Methylenetetrahydrofolate Reductase A1298C Gene Polymorphisms Research Articles

Associations of serum 25-hydroxyvitamin D with serum folate, cobalanin, and homocysteine concentrations and methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in healthy adults.

The aim of this study was to investigate the associations of serum 25-hydroxyvitamin D [25(OH)D] with various demographic, anthropometric, and genetic characteristics and biochemical parameters in healthy Greek adults. Demographic (age and sex), anthropometric (body mass index/BMI), and genetic (MTHFR gene polymorphisms) characteristics and biochemical parameters (serum folate, cobalamin/Cbl, and total homocysteine/tHcy concentrations), which had been recorded and measured, among others, in the framework of periodic medical examination (military personnel) or check-up (non-military personnel) of 383 healthy Greek adults (199 men and 184 women) were analyzed. Serum 25(OH)D, tHcy, folate, and Cbl levels were determined using immunoassay methods. The MTHFR C677T and A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. Serum 25(OH)D concentrations were correlated with Cbl levels and MTHFR C677T gene polymorphism, while they had a reverse correlation with serum tHcy levels, age, and BMI. There was no significant correlation between serum 25(OH)D concentrations and sex, serum folate levels, and smoking status. Individuals with the 677TT genotype had statistically significantly lower serum 25(OH)D levels than those with the 677CC or 677CT genotype, while individuals with the 1298CC genotype had statistically significantly higher serum 25(OH)D levels than those with 1298AA or 1298AC genotype. Moreover, the reverse correlation between the serum 25(OH)D and tHcy levels was statistically significant in all six MTHFR genotypes. Serum 25(OH)D levels are associated with age, BMI, serum tHcy, and Cbl levels and MTHFR C677T gene polymorphism. The most significant finding of our study is the observed reverse correlation of serum 25(OH)D levels with serum tHcy levels. Considering that vitamin D deficiency and hyperhomocysteinemia (HHcy) are associated with an increased risk for cardiovascular diseases (CVDs), we suggest that individuals with high serum tHcy levels should be further investigated for, inter alia, their serum 25(OH)D levels.

INFLUENCE OF THE METHYLENE TETRAHYDROFOLATE REDUCTASE (MTHFR) GENE POLYMORPHISMS ON SERUM FOLATE, COBALANIN AND HOMOCYSTEINE LEVELS IN HEALTHY GREEK ADULTS

Objective: Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme of homocysteine metabolism participating in the folate cycle. It is well known that hyperhomocysteinemia is associated with an increased risk for cardiovascular disease. 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. Design and method: The MTHFR C677T and A1298C gene polymorphisms were genotyped in 383 healthy Greek adults (199 men; mean age±SD: 37.3±8.2 years) using polymerase chain reaction and reverse hybridization. Serum folate, Cbl and total Hcy (tHcy) levels were determined using immunoassays methods. Results: 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 individuals with 677TT genotype had significantly lower serum folate and significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. On the contrary, the A1298C gene polymorphism had no significantly influence on serum folate and tHcy levels. Conclusions: 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.

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.

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.

The association of methylene tetrahydrofolate reductase (MTHFR) A1298C gene polymorphism, homocysteine, vitamin B12, and folate with coronary artery disease (CAD) in the north of Iran

Abstract Background We pursued to find out the possible association of Methylene tetrahydrofolate reductase (MTHFR) A1298C gene polymorphism, blood homocysteine, vitamin B12, and folate with Coronary artery disease (CAD) in the study population in Guilan, north of Iran. Material and Methods Ninety patients with CAD and 76 healthy controls were evaluated. MTHFR A1298C polymorphism and its genotype frequency, the plasma level of homocysteine, vitamin B12 and folate were evaluated by using ARMS-PCR, ELISA, and Chemiluminescence methods, respectively. Results The frequency of genotypes, A, AC and CC in CAD were 40, 35.6, 24.4%, respectively which was significantly different (p=0.016) from the control group that were 26.3, 57.9 and 15.8%, respectively. The serum level of vitamin B12 and folate in genotype A1298C were not statistically significant between two groups (p&gt;0.05), however, the plasma homocysteine in patients with CAD was remarkably higher than the control group (p&lt;0.001). Additionally, in CAD patients the plasma level of homocysteine in the AC genotype was significantly higher than the control subjects (p=0.005). Conclusion It is thus concluded that MTHFR A1298C gene polymorphism is associated with CAD. It seems that the AC genotype of MTHFR A1298C polymorphism might have a protective effect on CAD.

Methylenetetrahydrofolate reductase gene polymorphisms in the risk of polycystic ovary syndrome and ovarian cancer.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) in hormone metabolism pathways might cause metabolic disturbances and contribute to the development of polycystic ovary syndrome (PCOS) and ovarian cancer, but the published studies were inconsistent. The aim of the present study was to evaluate the MTHFR C677T (rs1801133) and A1298C (rs1801131) gene polymorphisms in the risk of PCOS and ovarian cancer by meta-analysis. A comprehensive electronic search was conducted in databases for studies published from 1995 to 2020. The pooled ORs were calculated by Revman 5.2 software. Twenty-nine articles including 45 case–control studies were included. We found that MTHFR C677T polymorphisms were correlated with elevated PCOS risk (TT vs. CT+CC: OR = 1.41, 95%CI = 1.20–1.67; TT+CT vs. CC: OR = 1.54, 95%CI = 1.07–2.22; CT vs. CC+TT: OR = 1.18, 95%CI 1.04–1.33; TT vs. CC: OR = 1.47, 95%CI = 1.03–2.11; T vs. C: OR = 1.25, 95%CI = 1.06–1.47), which were more obvious in Middle Eastern subgroup. MTHFR A1298C polymorphisms were also associated with overall PCOS susceptibility (CC vs. AC+AA: OR = 2.55, 95% CI = 1.61–4.03; CC+AC vs. AA: OR = 1.84, 95%CI = 1.04–3.28; CC vs. AA: OR = 2.66, 95%CI = 1.68–4.22; C vs. A: OR = 1.67, 95%CI = 1.03–2.71), which were mainly reflected in Asian subjects. For ovarian cancer, MTHFR C677T polymorphisms were only related with elevated ovarian cancer risk in Asian population, while no significant association was found for A1298C polymorphisms. This meta-analysis suggested that MTHFR C677T and MTHFR A1298C polymorphisms were correlated with elevated PCOS risk. MTHFR C667T only posed a higher risk for ovarian cancer in Asians instead of other populations, while MTHFR A1298C polymorphisms were not related to ovarian cancer risk. Further studies are needed to validate the conclusion.

Association of Intake Folate and Related Gene Polymorphisms with Breast Cancer.

Breast cancer is one of the most common malignancies in women worldwide and is associated with a variety of risk factors. Folate and vitamin B12 are key elements of the one-carbon metabolism pathway where methylenetetrahydrofolate reductase (MTHFR) plays a significant role. Though many molecular and epidemiological studies have been performed to explore the relationship between intake folate, vitamin B12, MTHFR gene polymorphism and breast cancer risk, there is no consensus to date. By reviewing the relevant literatures and summarizing the potential effect of dietary folate intake on MTHFR genes polymorphism and breast cancer risk, we conclude that MTHFR C677T gene polymorphism is associated with breast cancer risk among Asian, but not Caucasians, and the MTHFR A1298C gene polymorphism is not a susceptibility factor of breast cancers. Concomitant low activity of MTHFR enzyme resulted from C677T gene polymorphism and low dietary folate intake is associated with increased breast cancer risk.

Association between end-stage diabetic nephropathy and MTHFR (C677T and A1298C) gene polymorphisms.

Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T and A1298C polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with Diabetic nephropathy. This study aimed to investigate the influence of the C677T and A1298C polymorphisms on the progression chronic kidney disease in diabetic nephropathy of south Indian population. We genotyped 145 DN cases and 100 controls for the C677T and A1298C polymorphisms using PCR-RFLP based protocols, and all diabetic nephropathy cases divided into two groups based on CKD stages: 60 DN cases were early stage (CKD1 to CKD3) and 85 DN cases were advanced stage (CKD4 and CKD5). Association χ2 and univariate analysis were performed. The C677T (OR = 4.2; 95% CI = 2.31-7.64 and P = 0.001) and A1298C (OR = 2.8; 95% CI = 1.05-7.57 and P = 0.033) polymorphism was shown that the significant association between the cases and control. Furthermore, the MTHFR gene polymorphism C677T (OR = 2.48; 95% CI = 1.25-4.9 and P = 0.008) was observed that the significant contribution of the progression of CKD in DN. These findings suggest that the C677T and A1298C polymorphism of MTHFR gene was associated with diabetic nephropathy in a south Indian population. Furthermore, the present study provides evidence that the C677T polymorphism was associated with CKD progression in DN.

Meta-Prediction of MTHFR Gene Polymorphism and Air Pollution on the Risks of Congenital Heart Defects Worldwide: A Transgenerational Analysis.

Congenital heart disease (CHD) is the leading cause of death in children, and is affected by genetic and environmental factors. To investigate the association of air pollution with methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and the risk of CHD, we included 58 study groups of children and parents, with 12,347 cases and 18,106 controls worldwide. Both MTHFR C677T (rs 1801133) and A1298C (rs 1801131) gene polymorphisms were risks for CHD in children with transgenerational effects from their parents. Countries with greater risks of CHD with a pooled risk ratio (RR) > 2 from MTHFR 677 polymorphisms included Germany, Portugal, China, and Egypt for children; and Brazil, Puerto Rico, Mexico, China, and Egypt for mothers. Whereas, countries with greater risk of CHD with RR > 2 from MTHFR 1298 polymorphisms included Taiwan, Turkey, and Egypt for children; and Brazil, China, and Egypt for mothers. Additionally, meta-prediction analysis revealed that the percentages of MTHFR 677TT and TT plus CT polymorphisms together were increased in countries with higher levels of air pollution, with a trend of increased CHD risks with higher levels of air pollution for children (p = 0.07). Our findings may have significant implications for inflammatory pathways in association with MTHFR polymorphisms and future intervention studies to correct for folate-related enzyme deficits resulted from MTHFR polymorphisms to prevent CHDs for future generations.

ASSOCIATION OF MTHFR A1298C GENE VARIANT, DNA DAMAGE, AND TOTAL ANTIOXIDANT STATUS WITH THE RISK OF TYPE 2 DIABETES MELLITUS AND ITS COMPLICATIONS

Objectives: We have examined the association of methylenetetrahydrofolate reductase (MTHFR) gene A1298C variant, DNA damage, and total antioxidant status (TAS) in patients with type 2 diabetes mellitus (T2DM) with and without complications and in healthy controls.Methods: A total of 300 subjects including 100 patients with complications, 100 patients without complications, and 100 controls were included. TAS was assessed by ferric reducing ability of plasma assay. DNA damage was analyzed in lymphocytes using the comet assay. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to study the MTHFR A1298C gene polymorphism among the study subjects.Results: The results revealed that the MTHFR 1298 AC+CC genotypes were associated with increased risk (2 fold) for diabetes and its complications. When the effect of DNA damage was analyzed, significant differences between individuals with mutant and normal genotype among the diabetic patients (with and without complications) was observed (p≤0.001). In contrary, no significant difference was found between TAS and 1298 genotypes (AA vs. AC+CC) in Type 2 diabetes patients (with and without complications), p=0.338. We also found a significant difference between the genotypes of the MTHFR A1298C and DNA damage, TAS in T2DM patients (with &amp; without complications) when compared to controls, p&lt;0.001.Conclusions: Our findings suggest that the MTHFR A1298C gene polymorphism is considered as a risk factor for the development of diabetes and its complications among south Indians. Therefore, increased DNA damage and decreased TAS along with the occurrence of a mutant genotype in an individual with diabetes may be at an increased risk for the development of chronic complications.

Opposite impact of Methylene tetrahydrofolate reductase C677T and Methylene tetrahydrofolate reductase A1298C gene polymorphisms on systemic inflammation.

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been found to be related with many diseases. Systemic inflammation is now considered as a major predisposition factor for diseases including diabetes mellitus (DM), coronary arterial disease (CAD), stroke, and cancer. This study aimed to investigate whether systemic inflammation is a possible underlying pathogenesis for MTHFR gene polymorphism-related disease. A total of 292 patients were enrolled, and single nucleotide polymorphisms for MTHFR C667T and A1298C were genotyped. Systemic inflammation markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were collected. In our study population, MTHFR 677 variants had significant higher NLR level than MTHFR 677 wild type (3.77±0.26 vs 3.06±0.18, P=.028). Logistic regression analysis showed that MTHFR 677 variants were significantly associated with increased NLR level. MTHFR 1298 variants showed the opposite effects which tended to have lower level of NLR (3.21±0.16 vs 3.79±0.34, P=.087) and PLR (137.0±4.8 vs 157.7±9.4, P=.052) than MTHFR 1298 wild type. General linear model showed that there was no statistically significant interaction between MTHFR C667T and A1298C gene polymorphism on NLR or PLR. This study indicates that MTHFR C677T and MTHFR A1298C gene polymorphisms have opposite effect on systemic inflammation, and systemic inflammation may contribute to the pathogenesis for diseases associated with MTHFR C667T gene polymorphism.

Association of MTHFR C677T and A1298C gene polymorphisms with methotrexate efficiency and toxicity in Algerian rheumatoid arthritis patients

Methotrexate (MTX) is the most used drug in rheumatoid arthritis (RA) treatment. However, it shows variability in clinical response, which is explained by an association with genetic polymorphisms. This study aimed to elucidate the role of the two gene polymorphism C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) in response to MTX in Algerian RA patients. Study included 54 early RA patient treated with MTX for one year. MTX efficiency and toxicity were evaluated at 6 and 12 months respectively and the two gene polymorphisms were genotyped. No association was found between A1298C polymorphism and MTX toxicity. However, T allele of the C677T polymorphism was associated with the occurrence of MTX adverse effects (p = 0,019, OR: 3,63, 95% CI [1,12 - 12,80]). No association was found between C677T polymorphism and MTX efficiency, while A allele of the A1298C polymorphism was associated with good and moderate response (p = 0,02, OR = 3,28, 95% CI: [1,11– 9,42]). The study of RA biological markers kinetics showed that MTX did not affect antibodies rate unlike inflammatory markers. Our study suggests that MTHFR C677T and A1298C genotyping are associated to MTX toxicity and efficiency, respectively, in RA patients. This offers new perspectives in the personalization of RA treatment in Algeria.

Lack of association between MTHFR A1298C polymorphism and outcome of methotrexate treatment in rheumatoid arthritis patients: evidence from a systematic review and meta-analysis.

The aim of this study was to evaluate the association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphism A1298C and methotrexate (MTX) outcome in rheumatoid arthritis (RA) patients. We conducted a meta-analysis of the relevant published literature through to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effect models. A total of 1325 cases (10 studies) of MTX efficacy and 2777 cases (18 studies) of MTX toxicity in RA patients were analyzed. Pooled results showed that MTHFR gene A1298C polymorphism was not significantly related to MTX toxicity or efficacy in RA patients. However, subgroup analysis indicated a significant association between MTHFR gene A1298C polymorphism and decreased MTX efficacy in the South Asian population (CCvs. CA+AA: OR=0.45, 95% CI=0.23-0.89, P=0.021). Also, MTHFR gene A1298C polymorphism in the partial folate supplementation group showed a relationship with decreased MTX efficacy (CCvs. CA+AA: OR=0.43, 95% CI=0.20-0.92, P=0.029) and toxicity (CCvs. CA+AA: OR=0.40, 95% CI=0.17-0.96, P=0.04; CCvs. AA: OR=0.38, 95% CI=0.16-0.94, P=0.035). Overall, our meta-analysis suggested no significant effect of MTHFR gene A1298C polymorphism on MTX outcome in RA patients. However, due to several limitations of our meta-analysis, the results should be interpreted cautiously and require further confirmation using high-quality studies.

Methylenetetrahydrofolate reductase A1298C genetic variant& risk of schizophrenia: A meta-analysis.

Background & objectives:Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate metabolism, whose role in schizophrenia is debatable. Numerous case-control studies have investigated the association of MTHFR A1298C polymorphism with schizophrenia, but results are controversial. The aim of the present study was to find the association between MTHFR A1298C gene polymorphism and schizophrenia.Methods:PubMed, Google Scholar, Science Direct and Springer link databases were searched for case-control association studies in which MTHFR A1298C polymorphism was investigated as a risk factor for schizophrenia. In all, 19 studies with 4049 cases and 5488 controls were included in this meta-analysis. Odds ratios (ORs) with 95 per cent confidence intervals (CIs) were used as an association measure.Results:The results of meta-analysis reported a significant association between A1298C polymorphism and schizophrenia risk in overall comparisons in all genetic models (C vs. A: OR=1.13, 95% CI=1.01-1.27, P=0.02; CC vs. AA: OR=1.20, 95% CI=1.03-1.39, P=0.02; AC vs. AA: OR=1.13, 95% CI=1.03-1.23, P=0.009; AC+CC vs. AA: OR=1.14, 95% CI=1.02-1.24, P=0.002; CC vs. AA+AC: OR=1.17, 95% CI=1.01-1.35, P=0.04).Interpretation & conclusions:MTHFR A1298C polymorphism was found to be a risk factor for schizophrenia and might have played a significant role in the pathogenesis of schizophrenia.

Influence of MTHFR Genetic Background on p16 and MGMT Methylation in Oral Squamous Cell Cancer.

Genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) enzyme may influence DNA methylation. Alterations in DNA methylation patterns of genes involved in the regulation of the cell cycle, DNA repair, cell adherence and metastasis process are known to contribute to cancer development. In this study, the influence of the MTHFR C677T and A1298C gene polymorphisms on global DNA methylation and site-specific methylation on p16 and O6-methylguanine-DNA methyltransferase (MGMT) gene promoters was investigated in patients with oral squamous cell cancer (OSCC). To this aim, methylation studies were carried out by using genomic DNA isolated from saliva samples of 58 OSCC patients and 90 healthy controls. The frequency of the CT/AC and TT/AA genotypes was significantly higher in patients than in controls. Whereas no difference in global DNA methylation levels was observed between patients and controls, a higher frequency of methylation at both p16 and MGMT gene promoters was detected in patients compared with controls. A significant association between MTHFR gene polymorphisms and p16 and MGMT gene promoter methylation was found. The frequency of p16 and MGMT methylation was around 60% in patients with either the CT/AC or TT/AA genotype. Our results suggest that hypermethylation of cancer-related genes may be affected by MTHFR polymorphisms.

Geographical and Ethnic Distributions of the MTHFR C677T, A1298C and MTRR A66G Gene Polymorphisms in Chinese Populations: A Meta-Analysis.

BackgroundThe geographical and ethnic distributions of the polymorphic methylenetetrahydrofolate reductase (MTHFR) mutations (C677T and A1298C) and methionine synthase reductase (MTRR) mutation (A66G) remain heterogeneous in China. The goal of this study was to estimate the pooled frequencies of the alleles and associated genotypes of these gene polymorphisms among healthy populations in Mainland China.Objective and MethodsWe systematically reviewed published epidemiological studies on the distributions of 3 genetic variants in Chinese healthy populations living in Mainland China through a meta-analysis. The relevant electronic databases were searched. All of the raw data of the eligible citations were extracted. The frequency estimates were stratified by geography, ethnicity and sex.ResultsSixty-six studies were identified with a total of 92277 study participants. The meta-analysis revealed that the frequencies of the MTHFR C677T, A1298C, and MTRR A66G gene polymorphisms varied significantly between different ethnic groups and along geographical gradients. The frequencies of the 677T allele and 677TT genotype increased along the southern-central-northern direction across Mainland China (all Pvalues≤0.001). The frequencies of the 1298C, 1298CC, 66G and 66GG genotypes decreased along the south-central-north direction across the country (all Pvalues≤0.001).ConclusionsOur meta-analysis strongly indicates significant geographical and ethnic variations in the frequencies of the C677T, A1298C, and A66G gene polymorphisms in the folate metabolism pathway among Chinese populations.

Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population

PurposeType 2 diabetes mellitus (T2DM) is the most common form of diabetes with clinical consequences giving rise to chronic multiple organ complications. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are genetic variations that have been linked to T2DM, and micro/macrovascular complications. The link between MTHFR and T2DM however is strongly dependent on the ethnic group studied. The objective of this study was to investigate the possible association between two MTHFR polymorphisms (C677T and A1298C) and T2DM and specifically examine if there are any associations with clinical and demographic characteristics among patients in the United Arab Emirates (UAE). MethodsThe study included 169 T2DM patients and 209 healthy controls. Genomic DNA was isolated and genotyped using TaqMan real-Time PCR assays for the MTHFR C677T and A1298C polymorphisms. ResultsThere were no significant differences in genotype and haplotype distributions observed between groups. A significant association was observed between the C677T polymorphism and history of cerebrovascular accident (CVA) (p=0.0330), history of nephropathy (p=0.0280) and levels of LDL cholesterol (p=0.0409). Also, the A1298C polymorphism was associated with hypertriglyceridemia (p=0.0305) in T2DM patients. ConclusionThese findings demonstrate that the MTHFR gene polymorphisms are not related to T2DM in the Emirati population. However, these polymorphisms can be used as risk markers for CVA, nephropathy, high LDL cholesterol and triglycerides in T2DM patients and allow timely treatment.

Are the methylenetetrahydrofolate reductase 1298 and 677 gene polymorphisms related to optic glioma and hamartoma risk in neurofibromatosis type 1 patients?

The methylenetetrahydrofolate reductase (MTHFR) gene plays a key role in carcinogenesis through its effects on DNA synthesis and methylation and also has a significant role in the etiology of many disorders, such as diabetes, migraine, and cardiovascular disease. Neurofibromatoses (NF) are autosomal dominant inherited diseases that can affect tissues such as bone and skin and predispose individuals to tumor development in various parts of the nervous system or body. Optic nerve glioma and brain tumors are common in children with NF, and leukemia and lymphoma incidence is also higher than normal. We therefore aimed to investigate the possible relationship between the MTHFR gene polymorphism and accompanying tumors such as neurofibroma, hamartoma, and optic glioma in children with NF1 found to have the MTHFR 677 and MTHFR 1298 gene polymorphism in this study. We included 55 pediatric patients diagnosed with NF1 between 2005 and 2014 in the study group. The control group included 44 healthy subjects without acute or chronic disease findings. A significant relationship was found between the MTHFR A1298C polymorphism and the incidence of optic glioma (p=0.014) (AA vs. AC: OR 11, 95% CI 1.27-95.17; AA vs. CC: OR 7.33, 95% CI 0.35-150.70). We also found a significant relationship between the MTHFR C1298C polymorphism and the incidence of hamartoma (p=0.019) (AA vs. AC: OR 2.12, 95% CI 0.662-6.809; p=0.203). Epilepsy incidence was high in subjects with MTHFR C677C. The MTHFR A1298C, C1298C, and C677C gene polymorphisms can be associated with a higher optic glioma, hamartoma, and epilepsy incidence, respectively, in patients diagnosed with neurofibromatosis type 1.

Association of methylenetetrahydrofolate reductase gene polymorphisms with polycystic ovary syndrome

To assess the association of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene with the susceptibility to polycystic ovary syndrome (PCOS). Blood samples of 115 PCOS patients and 58 fertile women (for whom PCOS has been excluded) were collected for DNA extraction. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for determining the C677T and A1298C polymorphisms. A database has been set up with Epidata and a significance test was performed with a statistical analysis system. A significant difference has been found in the allele frequencies of MTHFR gene 677 C and T polymorphisms between the two groups (P<0.01), for which T allele has increased the risk for PCOS by 2.06 times. Heterozygous and homozygous genotypes at position 677 (CT and TT) were more common among PCOS cases than controls, with an OR of 3.91 (95%CI: 1.70-8.97) and 4.39 (95%CI: 1.77-10.89), respectively. There was no statistical difference in genotypic distribution of MTHFR gene A1298C polymorphism (P>0.05). In the PCOS group, there was a significant difference with an OR of 6.40 (95%CI: 1.71-23.95) for an increased risk of insulin resistance in homozygous C677T mutations (TT) compared with the wild genotype (CC, P<0.01). The PCOS group and the control group also differed significantly in their red blood cell folate levels (P<0.01), but not in serum vitamin B12 and homocysteine levels (P>0.05). MTHFR gene C677T polymorphism is associated with PCOS, for which CT and TT genotypes can increase the risk of PCOS. The TT genotype can also increase the risk of insulin resistance in PCOS patients. The A1298C polymorphism of the MTHFR gene is not associated with the occurrence of PCOS. The folate level in red blood cells of PCOS patients is lower, for whom folate should be supplemented.

A Meta-Analysis of the Relationship between MTHFR Gene A1298C Polymorphism and the Risk of Adult Stroke

Background: The association between methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and adult stroke remains controversial. The present article was designed to clarify this relationship through pooled analysis of the numerous epidemiological studies focusing on this association. Methods: We comprehensively searched all published papers in electronic database including PubMed, Embase, Web of Science, Chinese Biomedical Literature on disc (CBMdisc) and China National Knowledge Infrastructure (CNKI) up to 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for allelic (C allele vs. A allele), additive (CC vs. AA), dominant (CC+AC vs. AA), and recessive (CC vs. AA+AC) models were calculated. Subgroup and sensitivity analyses were performed to detect the heterogeneity and examine the reliability of results, respectively. Begg's funnel plots and Egger's regression test were used to assess the potential publication bias. Results: A total of fifteen studies containing 2,361 cases and 2,653 controls were included in the final meta-analysis. The combined results of overall analysis showed that there was significant association between MTHFR gene A1298C polymorphism and adult stroke (allelic model: OR = 1.36, 95% CI = 1.11-1.67; additive model: OR = 1.88, 95% CI = 1.12-3.18; dominant model: OR = 1.33, 95% CI = 1.08-1.65 and recessive model: OR = 1.77, 95% CI = 1.07-2.94, respectively). On subgroup analysis by ethnicity of study population, significant association was shown in meta-analysis based on Asian population (allelic model: OR = 1.40, 95% CI = 1.19-1.65; additive model: OR = 2.58, 95% CI = 1.34-4.96; dominant model: OR = 1.44, 95% CI = 1.20-1.73 and recessive model: OR = 2.12, 95% CI = 1.20-3.76, respectively), but not in Caucasian population (allelic model: OR = 1.30, 95% CI = 0.93-1.82; additive model: OR = 1.65, 95% CI = 0.81-3.33; dominant model: OR = 1.17, 95% CI = 0.86-1.61 and recessive model: OR = 1.70, 95% CI = 0.83-3.50, respectively). In addition, the heterogeneity was effectively removed or decreased by limiting the included studies with population of Asian ethnicity. Furthermore, the corresponding pooled ORs were not materially changed in all genetic models of meta-analysis after limiting the included studies with population-based controls. However, except the recessive model, publication bias presented in the allelic, additive, dominant models identified by the Begg's funnel plots and Egger's regression test. Conclusions: In conclusion, the overall analysis suggests that MTHFR gene A1298C polymorphism plays an important role in the development of adult stroke. Genotype CC of MTHFR-1298A/C could increase the risk of stroke and may act as a predictor for clinical evaluation, especially in the Asian population. More studies with large-scale and different ethnicities are required to further confirm our findings. i 2014 S. Karger AG, Basel