MTHFR A1298C Gene Polymorphisms Research Articles

The effects of folinic acid and l-methylfolate supplementation on serum total homocysteine levels in healthy adults

Hyperhomocysteinemia is recognized as a risk factor for several diseases and conditions. The aim of this study was to investigate and compare the efficacy of two total homocysteine (tHcy)-lowering treatments including folinic acid or l-methylfolate in healthy Greek adults. Two hundred and seventy-two healthy Greek adults (143 men, 129 women; mean age±SD: 43.0±15.3 years), with serum tHcy levels ≥10μmol/L received randomized folinic acid ("Folinic acid Group") or l-methylfolate ("l-methylfolate Group") orally for three months. All subjects with serum cobalamin (Cbl) levels <300pg/mL additionally received 1mg hydroxycobalamine intramuscularly twice a week for the first month only. Serum folate, Cbl and tHcy levels were determined using immunoassays methods at the beginning and the end of the study period. The MTHFR C677T and MTHFR A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. At the end of the 3-month intervention period, the levels of serum folate and Cbl increased significantly, whereas the levels of serum tHcy decreased significantly in the two groups. The individuals with MTHFR 677TT genotype had a significantly higher reduction in serum tHcy levels than the individuals with the MTHFR 677CC or MTHFR 677CT genotypes. Although the "Folinic acid Group" had a considerably higher increase in their serum folate levels (but not Cbl) than the "l-methylfolate Group", the reduction of serum tHcy levels between the two groups was not substantially different. The individuals with MTHFR 677CT genotype had a statistically significant higher reduction in serum tHcy levels when supplemented with folinic acid rather than l-methylfolate. The administration of folinic acid compared to l-methylfolate caused a higher increase of serum folate levels but no difference in the reduction of serum tHcy levels. The reduction of serum tHcy levels was influenced by the existence of MTHFR C677T and not MTHFR A1298C gene polymorphisms. The individuals with MTHFR 677CT genotype appear to benefit more by folinic acid than l-methylfolate supplementation.

Role of MTHFR 677C>T and 1298A>C gene polymorphisms on renal toxicity caused by lead exposure in wastewater treatment plant workers

Environmental and occupational lead (Pb) exposures continue to pose major public health problems. Wastewater treatment plant (WWTP) workers proved are exposing to high Pb concentrations in sludge departments. The aim of the work was to investigate the role of MTHFR C677T and MTHFR A1298C gene polymorphisms on alteration of oxidative stress and homocysteine levels in WWTP workers exposed to high Pb concentrations, and study its relations with renal functions. The study included 90 WWTP workers from Abu-Rawash WWTP. Homocysteine, creatinine, urea, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured. Polymorphisms of MTHFR C677CT and MTHFR A1298C genes were studied using PCR/RFLP. Urine Pb concentrations were also measured. About 32.2% of the workers were with detectable Pb levels. Pb, homocysteine, and MDA levels were significantly higher among workers carrying TT polymorphism compared to other MTHFR C677T gene polymorphisms, while TAC was significantly lower among them compared to other polymorphisms. The same results were found among workers carrying CC compared to other MTHFR A1298C gene polymorphisms. WWTP workers carrying MTHFR 677TT and MTHFR 1298CC are more susceptible to elevation of homocysteine and the urinary Pb compared to the workers with the other polymorphisms. Furthermore, those workers were found to have increase in urea and creatinine. Therefore, MTHFR C677T and MTHFR A1298C gene polymorphisms could be used for prediction of the susceptibility to the risk of kidney impairments among WWTP workers in the sludge departments caused by their exposure to high Pb in their workplace.

FOLINIC ACID OR L-METHYLFOLATE SUPPLEMENTATION FOR THE TREATMENT OF HYPERHOMOCYSTEINEMIA

Objective: Hyperhomocysteinemia (HHcy) is recognized as a risk factor for for cardiovascular disease. The aim of this study was to investigate and compare the efficacy of two tHcy-lowering treatments including FNA or L-methylfolate in healthy Greek adults. Design and method: Two hundred and seventy two (272) health Greek adults (143 men; mean age±SD: 43.0±15.3 years), with elevated serum tHcy levels (&gt;10 mmol/L) received randomized folinic acid (Group 1) or L-methylfolate (Group 2) orally both with hydroxycobalamine im for three months. Serum folate, Cbl and tHcy levels were determined using immunoassays methods at the beginning and the end of the study period. The MTHFR C677T and A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. Results: At the end of the 3-month intervention period the levels of serum folate and Cbl were significantly increased, whereas serum tHcy concentrations were significantly decreased in both groups. The individuals with 677TT genotype had significantly higher reduction of serum tHcy levels than individuals with the 677CC or 677CT genotypes. Although the individuals of Group 1 had significantly greater increase of their serum folate levels than those of Group 2, the reduction of serum tHcy concentrations between the two groups did not differ significantly. The individuals with 677CT genotype had statistically significant greater reduction of serum tHcy levels when received folinic acid than methylfolate supplementation. Conclusions: The tHcy-lowering treatment which included FNA supplementation compared to treatment which included L-methylfolate supplementation caused a greater increase of serum folate levels but no difference in reduction of serum tHcy levels. The reduction of serum tHcy levels was influenced by the existence of MTHFR C677T and not A1298C gene polymorphisms. The individuals with 677CT genotype appear to benefit more by the treatment which included FNA than L-methylfolate supplementation.

Associations of Serum Total Homocysteine Levels with Various Demographic, Clinical and Genetic Characteristics in Healthy Greek Adults.

The aim of this study was to investigate the association of serum total Hcy (tHcy) levels with various demographic, clinical and genetic characteristics in healthy Greek adults. Anthropometric characteristics (height, weight), systolic and diastolic blood pressure, complete blood count and biochemical assessments, were recorded and measured among 383 Greek adults (199 men). Serum folate, Cobalamin (Cbl) and tHcy levels were determined using immunoassays methods. The MTHFR C677T and A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. MTHFR C677T gene polymorphism, serum folate and Cbl levels were correlated with serum tHcy levels independently. The individuals with 677TT genotype had significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. Regarding the MTHFR C677T gene polymorphism, the existence of the T allele was associated with statistically significantly lower serum folate and higher serum tHcy levels than C allele. Regarding the MTHFR A1298C gene polymorphism, the existence of the C allele was associated with statistically significant lower serum tHcy levels than A allele. Furthermore, there was no significant correlation between the serum tHcy levels and demographic (except age) or clinical characteristics (sex, BMI, smoking status, SBP, DBP, HGB, HCT, TC, TG, HDL-C, LDL-C, TC/HDL-C). Serum tHcy levels are influenced by the existence of MTHFR C677T gene polymorphism (mainly 677TT genotype), serum folate and Cbl levels. Individuals with hyperhomocysteinemia should be further investigated for the existence of MTHFR C677T gene polymorphism, with the aim to determine the suitable treatment.

Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome: A protocol for systematic review and/or meta-analysis.

Background:Down syndrome (DS) is one of the most common chromosomal abnormalities among live-born babies and one of the best-known intellectual disability disorders in humans. Errors leading to trisomy 21 are primarily arising from defects in chromosomal segregation during maternal meiosis (about 88% of cases), and the focus of many investigations has been to identify maternal risk factors favoring chromosome 21 malsegregation during oogenesis. Maternal polymorphisms of genes required for folate metabolism are the most investigated risk factors for the birth of children with DS. Through this review, we sought to investigate the association of the polymorphisms “C677T” and “A1298C” of the MTHFR gene with maternal risk for DS.Methods:We will use the databases PubMed, Embase, Scopus and Web of Science to search for case-control studies published from 1999 up to September 2021 without language restriction. Results will be presented as relative risks and 95% confidence intervals for dichotomous outcomes and mean differences, or standardized mean differences along with 95% confidence intervals, for continuous outcomes. The all data synthesis will be analyzed on the Review Manager 5.2 version software.Results:This study will be able to clarify all the doubts we seek and that it will be able to provide accurate data that will be able to describe how these polymorphisms can act to increase the predisposition for the birth of children with DS in different populations and under different dietary conditions.Conclusions:This study will clarify the relationship between C677T and A1298C polymorphisms MTHFR gene with increased the maternal risk for Down syndrome.Registration:This systematic review and meta-analysis protocol has been registered on the Prospective Registry of International Systematic Review and Meta-analyses: CRD42021269338.

Impact of MTHFR C677T and A1298C gene polymorphisms on MTX drug toxicity and efficacy profile of RA patients in North India

ObjectiveTo investigate the effect of two different methylenetetrahydrofolate (MTHFR) gene loci C677T and A1298C polymorphisms on Rheumatoid arthritis (RA) and their association in response to methotrexate (MTX) therapy. Subjects and methods110 individuals (60 RA patients and 50 healthy controls) were enrolled from different regions of north India. MTX drug response was evaluated by questionnaire data analysis, disease activity score (DAS-28) and analysis of hepatic, renal and other serological parameters. MTHFR C677T and A1298C polymorphisms were genotyped using restriction fragment length polymorphism- polymerase chain reaction (RFLP-PCR). Independent t-test was applied to compare the means and ANOVA with Bonferroni correction for multiple comparison of genotypically classified groups. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by applying χ2 test, p-value < .05 was considered significant. ResultsThe study found significant differences in all the serological parameters of controls and RA patients except protein and serum SGPT. Elevated transaminases, triglycerides, cholesterol, creatinine, C-reactive protein (CRP), uric acid and albumin are the indicators of MTX adverse effects along with disease severity. Questionnaire analysis showed loss of appetite, weak digestion, low BMI, and weight loss are common features in all the patients after starting MTX therapy. Significant association was found between 677TT genotype with elevated levels of triglycerides. While other parameters such as SGOT, SGPT, CRP, uric acid and cholesterol were insignificantly higher in patients with 677TT polymorphism. 1298CC polymorphism was associated with high CRP levels and 1298 AC with higher triglycerides along with cholesterol in RA patients. However, in controls, only albumin showed significant association with 1298AA genotype. Association of MTHFR C677T polymorphism was insignificant (677CT- OR: 0.905, 95%CI: 0.355–2.307; 677TT- OR: 1.035, 95%CI: 0.338–3.989; p-value = 1) and A1298C polymorphism was also insignificant (1298AC- OR: 0.562, 95%CI: 0.200–1.575, p-value = .4; & 1298CC- OR: 0.502, 95%CI: 0.146–1.717 with p-value = .403) with RA. ConclusionThe results of this study suggest that none of these alleles are predictive for RA disease susceptibility. However, it has a significant impact on its severity with respect to CRP, triglycerides and cholesterol.

The Genetic Profile of Thrombophilia in Reproductive Disorders

Some cases of reproductive disorders have a thrombotic etiology. Considering the importance of establishing the cause of miscarriage, we investigated the incidence and associated risks of the most common thrombophilic genes polymorphism - FV G1691A, FV H1299A, Prothrombin G20210A, PAI-1, Factor XIII V34L, MTHFR C677T, MTHFR A1298C and EPCR genes, in women with reproductive disorders. In our research we included 139 women with reproductive disorders and risk for hereditary trombophilia and 139 healthy females without any personal or family history of vein thrombosis or recurrent pregnancy loss. For detection of thrombophilic genes polymorphism we used CVD StripAssay�(ViennaLab, Austria) and the tests� protocols were followed as described by the manufacturer. Our results showed that the concomitant presence of MTHFR A1298C and Factor XIII V34L gene polymorphism had a significant association for recurrent pregnancy loss, while FV H1299A (R2) and MTHFR A1298C gene polymorphisms were correlated with subfertility. We therefore consider that these patients should be recognized as high risk for poor pregnancy outcomes and monitored with specialized follow-up.

The Genetic Profile of Thrombophilia in Reproductive Disorders

Some cases of reproductive disorders have a thrombotic etiology. Considering the importance of establishing the cause of miscarriage, we investigated the incidence and associated risks of the most common thrombophilic genes polymorphism - FV G1691A, FV H1299A, Prothrombin G20210A, PAI-1, Factor XIII V34L, MTHFR C677T, MTHFR A1298C and EPCR genes, in women with reproductive disorders. In our research we included 139 women with reproductive disorders and risk for hereditary trombophilia and 139 healthy females without any personal or family history of vein thrombosis or recurrent pregnancy loss. For detection of thrombophilic genes polymorphism we used CVD StripAssay�(ViennaLab, Austria) and the tests� protocols were followed as described by the manufacturer. Our results showed that the concomitant presence of MTHFR A1298C and Factor XIII V34L gene polymorphism had a significant association for recurrent pregnancy loss, while FV H1299A (R2) and MTHFR A1298C gene polymorphisms were correlated with subfertility. We therefore consider that these patients should be recognized as high risk for poor pregnancy outcomes and monitored with specialized follow-up.

Prevalence of factor V leiden, MTHFR C677T and MTHFR A1298C polymorphisms in patients with deep vein thrombosis in Central Iran.

Deep vein thrombosis (DVT) is a common disease, especially among elderly patients, which is associated with high costs of treatment and high rates of recurrence. The risk factors for venous thrombosis are primarily related to hypercoagulability, which can be genetic or acquired, or because of immobilization and venous stasis. Among relevant genetic markers are a number of common polymorphisms and mutations in the genes coding for Factor V leiden and methylenetetrahydrofolate reductase. Differential associations of these polymorphisms have been reported in different populations with DVT due to ethnic variations. However, no study has been reported with respect to these polymorphisms in DVT in Iran. Thus, the aim of the present study is to determine the prevalence of FVL, MTHFR C677T and MTHFR A1298C gene polymorphisms in patients with DVT in central Iran. In the present cross-sectional study, a total of 100 patients with first and recurrent episodes of DVT and age less than 70years were recruited during 2016-2017. Blood sample was collected from the recruited patients and FVL mutation was screened using ARMS-PCR method, MTHFR C677T and MTHFR A1298C mutations were screened using PCR-RFLP method. The results revealed that MTHFR A1298C gene polymorphism in both homozygote and heterozygote form was found to be most frequent i.e. 77% among cases, followed by MTHFR C677T (67%) and FVL (17%). The study highlights the importance of screening of these genetic markers among patients with DVT in this region.

MTHFR C677T and A1298C polymorphisms may contribute to the risk of Parkinson's disease: A meta-analysis of 19 studies.

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been reported to be a candidate gene for susceptibility to Parkinson's disease (PD), but results of different studies are conflicting. Here, we conducted a meta-analysis of published case-control studies to evaluate the association between MTHFR C677T and A1298C gene polymorphisms with the risk of PD. Electronic search through PubMed, EmBase, ScienceDirect and Cochrane Library was conducted to identify all relevant studies. A total of 19 studies with 2746 cases and 8967 controls were included. No significant association between MTHFR C677T polymorphism and PD risk was found in the overall population in all five genetic models. In the subgroup analysis stratified by ethnicity, a significant association between MTHFR C677T and PD risk was observed in the dominant model in Caucasians (OR=1.175, 95%CI: 1.008-1.369, P=0.040), but not in Asians. Significant association was found between MTHFR A1298C polymorphism and PD risk in the overall population in the dominant (OR=1.168, 95%CI: 1.008-1.353, P=0.039) and heterozygous model (OR=1.172, 95%CI: 1.004-1.367, P=0.044). But in the subgroup analysis, no association was found between MTHFR A1298C and PD neither in Caucasians nor in Asians. Our meta-analysis suggests that MTHFR C677T polymorphism may be associated with increased PD risk in Caucasians and MTHFR A1298C polymorphism may also increase susceptibility to PD.

MTHFR C677T, A1298C and MS A2756G Gene Polymorphisms and Male Infertility Risk in a Chinese Population: A Meta-Analysis.

BackgroundMethylenetetrahydrofolate reductase gene (MTHFR C677T and A1298C) and methionine synthase gene (MS A2756G) polymorphisms have shown an association with male infertility risk in several ethnic populations. Although several studies have evaluated these associations in Chinese populations, their small sample sizes and inconsistent outcomes have prevented strong conclusions. Therefore, the present meta-analysis was performed with published studies to evaluate the associations of the three single nucleotide polymorphisms (SNPs) and male infertility in a Chinese population.MethodsWe conducted a search of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), China biology medical literature (CBM), VIP, and Chinese literature (Wan Fang) databases up to May 31, 2016. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were used to assess the strength of associations with a random-effect model or a fixed-effect model based on the heterogeneity analysis results. Sensitivity analysis was used to confirm the reliability and stability of the meta-analysis.ResultsA total of nine studies, including 1,713 cases and 1,104 controls, were included in the meta-analysis. The pooled results indicated that the MTHFR C667T polymorphism was significantly associated with increased risk of male infertility in the Chinese population in the allele model (T vs. C: OR = 1.47, 95%CI = 1.32–1.63), the dominant model (TT + CT vs. CC: OR = 1.51, 95%CI = 1.30–1.77), the additive model (TT vs. CC: OR = 2.08, 95%CI = 1.68–2.58) and the recessive model (TT vs. CT+CC: OR = 1.58, 95%CI = 1.31–1.90), whereas the MTHFR A1298C and MS A2756G polymorphisms were not risk factors. There was no significant heterogeneity in any genotype contrasts among the studies. The sensitivity analysis indicated that the results of this meta-analysis were relatively stable.ConclusionThis study suggests that the MTHFR C667T polymorphism may contribute to the genetic susceptibility to male infertility in the Chinese population, whereas MTHFR A1298C and MS A2756G polymorphisms may be unrelated to male infertility. Studies with larger sample sizes and representative population-based cases and well-matched controls are needed to validate our results.

MTHFR C677T and A1298C Gene Polymorphisms and Ischemic Heart Disease (IHD) in a Sri Lankan Population - A Preliminary Study

MTHFR C677T and A1298C Gene Polymorphisms and Ischemic Heart Disease (IHD) in a Sri Lankan Population - A Preliminary Study

Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for preeclampsia: a meta-analysis.

MTHFR C677T and A1298C have been associated with the risk of preeclampsia (PE), but with conflicting results. We performed this meta-analysis to derive a more precise estimation of the association between MTHFR polymorphisms and PE. An electronic search of PubMed and Chinese Biomedicine database was conducted to select studies for meta-analysis. 54 case controlled studies containing MTHFR C677T and A1298C gene polymorphisms were chosen, and odds ratio (OR) with confidence interval (CI) was used to assess the strength of this association. These studies evaluated 7398 cases and 11230 controls for MTHFR C677T. The overall results suggested that MTHFR C677T was associated with the risk of PE. (T vs. C: OR = 1.157, 95% CI: 1.057-1.266, p = 0.002; TT + CT vs. CC: OR = 1.165, 95% CI : 1.049-1.293, P = 0.004; TT vs. CT + CC: OR = 1.371, 95% CI: 1.153-1.63, p < 0.001). We also evaluated 1103 cases and 988 controls for MTHFR A1298C but could not demonstrate an increased risk of PE for this polymorphism (p = 0.667). A symmetric funnel plot, the Egger's test (p = 0.819) suggested a lack of publication bias. This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk for PE, especially in the case of Asians and Caucasians.

Serum Homocysteine and MTHFR C677T and A1298C gene polymorphisms in Type 2 Diabetic Patients with Nephropathy in Sector of Egyptian Population

Serum Homocysteine and MTHFR C677T and A1298C gene polymorphisms in Type 2 Diabetic Patients with Nephropathy in Sector of Egyptian Population

MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases

ObjectiveTo investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children. Material and methodsMTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method. ResultsWe found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD. ConclusionsOur study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD.

Folate Metabolism Gene Polymorphisms MTHFR C677T and A1298C and Risk for Down Syndrome Offspring

Abstract Objectives MTHFR C677T and A1298C have been associated with the risk of having an infant with Down syndrome (DS), but results were conflicting. We performed this meta-analysis to derive a more precise estimation of the association between maternal MTHFR polymorphisms and DS. Study design An electronic search of PubMed and Chinese Biomedicine database was conducted to select studies for meta-analysis. Twenty-eight case–control studies containing MTHFR C677T and A1298C gene polymorphisms were chosen, and odds ratio (OR) with confidence interval (CI) was used to assess the strength of this association. Results Case–control studies including 2806 cases and 4597controls for MTHFR C677T were identified. The overall results suggested that the variant genotypes MTHFR C677T were associated with DS risk (TT+CT vs. CC: OR = 1.305, 95% CI: 0.125–1.514, p = 0). In the stratified analysis, individuals with the T-carriers genotype in the dominant model had increased risk of DS (OR = 1.171, 95% CI: 0.976–1.405, p = 0.09) in Caucasian subjects and in Asian subjects (OR = 1.749, 95% CI: 1.084–2.824, p = 0.022). In addition, case–control studies including 1854 cases and 2364 controls for MTHFR A1298C were chosen. Associations between MTHFR A1298C and the risk of having a child with DS were not found. A symmetric funnel plot, the Egger's test (p = 0.126) suggested a lack of publication bias. Conclusion This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk for DS offspring.

Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for Down syndrome offspring: a meta-analysis

MTHFR C677T and A1298C have been associated with the risk of having an infant with Down syndrome (DS), but results were conflicting. We performed this meta-analysis to derive a more precise estimation of the association between maternal MTHFR polymorphisms and DS. An electronic search of PubMed and Chinese Biomedicine database was conducted to select studies for meta-analysis. Twenty-eight case-control studies containing MTHFR C677T and A1298C gene polymorphisms were chosen, and odds ratio (OR) with confidence interval (CI) was used to assess the strength of this association. Case-control studies including 2806 cases and 4597controls for MTHFR C677T were identified. The overall results suggested that the variant genotypes MTHFR C677T were associated with DS risk (TT+CT vs. CC: OR=1.305, 95% CI: 0.125-1.514, p=0). In the stratified analysis, individuals with the T-carriers genotype in the dominant model had increased risk of DS (OR=1.171, 95% CI: 0.976-1.405, p=0.09) in Caucasian subjects and in Asian subjects (OR=1.749, 95% CI: 1.084-2.824, p=0.022). In addition, case-control studies including 1854 cases and 2364 controls for MTHFR A1298C were chosen. Associations between MTHFR A1298C and the risk of having a child with DS were not found. A symmetric funnel plot, the Egger's test (p=0.126) suggested a lack of publication bias. This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk for DS offspring.

Relationships among MTHFR a1298c Gene Polymorphisms and Methylation Status of Dact1 Gene in Transitional Cell Carcinomas

The purpose of this study was to determine the relationship between methylation status of the Dact1 gene and MTHFR a1298c polymorphic forms in transitional cell carcinoma tissues in a Chinese population. Polymorphisms of folate metabolism enzyme gene MTHFR were assessed by restrictive fragment length polymorphism (RFLP) methods and PCR-based DNA methylation analysis was used to determine the CpG island methylation status of the Dact1 gene. Associations between the methylation status of the Dact1 gene and clinical characteristics, as well as MTHFR a1298c polymorphisms, were analyzed. aberrant methylation of the Dact1 gene was found in 68.3% of cancer tissues and 12.4% of normal tissues,. The methylation rate of the Dact1 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs. 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables, variant allele of MTHFR a1298c was found to be associated with methylation of the Dact1 gene. Compared with wild type CC, the odds ratio was 4.33 (95% CI: 1.06-10.59) for AC and 4.95 (95% CI: 1.18-12.74) for AA. The N stage in TNM staging and the occurrence of lymph node metastasis were associated with an MTHFR 1298 AAμAC genotype (P<0.05). MTHFR 1298 AC and AA genotypes might help maintain a normal methylation status of the Dact1 gene, aberrant CpG island methylation of which is closely related to the genesis and progression of transitional cell carcinoma.

MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms

Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83-1.32) and OR=0.81 (95% CI 0.53-1.24), respectively; toxicity: OR=1.38 (95% CI 0.90-2.12) and OR=1.19 (95% CI 0.80-1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.

MTHFR Gene Polymorphisms and Response to Chemotherapy in Colorectal Cancer: A Meta-Analysis

Pharmacogenetic studies investigating the relationship between MTHFR gene polymorphisms and response to fluorouracil-based chemotherapy in patients with colorectal cancer have produced inconclusive results. In an attempt to interpret these results, a meta-analysis of all eligible studies published up until January 2009 was carried out. A total of ten studies relating MTHFR C677T and six studies relating MTHFR A1298C to the response to chemotherapy in patients with colorectal cancer were included in the meta-analysis and random effects pooled odds ratios were estimated. The heterogeneity between studies, the sources of potential bias and the consistency of genetic effects across ethnicities were explored. Cumulative and recursive cumulative meta-analyses were also performed. For both the C677T and A1298C polymorphisms, the main analysis revealed nonsignificant heterogeneity and a lack of association under the allele contrast, the recessive and dominant models. The subgroup analysis by ethnicity did not change this pattern of results. The lack of stability of the relative change of odds ratio in the recursive cumulative meta-analysis for both polymorphisms indicated the need for more evidence to support a definite lack of association. There was no differential magnitude of the effect in large versus small studies. The available evidence indicates that MTHFR C677T and A1298C gene polymorphisms cannot be considered as reliable predictors of response to fluorouracil-based chemotherapy in patients with colorectal cancer.