a candidate gene for the development of PCOS, and its polymorphic variants have a negative effect on the level of Hcy. The combination of MTHFR C677T and A1298C, MTHFR C677T and MTR A2756G, MTR A2756G and MTRR A66G gene mutations are associated with a greater increase in Hcy and the risk of developing PCOS compared to any individual monomutation. Conclusions. The MTHFR gene polymorphism and the synergistic effect of the MTHFR, MTR, MTRR gene mutations can be important genetic determinants for homocysteine levels and the risk of PCOS.

Impact of Genetic Variations on Thrombotic Risk in Saudis with Sickle Cell Disease

Background Sickle cell disease (SCD) is a Mendelian disease characterised by multigenic phenotypes. Previous reports indicated a higher rate of venous thromboembolism (VTE) in SCD patients. A number of candidate polymorphisms in certain genes (e.g. FVL, PRT, and MTHFR) were previously reported as risk factors for VTE in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlay VTE in SCD patients. Methodology A genome-wide association study involving Saudi SCD adult patients with a history of VTE (n=65) and control patients without VTE history (n=285) was performed. Genotyping used the 10x Affymetrix Axiom array which includes 683,030 markers. Results No associations were identified between the targeted single nucleotide polymorphisms (SNPs) [FVL (rs6025), PRT (rs1799963), and MTHFR (rs1801133)] and VTE episodes in SCD patients. In contrast, GWAS analysis showed two genome-wide significant signals (P<5×10 -8) on chromosome (Chr) 11. These SNPs, rs35390334 and rs331532, are in strong linkage equilibrium (LD, r 2=0.97). A total of 35 other markers had an association threshold of P<5×10 -6. Four of these variants are located in olfactory receptor genes [OR51B5 (rs147062602), OR51V1 (rs7933549), OR51A1P (rs80034548), and OR52A5 (rs2472530)]. Conclusion No association between FVL, PRT, and MTHFR genes and VTE episodes was seen in Saudis with SCD. In contrast, two markers (rs35390334 and rs331532) showed significant genome-wide associations and less significant associations (P<5×10 -6) were identified for 35 other variants (24 of them are located on Chr 11). Further replication of these findings is needed.

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

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

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

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

Single-nucleotide polymorphism profiling by multimodal-targeted next-generation sequencing in methotrexate-resistant and -sensitive human osteosarcoma cell lines

Introduction: Methotrexate (MTX) is one of the most important drugs included in the first-line protocols to treat high-grade osteosarcoma (HGOS). Although several polymorphisms have been reported to be associated with drug response or MTX-related toxicity in pharmacogenetic studies, their role in the development of MTX resistance in HGOS is still unclear.Methods: Therefore, in this study, 22 single nucleotide polymorphisms (SNPs) in 4 genes of the folate metabolism, 7 MTX transporter genes, and 2 SNPs of the tumor protein p53 (TP53) gene were investigated using a custom multimodal-targeted next-generation sequencing (mmNGS) approach in 8 MTX-resistant and 12 MTX-sensitive human HGOS cell lines. The panel was validated by TaqMan genotyping assays.Results: High instability of TP53 rs1642785 was observed in all U-2OS/MTX variants. Allele changes of the solute carrier family 19 member 1/replication factor C subunit 1 (SLC19A1, previously known as RFC1) and rs1051266 were identified in all Saos-2/MTX-resistant variants in both DNA- and RNA- derived libraries compared to the parental Saos-2 cell line. Allele changes of methylenetetrahydrofolate reductase (MTHFR) rs1801133 were identified only in the RNA-derived libraries of the two U2OS variants with the highest MTX resistance level. Significantly upregulated gene expression associated with the development of MTX resistance was revealed for dihydrofolate reductase (DHFR) whereas SLC19A1 was downregulated. In addition, a fusion transcript of DHFR (ex4) and MutS Homolog 3 (MSH3) (ex9) was identified in the RNA libraries derived from the two U-2OS variants with the highest MTX resistance level.Conclusion: This innovative mmNGS approach enabled the simultaneous exploration of SNPs at DNA and RNA levels in human HGOS cell lines, providing evidence of the functional involvement of allele changes associated with the development of MTX resistance.

Role of circadian clock system in the mitochondrial trans-sulfuration pathway and tissue remodeling.

Previous studies from our laboratory revealed that the gaseous molecule hydrogen sulfide (H2S), a metabolic product of epigenetics, involves trans-sulfuration pathway for ensuring metabolism and clearance of homocysteine (Hcy) from body, thereby mitigating the skeletal muscle's pathological remodeling. Although the master circadian clock regulator that is known as brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (i.e., BMAL 1) is associated with S-adenosylhomocysteine hydrolase (SAHH) and Hcy metabolism but how trans-sulfuration pathway is influenced by the circadian clock remains unexplored. We hypothesize that alterations in the functioning of circadian clock during sleep and wake cycle affect skeletal muscle's biology. To test this hypothesis, we measured serum matrix metalloproteinase (MMP) activities using gelatin gels for analyzing the MMP-2 and MMP-9. Further, employing casein gels, we also studied MMP-13 that is known to be influenced by the growth arrest and DNA damage-45 (GADD45) protein during sleep and wake cycle. The wild type and cystathionine β synthase-deficient (CBS-/+) mice strains were treated with H2S and subjected to measurement of trans-sulfuration factors from skeletal muscle tissues. The results suggested highly robust activation of MMPs in the wake mice versus sleep mice, which appears somewhat akin to the "1-carbon metabolic dysregulation", which takes place during remodeling of extracellular matrix during muscular dystrophy. Interestingly, the levels of trans-sulfuration factors such as CBS, cystathionine γ lyase (CSE), methyl tetrahydrofolate reductase (MTHFR), phosphatidylethanolamine N-methyltransferase (PEMT), and Hcy-protein bound paraoxonase 1 (PON1) were attenuated in CBS-/+ mice. However, treatment with H2S mitigated the attenuation of the trans-sulfuration pathway. In addition, levels of mitochondrial peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC 1-α) and mitofusin-2 (MFN-2) were significantly improved by H2S intervention. Our findings suggest participation of the circadian clock in trans-sulfuration pathway that affects skeletal muscle remodeling and mitochondrial regeneration.

Folic acid blocks ferroptosis induced by cerebral ischemia and reperfusion through regulating folate hydrolase transcriptional adaptive program

Cerebral ischemia-reperfusion (I/R) injury is notably linked with folic acid (FA) deficiency. The aim of our investigation was to explore the effects and underlying mechanisms by which FA mitigates I/R, specifically through regulating the GCPII transcriptional adaptive program. Initially, we discovered that following cerebral I/R, levels of FA, methionine synthase (MTR), and methylenetetrahydrofolate reductase (MTHFR) were decreased, while GCPII expression was elevated. Secondly, administering FA could mitigate cognitive impairment and neuronal damage induced by I/R. Thirdly, the mechanism of FA supplementation involved suppressing the transcriptional factor Sp1, subsequently inhibiting GCPII transcription, reducing Glu content, obstructing cellular ferroptosis, and alleviating cerebral I/R injury. In summary, our data demonstrate that FA affords protection against cerebral I/R injury by inhibiting the GCPII transcriptional adaptive response. These findings unveil that targeting GCPII might be a viable therapeutic strategy for cerebral I/R.

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

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

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

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

Association of maternal genetic polymorphisms with fetal growth restriction syndrome in Russian pregnant women from Rostov region

BackgroundFetal growth restriction (FGR) is one of the main syndromes causing fetal morbidity and mortality. It was known to be associated with different factors including maternal, fetal, and environmental. However, the effect of genetic factors in FGR is not totally understood. Recently, researchers have focused on investigating genetic variants as possible markers of FGR. This especially concerns maternal genetic polymorphisms since they could serve as prenatal prognostic biomarkers. Accordingly, we aimed to study the association of several polymorphisms affecting vital processes of pregnancy with FGR in pregnant women. Targeted polymorphisms include methylenetetrahydrofolate reductase (MTHFR) 677C > T; methionine synthase reductase (MTRR) 66A > G; methionine synthase (MTR) 2756A > G; angiotensinogen (AGT) 704 T > C; and vascular endothelial growth factor A (VEGFA) 634C > G. In addition, this study examined SNP–SNP interactions, linkage disequilibrium (LD), and haplotypes association for these polymorphisms in the studied population.ResultsAccording to our data, MTRR 66(GG) carriers had increased FGR risk (OR = 3.18, 95% CI 1.31–7.72) while (AG) genotype was associated with lower FGR risk (OR = 0.37, 95% CI 0.17–0.84). AGT 704T > C also showed significant association with FGR with allele (T) as a risk factor. SNP–SNP interactions analysis revealed antagonistic relationship between these two polymorphisms and haplotypes association confirmed this finding. High LD possibility was shown between MTHFR 677C > T and MTR 2756A > G (D′ = 0.999) located on chromosome 1.ConclusionWe suggest MTRR 66A > G and AGT 704T > C as associated with FGR susceptibility with antagonistic interaction. Result will help to expand our understanding of FGR as a multifactorial syndrome and improve prenatal prognosis using maternal genetic biomarkers, but further studies in different populations are needed to confirm findings.

Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and other thrombophilia genes in patients with acute pulmonary embolism

Abstract Background Venous thromboembolism (VTE) is a serious threat to life and health, commonly known as the silent killer. Recent study has found that VTE is a polygenetic disease and more than 60% of deep vein thrombosis risk is influenced by genetic factors [1]. PAI-1 is a serine protease with negative feedback to fibrinolysis, activating and inhibiting coagulation [2]. The aim of this study was to elucidate the clinical impact of the PAI-1 4G/5G polymorphism and other thrombophilia in patients with acute PE. Methods A total of 58 subjects with acute PE and 60 healthy controls, were recruited in Institute of Cardiology. The accuracy of the RT-PCR method for detecting F5 G1691A (FVL) and PAI-1 4G/5G polymorphisms was evaluated by using sequencing method as the gold standard. Moreover, the association of the PAI-1 4G/5G polymorphism with susceptibility, treatment efficacy and recurrence status were explored. Eventually, we evaluated the association with inherited thrombophilia genes, such as the coagulation Factor V Leiden, prothrombin G20210A, FGB-455 G/A and methylenetetrahydrofolate reductase C677T and 1298 A/C. Results It was noted that the vast majority of patients with acute PE (87.9%) present polymorphism in the PAI-1 gene (29.3% homozygous (4G/4G) and 58.6% heterozygous (5G/4G)). Eleven patients out of 58 (19% of patients) showed factor V Leiden mutation and 19 patients out of 58 (32,7% of patients) showed mutation in FGB-455 G/A (2 homozygotes); MTHFR C677T gene mutation was found in 55,2%, while prothrombin 20210A gene mutation was presented in 6 patients (10.3% of patients). Nine patients (15,5% of patients) presented with chronic complication of VTE and 38.7% of patients showed recurrent pulmonary embolism. More than a half of patients (51.9%) had multiple gene mutation and only one presented with mutations in three studied genes. It showed a significant difference in the occurrence of other thromboses in the body and significant increase in the recurrence of pulmonary embolism and residual complications in these patients. It was also observed that individuals with the 4G/5G genotype had lower neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) than the 5G/5G genotype. Furthermore, it was underlined that the patients with the 5G/5G genotype were more likely to achieve complete recanalization compared to the 4G/4G genotype. Individuals carrying the 5G/5G genotype were more likely to develop a recurrence-free status as compared to those with the 4G/4G or 4G/5G genotypes. PAI-1 antigen levels in the VTE group were significantly higher than those in the HC group. Conclusion The PAI-1 4G/5G polymorphism has potential value in assessing the prognosis of patients with VTE. This study has laid the foundation for the application of PAI-1 4G/5G polymorphism in the personalized management and monitoring of patients with VTE. According to this study results PAI-1 4G/5G polymorphism could be included in laboratory testing panel of thrombophilia.

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

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

Allelic variants of folate metabolism genes among students in Arctic Russia

AIM: To assess the prevalence of allelic variants of folate metabolism genes in Russian and Indian students living in the Arctic region of Russia.&#x0D; METHODS: A cross-sectional study was performed on a sample of ethnic Indians, students at the Faculty of General Practitioner of the Northern State Medical University, living in Arkhangelsk and ethnic Russians who were born in Arkhangelsk region. The study included 117 ethnic Indians and 195 Russian participants. A survey of participants and a molecular genetic study of the nucleotide sequence in the genes involved in the exchange of folate by real-time PCR were carried out. A group of ethnic Indians was compared with Russians according to 4 variants of the nucleotide sequence in the genes involved in folate metabolism.&#x0D; RESULTS: Statistically significant differences were observed in the frequency distribution of the T allele of the MTHFR gene polymorphism (rs1801133) (p=0.001). Among Russians, the occurrence of the T allele was found to be 26.3%, whereas among Indians, it was only 7.7%. At the same time, no statistically significant differences were found in the distribution of other polymorphic variants of the folate cycle genes between the groups. The mutant allele G of the MTRR gene polymorphism (rs1801394) was the most frequently occurring polymorphism among the participants.&#x0D; CONCLUSION: Greater prevalence of the unfavorable allele T of the MTHFR gene (rs1801133) compared to the group of ethnic Indians may suggest an elevated susceptibility to folate metabolism disorders in the Russian population

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

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

A randomized trial evaluating the association between related gene polymorphism and nausea and vomiting induced by cisplatin multi-day chemotherapy

PurposeWe aim to investigate the correlation between gene polymorphisms and cisplatin chemotherapy-induced nausea and vomiting (CINV), which was prevented by olanzapine or aprepitant triple antiemetic regimen.MethodsBefore chemotherapy, the blood samples of 89 malignant tumor patients who received multi-day chemotherapy with cisplatin were collected for sequencing and typing. As there were duplicate patients enrolled in different chemotherapy cycles, there were a total of 190 cases. The patients were divided into two groups randomly, who received the triple antiemetic regimen of olanzapine or aprepitant combined with 5-HT3RA and dexamethasone. The main evaluation indicators were the total protection (TP) rate in the acute phase (0–24 h), the delayed phase (25–120 h) and the overall phase (0-120 h).ResultsUnivariate analysis was performed on genetic loci that reached H-W balance with TP. In the olanzapine group, increased TP in the acute phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. In the aprepitant group, increased TP in the acute phase was associated with the MTHFR rs1801131 TT (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1062613 CC (P < 0.05) genetype ect. Multivariate Logistic regression analysis showed that HTR3B rs7943062GG (P < 0.05) genotype etc. were correlated with increased TP in the delayed phase. MTHFR rs1801131TT genotype was associated with increased TP in the acute phase (P < 0.05) and delayed phase (P < 0.05).ConclusionThis study found that gene polymorphisms, including HTR3B (rs1062613, rs1176719, rs2276303), HTR3B (rs45460698, rs7943062), HTR3C (rs6766410), ERCC1 (rs3212986), ERCC4 (rs744154) and MTHFR(rs1801131), may be independent prognostic factors for CINV.

A study on the correlation between MTHFR and folic acid combined with trace elements for the prevention of fetal malformations in the first trimester of pregnancy.

This study aims to elucidate and examine the intricate interrelation between 5,10-methylenetetrahydrofolate reductase (MTHFR), combined folic acid (FA), and trace element supplementation as a preventive strategy against fetal malformations during the inaugural trimester of pregnancy. Eighty pregnant women selected from our hospital's early obstetrics department from May 2021 to August 2021. Pregnant women are divided into the MTHFR combined group, FA, and trace element group. Comparing the basic data of patients, analyzing adverse reactions in pregnant women, and total birth risk situation, detecting MTHFR gene polymorphisms, and analyzing the correlation between MTHFR and FA in the prevention of fetal malformations in early pregnancy. Compared with the north, the southern region is more prone to FA deficiency. MTHFR degree of the MTHFR combined group was positively correlated with fetal malformations. The deformity rate was negatively correlated with FA and trace elements. Pregnant women in the first trimester may have fetal malformations, and the malformation rate is negatively correlated with FA and positively correlated with MTHFR level. Importantly, the inverse relationship between FA supplementation and malformation incidence underscores its significance as a preventive measure.

The Role of Coagulation Gene Polymorphisms in Sars-CoV2 Infection in the Bergamo Area

Introduction: Given the great variability of the individual response to SARS-CoV2 infection, it is important to understand whether and how biological and genetic factors might predispose to the infection and to the degree of severity, including the development of systemic coagulopathy and thrombosis. In this study, we evaluated the frequency of prothrombotic allelic variants (AVs) in coagulation genes in a population of COVID-19 patients, to verify whether these polymorphisms, alone or in combination, are associated to an increased susceptibility to develop COVID-19 and/or a greater severity. Methods: A cohort of 358 patients (257M/101F; median age: 55 years) from the Bergamo area with two different degrees of COVID-19 severity, i.e., severe disease (hospitalized, n=212) or mild disease (non-hospitalized, n=146), was enrolled from April 2020 to June 2021 and followed-up for disease outcome and thrombosis. A cohort of 377 healthy subjects (177M/200F; median age: 49 years) from the same area without COVID-19 acted as a control group. DNA was analyzed for a panel of prothrombotic/inflammatory single nucleotide polymorphisms (SNPs) including FII rs1799963, FV rs6025, FV rs118203907, FXIIIA1 rs5985, FGB rs1800790, MTHFR rs1801131 and MTHFR rs1801133 as well as two SNPs located in the coding region of angiotensin-converting enzyme (ACE2) gene, namely ACE2 rs140312271 and ACE2 rs41303171. Statistical analysis was performed using SPSS statistical software. Results: Among the AVs analyzed, the rs6025 polymorphism of FV gene (FV Leiden) was more frequent in COVID-19 patients than in the control group. By a logistic regression corrected for age and gender, FV Leiden was associated with a 3-fold risk of developing COVID-19 (OR: 3.2 [95% CI 1.02-10]). In contrast, the rs41303171 polymorphism of the ACE2 gene was more frequent in the control group and was a protective factor for COVID-19 (OR: 0.12 [95% CI 0.02-0.99]) even after correction for age and gender. No significant differences appeared in the frequency of the other SNPs alone or in combination. Within the COVID-19 patient cohort, the rs1801131 SNP of MTHFR gene was associated with less severe COVID-19 disease. In the hospitalized severe cohort, 17 (8%) patients developed an overt venous thromboembolic event, and 7 COVID-19-related deaths (4%) were recorded. No significant associations were found between any of the AVs analyzed and the outcomes of thrombosis and death. However, the analyses of circulating biomarkers of clotting (i.e. D-dimer, FVIII, fibrinogen, prothrombin fragment 1+2 [F1+2], and FXIII), fibrinolysis (i.e. tissue plasminogen activator [tPA], and plasminogen activator inhibitor-1 [PAI-1]) and endothelial cell activation (i.e. thrombomodulin [TM], and von Willebrand Factor [vWF]), and the neutrophil-to-lymphocyte ratio (NLR) as an inflammatory biomarker revealed thathaving fibrinogen (OR: 4.9 [95% CI 1.04-23.1]), vWF:Ag (OR: 11.8 [95% CI 2.1-66.9]) and NLR (OR: 26.1 [95% CI 2.9-237] levels above the 75th percentile was significantly associated with death. Of interest, in the same hospitalized patient group, but not in the control group, the presence of FXIII SNPs was significantly associated with high levels of F1+2. Conclusions: Our study shows that the FV Leiden polymorphism predisposes to COVID-19 infection, while the rs41303171 ACE2 polymorphism has a protective role. In addition, the rs1801131 SNP of gene MTHFR correlates with a milder COVID-19 disease. In patients with severe COVID-19, the inflammatory marker NLR, and the circulating hemostatic proteins vWF and fibrinogen are associated with mortality.

MTHFR C677T and A1298C polymorphism’s effect on risk of colorectal cancer in Lynch syndrome

Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10–80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.

Central Retinal Vein Occlusion in 12-year-old Girl with Methylenetetrahydrofolate Reductase Mutation: A Case Report and Review of the Literature.

This case report describes a central retinal vein occlusion (CRVO) in a healthy 12-year-old girl who developed retinal neovascularization at 24 years of age. To our knowledge, this is the longest time between a reported pediatric CRVO event and neovascularization. The patient underwent a full history, physical exam, and laboratory workup to determine potential risk factors contributing to the vascular event. Fundus photos, optical coherence tomography and fluorescein angiography were performed throughout the patient's treatment course. Family history was non-contributory, but laboratory testing revealed a mildly elevated homocysteine level and homozygous C677T mutation in methylenetetrahydrofolate reductase. As a result, she was started on folate supplementation. The patient has had no further ocular or systemic thrombotic events to date. Pediatric patients presenting with CRVO should undergo a systemic workup and require long-term follow-up to avoid complications such as intraocular hemorrhage, tractional retinal detachments, and neovascular glaucoma.

Molecular Mechanism Biomarkers Predict Diagnosis in Schizophrenia and Schizoaffective Psychosis, with Implications for Treatment.

Diagnostic uncertainty and relapse rates in schizophrenia and schizoaffective disorder are relatively high, indicating the potential involvement of other pathological mechanisms that could serve as diagnostic indicators to be targeted for adjunctive treatment. This study aimed to seek objective evidence of methylenetetrahydrofolate reductase MTHFR C677T genotype-related bio markers in blood and urine. Vitamin and mineral cofactors related to methylation and indolamine-catecholamine metabolism were investigated. Biomarker status for 67 symptomatically well-defined cases and 67 asymptomatic control participants was determined using receiver operating characteristics, Spearman's correlation, and logistic regression. The 5.2%-prevalent MTHFR 677 TT genotype demonstrated a 100% sensitive and specific case-predictive biomarkers of increased riboflavin (vitamin B2) excretion. This was accompanied by low plasma zinc and indicators of a shift from low methylation to high methylation state. The 48.5% prevalent MTHFR 677 CC genotype model demonstrated a low-methylation phenotype with 93% sensitivity and 92% specificity and a negative predictive value of 100%. This model related to lower vitamin cofactors, high histamine, and HPLC urine indicators of lower vitamin B2 and restricted indole-catecholamine metabolism. The 46.3%-prevalent CT genotype achieved high predictive strength for a mixed methylation phenotype. Determination of MTHFR C677T genotype dependent functional biomarker phenotypes can advance diagnostic certainty and inform therapeutic intervention.