MTHFR A1298C Polymorphisms Research Articles

Duboka venska tromboza i rekurentna plućna embolija kod pacijenta sa trombofiličnim mutacijama i generalizovanom psorijazom - prikaz slučaja

Abstract: Introduction: Genetic risk factors that increase venous thromboembolism risk are disorders in the synthesis or activity of coagulation factors. Factor V Leiden, prothrombin (20210-A), antithrombin deficiency, protein C and protein S deficiency, and hyperhomocysteinemia are the most common venous thromboembolism-related gene mutations. When genetic factors are combined with non-provoking risk factors (obesity, psoriasis, smoking and previous venous thromboembolism) the result is increased venous thromboembolism risk for each factor individually. Previous venous thromboembolism is one of the strongest risk factors, even in patients actively treated with anticoagulants. Patients are more likely to have recurrent venous thromboembolism with longer duration. Psoriasis is a complex immune-mediated disease, associated with cardiovascular risk, hypercoagulability markers and elevated homocysteine. Lots of observational reports suggest increased incidence of venous thromboembolic events in patient with psoriasis. Case presentation: We present patient with inherited thrombophilia and chronic diffuse plaque psoriasis complicated with deep venous thrombosis and pulmonary embolism. DNA analysis indicates the presence of homozygosis for Factor V Leiden mutation as well as heterozygosis for Factor XIII V34L, PAI-1 5G/4G and MTHFR A1298C polymorphism. Dermatological anamnesis is positive for plaque psoriasis since 12 years ago. Conclusion: The presentation of this case indicates an association between venous thromboembolism and chronic psoriasis. All patients with recurrent thromboembolism, hereditary thrombophilia, and moderate to severe psoriasis should be considered to be at higher risk for venous thromboembolism and appropriately treated.

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.

One‑carbon metabolism factor MTHFR variant is associated with saccade latency in Spinocerebellar Ataxia type 2

BackgroundSpinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder due to a CAG-repeat expansion. This work is intended to identify modifiers of the clinical phenotype in SCA2, following up on recent genome-wide association analyses that demonstrated the prominent role of DNA-damage repair and methylation for the severity and progression of polyglutamine diseases. In particular, we assessed the impact of MTHFR as rate-limiting enzyme in DNA methylation pathways, which modulates cerebellar neurotransmission and motor neuron atrophy. MethodsA sample of 166 Cuban SCA2 patients and of 130 healthy subjects from the same geographical and ethnic background was selected. The ATXN2 CAG repeat length was determined by PCR followed by polyacrylamide gel electrophoresis. Two amino acid substitutions known to decrease the enzyme activity of MTHFR, encoded by C677T and A1298C polymorphisms, were assessed by PCR/RFLP. ResultsNo significant differences were observed for C677T or A1298C alleles or genotype frequencies between cases and controls, confirming that disease risk in SCA2 does not depend on MTHFR activity. However, MTHFR A1298C genotypes showed a significant association with saccade latency. Conclusions\\MTHFR A1298C polymorphism is associated with saccade latency in SCA2 patients, but not with disease risk, age at onset or maximal saccade velocity. These results provide evidence that folate-mediated one‑carbon metabolism might be important in the physiopathology of SCA2.

Can the genetic polymorphisms of the folate metabolism have an influence in the polycystic ovary syndrome?

To investigate the association of the genetic variants of the folate metabolism genes (MTHFR C677T; MTHFR A1298C; MTR A2756G; MTRR A66G and RFC-1 A80G) with the development of polycystic ovary syndrome (PCOS). This study included 203 women (99 women with PCOS and 104 controls). The genotyping was performed by PCR-RFLP. Chi-squared test and multiple logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the SNPstat program. The results were presented in odds ratio (OR) and confidence interval of 95% (CI-95%), with a significance level of 5% (p ≤ 0.05). The genotypic distribution of the RFC-1 A80G polymorphism showed significant difference between the two groups, showing that the heterozygous genotype (AG genotype) was most frequent in controls. The polymorphic homozygous (GG genotype) of MTRR A66G polymorphism were most frequent in controls. The T-C haplotype MTHFR C677T and A1298C polymorphisms were more frequent in the control group (OR = 0.19; CI 95% - 0.04 to 0.93 e p = 0.042). The multivariate analysis evidenced that family history of PCOS was more frequent in the PCOS group (OR = 3.29; CI 95% - 1.48 to 7.31; p = 0.003). In our casuistry, the polymorphic homozygous of MTRR A66G polymorphism gene and heterozygous of RFC-1 A80G polymorphism gene, the haplotype T-C C677T and A1298C polymorphisms of MTHFR gene, can be associated with protective factors for the disease.

Maternal Haplotypes in DHFR Promoter and MTHFR Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency: Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS)

Childhood acute lymphoblastic leukemia (ALL) peaks around age 2–4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated DHFR and MTHFR gene variants in 235 ALL children and their mothers to disclose their role in determining ALL onset age and survival. Pyrosequence of DHFR 19bp ins/del (rs70991108; W/D), MTHFR C677T (rs1801133; C>T), and MTHFR A1298C (rs1801131; A>C) was assessed in children and in 72% of mothers for dyad-analysis comparison. DHFR DD-children had delayed ALL onset compared to WW-children (7.5 ± 4.8 vs. 5.2 ± 3.7 years; P = 0.002) as well as MTHFR 1298 CC-children compared to AA-children (8.03 ± 4.8 vs. 5.78 ± 4.1 years; P = 0.006), and according to the strong linkage disequilibrium between MTHFR 677 T-allele and 1298C-allele, MTHFR TT-children showed early mean age of onset though not significant. Offspring of MTHFR 677 TT-mothers had earlier ALL onset compared to offspring of 677 CC-mothers (5.4 ± 3.3 vs. 7 ± 5.3 years; P = 0.017). DHFR/MTHFR 677 polymorphism combination influenced onset age by comparing DD/CC vs. WW/TT children (8.1 ± 5.7 vs. 4.7 ± 2.1 years; P = 0.017). Moreover, mother-child genotype combination gave 5.5-years delayed onset age in favor of DD-offspring of 677 CC-mothers vs. WW-offspring of 677 TT-mothers, and it was further confirmed including any D-carrier children and any 677 T-carrier mothers (P = 0.00052). Correction for multiple comparisons maintained statistical significance for DHFR ins/del and MTHFR A1298C polymorphisms. Unexpectedly, among the very-early onset group (<2.89 years; 25th), DD-genotype inversely clustered in children and mothers (4.8% vs. 23.8% respectively), and accordingly ALL offspring of homozygous DD-mothers had increased risk to have early-onset (adjusted OR (odds ratio) = 3.08; 1.1–8.6; P = 0.03). The opposite effect DHFR promoter variant has in tuning ALL onset-time depending on who is the carrier (i.e., mother or child) might suggest a parent-origin-effect of the D-allele or a two-faced epigenetic role driven by unbalanced folate isoform availability during the in-utero leukemogenesis responsible for the wide postnatal childhood ALL latency.

Association of MTHFR C677T and A1298C Polymorphisms with Glaucoma Risk: a Systematic Review Meta-Analysis based 42 Case-Control Studies

Aim: Several epidemiological studies have been performed to explore the association of MTHFR polymorphisms with glaucoma risk. However, the results were inconsistent or even inconclusive. Hence, we performed a meta-analysis to evaluate the association of MTHFR C677T and A1298C polymorphisms with glaucoma risk. Methods: A comprehensive literature search on PubMed, Google Scholar, EMBASE, and CNKI databases was performed to find all eligible studies up to January 30, 2019. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of such association. Results: A total of 42 case-control studies including 33 studies for MTHFR C677T and nine studies for A1298C polymorphism were selected. Pooled results showed that there was no significant association between the MTHFR C677T polymorphism and glaucoma risk. Similarly, no associations were found in subgroup analysis based on ethnicity and glaucoma type. However, there was a significant association between the A1298C polymorphism and the increased risk of glaucoma under heterozygote model (OR=0.765, 95% CI=0.626-0.935, P=0.009). Moreover, the significant association between MTHFR A1298C polymorphism and glaucoma were found by ethnicity and primary open angle glaucoma (POAG). Conclusions: The present meta-analysis revealed that MTHFR A1298C polymorphism is significantly associated with the increased risk of glaucoma, but not MTHFR C677T polymorphism.

Association of MTHFR C677T, MTHFR A1298C, and MTRR A66G Polymorphisms with Neural Tube Defects in Tunisian Parents

Objective: This study aims to investigate the association of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms with neural tube defects (NTDs) in a Tunisian population. Methods: Genotyping was performed by polymerase chain reaction with restriction fragment length polymorphisms (PCR-RFLPs) using the restriction enzymes. Allele and genotype frequencies were compared between mothers and fathers of fetuses with NTDs with matched controls based on an association analysis using SPSS software. Results: MTHFR (C677T, A1298C) and MTRR A66G polymorphisms were found to be protector factors for NTD fetuses in the mother group. In addition, a combination of the three wild-type alleles C677/A1298/A66 has increased four-fold the incidence of NTDs (p = 0.004, OR = 3.96, 95% CI: 1.53–10.23). In the father group, MTHFR C677T was a risk factor for NTDs. However, no association was found between MTHFR A1298C, MTRR A66G, and the occurrence of this anomaly. The analysis of MTHFR C677T and MTRR A66G polymorphisms has demonstrated a significant difference in vitamin B₁₂ levels between recessive and dominant genotypes in case mothers (p < 0.05). Conclusion: Additional studies are required to better understand the roles of parental gene polymorphisms related to folate-homocysteine metabolism in the pathogenesis of NTD.

Common Variations in Prothrombotic Genes and Susceptibility to Ischemic Stroke in Young Patients: A Case-Control Study in Southeast Iran.

Background and Objective: Evidence indicates that genetic factors may be involved in the risk of ischemic stroke (IS). The aim of this study was to assess the effect of genetic polymorphisms located in exons or untranslated regions of MTHFR as well as FV genes on ischemic stroke. Materials and Methods: In this case-control study, 106 patients with IS and 157 healthy volunteers (age <50 years) were genotyped for MTHFR C677T, A1298C, C2572A and C4869G, FVL, and prothrombin G20210A polymorphisms. Results: The MTHFR 677CT genotype was more frequent in patients and increased risk of IS with Odds Ratio = 1.9. The MTHFR A1298C and C2572A polymorphisms were not associated with IS in dominant and recessive models. Our findings showed a significant decrease in the MTHFR 4869CG genotype in IS patients, and this variant was associated with a decreased risk of IS in the dominant model. The CAAT haplotype was associated with increased risk, and the GAAC haplotype was associated with decreased risk of IS compared to other haplotypes. There was no relation between FVL G1691A polymorphism and IS risk. Conclusions: The present study showed that the MTHFR 677CT genotype was more frequent and the MTHFR 4869CG genotype was less frequent in young IS patients.

The relevance of MTHFR C677T, A1298C, and MTRR A66G polymorphisms with response to male infertility in Asians

Although published studies have reported the association between MTHFR C677T (rs 1801133), A1298C (rs 1801131), and MTRR A66G (rs1801394) polymorphisms and male infertility in Asian populations, the results are conflicting. In order to accurately evaluate the relevance, a meta-analysis was performed.We searched for potential studies in 4 databases, containing PubMed, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang database until May 31, 2018. The summarized odds ratio (OR) with 95% confidence intervals (95% CI) were calculated to evaluate the relevance in 5 genetic models. The heterogeneity test, sensitivity analysis, and publication bias test was performed by Review Manager 5.3 software.Overall, 22 case–control studies with 5049 cases and 4157 controls were included in this meta-analysis, which contained 20 studies of MTHFR C677T polymorphism, 12 studies of MTHFR A1298C polymorphism and 4 studies of MTRR A66G polymorphism. The results indicated that MTHFR C677T, A1298C, and MTRR A66G polymorphisms were significantly associated with male infertility in Asian populations (Dominant model: MTHFR CC + CT vs TT: OR = 0.60, 95% CI (0.53, 0.67), P <.00001; MTHFR AA + AC vs CC: OR = 0.62, 95% CI (0.49, 0.79), P = .0001; MTRR AA + AG vs GG: OR = 0.60, 95% CI (0.45, 0.81), P = .001. Recessive model: MTHFR CC vs CT + TT: OR = 0.67, 95% CI (0.61, 0.74), P <.00001; MTHFR AA vs AC + CC: OR = 0.79, 95% CI (0.70, 0.88), P <.0001; MTRR AA vs AG + GG: OR = 0.70, 95% CI (0.56, 0.88), P = .002. Heterozygote model: MTHFR CC vs CT: OR = 0.74, 95% CI (0.67, 0.82), P <.00001; MTHFR AA vs AC: OR = 0.83, 95% CI (0.73, 0.93), P = .002; MTRR AA vs AG: OR = 0.76, 95% CI (0.60, 0.92), P = .02. Homozygote model: MTHFR CC vs TT: OR = 0.48, 95% CI (0.41, 0.56), P <.00001; MTHFR AA vs CC: OR = 0.61, 95% CI (0.39, 0.93), P = .02; MTRR AA vs GG: OR = 0.51, 95% CI (0.36, 0.72), P = .0001. Allele model: MTHFR C vs T: OR = 0.70, 95% CI (0.66, 0.75), P <.00001; MTHFR A vsC: OR = 0.82, 95% CI (0.71, 0.95), P = .01; MTRR A vs G: OR = 0.76, 95% CI (0.66, 0.88), P = .00003). Stratified analyses by geographical location and source of controls showed the same results. Sensitivity analyses indicated that the final consequences of this meta-analysis were stable, and the publication biases test had not found obvious asymmetry.This meta-analysis indicates that MTHFR C677T, A1298C, and MTRR A66G polymorphisms are the risk factors with susceptibility to male infertility in Asians.

A Look Back at 2018

A Look Back at 2018

The association between maternal methylenetetrahydrofolate reductase C677T and A1298C polymorphism and birth defects and adverse pregnancy outcomes.

Published studies indicate the MTHFR C677T and A1298C polymorphisms are associated with abnormal homocysteine levels, which may cause various pregnancy complications and birth defects. However, the results obtained from different studies have been inconsistent. Therefore, this meta-analysis explores the association between MTHFR polymorphisms and birth defects and adverse pregnancy outcomes. The PubMed, ScienceDirect, Embase, and China Biology Medicine literature databases and ClinicalTrials were searched. Analyses of public bias, meta-regression, subgroups, and sensitivity were used to ensure the robustness of our results. MTHFR C677T was significantly associated with recurrent pregnancy loss in developing countries (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.20-1.50) but not in developed countries (OR, 0.87; 95% CI, 0.68-1.11). No significant relationship was found between MTHFR A1298C and recurrent pregnancy loss (OR, 1.04; 95% CI, 0.93-1.18). MTHFR C677T and A1298C were not associated with preeclampsia (OR, 1.06; 95% CI, 0.97-1.16 and OR, 1.16; 95% CI, 0.97-1.39, respectively), and C677T was not associated with placental abruption (OR, 1.03; 95% CI, 0.87-1.21), intrauterine growth retardation (OR, 1.02; 95% CI, 0.90-1.15), or congenital heart disease (OR, 1.05; 95% CI, 0.89-1.25). MTHFR C677T, but not A1298C, was associated with neural tube defects (OR, 1.24; 95% CI, 1.08-1.42) and Down syndrome (OR, 1.65; 95% CI, 1.39-1.95). CONCLUSION: Although MTHFR C677T and A1298C are significantly associated with some types of congenital defects and adverse pregnancy outcomes, the impact of these polymorphisms is moderate.

Genetic variation in folate metabolism is associated with the risk of conotruncal heart defects in a Chinese population

BackgroundConotruncal heart defects (CTDs) are a subgroup of congenital heart defects that are considered to be the most common type of birth defect worldwide. Genetic disturbances in folate metabolism may increase the risk of CTDs.MethodsWe evaluated five single-nucleotide polymorphisms (SNPs) in genes related to folic acid metabolism: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), solute carrier family 19, member 1 (SLC19A1 G80A), methionine synthase (MTR A2576G), and methionine synthase reductase (MTRR A66G), as risk factors for CTDs including various types of malformation, in a total of 193 mothers with CTD-affected offspring and 234 healthy controls in a Chinese population.ResultsLogistic regression analyses revealed that subjects carrying the TT genotype of MTHFR C677T, the C allele of MTHFR A1298C, and the AA genotype of SLC19A1 G80A had significant 2.47-fold (TT vs. CC, OR [95% CI] = 2.47 [1.42–4.32], p = 0.009), 2.05–2.20-fold (AC vs. AA, 2.05 [1.28–3.21], p = 0.0023; CC vs AA, 2.20 [1.38–3.58], p = 0.0011), and 1.68-fold (AA vs. GG, 1.68 [1.02–2.70], p = 0.0371) increased risk of CTDs, respectively. Subjects carrying both variant genotypes of MTHFR A1298C and SLC19A1 G80A had a higher (3.23 [1.71–6.02], p = 0.0002) increased risk for CTDs. Moreover, the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms were found to be significantly associated with the risk of certain subtypes of CTD.ConclusionsOur data suggest that maternal folate-related SNPs might be associated with the risk of CTDs in offspring.

The association between MTHFR gene polymorphisms (C677T, A1298C) and oral squamous cell carcinoma: A systematic review and meta-analysis.

A consensus has not been reached regarding the association of MTHFR gene polymorphism and susceptibility to oral squamous cell carcinoma (OSCC). We performed a meta-analysis to better evaluate the association between MTHFR C677T, A1298C polymorphism and OSCC risk. The studies regarding the association of MTHFR C677T, A1298C polymorphisms and OSCC were identified in PubMed and EMBASE and Google Scholar. The pooled odd rates (ORs) with 95%CIs were estimated using a fixed-effect or random-effect model. The associations between MTHFR polymorphisms and OSCC risk were assessed under the dominant, recessive and additive models. A collective total of 1539 OSCC patients and 2131 normal controls were included across 13 studies. The minor T allele of MTHFR C677T was significantly associated with the increased risk of OSCC development(OR = 1.35, 95%CI 1.04–1.76). Individuals carrying the ‘‘T” allele (TT+CT) had a nearly 43% increased risk for OSCC development when compared with CC (OR = 1.43, 95%CI 1.02–1.99). Under additive model, the results also showed that individuals with CT or TT genotype were more susceptible to OSCC than CC (OR = 1.45, 95%CI 1.02–2.08; OR = 1.79, 95%CI 1.28–2.50; respectively). The subgroup analysis by ethnicity revealed that significant difference in C677T allele distribution could be observed in European (OR = 1.33, 95%CI 1.02–1.75) rather than Asian (OR = 1.59, 95%CI 0.91–2.78). No significant association of MTHFR A1298C polymorphism and OSCC risk could be observed. The present study revealed that T allele and TT genotype of MTHFR C677T polymorphism were significantly associated with the increased risk of OSCC development.

Relationship between MTHFR gene polymorphisms (C677T and A1298C) and chronic lymphocytic leukemia in the Turkish population

ObjectiveChronic lymphocytic leukemia (CLL) is a neoplastic disease that influences B cell lymphocytes. CLL is the most common kind of leukemia accounting for approximately 30% of all hematological malignancies. The functions of MTHFR enzyme are a critical juncture in the DNA synthesis, and in methylation of metabolic reactions. Two common genetic polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association between MTHFR gene polymorphisms and the CLL risk. Materials and methodsIn the present study, MTHFR gene polymorphisms were investigated in a case-control study of 91 patients with CLL and 101 healthy control subjects using real time polymerase chain reaction (RT-PCR) assay in the Turkish population. Results & conclusionThe patients carrying 1298C allele or 1298CC genotype had a higher risk of CLL (P = .04, P = .005, respectively). Moreover, the patients carrying 677TT genotype had a lower risk of CLL than the other patients carrying 677CC and 677CT genotypes in recessive model (P = .03). Additionally, the CA haplotype block showed a protective effect against the risk of CLL (the C677/A1298, P = .0013).In conclusion, our results demonstrate for the first time MTHFR gene C677T and A1298C polymorphisms, especially A1298C, have a major effect on the risk of CLL in the Turkish patients. We suggest that considering the first contradictory results in Caucasians, further additional studies are necessary to elucidate the relationship of these polymorphisms with the risk of CLL disease in Caucasian populations.

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.

The rs4846049 polymorphism in the 3'UTR region of the MTHFR gene increases the migraine susceptibility in an Iranian population.

IntroductionMigraine is a painful complex neurovascular disease characterized by recurrent moderate-to-severe headaches. Increased level of homocysteine is related to dilation of cerebral vessels and endothelial injury that could trigger migraine attacks. Functional polymorphisms in the MTHFR gene affect homocysteine metabolism and, therefore, play an important role in the etiology of the disease.ObjectivesWe aimed to investigate the possible association between MTHFR gene rs4846049, C677T, and A1298C polymorphisms and the risk of migraine in Iranian population.MethodsIn this genetic association study, 498 individuals were enrolled, including 223 migraine patients and 275 healthy controls. Genotyping was performed using tetra-primer ARMS-PCR for rs4846049 and PCR-restriction fragment length polymorphism for C677T and A1298C polymorphisms.ResultsThe association between rs4846049 and C677T polymorphisms and migraine was observed. For the rs4846049 polymorphism, the association was detected under a dominant model (P=0.007; odds ratio [OR] =0.60; 95% confidence interval [CI], 0.41–0.87), and for the C677T polymorphism, the TT genotype frequency was significantly different in the studied groups (P=0.009; OR =2.48; 95% CI, 1.25–4.92). No significant differences in the genotype or allele frequencies were found for the A1298C polymorphism between the migraineurs and controls.ConclusionPresent data provide evidence for the association of rs4846049 and C677T polymorphisms in the MTHFR gene and migraine. Further studies are required to validate the significance of the studied genetic variations in diverse ethnic populations.

Two Common MTHFR Gene Polymorphisms (C677T and A1298C) and Fetal Congenital Heart Disease Risk: An Updated Meta-Analysis with Trial Sequential Analysis

Background/Aims: Published studies indicated that the MTHFR gene polymorphisms C677T and A1298C are associated with congenital heart disease (CHD) risk in children, but obtained inconsistent results. Our study aims to reach a more accurate association between these two polymorphisms and CHD risk. Methods: Eligible studies were obtained by screening the PubMed, Embase, China National Knowledge Infrastructure, Wan Fang and VIP databases based on designed searching strategy. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Moreover, a trial sequential analysis was introduced to confirm the positive results and an RNA secondary structure analysis was also applied to discover the potential molecular mechanism. Results: Based on thirty-two published articles, involving 6988 congenital heart disease subjects and 7579 healthy controls, the pooled results from the C677T polymorphism in the fetal population showed increased risks in allelic model (OR=1.32, 95%CI=1.14-1.53), recessive model (OR=1.69, 95%CI=1.25-2.30), dominant model (OR=1.35, 95%CI=1.11-1.64), heterozygote model (OR=1.20, 95%CI=1.01-1.41) and homozygote model (OR=1.75, 95%CI=1.31-2.33). An increased risk was only detected in the A1298C polymorphism in the overall fetal popalation in a recessive model (OR=1.42, 95%CI=1.10-1.84). In the subgroup stratified by region, sample size, genotyping method and source of controls, the increased risks were widely observed in both the C677T and A1298C polymorphisms with CHD risk. Furthermore, trial sequential analysis confirmed our positive results, and the RNA secondary structure analysis detected the changes in the RNA secondary structure caused by the mutant 677T allele and 1298C allele. Conclusion: In summary, we found that the MTHFR C677T polymorphism is associated with a significant increased risk in congenital heart disease in the fetal population. Moreover, an increased risk in the CC genotype of MTHFR A1298C polymorphism was observed, but the protective role of the 1298C allele needs further study.

MTRR A66G, RFC1 G80A, and MTHFR C677T and A1298C Polymorphisms and Disease Activity in Mexicans with Rheumatoid Arthritis Treated with Methotrexate.

Aim: To investigate the relationships of polymorphisms in genes whose protein products are related in the metabolic pathway of folic acid, particularly MTRR A66G, RFC1 G80A, and MTHFR C677T and A1298C, and disease activity in Mexican patients with rheumatoid arthritis (RA) treated with methotrexate (MTX).Materials and Methods: Sixty-eight patients with RA were included in the study who were being treated with MTX, either with or without other drugs. In addition to general data, disease activity was measured by the disease activity score 28 (DAS28). Single nucleotide polymorphisms (SNPs) genotyping was performed by allelic discrimination using real-time polymerase chain reaction.Results: Differences in genotype (homozygotic or heterozygotic for each allele), allele distributions, and phenotype were not statistically different between the RA group and control populations. We did not find any association between the studied polymorphisms and disease activity nor with the intragroup variables (e.g., clinical activity, body mass index, and single- or combined-drug treatment) or between genetic markers; we also did not find any association within the RA group or between the RA group and control populations.Conclusion: Additional studies of more polymorphisms related to this or other metabolic pathways are required to determine the influence of genetics on disease activity in RA.

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.