Methylenetetrahydrofolate Reductase C677T Research Articles

Association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms with serum folate, cobalanin and homocysteine concentrations in Greek adults

Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme of homocysteine metabolism participating in the folate cycle. The aim of this study was to investigate the association of MTHFR C677T and MTHFR A1298C gene polymorphisms with serum folate, cobalamin (Cbl) and homocysteine (Hcy) concentrations in healthy Greek adults. The MTHFR C677T and A1298C gene polymorphisms were genotyped in 383 healthy Greek adults (199 men and 184 women) using polymerase chain reaction and reverse hybridization. Serum folate, Cbl and total Hcy (tHcy) levels were determined using immunoassays methods. Among the 383 individuals, 73 (19.1%) were normal (CC), 202 (52.7%) were heterozygous (CT) and 108 (28.2%) were homozygous (TT) regarding the MTHFR C677T gene polymorphism, while 263 (68.7%) were normal (AA), 105 (27.4%) were heterozygous (AC) and 15 (3.9%) were homozygous (CC) regarding the MTHFR A1298C gene polymorphism. The overall C and T allele frequency for the MTHFR C677T gene polymorphism was 45.4% and 54.6%, respectively, while the overall A and C allele frequency for the MTHFR A1298C gene polymorphism was 82.3% and 17.6%, respectively. The MTHFR C677T and not the A1298C gene polymorphism had a significantly influence on serum folate and tHcy levels. The individuals with 677TT genotype had significantly lower serum folate and significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. Serum folate and tHcy levels are influenced by the existence of the MTHFR C677T gene polymorphism (mainly 677TT genotype). Individuals with low serum folate levels and/or high serum tHcy levels should be further investigated for a possible existence of MTHFR C677T and not A1298C gene polymorphisms, with aim to determine the suitable treatment.

Lack of Association of C677T Methylenetetrahydrofolate Reductase Polymorphism with Breast Cancer Risk in Mali.

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in the metabolism of folates and homocysteine, which in turn can affect gene expression and ultimately promote the development of breast cancer. Thus, mutations in the MTHFR gene could influence homocysteine, methionine, and S-adenosylmethionine levels and, indirectly, nucleotide levels. Imbalance in methionine and S-adenosylmethionine synthesis affects protein synthesis and methylation. These changes, which affect gene expression, may ultimately promote the development of breast cancer. We therefore hypothesized that such mutations could also play an important role in the occurrence and pathogenesis of breast cancer in a Malian population. In this study, we used the PCR-RFLP technique to identify the different genotypic profiles of the C677T MTHFR polymorphism in 127 breast cancer women and 160 healthy controls. The genotypic distribution of the C677T polymorphism in breast cancer cases was 88.2% for CC, 11.0% for CT, and 0.8% for TT. Healthy controls showed a similar distribution with 90.6% for CC, 8.8% for CT, and 0.6% for TT. We found no statistical association between the C677T polymorphism and breast cancer risk for the codominant models CT and TT (p > 0.05). The same trend was observed when the analysis was extended to other genetic models, including dominant (p = 0.50), recessive (p = 0.87), and additive (p = 0.50) models. The C677T polymorphism of MTHFR gene did not influence the risk of breast cancer in the Malian samples.

Correlation between methylenetetrahydrofolate reductase gene-specific methylation and recurrent spontaneous abortion

ABSTRACT Objective: To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) gene-specific methylation and recurrent spontaneous abortion (RSA). Methods: A total of 50 RSA patients who visited our hospital were recruited in the study group; 50 multiparous women who underwent physical examinations during the same period were enrolled in the control group. The levels of homocysteine, folic acid, and vitamin B12 and their MTHFR gene polymorphism and specific methylation were measured in both groups. The Logistic regression equation was used to analyze the correlation between MTHFR gene-specific methylation and RSA. Results: The methylated allele MM was not found in the control group, and the frequency in the study group was 1.19%. The frequency of the MU genotype in the study group 32.93% was higher than that in the control group 12.45%. The frequency of methylated alleles of CC and CT genotypes carrying MTHFR C677T polymorphism in the study group was higher than that in the control group (P < 0.05). There was no significant difference in the TT genotype between the two groups (P > 0.05). Multivariate Logistic regression analysis exhibited that patients with methylated alleles of CC genotype had a risk of RSA increased by 1.167 times, and the risk increased by 2.500 times in patients with methylated alleles of CT genotype (P < 0.05). 83.33% of RSA patients carrying methylated alleles affected hyperhomocysteinemia. In patients with elevated homocysteine levels, the risk of RSA caused by methylated allele was significantly increased by 7.321 times. Conclusion: MTHFR gene-specific methylation can significantly increase the risk of RSA.

Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of MTHFR C677T and A1298C genes and the toxicity responses of MTX. The MTHFR C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. The MTHFR C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179-2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042-2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251-0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183-31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033-3.518, P<0.05). The MTHFR A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed. Advancements in MTHFR genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.

Combined Parental Thrombophilia Gene Mutation Defects in Couples with Repeated Pregnancy Loss.

Several genetic mutations in female thrombotic defects have recently been shown to affect recurrent pregnancy loss (RPL); however, it is unclear which common parental mutations are involved in thrombosis-associated repeated pregnancy loss RPL. In this study, the prevalence of some combined parental thrombophilia gene mutation defects was studied in couples with RPL. The observational study was done in babol infertility research center (Iran) in 2022. Sixty-two infertile women with a history of RPL and their male partners (124 individuals) participated in this study. The frequencies of common defects associated with methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, factor V Leiden, protein C, protein S and homocysteine were analysed in these couples. The data were statistically analysed using the Mann-Whitney test. Sixty-two couples (124 individuals) were analysed. 56.2% of couples with a history of RPL had MTHFR C677T and 23.1% had MTHFR A1298C. Forty percent of couples showed homocysteine deficiency and 12.5% protein C deficiency. Other genes tested were only observed in the mother or father but not both. Results obtained with RPL couples demonstrate the importance of further investigating combined parental thrombophilia gene mutation defects (not only maternal).

Association of methylenetetrahydrofolate reductase polymorphism and male infertility in type 2 diabetes mellitus patients

INTRODUCTION: As per World Health Organization, Infertility is a condition which is characterized by not getting conceived with more than 1-year of unprotected sexual intercourse without usage of any contraceptive aids. Folate has a significant role in the metabolism of the cells, like nucleic acids synthesis, gene expression by means of remethylation of the homocysteine into methionine. In the males, deficiency of folate leads to reduced proliferation of the sperm cells. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase genes result in alterations of the methylations resulting pathological conditions being a potential risk factor for male infertility. MATERIALS AND METHODS: A total of 100 diabetic infertile males were selected as the study group and 100 nondiabetic fertile males were included as the control group. Blood samples were analyzed for the MTHFR polymorphisms. DNA extraction was done and the extract is subjected to polymerase chain reaction amplification. The resultant is subjected to electrophoresis for MTHFR gene allele confirmation. Statistical analysis was done using IBM SPSS Statistics 20 package. Chi-square test, odds ratio has been done and P &lt; 0.05 is considered statistically significant. RESULTS: Genotype frequencies of MTHFR C677T, A1298C in all the subjects were analyzed for the Hardy–Weinberg law of genetic equilibrium. Mutant polymorphisms of MTHFR C677T, i.e., thymine-thymine and cytosine-thymine were increased significantly. Similarly, MTHFR A1298C mutant polymorphisms, i.e. adenine-cytosine, cytosine-cytosine were increased significantly in the infertile group than in the fertile group. DISCUSSION: Mutations of both MTHFR C677T, A1298C are found to be linked with lowered enzyme activity. We found that the occurrence of mutant homozygous and mutant heterozygous genotypes was increased in a diabetic male infertile group when compared to nondiabetic fertile group. Hence, it can be concluded that presence of single-nucleotide polymorphisms of MTHFR will increase the risk of infertility in diabetic male population.

MTHFR C677T POLYMORPHISM: A MATERNAL RISK FACTOR FOR HAVING A MENTALLY RETARDED CHILD IN INDIA

The present case-control study examined the association of genetic polymorphism with mental retardation. One common polymorphism (SNPs), C677T in the 5,10- methylenetetrahydrofolate reductase (MTHFR) gene involved in folate metabolism, is known to lower the activity of this enzyme. One hundred sixty mothers (with MR and normal children), from the Eastern Uttar Pradesh, India, were genotyped for MTHFR C677T SNP. Significant association with this SNP was detected, more specifically, with T allele in the mothers of MR children. The relative risk of T (C677T) in mothers for MR-affected pregnancy was 3 (OR 3.179, 95% CI 1.40-7.78). The results indicated statistically significant associations between maternal MTHFR C677T polymorphism and congenital heart defects in foetus under different genetic models.

The effect of hereditary thrombotic factors and comorbidities on the severity of COVID-19 disease.

Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide and presents critical challenges for public health. Due to its chronic and systemic course, COVID-19 is currently accepted as a multi-systemic infectious disease. Here we explore the possible association between disease course and hereditary thrombotic factors and comorbidities. The patients admitted to the COVID-19 center in the Istanbul Faculty of Medicine were recruited for the study. The patients were classified according to the clinical course, severe vs. mild. Five polymorphic loci were analyzed by multiplex PCR: Factor V Leiden (FVL), FII G20210A, Beta-fibrinogen G-455A, and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C. FII G20210A and Beta-fibrinogen G-455A genotypes were significantly higher in the study group compared to the literature. Wildtype genotype (GG) in Factor V Leiden locus was significantly associated with low D-Dimer levels (p =0.013). The GA genotype increased the D-Dimer levels 2.55-times compared to the GG genotype (p =0.003). Moreover, the Beta-fibrinogen G-455G genotype was significantly higher in the LDH>250 group (p =0.046). The presence of solid tumors in patients with COVID-19 was related to the severity of the disease course. No evidence of a correlation between the severity of the disease and all five thrombotic mutations was found, whereas the FII G20210A and Beta-fibrinogen G-455A mutations were significantly high compared to previously reported Turkish population data and global carrier rates. This finding will need to be verified by further studies with larger samples since it may reflect a likelihood of having the COVID-19 disease. The high carrier frequency of FVL mutation was more likely present in the D-dimer high group generating an increase in the D-dimer levels 2.55-times compared to the wildtype.

Association of C677T Polymorphism of Methylenetetrahydrofolate Reductase with Metabolic Syndrome among Eastern Indian Women: A Case-control Study

Introduction: Polymorphisms of Methylene Tetrahydrofolate Reductase (MTHFR) gene have been associated with hyperhomocysteinaemia, which in turn may lead to hypertension, insulin resistance and abnormality of lipid metabolism. All these abnormalities are also components of Metabolic Syndrome (MetS). Thus, there is possibility of an association between MetS and MTHFR polymorphism. Literature search revealed paucity of data on this association, particularly from India. Aim: To evaluate the association of C677T polymorphism of MTHFR gene with MetS, among women of eastern Indian population. Materials and Methods: A hospital-based case-control study was conducted in the Department of Biochemistry, Calcutta National Medical College, Kolkata, West Bengal, India, between December 2016 to June 2018. Anthropometric and biochemical profiling of all 417 study subjects were done. Genetic workup was done by Polymerase Chain Reaction (PCR), using suitable primer, followed by restriction fragment length polymorphism analysis using Hinf 1 enzyme to identify MTHFR C677T polymorphism. Subjects were divided into two groups according to presence or absence of MetS as per International Diabetic Federation worldwide definition and compared with Mann-Whitney U Test. Logistic regression analysis was also performed. Results: Out of enrolled 417 female subjects, 243 were categorised as MetS group. Mean age (in years), of MetS group (48.70±9.03) was found to be significantly higher (p&lt;0.001) than that of control group (42.83±10.90). A total of 45 (25%) females with MetS exhibited the presence of heterozygous CT genotype; that was significantly higher (p=0.026) than the non MetS group 21 (14.9%). The mutant T allele frequency was also significantly higher among the subjects suffering from MetS; 45 (12.5%)compared to 21 (7.4%) in the control group (p=0.036). Multiple logistic regression analysis revealed the odds of developing MetS among subjects with heterozygous CT genotype was 7.721 times (CI: 2.38-25.05) compared to those with wild genotype. Conclusion: C677T polymorphism of MTHFR gene was associated with the occurrence of MetS among woman.

Homocysteine Reduction for Stroke Prevention: Regarding the Recent AHA/ASA 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.

Associative role of methylenetetrahydrofolate reductase and thymidylate synthase 6bp del gene polymorphism in preterm delivery

Abstract Objective: Preterm delivery is a major adverse birth outcome, approximately 15 million babies are born prematurely every year. There are several causes for preterm deliveries. This study focuses on folate metabolic pathways. Dietary folate plays a crucial role in premature labor. We examined the relationship between methylenetetrahydrofolate reductase (MTHFR) (C677T) and thymidylate synthase (TYMS) 6bpdel polymorphism. Materials and Methods: A total number of 300 pregnant women were selected for this study; among which (n = 150) were preterm and (n = 150) were term delivery cases. The selected samples were further processed for molecular polymerase chain reaction-restriction fragment length polymorphism analysis. The demographic profile of birth status resulted significantly with (P = 0.0001) proving chances of high infant mortality due to prematurity. Results: The genotype distribution of MTHFR C677T showed significant data (P = 0.0021) whereas insignificant genotypic distribution was observed for the TYMS gene (P = 0.067). Our results imply that genes that are involved in the folate pathway play a crucial role in early pregnancy. Conclusion: Advanced and better strategies can be brought to an improved intervention of folate at the time of pregnancy which will help to reduce the rate of premature deliveries.

The association between MTHFR polymorphism, dietary methyl donors, and childhood asthma and atopy.

Studies investigating the genetic association of the C677T methylenetetrahydrofolate reductase (MTHFR) genotype and dietary methyl donors with asthma and atopy are limited, and have variable results. To investigate the effect of dietary methyl donor intake on the risk of childhood asthma and atopy, based on the C677T polymorphism in the MTHFR gene. This cross-sectional study included 2,333 elementary school children aged 6-8 years across Korea during 2005 and 2006, as part of the first Children's Health and Environmental Research survey. Genotyping for the MTHFR (rs1801133) polymorphism was performed using the TaqMan assay. Multivariable-adjusted logistic regression analysis was performed to determine a descriptive association between the dietary methyl donor intake, MTHFR polymorphism, and childhood asthma and atopy. Intake of dietary methyl donors like folates was significantly associated with a decreased risk of the wheezing symptom, in the past 12 months, and "ever asthma" diagnosis, respectively. Vitamin B6 intake was also associated with a decreased atopy risk. The T allele of the MTHFR (rs1801133) gene was significantly associated with a decreased risk of atopy. Increased intakes of folate, vitamin B2, and vitamin B6 were protective factors against atopy, especially in children with the T allele on the MTHFR gene, compared to those with lower intakes and the CC genotype. High intakes of dietary methyl donors were associated with reduced risk of atopy and asthma symptoms. These may have additive effects related to the susceptibility alleles of the MTHFR gene. The clinical implications require evaluation.

Genetic Counseling in a Couple with Primary Infertility

Background: Couples unable to conceive and bear children could feel deep disappointment, often leading to depression. Infertility is one of the main reasons couples are not able to have children. Genetic counseling role in infertility ranges from explanation about possible genetic causes of infertility, pregnancy planning, and advice for treatment. Case Presentation: A couple with 16 years of infertility was referred to the genetic clinic at National Diponegoro Hospital. The 42 years old female had previous history of diabetes mellitus, obesity, and had treatment of epilepsy/seizure 15 years ago with routine carbamazepine therapy for 2 years, while her 42 years old husband had active hepatitis B infection for 15 years. This couple underwent insemination program twice and once completed In Vitro Fertilization (IVF), both management bearing no successful implantation or viable pregnancy. Recently, she underwent a laparoscopy procedure, which gave new diagnosis of endometriosis and adenomyosis. Chromosomal examination and Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C alleles analysis were done in our laboratory. Both individuals carried normal karyotypes and MTHFR analysis was homozygote wild type allele. Currently, this couple has accepted their conditions. They still want to bear a child although she is at a crucial ageConclusion: Infertility is a challenging and comprehensive problem. As healthcare professionals, we encounter problems not only in diagnosis and management, but also psychological and emotional dilemma. Genetic counseling is needed to solve the problems and avoid patient’s psychological distress.

Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Gene Polymorphism as Risk Factors for Essential Hypertension

Hypertension has relatively large morbidity and mortality rates throughout the world, including in Indonesia. The prevalence of hypertension tends to be greater in patients with a family history of hypertension. This is thought to be influenced by polymorphisms in the

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.

MTHFR polymorphism's influence on the clinical features and therapeutic effects in patients with migraine: An observational study.

Our study aimed to evaluate the influence of methylenetetrahydrofolate reductase (MTHFR) polymorphism on the clinical features and therapeutic effects in patients with migraine. The data of 135 patients with migraine were collected from January 2021 to December 2021. The MTHFR C677T polymorphism was analyzed. The pain intensity was evaluated using a numerical rating scale (NRS) during treatment. The levels of folic acid, homocysteine (Hcy), vitamin B12, interleukin-2 (IL-2), IL-4, and ferritin, and changes of NRS were compared between folic acid and conventional treatment groups stratified by different genotypes of MTHFR in migraine patients. The levels of Hcy and ferritin in male patients were higher than that in female patients (P < 0.05); Compared with CC and CT genotype groups, the TT genotype group showed significantly higher Hcy levels (P < 0.05) and lower folic acid levels (P < 0.05); In both folic acid and conventional treatment groups, a significant decrease in NRS score was observed in different genotypes post-treatment (P < 0.05). Patients with TT genotype in the folic acid treatment group showed better therapeutic efficacy than conventional treatment group (P < 0.05). There is no significant difference in the therapeutic efficacy in other genotypes between the two groups (P > 0.05). The MTHFR C677T genotyping may provide a new method to guide and optimize individualized medication for migraine patients.

Association of paternal MTHFR polymorphisms (C677T) with clinical outcomes in ICSI treatment.

This study aims to investigate the association between paternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T) and embryonic development, pregnancy, and neonatal outcomes in intracytoplasmic sperm injection (ICSI) treatment. A total of 191 infertile men undergoing ICSI treatment at the Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, were recruited between January 2020 and June 2021. The MTHFR C677T polymorphism genotyping was evaluated in these male patients, and they were stratified into three groups according to genotyping results: Control (CC), heterozygote mutated (CT), and mutated homozygote (TT). In addition, we conducted a comparative analysis of embryonic development, pregnancy, and neonatal outcomes among these three groups. The embryonic development (including normal fertilization rate (80.14% vs. 83.06% vs. 85.10%; p = 0.37), high-quality embryo rate (45.26% vs. 43.69% vs. 46.04%; p = 0.72), blastocyst formation rate (42.47% vs. 43.18% vs. 39.38%; p = 0.62), implantation rate (42.47% vs. 36.25% vs. 41.22%; p = 0.62), and clinical pregnancy rate (64.71% vs. 58.75% vs. 66.67%; p = 0.59) were not comparable among these three groups. Moreover, no significant difference was observed in terms of pregnancy outcomes (including miscarriage rate (24.24% vs. 12.77% vs. 22.5%; p = 0.35) and live birth rate (49.02% vs. 51.25% vs. 51.66%; p = 0.96)). Additionally, no marked difference was observed in terms of neonatal outcome (including, preterm delivery rate (24% vs. 14.63% vs. 9.67%; p = 0.35), birth height (p = 0.75), birth weight (p = 0.35), neonatal sex (p = 0.48), gestational age at delivery (p = 0.24), Apgar score (p = 0.34), and birth defects (0% vs. 2% vs. 9%; p = 0.23) among the study groups. The paternal MTHFR C677T polymorphism is not associated with embryo quality, pregnancy, or neonatal outcomes in ICSI treatment. Therefore, in our population, MTHFR polymorphisms do not provide helpful information in explaining ICSI failure.

The combined effects of GSTM1/GSTT1 and MTHFR C677T polymorphisms on the systemic arterial hypertension susceptibility: A genetic association study in Brazilian diabetic patients

This genetic association study included 150 hypertensive diabetic patients and 150 normotensives non-diabetic subjects. Glutathione S-transferases M1 and T1 (GSTM1/GSTT1) deletion polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T SNP (rs1801133) genotyping were performed by SYBR Green multiplex real-time and RFLP-PCR, respectively. Both GSTM1 and GSTT1 null (OR = 4.52, p = 0.04, and OR = 4.27, p = 0.01) and mutant (677TT) genotypes (OR = 2.95, p = 0.02) conferred risk to hypertension susceptibility. The combined genotypes (MTHFR:GSTT1:GSTM1) revealed a significant association: W/−/+, W/+/−, H/−/−, H/−/+, M/+/−, and M/+/+. These findings suggesting a probable oxidative hypothesis for hypertensive diabetic patients from the interaction of the detoxification mechanism and the homocysteine metabolism. The imbalance in antioxidant enzymes contributes to the establishment of oxidative stress in conjunction with hyperhomocysteinemia and reactive oxygen species production. We concluded that these findings suggest that both polymorphisms may contribute to hypertension susceptibility in diabetic patients.

763 ACTIVATION OF SIRT1 ATTENUATES VASCULAR DYSFUNCTION AND THROMBOSIS IN MTHFR DEFICIENCY

Abstract Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.

Association of Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in breast cancer patients of Bihar: Case-control study

Breast cancer (BC) is the most frequent cancer in women globally and the main cause of cancer-related mortality. MTHFR C677T is a functional polymorphism in the genes encoding a one-carbon metabolism enzyme that affect folate metabolism and may be associated with breast cancer susceptibility. We have conducted a case-control study taking 100 cases of diagnosed breast cancer and 100 healthy control. PCR-RFLP technique was used to detect the genotype of C677T polymorphism in the study population.About 35% of cases had normal genotype(C677C), 49% had the genotype C677T &amp; rest 16% had the genotype T677T for MTHFR. Among control the frequency of C677C genotype was 55% C677T was 40% &amp; T677T was 5%. C677T &amp; T677T MTHFR genotype were more common in case as compared to control [χ2 (2, N = 200) = 11.12, p = 0.004]. T allele frequency was significantly higher in case (40%) as compared to control (5%) [χ2 (1, N = 400) = 10.91, p = 0.001]. Cases with MTHFR 677TT genotype had a significantly higher risk of BC than 677CC individual [OR=1.64 (1.03 to 2.10)] and increasing T-allele was significant in BC [OR=1.07 (0.71 to 1.33)] (P for trend = 0.04).C677T of MTHFR gene has a strong correlation with breast cancer in the studied population and can be used as a prognostic marker for the development of breast cancer.