Methylenetetrahydrofolate Reductase Rs1801133 Research Articles

Methylenetetrahydrofolate Reductase Gene rs1801133 and rs1801131 Polymorphisms and Essential Hypertension Risk: A Comprehensive Analysis.

Background Essential hypertension (EH) is a common and multifactorial disorder that is likely to be influenced by multiple genes. The methylenetetrahydrofolate reductase (MTHFR) gene rs1801133 and rs1801131 polymorphisms influence MTHFR enzyme activity and plasma homocysteine concentration. In addition, variations in MTHFR functions likely play roles in the etiology of EH. Thus far, a large number of studies investigating the associations between the MTHFR polymorphisms and EH have provided controversial or inconclusive results. To better assess the purported relationship, we performed a comprehensive analysis of 52 published studies. Objective and Methods. Eligible studies were identified by searching the PubMed, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the potential association between the MTHFR rs1801133 polymorphism and EH. Results Overall, 10712 patients and 11916 controls were involved; we observed significantly increased association between the MTHFR rs1801133 polymorphism and EH risk (such as T vs. C: OR = 1.38, 95% CI = 1.25 − 1.54, P ≤ 0.001), with similar results evident within race subgroups (such as Asian: T vs. C: OR = 1.47, 95% CI = 1.30 − 1.67, P ≤ 0.001; compared to Chinese: T vs. C: OR = 1.54, 95% CI = 1.33 − 1.79, P ≤ 0.001). Similar associations were also found in subgroups defined by the source of controls and genotype methods. To our regret, based on the limited studies, no association was detected for rs1801131 polymorphism. Conclusions Our study provides evidence that the MTHFR rs1801133 null genotype may increase EH risk. Future studies with larger sample sizes are warranted to evaluate this association in more detail.

The MCP-1 rs1024611 and MTHFR rs1801133 gene variations and expressions in alopecia areata: A pilot study.

BackgroundMonocyte chemoattractant protein‐1 (MCP‐1) is highly expressed by lymphocytes at skin sites affected by alopecia areata (AA). Variations in MCP‐1 as well as in methylene‐tetrahydrofolate reductase (MTHFR), a key enzyme related to many inflammatory pathologies, have been associated with several autoimmune disorders. This study was designed to test a possible association between MCP‐1 and MTHFR variations and altered expression of their genes and the risk of AA.MethodsBlood samples of patients (60) suffering from AA as well as healthy subjects (60) were collected. Gene expression levels of MCP‐1 and MTHFR were evaluated by real‐time reverse‐transcription polymerase chain reaction analysis. Moreover, MCP‐1 rs1024611 (A‐2518G) and MTHFR rs1801133 (C677T) polymorphisms were genotyped by using polymerase chain reaction‐restriction fragment length polymorphism assays.ResultsIn contrast to MCP‐1, the MTHFR gene expression was found to be significantly higher in patients than in controls. Further stratification of the patients revealed that polymorphic genotypes in MCP‐1 (AG + GG) and MTHFR (CT + TT) could significantly alter gene expression levels. Elevation of MCP‐1 expression was significantly associated with the total number of variant MCP‐1 and MTHFR alleles. However, no statistically significant difference was noticed in the genotypic distribution of MCP‐1 and MTHFR variations between patients and controls.ConclusionIn summary, despite MCP‐1 rs1024611 and MTHFR rs1801133 variations are not associated with AA risk, they may implicate the disease pathogenesis by influencing MCP‐1 activity.

Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk: An update meta-analysis and trial sequential analysis.

Aim:To evaluate the associations between the methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and hepatocellular carcinoma (HCC) with meta-analysis and trial sequential analysis.Methods:PubMed, Embase, the Google Scholar, Wan fang database, VIP database, and China National Knowledge Infrastructure were extensively searched before April 2021. Odds ratios (ORs) and 95% confidence interval (95% CI) were calculated. Review Manager Version 5.3, STATA version 12.0 and TSA 0.9.5.10 Beta software were used.Results:Nineteen studies with 6941 HCC patients and 9436 controls were finally included. The MTHFR rs1801133 (C677T) SNP was associated with increased HCC risk under heterozygote genetic model (OR = 1.10, 95% CI = [1.01, 1.20]). For Subgroup analysis, increased risks of HCC were detected in Mongoloid, Chinese. For MTHFR rs1801131 (A1298C) SNP, increased risk of HCC was only observed in Caucasians (allelic: OR = 1.86, 95% CI = [1.49, 2.31]; homozygote: OR = 3.39, 95% CI = [2.18, 5.27]), interesting decreased risk was detected in Mongoloid (recessive: OR = 0.30, 95% CI = [0.15, 0.58]; homozygote: OR = 0.41, 95% CI = [0.24, 0.72]). Sensitivity analysis indicated stability in our results. Publication bias was not detected based on Begg test and Egger test. Trial sequential analysis indicated further studies to confirm the associations in MTHFR C677T polymorphism.Conclusion:The MTHFR rs1801133 SNP was associated with an increased risk of HCC in Mongoloid population especially in Chinese. Increased HCC risk is also observed in Caucasian population for the MTHFR rs1801131 SNP, and decreased risk of HCC is remarkably discovered in Mongoloid and Chinese subgroups, which need further validation.

Association of MTHFR 677C>T and 1298A>C genetic polymorphisms with colorectal cancer: Genotype and haplotype analysis in a Southeast Iranian population

BackgroundThe methylenetetrahydrofolate reductase (MTHFR) gene is involved in DNA methylation, synthesis and repair, which influences the risk of cancers. Many studies have demonstrated that the MTHFR rs1801133 and rs1801131 polymorphisms are linked with the risks of colorectal cancer (CRC). However, no study has probed the relationship between these polymorphisms and CRC risk in southeast Iranian population. Therefore, the aim of this study was to investigate the association of these two polymorphisms with CRC risk in a case-control investigation. MethodsA total of 200 confirmed CRC patients and 200 healthy controls (matched to sex and age) were recruited from the Southeast of Iran between 2014 and 2019. Genomic DNA was extracted and genotyped for the polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism method. The relationship between the polymorphism and CRC risk was evaluated by logistical regression analysis. ResultsMTHFR 667C>T polymorphism was significantly associated with a lower risk of CRC (TT vs CC: p-value = 0.021; CT vs CC: p-value = 0.047; CT+TT vs CC: p-value = 0.017). The T-allele was associated with decreased risk for CRC (p-value = 0.012). However, we did not observe any association of 1298A>C with CRC. Furthermore, stratified analysis showed that MTHFR 667C>T polymorphism was correlated with tumor location in CRC patients. The frequency of T-A haplotype was significantly higher in the healthy controls compared to CRC patients (p-value = 0.021). ConclusionIn conclusion, the T-allele of MTHFR 667C>T polymorphism was related to decreased susceptibility to CRC in this Iranian population. Moreover, the CT-AA and TT-AA combined genotypes and T-A haplotype of MTHFR 667C>T and 1298A>C polymorphisms were associated with decreased risk of CRC.

Association of MTHFR C677T variant genotype with serum folate and Vit B12 in Iranian patients with colorectal cancer or adenomatous polyps

BackgroundThe incidence of colorectal cancer (CRC) has increased during recent years in Iran and other developing countries. Clinical studies suggest that essential folate dietary intake and moderate deficiency of methylenetetrahydrofolate reductase (MTHFR) may protect and reduce the risk of CRC. The present study aimed to investigate the clinical significance of C677T polymorphism within the MTHFR gene and its correlation with the serum folate and Vit B12 in the Iranian population suffering from CRC.MethodsBlood samples were taken from 1017 Iranian individuals (517 cases and 500 controls) who were referred for colonoscopy. TaqMan probe assay was performed for C677T MTHFR polymorphism. Sera were fractionated from the blood samples of 43 patients and controls and folate and Vit B12 concentrations were measured by a monobind kit. The correlation of MTHFR polymorphisms and folate/vitamin-B12 with CRC risk was analyzed.ResultsIn the current study, we found the frequency of three different genotypes of MTHFR polymorphism in the Iranian population i.e., CC, CT, and TT, to be 51.31, 26.73, 21.96 and 61, 32.2, 6.8 in case and control groups, respectively. The homozygote genotype of MTHFR rs1801133 polymorphism is associated with an increased risk of CRC by 3.68, 1.42, and 3.74-fold in codominant, dominant, and recessive models respectively (p value < 0.01). Our study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups (p value > 0.05).ConclusionsThis study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups. Furthermore, our results demonstrated a higher risk association for 677TT and 677TT + C677T genotypes of MTHFR compared with 677CC carriers among CRC patients.

Associations of LRP5 and MTHFR Gene Variants with Osteoarthritis Prevalence in Elderly Women: A Japanese Cohort Survey Randomly Sampled from a Basic Resident Registry.

ObjectiveOsteoarthritis (OA) is a common and degenerative joint disorder in the elderly. A greater importance of understanding the relationship between genetic factors and OA prevalence has emerged with population aging. We therefore investigated the associations of several bone disease-related genetic variants with the prevalence of OA and osteoporosis in Japanese elderly women from the Obuse study cohort, which was randomly sampled from a basic town resident registry.Methods and ResultsIn total, 206 female participants (mean ± standard deviation age: 69.7 ± 11.0 years) who completed OA, bone mineral density, and genotype assessments were included. The number of patients diagnosed as having knee/hip OA and osteoporosis was 59 (28.6%) and 30 (14.6%), respectively. Fisher’s exact testing revealed significant relationships between the minor T allele of LDL receptor related protein 5 (LRP5) rs3736228 and the prevalence of knee/hip OA and osteoporosis. The respective odds ratios (ORs) of the TT genotype for knee/hip OA and osteoporosis were 7.28 (95% confidence interval [CI] 2.22–28.08) and 5.24 (95% CI 0.95–26.98). An additional subgroup analysis for knee OA revealed that the frequency of the common C allele of methylenetetrahydrofolate reductase (MTHFR) rs1801133 had a statistically significant protective association with the prevalence of knee OA (OR 0.58, 95% CI 0.35–0.97).ConclusionIn sum, the present study demonstrated significant associations of LRP5 rs3736228 and MTHFR rs1801133 with knee/hip OA and osteoporosis prevalences and knee OA prevalence, respectively, in Japanese elderly women. These results will help further the understanding of OA pathogenesis and related genetic risk factors.

Genetic Polymorphisms in Enzymes Involved in One-Carbon Metabolism and Anti-epileptic Drug Monotherapy on Homocysteine Metabolism in Patients With Epilepsy.

Aims: To investigate the effects of single nucleotide polymorphisms (SNPs) in genes of one-carbon metabolism (OCM) related enzymes and anti-epileptic drug (AED) monotherapy on homocysteine (Hcy) metabolism in patients with epilepsy, and to further explore specific SNPs that may increase patients' susceptibility to the effects of AEDs on the Hcy imbalance.Method: This case-control study analyzed 279 patients with epilepsy, including patients receiving monotherapy with valproate (VPA) (n = 53), oxcarbazepine (OXC) (n = 71), lamotrigine (LTG) (n = 55), or levetiracetam (LEV) (n = 35) and patients who had not taken any AEDs (controls, n = 65) for at least 6 months. Serum levels of vitamin B12 (vit B12), folate (FA) and Hcy were measured, and 23 SNPs in 13 genes of OCM-related enzymes were genotyped in all patients.Results: Methylenetetrahydrofolate reductase (MTHFR) rs1801133 was associated with elevated serum Hcy levels in patients with epilepsy (P < 0.001), and patients presenting the TT genotype exhibited higher serum Hcy levels than patients with the CC (P < 0.001) or CT (P < 0.001) genotype. A subsequent multiple linear regression analysis showed that AED monotherapy with VPA (vs. control: P = 0.023) or OXC (vs. control: P = 0.041), and genotypes of MTHFR rs1801133 TT (vs. CC: P < 0.001; vs. CT: P < 0.001), transcobalamin 2 (TCN2) rs1801198 CC (vs. GC: P = 0.039) and folate receptor 1 (FOLR1) rs2071010 AA (vs. GA: P = 0.031) were independent risk factors for higher Hcy levels. In the subgroup analysis of patients taking OXC, we found that patients with genotypes of MTHFR rs1801133 TT (vs. CC: P = 0.001; vs. CT: P < 0.001) and TCN2 rs1801198 CC (vs. GC: P = 0.021; vs. GG: P = 0.018) exhibited higher serum Hcy levels.Conclusions: VPA, OXC, and genotypes of MTHFR rs1801133 TT, TCN2 rs1801198 CC, and FOLR1 rs2071010 AA are all independent risk factors for elevated Hcy levels in patients with epilepsy. Moreover, genotypes of MTHFR rs1801133 TT and TCN2 rs1801198 CC may increase patients' susceptibility to the effect of OXC on disrupting Hcy homeostasis.

Effect of polymorphisms of MTHFR in controlled ovarian stimulation: a systematic review and meta-analysis.

Although several studies have reported a potential impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on controlled ovarian stimulation (COS), the results remain controversial. The aim of the systematic review and meta-analysis was to evaluate the effect of MTHFR polymorphism on COS outcomes. PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to December 2, 2020. COS clinical outcomes based on gene polymorphisms were included. Two reviewers independently extracted the data. The primary outcome was the number of oocytes retrieved. The secondary outcomes were the number of metaphase II (MII) oocytes, stimulation duration, basal follicle-stimulating hormone (FSH) level, FSH dosage, positive pregnancy test, ongoing pregnancy rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Meta-analysis was performed using a fixed-effect model or random-effect model with Review Man 5.3.5. Mean difference (MD) with 95% confidence intervals (95%CIs) was calculated for continuous outcomes. The quality assessment of included studies was evaluated by using the Newcastle-Ottawa Scale. Eleven studies were included in the systematic review, and seven studies with 2015 participants were included in the meta-analysis. Basal FSH level was significantly lower in CC homozygotes than TT homozygotes (four studies, 867 participants, MD - 0.54, 95%CI - 0.85 to - 0.23, P = 0.0006; I2 = 0%) of MTHFR (rs1801133). FSH dose was significantly fewer in CC homozygotes compared with CT heterogeneous (three studies, 949 participants, MD - 75.78, 95%CI - 135.23 to - 16.33, P = 0.01; I2 = 32%) or CT/TT model (three studies, 1097 participants, MD - 80.18, 95%CI - 135.54 to - 24.81, P = 0.005; I2 = 42%). Differences in the oocytes retrieved and stimulation duration were insignificant. Gene variants on MTHFR (rs1801133) and MTHFR (rs1801131) were reported in ongoing pregnancy rate, clinical pregnancy rate, and live birth rate. Studies to date indicate that polymorphisms of MTHFR could influence basal FSH level and FSH dose. The results could be useful to promote clinical practice on COS protocols. Further studies are needed to evaluate the clinical relevance of the multigene combination on COS.

The protective effects of the methylenetetrahydrofolate reductase rs1801131 variant among Saudi smokers.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism plays a fundamental role in susceptibility to various diseases, including cancers and autoimmune diseases. In the current study, we aimed to compare genotype and allele frequency variations of rs1801131, one of the most common variants found in the MTHFR gene, among Saudi smokers and non-smokers. We hypothesized that genetic variations of this gene are responsible for many diseases, particularly those caused by cigarette smoking (CS) such as pulmonary diseases, oral cancer and lung cancer. We performed a case-control study on a sample of 235 healthy smokers and 239 healthy non-smokers in Saudi Arabia. The rs1801131 SNP genotypes were determined using a genotyping assay and multiple in silico algorithmic software programs were used to identify the effects and structural functions of the rs1801131 (Glu429Ala) mutation. Using chi-squared tests, we found that, among smokers, TG and GG genotype carriers had 0.209-fold (OR = 0.209, P < 0.005) and 0.427-fold (OR = 0.427, P = 0.003) lower risks of CS-related disease compared to TT reference genotypes. In addition, this protective effect was observed in Saudi smokers independent of age, gender, types of smoking, duration, and average daily smoking consumption. Filling a research gap by exploring this topic in the Saudi population, the current findings indicate that genotype and allele distributions of MTHFR rs1801131 polymorphism present fundamental protective effects against the risk of CS-related disease. These findings should be verified in future studies with larger sample sizes, different ethnicities, and patients suffering from CS-related diseases, such as oral cancer and lung cancer.

Methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF) polymorphisms in Brazilian patients with Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC)

OBJECTIVE:The folate pathway is involved in hepatic carcinogenesis and angiogenesis. Polymorphisms in genes related to such processes, including methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF)] may play an important role in the development of hepatocellular carcinoma (HCC). The objective of this study was to evaluate MTHFR and VEGF polymorphisms in Brazilian patients with hepatitis C virus (HCV)-related HCC.METHODS:A total of 119 patients diagnosed with confirmed HCC and HCV were included in the study. SNP genotyping assays were performed using real-time PCR. VEGFA (rs2010963, rs3025039, and rs833061) and MTHFRC677T (rs1801133, rs1801131) polymorphisms were evaluated.RESULTS:The C alleles of MTHFR (rs1801131) and VEGF (rs2010963) were associated with protection against the development of multinodular HCC, while the T allele of MTHFR (rs1801133) was associated with a higher risk of multinodular presentation [p=0.04 OR 1.835 CI (1.022-3.297)]. Multivariate analysis revealed that the GG/GC genotypes of VEGF rs2010963 were independently associated with multinodular tumors at diagnosis (p=0.013; OR 4.78 CI (1.38-16.67)].CONCLUSION:Our results suggest that these polymorphisms may increase the risk of rapid tumor progression in patients with HCV infection. This subgroup of patients with HCC and who present polymorphism is more likely to be diagnosed with multinodular disease and not be amenable to receiving curative treatments. These data must be validated in larger cohorts, and the screening intervals can be customized based on genetic history.

Associations of methylenetetrahydrofolate reductase gene (MTHFR) rs1801131 and rs1801133 polymorphisms with susceptibility to vitiligo: A meta-analysis.

Vitiligo is a common pigmentary skin disorder, and genetic factors were acknowledged to be greatly associated with the pathogenesis of this disease. Recently, increasing studies investigated the associations of methylenetetrahydrofolate reductase (MTHFR) rs1801131 and rs1801133 polymorphisms with risks of vitiligo, but the results still remained controversial. The current meta-analysis was conducted to further evaluate the association of MTHFR polymorphisms with risk of vitiligo. Eligible studies were searched in PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP), and Wan Fang Database until October 2020. All analyses were carried out using the Review Manager 5.3 software. A total of 6 studies that involved MTHFR rs1801131 and/or rs1801133 polymorphism were finally included, which enrolled 3599 participants. Our results showed that no correlations were found between MTHFR rs1801131, rs1801133 polymorphisms and vitiligo risks in overall group. However, subgroup analysis revealed that rs1801131 polymorphism was significantly associated with increased vitiligo risk in the allelic (C vs A: OR=1.15, 95% CI=1.02-1.29, P=.02) and homozygous models (CC vs AA: OR=1.48, 95% CI=1.10-2.01, P=.01) in Asian population and that the rs1801133 polymorphism was significantly associated with decreased vitiligo risk in the allelic model (T vs C: OR=0.82, 95% CI=0.74-0.92, P=.0005) also in Asian population. This meta-analysis confirmed the associations of MTHFR rs1801131 and rs1801133 polymorphisms with vitiligo risks and provided comprehensive insight into the pathogenesis of vitiligo.

MTHFR rs1801133 polymorphism in Bangladeshi population – its prevalence and detection

Methylenetetrahydrofolate reductase (MTHFR) has been reported as a key enzyme not only for intracellular folate homeostasis but also for metabolism. A particular variant (G677A) leads to an altered amino acid, which ultimately causes decreased enzyme activity and may modulate the risk of causing several chronic diseases. The purpose of this study was to detect the pervasiveness of this variant MTHFR rs1801133 G677A in the Bangladeshi population. We applied allele-specific polymerase chain reaction (AS-PCR) to determine the genotypes at the rs1801133 in the Bangladeshi population. We performed targeted sequencing of the AS-PCR product of randomly selected samples. Out of the 181 Bangladeshi individuals, 71.8% had homozygous 677GG genotype, while 28.2% comprised of heterozygous 677GA genotype. No individual with the homozygous 677AA genotype was found in this representative Bangladeshi population. The 677G alleles had higher frequency (0.856) compared to 677A alleles (0.144) at the rs1801133 locus. Though the more risky homozygous 677AA genotype at the rs1801133 locus is absent in the Bangladeshi population, further association studies can be performed to identify the role of MTHFR mutation in the susceptibility to different multifactorial diseases.

Study on Maternal SNPs of MTHFR Gene and HCY Level Related to Congenital Heart Diseases

The aim of this study is to evaluate the relationship between maternal single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) gene with plasma homocysteine (HCY) level and offspring congenital heart diseases (CHDs). 338 mothers with offspring CHDs as case group and 306 mothers of normal children as control group were recruited. Their pregnant histories were interviewed by questionnaire and the MTHFR rsl801133 and rsl801131 were genotyped. The case–control analysis was used to find out the relationship between maternal SNPs of MTHFR gene and offspring CHDs. And the plasma HCY concentration of the mothers of CHDs children was detected. This case–case study was intended to find out the relevance between maternal HCY level and SNPs of MTHFR gene. There were significant differences in the gender of children, occupation of mothers, family history with CHDs, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHDs group and control group (P < 0.05). MTHFR rs1801133 was significantly associated with their offspring CHDs in mothers. The polymorphism of maternal MTHFR rs1801133 increased plasma HCY level, especially the homozygous mutation. Besides the environmental factors, our results suggested that the maternal MTHFR rs1801133 polymorphism might be a risk factor of their offspring CHDs, which may be due to the hyperhomocysteinemia by abnormal metabolism of HCY.

MTHFR rs1801133 Polymorphism Is Associated With Liver Fibrosis Progression in Chronic Hepatitis C: A Retrospective Study.

Background: The MTHFR (methylenetetrahydrofolate reductase) rs1801133 polymorphism leads to higher circulating levels of homocysteine, which is related to several liver diseases. We aimed to evaluate the relationship between MTHFR rs1801133 polymorphism and liver fibrosis progression in HCV-infected patients.Methods: We conducted a preliminary retrospective cohort study in 208 non-cirrhotic HCV-infected patients. These subjects had at least two liver stiffness measurements (LSM), which were assessed using transient elastography, and no patient had cirrhosis at baseline. We analyzed the association between MTHFR rs1801133 and outcome variables using Generalized Linear Models.Results: HCV-infected patients were 47 years old, around 54% were males, a low frequency of high alcohol intake (13.5%) or prior use of intravenous drugs (10.1%). A total of 26 patients developed cirrhosis (LSM1 ≥ 12.5) during a median follow-up of 46.6 months. The presence of the rs1801133 C allele showed an inverse association with the LSM2/LSM1 ratio (adjusted AMR = 0.90; 95%CI = 0.83–0.98; p = 0.020) and the cirrhosis progression (adjusted OR = 0.43; 95%CI = 0.19–0.95; p = 0.038). Besides, rs1801133 CT/CC genotype had an inverse association with the LSM2/LSM1 ratio (adjusted AMR = 0.80; 95%CI = 0.68–0.95; p = 0.009) and the cirrhosis progression (adjusted OR= 0.21; 95%CI = 0.06–0.74; p = 0.015).Conclusions: MTHFR rs1801133 C allele carriers presented a diminished risk of liver fibrosis progression and development of cirrhosis than rs1801133 T allele carriers. This statement supports the hypothesis that MTHFR rs1801133 polymorphism appears to play a crucial role in chronic hepatitis C immunopathogenesis.

Involvement of MTHFR rs1801133 in the Susceptibility of Acute Lymphoblastic Leukemia: A Preliminary Study.

Acute lymphoblastic leukemia (ALL), a common blood cancer, is characterized by the interaction between genetic and environmental factors. Several variants of the Methylenetetrahydrofolate reductase (MTHFR), mainly the C677T (rs1801133), may affect susceptibility to ALL. The authors conducted this case-control study to evaluate the relationship between this variant of the MTHFR gene and the risk of ALL. Forty-one patients with ALL and 35 non-ALL controls recruited in this study were genotyped utilizing polymerase chain reaction-restriction fragment length polymorphism methodology. The MTHFR 677CT genotype was significantly more frequently found in patients with ALL having a 2-fold increase in risk (P <0.01). Our results suggest that rs1801133 of MTHFR is a predictive risk marker to ALL in Tunisian ALL.

Polymorphisms of SLC19A1 80 G>A, MTHFR 677 C>T, and Tandem TS Repeats Influence Pharmacokinetics, Acute Liver Toxicity, and Vomiting in Children With Acute Lymphoblastic Leukemia Treated With High Doses of Methotrexate.

Introduction: High dose methotrexate (HD-Mtx) is highly effective and significantly improves overall acute lymphoblastic leukemia (ALL) patients survival. The pharmacodynamics of Mtx depends on the polymorphism of genes encoding proteins engaged in the folate metabolism pathway. The aim of the current study is to determine the relationship between variants of folate metabolism-related genes and the frequency of acute toxicities of HD-Mtx.Material and Methods: A group of 133 patients aged 1.5–18.1 years (median: 6.3) was treated in accordance with the ALL-IC-2002 and ALL-IC-2009 protocols. The following polymorphisms were determined: 80 G>A SLC19A1 (solute carrier family 19 member 1; rs1051266) with direct DNA sequencing, as well as 677 C>T MTHFR (methylenetetrahydrofolate reductase; rs1801133) and the tandem repeats of the TS (thymidylate synthase) with PCR technique. HD-Mtx organ toxicities were evaluated based on the laboratory tests results and the National Cancer Institute criteria.Results: In patients with genotypes AA for SLC19A1 and CC or CT for MTHFR Mtx steady state concentrations (Css) and AUCinf were distinctly higher. In patients with genotype 3R/3R for TS initial elimination rate constant was significantly higher (P = 0.003). Patients receiving Mtx at the dose of 5 g/m2 had lower clearance (4.35 vs. 8.92 L/h/m2) as compared to the ones receiving 2 g/m2 that indicates non-linear Mtx elimination at the higher dose. Liver impairment was the most frequently observed toxicity. The homozygous genotype was associated with a significantly higher incidence of hepatic toxicity for both the SLC19A1 (P = 0.037) and TS (P = 0.002). Logistic regression analysis indicated an increased risk of vomiting for the 2R/3R genotype of the TS gene (OR 3.20, 95% CI 1.33–7.68, P = 0.009) and for vomiting and hepatic toxicity for the 3R/3R genotype (vomiting: OR 3.39, 95% CI 1.12–10.23, P = 0.031; liver toxicity: OR 2.28, 95% CI 1.05–4.95, P = 0.038). None of the acute toxicities differed between the analyzed dosing groups.Conclusions: Determination of polymorphisms of SLC19A1, MTHFR, and TS genes might allow for a better prior selection of patients with higher risk of elevated Mtx levels. Our study is the first one to report the increased risk of hepatotoxicity and vomiting in patients with TS polymorphisms.

Polymorphisms within methotrexate pathway genes: Relationship between plasma methotrexate levels, toxicity experienced and outcome in pediatric acute lymphoblastic leukemia.

Objective(s):The current study aimed to investigate the relationship of genetic polymorphism and plasma methotrexate (MTX) levels, toxicity experience and event free survival (EFS) in pediatric acute lymphoblastic leukemia (ALL). Materials and Methods:The study included 74 ALL patients. Polymerase chain reaction and genotyping of methylene tetrahydrofolate reductase (MTHFR) rs1801133, MTHFR rs1801131, ATP-binding cassette superfamily B1 (ABCB1) rs1045642, ATP-binding cassette superfamily G2 (ABCG2) rs2231142 and solute carrier 19A1 (SLC19A1) rs1051266 genetic variations were performed. The plasma MTX levels were investigated at 48 hr after the first dose of MTX infusion.Results:MTHFR rs1801133 TT genotype, ABCBa1 rs1045642 CT genotype and ABCG2 rs2231142 CA genotype revealed a statistically significant association with the MTX plasma levels (P<0.01, P<0.05, P<0.05, respectively). The MTHFR rs1801133 TT genotype had a statistically significant association with hematopoietic toxicity (P<0.01) and interventions (P<0.05). The MTHFR rs1801131 AC genotype was related to the decreased hepatic toxicity (P<0.05). The SLC19A1 rs 1051266 GA genotype was related to the increased hepatic toxicity (P<0.05). Only the ABCB1 rs1045642 CT and TT genotypes had a statistically significant correlation with EFS (P<0.05, P<0.05, respectively). Conclusion:Our findings showed that genetic polymorphism could be associated with plasma MTX levels, toxicity experienced and EFS in Iranian pediatric ALL.

Combination of Exercise and Vegetarian Diet: Relationship with High Density-Lipoprotein Cholesterol in Taiwanese Adults Based on MTHFR rs1801133 Polymorphism.

We examined the association between high-density lipoprotein cholesterol (HDL-C), and exercise and vegetarian diets, in Taiwanese adults, based on the Methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism. Using regression models, we analyzed historical data collected from 9255 Taiwan Biobank (TWB) participants from 2008 through 2015. Exposure to exercise was associated with higher HDL-C (β = 1.0508 and 1.4011 for GG and GA + AA individuals, respectively), whereas a vegetarian diet was associated with lower HDL-C (β = −6.2793 and −4.6359 for those with GG and GA + AA genotype, respectively). We found an interaction between exercise and diet among GG individuals (p = 0.0101). Compared with no exercise/no vegetarian diet, vegetarian diet/no exercise was associated with a 5.1514 mg/dl reduction in HDL-C among those with GG genotype (β = −5.1514, p < 0.0001) and a 4.8426 mg/dl reduction (β = −4.8426, p < 0.0001) among those with GA + AA genotype. Vegetarian diets in combination with exercise predicted a 6.5552 mg/dl reduction in HDL-C among GG individuals (β = −6.5552) and a 2.8668 mg/dl reduction among GA + AA individuals (p < 0.05). These findings demonstrated that vegetarian diet alone was associated with lower HDL-C, no matter the rs1801133 genotype. However, the inclusion of regular exercise predicted much lower levels among GG individuals, whereas levels among GA + AA individuals were relatively higher.

Association between methylenetetrahydrofolate reductase gene rs1801131 A/C polymorphism and urinary tumors\u2019 susceptibility

BackgroundThe methylenetetrahydrofolate reductase (MTHFR) rs1801131 A/C variant results in a decrease in MTHFR enzymatic activity, which may play an important role in folate metabolism and is also an important source of DNA methylation and DNA synthesis. Several case-control studies have been conducted to assess the association of MTHFR rs1801131 polymorphism with the risk of urinary cancers, yet with conflicting conclusions. To derive a more precise estimation of above relationship, the association between the MTHFR rs1801131 A/C polymorphism and the risk of urinary cancer was performed.MethodsA total of 28 case-control studies was identified. The odds ratios (OR) with 95% confidence intervals (CI) was calculated to assess.ResultsOn one hand, we found that the MTHFR rs1801131 A/C polymorphism was associated with increased whole urinary cancers’ risk (for example CA vs. AA: OR = 1.12. 95%CI = 1.01–1.24). On the other hand, we found that the MTHFR rs1801131 A/C polymorphism might increase bladder cancer risk both in Asian (C-allele vs. A-allele: OR = 1.35. 95%CI = 1.15–1.60) and African populations (CA vs. AA: OR = 1.63. 95%CI = 1.17–2.25).ConclusionsOur current analysis suggested that MTHFR rs1801131 A/C is associated with urinary cancers, especially bladder cancer.

Methylenetetrahydrofolate reductase C677T (Ala>Val, rs1801133 C>T) polymorphism decreases the susceptibility of hepatocellular carcinoma: a meta-analysis involving 12,628 subjects.

C677T (Ala>Val, rs1801133 C>T), a non-synonymous variant of methylenetetrahydrofolate reductase (MTHFR) gene, has been found to be associated with an impair enzyme activity of MTHFR. The relationship of MTHFR rs1801133 with hepatocellular carcinoma (HCC) has been extensively investigated. However, the findings were conflicting. Recently, more investigations have been conducted on the relationship of MTHFR rs1801133 with HCC. To obtain a more precise assessment on the effect of this non-synonymous variant to the development of HCC, a pooled-analysis was performed. This meta-analysis consisted of 19 independent case–control studies. By using the odds ratio (OR) combined with 95% confidence interval (CI), the relationship of MTHFR rs1801133 with HCC risk was determined. A total of 19 independent case–control studies were included. Finally, 6,102 HCC cases and 6,526 controls were recruited to examine the relationship of MTHFR rs1801133 with HCC risk. In recessive model (TT vs. CC/CT), the findings reached statistical significance (OR, 0.90; 95%CI, 0.82–0.98; P = 0.016). Subgroup analysis also found an association between MTHFR rs1801133 polymorphism and the decreased risk of HCC in hepatitis/virus related patients (recessive model: OR, 0.85; 95%CI, 0.72–0.99; P = 0.035, and allele model: OR, 0.90; 95%CI, 0.81–0.99; P = 0.028). Subgroup analyses indicated that extreme heterogeneity existed in Asian population, larger sample size investigation, hospital-based study and normal/healthy control subgroups. The shape of Begger’s seemed symmetrical. Egger’s linear regression test also confirmed these evaluations. Sensitivity analyses suggested that our findings were stable. In summary, our results highlight that MTHFR rs1801133 polymorphism decreases HCC susceptibility. The relationship warrants a further assessment.