Methylenetetrahydrofolate Reductase 677T Research Articles

Methylenetetrahydrofolate Reductase 677T Allele Is a Risk Factor for Arterial Thrombosis in Chinese Han Patients with Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies (aPL) and thrombotic or obstetric events. Given the heterogeneity of the clinical manifestations, it is likely that genetic and acquired factors are involved in the pathogenesis of APS. The inherited polymorphisms of the thrombophilic gene, including methylenetetrahydrofolate reductase (MTHFR) C677T, type 1 plasminogen activator inhibitor (PAI-1) 4G/5G, factor V Leiden (FVL) G1691A, prothrombin (PT) G20210A, antithrombin (AT), and fibrinogen (Fg) polymorphisms, were analyzed in 67 aPL(+) patients from the Chinese Han population, including 41 APS patients and 26 persistent aPL carriers. The MTHFR C677T genotypes of 105 healthy controls, and the PAI-1 4G/5G polymorphism of 120 healthy controls, from the Chinese Han population were acquired for this study. Both the MTHFR C677T genotype (χ2 = 10.67, p = 0.004) and C/T allele distribution (χ2 = 5.92, p = 0.019) between the aPL(+) patients and healthy controls were found to be significantly different. Furthermore, we observed that the patients with at least one T allele had a higher risk of arterial thrombosis (CT vs. CC, OR 11.00, p= 0.025; CT + TT vs. CC, OR 10.27, p = 0.018). The C677T mutation of MTHFR is a risk factor for arterial thrombosis in Chinese Han patients with APS.

Associations of Genetic Variants of Methylenetetrahydrofolate Reductase and Serum Folate Levels with Metabolic Parameters in Patients with Schizophrenia.

The one-carbon metabolism pathway is a suitable candidate for studying the genetic and epigenetic factors contributing to metabolic abnormalities in patients with schizophrenia. We recruited 232 patients with schizophrenia and analyzed their serum folate, vitamin B12, and homocysteine levels and metabolic parameters to investigate the associations of genetic variants of methylenetetrahydrofolate reductase (MTHFR) and folate levels with metabolic parameters. MTHFR C677T and MTHFR A1298C were genotyped. Results showed that MTHFR 677T allele carriers had lower levels of total cholesterol and low-density lipoprotein cholesterol than those with the 677CC genotype. Metabolic parameters did not differ between MTHFR 1298C and 1298AA carriers. Patients with a low folate level had a lower high-density lipoprotein cholesterol level than those with a normal folate level, but the effect disappeared after adjustment for age, sex, and types of antipsychotics used. We found significant interactions between MTHFR A1298C and the folate level status (low vs. normal) in terms of body mass index and waist circumference. In conclusion, genetic variants in one-carbon metabolism might play a role in antipsychotic-induced metabolic abnormalities. Prospective studies on drug-naïve, first-episode patients with schizophrenia are warranted to identify key regions of DNA methylation changes accounting for antipsychotic-induced metabolic abnormalities.

Association of MTHFR C677T Polymorphism With Antipsychotic-Induced Change of Weight and Metabolism Index.

Although antipsychotic medication contributed to the improvement of psychotic symptoms and reduced relapse, it induced weight gain and metabolic syndrome during antipsychotic medication treatment, which was seriously concerning. To investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene C677T (rs1801133) polymorphism with antipsychotic-induced weight gain and metabolism parameter change, we employed 1,868 patients with schizophrenia in this study and randomly allocated them to seven antipsychotic medication treatment groups. All patients received antipsychotics monotherapy and were followed up for 6 weeks. Height, body weight, and metabolic parameters of the patients were measured at baseline and at 2, 4, and 6 weeks after antipsychotic treatment. We genotyped blood DNA from patients for MTHFR C677T polymorphisms and performed quantitative analyses using analysis of variance (ANOVA) and the analysis of covariance (ANCOVA) among three genotype groups.We found a predominant association between MTHFR C677T and body weight mass index (BMI) change after 6-week risperidone treatment. After 6-week treatment of risperidone, the BMI change rate (%) of MTHFR C677 carriers was significantly higher than that of MTHFR TT genotype carriers [CC (2.81 ± 6.77)%, CT (3.79 ± 5.22)%, TT (1.42 ± 3.53)%, F = 4.749, P = 0.009]. Some of the abnormal metabolic parameters were found to be associated with the MTHFR 677T, including higher levels of low-density lipoprotein and waist circumference. Validation was performed in an independent cohort, consisting of 252 patients with schizophrenia treated with three atypical antipsychotic drugs. Overall, the MTHFR C677 was associated with high risk of antipsychotic-induced weight gain and metabolism abnormalities.

The association between 5, 10 - methylenetetrahydrofolate reductase and the risk of unexplained recurrent pregnancy loss in China: A Meta-analysis.

Backgroud:To analyze the correlation between gene polymorphisms of 5,10- methylenetetrahydrofolate reductase (MTHFR) and risk of unexplained recurrent pregnancy loss (URPL) in Chinese women.Methods:Eligible studies were searched in Pubmed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Established inclusion criteria were used to screening articles, subsequently evaluate the quality of the included studies, Stata 16.0 PM and RevMan 5.3 software were conducted for meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was determined to assess the relationship between MTHFR and risk of URPL in Chinese women.Results:For MTHFR C677T, fifty studies were included, involving 6677 URPL cases and 8111 controls. The overall results showed that MTHFR C677T was significantly correlated with URPL risk, especially in the homozygous model (TT vs CC; OR 3.06; 95% CI 2.56–3.66). For MTHFR A1298C, twenty-first studies were included, involving 3439 URPL cases and 3155 controls. The results showed that MTHFR A1298C was also significantly correlated with URPL risk in recessive (CC vs AC + AA; OR 1.55; 95% CI 1.25–1.93) and homozygous (CC vs AA; OR 1.53; 95% CI 1.22–1.91) models. In addition, sub-group results showed that no significant difference between north and south China populations in the MTHFR gene polymorphisms and URPL risk. Of note, the patients carrying MTHFR C677T and MTHFR A1298C joint mutants had no synergistic effect (OR 2.71; 95% CI 0.84–8.70) on the occurrence of URPL compared with the wild-type homozygous genotype (MTHFR 677CC/ MTHFR 1298AA).Conclusion:Studies included in this meta-analysis suggested that MTHFR 677T allele and 677TT genotype and MTHFR 1298CC genotype were both associated with URPL; testing MTHFR C677T gene polymorphism was a more appropriate target compared with other mutations in the prediction of URPL.

Association Study of MTHFR C677T Polymorphism and Birth Body Mass With Risk of Autism in Chinese Han Population.

Objective: To explore the association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with birth body mass and risk of autism in Chinese Han population.Methods: A total 1,505 Chinese Han autism patients were recruited, using the Diagnostic and Statistical Manual of Mental Disorders, 4th revised version (DSM-IV-R) diagnostic criteria for autism, and 1,308 sex-matched healthy controls were also enrolled for the study. All the participants' birth body masses were counted according to the medical records. The MTHFR C677T genotypes were detected using the polymerase chain reaction-restrict fragment length polymorphism (PCR-RFLP) method. The association between C677T polymorphism, birth body mass, and risk of autism were analyzed using the chi-square tests.Results: The present study found that the MTHFR 677T was significantly associated with risk of autism [P = 0.004, odds ratio (OR) = 1.18, 95% CI = 1.02–1.29). The autism children more frequently showed low birth body mass (<2.5 kg) than healthy control subjects (8.6 vs. 5.3%, P = 0.001, OR = 1.67, 95% CI = 1.24–2.26). The interactive effects between MTHFR 677T and low birth body mass (P = 0.0001, OR = 2.18, 95% CI = 1.44–3.32) were also significantly associated with risk of autism.Conclusions: The MTHFR C677T polymorphism and low birth body mass may be associated with risk of autism in Chinese Han population.

Methylenetetrahydrofolate reductase C667T polymorphism and susceptibility to late-onset Alzheimer's disease in the Italian population.

This study is a meta-analysis of the published studies on the relationship between methylenetetrahydrofolate reductase (MTHFR) C667T polymorphism and the risk of late- onset Alzheimer 's disease (LOAD) in Italian cohorts. We conducted a search on the electronic databases PubMed/Medline, Web of Science and Scopus. All cohort and case-control studies investigating the association between MTHFR 677T polymorphism and LOAD in Italian population published any time to May 8, 2020 were included in the analysis. From an initial screening of 136 articles, 4 were included into the systemic review. The pooled analysis based on the co-dominant model revealed that the MTHFR C677T polymorphism was associated with a significant risk of LOAD among Italian cohorts (TC vs. CC: OR=1.20, 95% CI=1.06-1.36, P=0.004, I2=0%). Conversely, the pooled analysis based on the allelic model demonstrated a non-significant relationship between the MTHFR C677T polymorphism and susceptibility to LOAD in Italians (OR: 1.25, 95% CI: 0.99-1.59, P=0.060, I2=14.6%). Moreover, Italian subjects with MTHFR 677TT genotype resulted to have a significantly increased susceptibility to LOAD (OR=1.75, 95% CI=1.23-2.50, P=0.002, I2=0%). The present meta-analysis showed only trend of association between MTHFR C677T polymorphism and LOAD in Italian population; however, it also demonstrated an increased susceptibility of LOAD in patients having MTHFR 677TT genotype. Further studies are needed to establish whether MTHFR polymorphisms can be used as non-invasive biomarker for LOAD.

Methylene Tetrahydrofolate Reductase Gene Polymorphism C677T &amp; Risk of Type two Diabetes Mellitus in Beni-Suef Governorate

Background: Methylene Tetrahydrofolate Reductase (MTHFR) is known to be a regulatory enzyme of homocysteine metabolism. In many ethnic groups point mutations in MTHFR gene are implicated in the pathogenesis of diabetic nephropathy (DN) and other complications of type II diabetes mellitus (T2DM). Aim of the work: The aim of this study was to assess if MTHFR C677T gene polymorphism was one of the risk factors for the development of diabetic nephropathy as well as other complications in type 2 diabetes mellitus patients. Subjects and methods: The MTHFR C6777T polymorphisms were detected in 50 persons by PCR-RFLP. Subjects were divided into 2 groups; 30 patients with type II DM and 20 persons who were non-diabetic healthy controls. Results: The presence of MTHFR 677T allele did not increase the risk of complications in T2DM patients. The presence of mutant genotypes CT and TT did not increase the risk of nephropathy or other complications in the subjects having a C677T mutation. Conclusion: Methylene Tetrahydrofolate Reductase (MTHFR) C677T gene mutation was neither associated with an increased risk of diabetic nephropathy nor other complications of type II diabetes mellitus.

Investigating the methylation status of DACT2 gene and its association with MTHFR C677T polymorphism in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the common causes of cancer death in Iranian population. Both genetic and epigenetic changes have been implicated in CRC pathogenesis. DACT2 gene as one of the WNT signaling pathway inhibitor was shown to display tumor suppressor activity in many cancers. The aim of present study was to investigate the methylation status of DACT2 gene and its association with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in CRC patients. Fifty formalin-fixed paraffin-embedded cancerous and adjacent healthy tissuesobtained from CRC patient were investigated. Genomic DNA was isolated using a FFPE commercial DNA extraction kit. The methylation status was evaluated by methylation specific PCR. Genotyping of MTHFR C677T polymorphism was performed using PCR-RFLP technique. Statistical analysis was done by GraphPad Prism 8. Results indicated that the frequency of methylated DACT2 gene was significantly higher in cancerous tissue relative to adjacent healthy tissue (P<0.001). DACT2 gene methylation was significantly more common among carriers of MTHFR 677CC genotype (P=0.035) and significantly less common among carriers of MTHFR 677T allele (P value =0.006). In conclusion the present study identified DACT2 gene methylation as a significant risk factor for CRC development. Moreover, the low frequency of DACT2 gene methylation among carriers of MTHFR 677T allele may confer a protective role for this common polymorphism against CRC risk.

The relationship between plasma homocysteine levels and MTHFR gene variation, age, and sex in Northeast China.

Hyperhomocysteinemia (HHcy) is the risk factor for cardiovascular disease and stroke. However, the impacts on the genetic variation of methylene tetrahydrofolate reductase (MTHFR) on plasma homocysteine levels in the Northeast Chinese population have not been studied. Therefore, this study was carried out to determine the relationship between HHcy and MTHFR gene variation, and whether it was influenced by age and sex of the population in Northeast China. A total of 466 subjects were randomly enrolled in this study. According to the homocysteine levels (Hcy ≥ 15 μmol/L) of the subjects, they were divided into hyperhomocysteine (HHcy = 206) and normal homocysteine (Hcy = 260). Polymerase chain reaction/high-resolution dissolution curve and homocysteine determination kit methods were used for genotype testing and homocysteine detection, respectively. High plasma homocysteine levels are associated with MTHFR 677T and 1298A [P < 0.00, odds ratio (confidence interval) = 1.842 (1.418-2.394) >1], which is related to increasing age (Prange = 0.0005-0.0161), with the homocysteine levels of males higher than females (P < 0.0001). High plasma homocysteine levels were linked to the MTHFR gene mutation. In addition, plasma homocysteine levels increased significantly with age with male's homocysteine levels higher than that of females.

Association between Decreased Plasma Folate Levels and MTHFR C677T, and MTRR A66G Gene Polymorphisms as Determinants for Elevated Total Homocysteine Concentrations in Pregnant Women

Aims: The aims of this paper were to examine the association between gene polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G with levels of plasma folate and tHcy. Methods: Peripheral venous blood samples were obtained from 143 pregnant women, who had been fasted for more than 10 hours. Plasma tHcy and folate concentrations were measured in plasma specimens. The genotypes for polymorphisms were identified by the PCR-restriction fragment length polymorphism (RFLP). Results: Our results demonstrated that MTHFR 677T allele was the predictors of plasma folate levels in pregnant women. While MTHFR 677TT genotype and MTRR 66G allele were the predictors of plasma tHcy concentrations. Plasma folate levels were negatively correlated with tHcy concentrations (Pearson’s correlation coefficient r=-0.358, p=0.000012). With the increase of gestational weeks, the levels of plasma folate was first risen and then fall, whereas, there was a downtrend between gestational weeks and tHcy levels. Conclusion: Plasma folate status and total homocysteine level associated with MTHFR C677T and MTRR A66G gene polymorphisms in pregnant women. According to our study, the pregnant women of homozygous mutation of MTHFR 677TT and/or MTRR 66GG genes generally have lower levels of folate. Therefore, we recommend that pregnant women with 677TT and 66GG genotypes should supplement the appropriate dosage of folic acid based on their genotypes.

The Frequency of the 677C>T and 1298A>C Polymorphisms in the Methylenetetrahydrofolate Reductase (MTHFR) Gene in the Population.

Background:The gene for 5,10-methylenetetrahydrofolate reductase (NAD(P)H) or MTHFR gene encodes protein methylenetetrahydrofolate reductase (MTHFR), an enzyme important in folate metabolism.Aim:The aim of this study was to determine the frequencies of 677C>T and 1298A>C polymorphisms in the MTHFR gene of healthy subjects from the population.Material and methods:The blood samples were collected from 164 unrelated and healthy donors from population consisted of 98 females and 66 males. Both the MTHFR 677C>T and 1298A>C single nucleotide polymorphisms (SNPs) were analyzed by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Linkage disequilibrium (LD) between pair of SNPs was calculated through Haploview analysis.Results:The frequency of MTHFR 677T allele in the population (32.62%) was in agreement with the frequency of this allele in most other populations, however, the frequency of MTHFR 1298C allele (38.41%) was higher than that reported for most other populations in the world. Haploview analysis showed a relatively strong LD between 677C>T and 1298A>C SNPs with D′ values of 0.87.Conclusion:Regarding the two MTHFR polymorphisms, three of the nine combined genotypes were present in 87.2% of the population. 33.54% subjects were complex heterozygous (677CT/1298AC genotype), 34.15% subjects had 677CC/1298AC and 19.51% of 677CT/1298AA genotype. The subjects with 677TT genotype had a 1298AA or 1298AC genotype while subjects with 1298CC genotype had only 677CC genotype. The subjects with 677CC/1298AA genotype were only 3.05%. We were not found triple 677CT/1298CC and quadruple 677TT/1298CC mutation suggesting decreased viability of embryos with increased numbers of mutant alleles.

The methylenetetrahydrofolate reductase 677T-1298C haplotype is a risk factor for acute lymphoblastic leukemia in children.

The etiology of acute lymphoblastic leukemia (ALL) is complex, linked with both environmental exposures and genetic factors. Functional variants of the methylenetetrahydrofolate reductase (MTHFR) gene result in disturbance in folate metabolism and may affect susceptibility to cancer. The study was performed to evaluate whether MTHFR C677T and A1298C polymorphisms, analyzed separately and together, are associated with the development of ALL in a population under 18 years of age of Caucasian ancestry.The study included 117 pediatric patients (59% males, mean age at diagnosis 7.4 ± 5.2 years) with ALL, confirmed by conventional immunophenotyping surface-marker analysis and 404 healthy control subjects (48.5% men, mean age 37.7 ± 11.3 years). The MTHFR C677T and A1298C genotypes were analyzed using allele discrimination tests with Taq-Man fluorescent probes.The MTHFR 677TT genotype was related to a 2-fold increase in risk of ALL (P = .014). The 677T-1298C haplotype was found in ALL patients but not in controls (frequency 0.598%; P <.0001). The observed frequency of carriers of this rare haplotype was 12%, including 677CT/1298CC (1.7%), 677TT/1298AC (6.0%), and 677CT/1298AC (4.3%) genotypes.The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL in Polish population under 18 years of age. Further studies of haplotype composition in subjects with the 677CT/1298AC genotype are necessary to assess the risk of childhood ALL.

The Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Late-Onset Alzheimer's disease: Further Evidence in an Italian Multicenter Study.

A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ɛ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects. Genotyping for rs1801133 was performed with PCR-RFLP techniques. In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01-1.43) and carriers of the MTHFR 677T allele (CT+TT versus CC: OR = 1.34; 95% CI = 1.03-1.73) resulted in increased LOAD risk. Similarly, in APOEɛ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25-6.32). Very interestingly, also in non-APOEɛ4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03-1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOEɛ4 or in non-APOEɛ4 carriers.

Presence of the methylenetetrahydrofolate reductase gene polymorphism MTHFR C677T in molar tissue but not maternal blood predicts failure of methotrexate treatment for low-risk gestational trophoblastic neoplasia

Gestational trophoblastic neoplasia (GTN) is a rare tumor, and its genomic constitution is different from the maternal genome because of its gestational origin. Methotrexate (MTX) is a standard chemotherapeutic agent for low-risk GTN. An association between polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and MTX treatment outcome has been reported in various diseases. Thus, we examined the association between clinical outcome and MTHFR polymorphisms in both tumor and blood DNA of low-risk GTN patients.MTHFR C677T (rs1801133) and A1298C (rs1801131) were genotyped using high-resolution melting assays in 62 Japanese low-risk GTN patients and in 52 antecedent molar tissues. We compared the genotypes of MTHFR polymorphisms with the clinical outcome of 5-day MTX treatment.Twenty-five patients entered remission and 37 patients developed drug resistance or adverse effects that necessitated a drug change. The MTHFR 677T allele in molar tissue was significantly related to the need for drug change (P=0.006; odds ratio [OR], 3.13; 95% confidence interval [CI], 1.31–7.49), in contrast to MTHFR 1298C (P=0.18; OR, 0.63; 95% CI, 0.32–1.25). The MTHFR 677T and 1298C alleles obtained from patients’ blood DNA were not related to MTX treatment outcome (P=0.49; OR 1.31; 95% CI, 0.61–2.91 and P=0.10; OR 0.52; 95% CI, 0.22–1.15, respectively).These data demonstrate for the first time that the genotype of MTHFR 677TT in molar tissue is associated with ineffective MTX treatment in Japanese low-risk GTN patients.

Investigating the link between MCP-1 A-2518G, RANTES G-403A, CX3CR1 V249I and MTHFR C677T gene polymorphisms and the risk of acute myocardial infarction among Egyptians

BackgroundAcute myocardial infarction (AMI) is one of the leading causes of death among Egyptians. Monocyte chemoattractant protein-1 (MCP-1), regulation on activation normal T cell expressed and secreted (RANTES) and fractalkine (FKN) are chemokines that act as components of inflammatory response while methylenetetrahydrofolate reductase (MTHFR) is important enzyme in folate metabolism essential for homocysteine metabolism. Hyperhomocysteinemia has been linked to AMI. MCP-1 A-2518G, RANTES G-403A, CX3CR1 V249I and MTHFR C677T are important polymorphisms identified in MCP-1, RANTES, CX3CR1 and MTHFR genes respectively. There are conflicting data in the literature about their association with AMI. Therefore, the aim of the current study was to investigate the contribution of these gene variants to risk of AMI among Egyptians. Subjects and methodsThe study comprised 200 subjects; 100 AMI patients and 100 age-matched healthy controls. The MCP-1, RANTES, CX3CR1 and MTHFR genotypes were determined by restriction fragment length polymorphism (PCR-RFLP). ResultsGenotypes distributions for RANTES, fractalkine and MTHFR genes were significantly different between AMI patients and controls (p=0.0221, 0.0498 and 0.0083) while those results in MCP-1 were not significantly different. A significant risk for AMI with concurrent presence of RANTES (AG/AA), fractalkine (VV) and MTHFR (CT/TT) genotypes was observed. Conclusions1 - Each of MTHFR 677T, RANTES-403A and CX3CR1 249V alleles is considered an independent risk factor for AMI. 2 - Concurrent presence of high risk genotypes of RANTES (AG/AA), fractalkine (VV) and MTHFR (CT/TT) increases risk of AMI more than their individual risks. 3 - MCP-1 polymorphism is not associated with AMI among Egyptians.

Retrospective case-control study of correlation between MTHFR gene and OSCC risk in North India.

Oral squamous cell carcinoma (OSCC) occurrence appears to be the number one among all cancers in India. Folate is a methyl donor during DNA methylation, as it provides substrate for methylenetetrahydrofolate reductase (MTHFR) to convert 5,10-MTHF to 5-MTHF and subsequently metabolizes it to methionine. The purpose of this study was to identify MTHFR C677T gene polymorphism in patients with OSCC. A total of 350 OSCC cases and 350 healthy controls participated in this study. MTHFR C677T single-nucleotide polymorphism was evaluated by PCR-RFLP. In the present study, MTHFR gene 677CC, CT, and TT genotype frequencies of the total OSCC cases were 74.8; 19.4 and 5.71; and 88.5, 9.42, and 2.0% in controls. The average frequency of the MTHFR 677T allele was 15.4% in OSCC cases compared to 6.71% in the controls. The CT genotype occurrence prevailed more in patients than controls in contrast to TT genotype, although both the genotypes were statistically significant for OSCC. Moreover, we found that T allele was significant in cases of smoking and tobacco chewing. In this study, we found that the homozygous mutant T allele appeared to have significantly higher risk of OSCC especially in late stages and therefore supporting in OSCC susceptibility and its progression.

The T Allele of MTHFR c.C677T and Its Synergism with G (Val 158) Allele of COMT c.G472A Polymorphism Are Associated with the Risk of Bipolar I Disorder.

The aims of the present study were to investigate the association between methylenetetrahydrofolate reductase (MTHFR) c.C677T (p.A222V) and catechol-O-methyltransferase (COMT) c.G472A (p.V158M) polymorphisms and their synergism with respect to bipolar I disorder (BID). Within an ethnic Kurdish population from Western Iran the MTHFR c.C677T and COMT c.G472A polymorphisms were studied in 150 patients with BID and 149 gender- and age-matched healthy individuals using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In the presence of MTHFR 677T allele and MTHFR TT genotype, the risk of BID was 1.44 times (p = 0.046) and 1.81-fold (p = 0.029), respectively. The frequency of COMT 472G allele compared to the A allele in cases and controls was not significant (p = 0.078); however there was a synergism between the presence of MTHFR 677T and COMT 472G alleles that increased the risk of BID by 2.58-fold (p = 0.003). Our findings indicate that the presence of the lower activity allele of MTHFR (677T) increased the risk of BID. In addition, the concomitant presence of the MTHFR 677T allele with the COMT 472G allele was associated with increased susceptibility to BID in our population.

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

DNA methylation and nucleic acid biosynthesis are two crucial phenomena for normal chromosomes segregation. From our earlier studies, MTHFR 677T individually and in combination with other gene polymorphisms, micronutrient deficiency and hyperhomocysteinemia was shown to be associated with risk in Down syndrome (DS) mothers. Remethylation and nucleic acid biosynthesis pathways are dependent on the activity of Methylenetetrahydrofolate reductase (MTHFR) and Thymidylate synthase (TYMS) respectively, competing for common substrate molecule 5,10-methelenetetrahydrofolate (5,10-MTHF). Role of MTHFD1 1958 G>A (affecting synthesis of 5,10-MTHF), MTHFR 677 C>T (affecting methylation), TYMS 5'UTR 28 bp repeat polymorphism and TYMS 3'UTR 6bp deletion polymorphism (affecting nucleic acid biosynthesis) in a cohort of 200 case mothers and 187 control mothers (also 146 case triads: mother, father, and child) were studied. We observed a significant association of MTHFR 677 C>T in a co-dominant model (p=0.0428) and dominant model (0.0194) as well as TYMS 5'UTR 28 bp repeat polymorphism in a recessive model (p=0.0005) and dominant model (0.0161). Genetic combination analysis revealed a significant additive effect of certain genotypic combinations (especially combination of MTHFR 677T and TYMS 2R alleles with other alleles or genotypes) in increasing risk. Weak linkage disequilibrium (LD) was observed between TYMS 5' and 3' UTR regions polymorphism in LD analysis. Transmission disequilibrium test (TDT) analysis revealed a consistent trend of preferential allele's transmission from parents. We concluded that genetic interaction of remethylation pathway and the nucleic acid metabolic pathway was significantly associated with risk factors for DS childbirth. However, replication studies are required to validate our observation in the population.

Polymorphisms in folate-metabolizing genes as risk factors for

Objectives: Down syndrome (DS) may be associated with congenital heart defects (CHD). Folate-metabolizing genes have been suspected as risk factors in DS and in CHD. We investigated the role of methylenetetrahydrofolatereductase( MTHFR ) C677T andA1298Cpolymorphisms and methionine synthase ( MTR ) A2756G polymorphism as risk factors for CHD in DS offspring. Material and M ethods: This study included 116 DS children and their Egyptian mothers. Atrial septal defects, ventricular septal defects and patent ductus arteriosus were the defects considered. Mothers were divided into CHD-DS mothers and normal hearts-DS mothers. The analysis of MTHFR C677T andA1298Cpolymorphisms and MTR A2756G polymorphism was performed by PCR-RFLP. Allele/genotype frequencies were determined. Odd ratios and 95% confidence intervals were measured. Results: The distribution of different genotypes and allele frequencies of the three polymorphisms showed no significant differences between both groups of DS mothers, however, the genotypes of both MTHFR 677T and MTR 2756A together showed a significant p -value (0.035), but with an odd ratio of 0.39 (95% CI: 0.09-1.4). Conclusion: According to the results, MTR A2756G polymorphism and MTHFR C677T and A1298C polymorphisms could not be considered as maternal risk factors in Egyptian mothers for CHD in DS offspring. Further studies in different populations are needed.

Association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and carotid intima medial thickness progression in post ischaemic stroke patient.

Hyperhomocysteinemia is associated with an increased risk of atherosclerosis. The main cause of elevated levels of homocysteine is 677T allele, the gene encoded by methylenetetrahydrofolate reductase (MTHFR). Carotid atherosclerosis progression, which can be measured by examination of carotid intima-media thickness (C-IMT), is a predictor of recurrent ischemic stroke. The objective of this study was to determine a relationship between MTHFR polymorphism, homocysteine ​​levels, and increased C-IMT in post- ischemic stroke patients. This was an epidemiological prospective observational cohort study involving 71 patients with post-ischemic stroke subject of the first (onset 1 month) admitted in the Neurology Clinic of Kariadi Hospital during 2012 to 2013. C-IMT was examined using carotid duplex ultrasound at 1(st), 6(th), and 12(th) month after stroke onset. MTHFR gene polymorphism was examined using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Homocysteine level was measured using Axis(®) Homocysteine EIA. We found 3 categories of MTHFR gene variation, i.e., 677T/T, 677T/C, and 677C/C. The most frequent allele was MTHFR 677C (88.9%), while the MTHFR 677T allele frequency was 11.1%. The majority allele of the subject population was 677C/C, however, there were 3 subjects (4.2%) who had 677T/T allele. The 677T/T allele group had normal homocysteine level and the lowest mean C-IMT among others. This study supports that the MTHFR 677T allele polymorphism is not associated with hyperhomocysteinemia as well as an increase in C-IMT in post ischemic stroke patients.