Methylenetetrahydrofolate Reductase A1298C Polymorphisms Research Articles

Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Variants, Folate Intake, and Susceptibility to Breast Cancer

Context: Breast cancer is the most common cancer among women, worldwide. Both genetic and environmental factors are involved in the risk of breast cancer. Folate is an essential nutrient that is involved in DNA synthesis, repair, and methylation. Single nucleotide polymorphisms (SNPs) in folate related genes, such as methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C are suitable candidates for investigation the role of these variants in susceptibility to breast cancer. Evidence Acquisition: Using the relevant English language studies from the search engines, such as MEDLINE/PubMed, EMBASE, and Scopus from 2005 to 2016, the present review looks at the role of MTHFR C677T and A1298C variants, synergism between these gene variants along with folate intake in susceptibility to breast cancer. Results: It seems the MTHFR C677T polymorphism is associated with the risk of breast cancer among Asians but not in Caucasians. However, the MTHFR A1298C polymorphism might not be a susceptibility factor for breast cancer. The MTHFR haplotypes alone or along with low dietary intake of folate were not involved in susceptibility to breast cancer. Conclusions: Association between MTHFR C677T polymorphism with the risk of breast cancer could be attributed to the lower activity of the MTHFR enzyme in the presence of 677T allele with reduced availability of folate that may result in uracil misincorporation in the DNA and cancer development. The absence of establishment of a role for MTHFR haplotypes and a synergism between low dietary intake of folate along with MTHFR polymorphisms in susceptibility to breast cancer might be due to differences in allelic frequency of MTHFR variants in various populations, stage of cancer, the familial and early onset cancer, and the influence of environmental factors. To establish the role of MTHFR haplotypes in relation to folate intake in susceptibility to breast cancer, more studies with adequate sample size that investigate the role of MTHFR gene polymorphisms along with dietary intake of folate in the risk of breast cancer are necessary.

Methylenetetrahydrofolate Reductase A1298C Polymorphism and Major Depressive Disorder.

Major depressive disorder (MDD) is a disorder that carries significant psychosocial and economic implications. Research efforts have focused on identifying biomarkers that can aid in the prediction, diagnosis, and efficacious treatment of MDD. Most of this focus has been placed on a polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T. MTHFR C677T is screened during MDD diagnosis in many protocols. However, MTHFR C667T poses conflicting data in various ethnic groups and geographic populations calling into question its utility. Another polymorphism, MTHFR A1298C, has often taken the back-seat to MTHFR C677T in respect to research focus. MTHFR A1298C is implicated in irregular homocysteine metabolism and aberrant folate cycles and, through this, it may play a role as either a driver in the development of MDD or as a predictive or diagnostic marker, possibly in combination with C677T. The number of studies evaluating MTHFR A1298C and the power of those studies is lacking and thus larger studies are required to confirm the association between this polymorphism and MDD.

Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women.

C677T polymorphism of the methylenetetrahydrofolate reductase ( MTHFR) gene was a risk factor for recurrent pregnancy loss (RPL), but few studies have confirmed a possible role of MTHFR A1298C polymorphism in RPL risk. This study was carried out to determine the influence of the MTHFR gene polymorphisms in RPL Syrian women. A case-control study was performed on 2 groups (106 healthy and 100 RPL women). The frequency of the MTHFR gene polymorphisms was determined by polymerase chain reaction based on restriction fragment length gene polymorphism. In the RPL group, the genotype frequencies of MTHFR C677T were CC (41%), CT (41%), and TT (18%), and in the control group, the frequencies were CC (62.2%), CT (36.7%), and TT (1%). Statistical analysis showed a homozygous TT genotype and T allele were significantly different in the RPL group ( P = .000003 and P = .000019, respectively). The genotype frequencies of MTHFR A1298C were AA (53%), AC (44%), and CC (8%) in the RPL group, whereas in the control group, these were AA (61.3%), AC (37.8%), and CC (1%). A significant difference in the CC genotype and C allelic frequencies in the RPL women was observed ( P = .014 and P = .064, respectively). The patients having compound heterozygous (677 CT/1298AC) were associated with an estimated 4.86-fold increase in risk of pregnancy loss compared to individuals with a wild type ( P = .012). Our findings indicate that RPL women with homozygous genotype for (C677T and A1298C) either alone or compound heterozygous genotypes have a high risk of pregnancy loss in Syrian women.

Associations between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in childhood malignancies: a meta-analysis.

As a common chemotherapy drug, methotrexate (MTX) has achieved remarkable clinical success. However, high inter-individual variability and unpredictable toxicity continue to challenge its use in clinical practices. Some studies suggest this variation is associated with a methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, but results remain unclear. In this meta-analysis, we include 14 studies that focus on MTHFR C677T and A1298C polymorphisms in pediatric patients with malignancy. We found significant associations of the MTHFR C677T polymorphism with hepatotoxicity (grade ⩾2; CC vs CT/TT: risk ratio (RR): 0.82, 95% confidence interval (CI): 0.67-0.99; P=0.04), hematological toxicity (grade 3-4; CC vs CT/TT: RR: 0.65, 95% CI: 0.44-0.97; P=0.03) in a dominant genetic model and mucositis (grade ⩾3) in all models (CC vs CT/TT: RR: 0.18, 95% CI: 0.04-0.87; P=0.03; CC/CT vs TT: RR: 0.10, 95% CI: 0.03-0.32; P⩽0.0001; CC vs TT: RR: 0.10, 95% CI: 0.02-0.50; P=0.005). No significant association was found with the MTHFR A1298C polymorphism. For children with malignancy, genotyping of the MTHFR C677T polymorphism is expected to be a useful tool in reducing toxicity and improving outcome in personalized MTX therapy.

Association between MTHFR A1298C polymorphism and male infertility: A meta-analysis.

There have been several epidemiological studies evaluating the potential association between the methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism and the risk of male infertility. However, the results obtained were inconsistent. Therefore, we performed a meta-analysis to further examine the association between the MTHFR A1298C polymorphism and male infertility. A comprehensive search was conducted to identify all eligible studies from the online literature databases published prior to January 15th, 2016. A total of 20 studies with 4293 cases and 4507 controls were included. An odds ratio (OR) and a 95% confidence interval (95% CI) were calculated to assess the strength of the association. A cumulative meta-analysis, sensitivity analysis and assessment of the publication bias were also performed in this study. The results showed that in the overall analysis, the association between the MTHFR A1298C polymorphism and male infertility was not significant. A stratified analysis by ethnicity revealed a significant increase in the risk of male infertility in the Asian population with the MTHFR A1298C polymorphism (especially in the heterozygote model: OR=1.20, 95% CI=1.01-1.44, P=0.994; the dominant model: OR=1.23, 95% CI=1.04-1.45, P=0.996; and the allele model: OR=1.20, 95% CI=1.04-1.39, P=0.985) but not in the Caucasian population. In the stratified analyses, no significant association was observed between the different types of male infertility. This meta-analysis suggests the MTHFR A1298C polymorphism may be a potential risk factor for male infertility, especially in the Asian population.

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.

Geographical and ethnic distribution of MTHFR gene polymorphisms and their associations with diseases among Chinese population.

Numerous studies have investigated the distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and their associations with diseases in China. In this study we conducted a systematic review and meta-analysis of these studies (715 eligible studies in total).Results revealed that the frequencies of the MTHFR C677T and A1298C polymorphisms varied markedly in different areas and ethnicities, and even showed geographical gradients. The MTHFR C677T polymorphism was significantly associated with 42 clinical disorders (p < 0.05), mostly relating to the diseases of circulatory system, birth defects and cancers. The association of the A1298C polymorphism with three diseases (coronary heart disease, breast cancer and neural tube defects fathers) was statistically significant (p < 0.05). However, according to the Venice criteria, only the associations of the C677T polymorphism with breast and ovarian cancers were assessed as having strong epidemiological credibility. This is the first study to provide a comprehensive assessment of the current status and gaps in genetic epidemiological study of the two polymorphisms in China, and its findings may be useful for medical and public health practices. Future studies are warranted to focus on the interactions of MTHFR genes with environmental exposure and with other genes, and to improve their methodological quality and reporting of findings.

Associations between C677T and A1298C polymorphisms of MTHFR and susceptibility to rheumatoid arthritis: a systematic review and meta-analysis.

Methylenetetrahydrofolatereductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. Although a number of studies have examined the association of the MTHFR C677T and A1298C polymorphisms with susceptibility to rheumatoid arthritis (RA), the conclusions are controversial. A comprehensive literature search using PubMed, Embase, the Cochrane Library, CNKI and Wanfang databases was conducted for relevant studies on the association between MTHFR polymorphisms and RA risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effect models. In total, 1854 cases and 1689 controls from 12 studies and 1525 cases and 1455 controls from 10 studies were included for the C677T and A1298C polymorphisms, respectively. Pooled results indicated that both C677T and A1298C polymorphisms were associated with RA susceptibility (C677T: TT vs. CC, OR = 1.31, 95% CI = 1.02-1.67, P = 0.032; TC vs. CC, OR = 1.32, 95% CI = 1.02-1.70, P = 0.032; TT + TC vs. CC, OR = 1.38, 95% CI = 1.07-1.78, P = 0.014; T vs. C, OR = 1.29, 95% CI = 1.06-1.57, P = 0.011; A1298C: CC vs. CA + AA: OR = 1.58, 95% CI = 1.20-2.06, P = 0.001). Further stratification based on ethnicity and geographic region indicated an association between the MTHFR C677T SNP and the risk of RA in Caucasian and patients in Africa. However, there is no evidence of significant association between A1298C polymorphism and RA risk in Caucasian or population in Africa. This meta-analysis indicates that MTHFR C677T and A1298C polymorphisms could be predictors of risk of RA and warrants validation in large and well-designed prospective studies.

T60 - Investigating The Role Of One-Carbon Metabolism Pathway In Complicated Alcohol Withdrawal States

Background Complicated withdrawal states in alcohol dependence syndrome (ADS) include alcohol withdrawal seizures (AWS) and delirium tremens (DT) and are associated with significant medical and psychiatric morbidity. Existing evidence suggests that in patients with chronic ADS, the associated deficiency of vitamin B12 and folic acid could lead to hyperhomocysteinemia through the inhibition of methionine synthase (MS) and methylene tetrahydrofolate reductase (MTHFR) enzymes of the one-carbon metabolism pathway. Hyperhomocysteinemia has been found to be associated with complicated alcohol withdrawal especially withdrawal seizures (AWS). The common variant of the MS A2756G gene has been found to be associated with lower plasma homocysteine levels. The homozygote variant of the MTHFR A1298C gene results in partial loss of enzyme activity. Thus, it may be worthwhile to study the above SNPs in patients with complicated alcohol withdrawal states and correlate the findings with plasma homocysteine, vitamin B12 and folate levels. Methods In our study, we aimed to investigate the association of MTR A2756G (responsible for the MS enzyme) and MTHFR A1298C polymorphisms with complicated withdrawal states i.e. AWS and delirium tremens (DT). We also measured levels of plasma homocysteine, vitamin B12 and folate in these patients. The sample consisted of a total of 150 male patients with ADS of which 84 patients had simple withdrawal state (SWS), 30 patients had DT and 36 patients had AWS. Assessments included a general physical examination, biochemistry panel, a complete blood count, assays of plasma homocysteine, vitamin B12 and folate along with genotyping for the MTR A2756G and MTHFR A1298C polymorphisms. Results There was no difference in the mean age at onset of dependence (SWS - 28.2 ± 5.7; DT - 28.2 ± 4.6; AWS - 27.9 ± 5, F = 0.03, p = 0.9). However, there was a significant association between the mean daily units of alcohol consumed and complicated alcohol withdrawal states. (SWS - 13.6 ± 3.7; DT - 19.8 ± 3.9; AWS - 17.1 ± 4.9, F = 27.8, p The study also found no differences in the serum homocysteine levels (SWS – 0.91; DT – 0.91; AWS – 0.88 nmol/ml, t = 0.9, p = 0.6), vitamin B12 levels (SWS – 274; DT – 265; AWS – 230 pg/ml, t = 1.2, p = 0.5), and folate levels (SWS – 99.3; DT – 99.1; AWS – 98.2 pg/ml, t = 2.4, p = 0.1). Although vitamin B12 and folic acid levels fell in the lower end of the normal range, no deficiency states were observed. No association was found between levels of plasma homocysteine, vitamin B12 & folic acid levels and complicated alcohol withdrawal states. No significant differences were found between the groups with respect to haematological and biochemical parameters examined. The two groups did not differ significantly with respect to genotype frequency of the SNPs examined (MTHFR A1298C and MTR A2756G). Discussion Our study finds that it is the quantity of alcohol consumed in a day that is associated with complicated withdrawal states with frequent heavy drinkers more likely to have severe withdrawal. It would be worthwhile to explore this further as no clear genetic risk factors emerged. The study was limited by its sample size, the use of cross-sectional sampling method and the exclusion of female patients from the study. However, it is one of the first studies to examine these SNPs in a south Indian population. The role of the one-carbon metabolism pathway in these states remains an important area of research with numerous possible treatment implications.

Methylene Tetrahydrofolate Reductase (MTHFR) rs868014 Polymorphism Regulated by miR-1203 Associates with Risk and Short Term Outcome of Ischemic Stroke

Background/Aims: Genetic polymorphisms of methylene tetrahydrofolate reductase (MTHFR) were associated with ischemic stroke risk. This study analyzed MTHFR polymorphisms at the 3'-untranslated region for association with risk and outcome of ischemic stroke in a Chinese Han population. Methods: 500 patients and 600 healthy volunteers were enrolled for MTHFR rs868014 genotyping identified bioinformatically. The binding of miR-1203 to MTHFR rs868014 was determined by luciferase assay, MTHFR expression was assessed using qRT-PCR, and plasma homocysteine levels were assayed by ELISA. Results: Cigarette smoking, alcohol consumption, diabetes, hypertension (all P <0.001), low levels of serum high-density lipoprotein-C (P = 0.01), and high levels of serum low-density lipoprotein-C (P = 0.005) were associated with an increased risk of developing ischemic stroke. BMI and total serum cholesterol concentration was not associated with ischemic stroke. MTHFR rs868014 TC and CC genotypes were significantly associated with increased risk of ischemic stroke compared with the TT genotype (OR: 1.52; 95% CI: 1.01-3.39 for TC genotype, while OR: 1.99; 95% CI: 1.29-3.88 for CC genotype). Furthermore, the MTHFR rs868014 SNP was associated with a poor short-term ischemic stroke outcome. qRT-PCR confirmed that MTHFR rs868014 TC or CC genotypes could facilitate miR-1203 binding leading to low MTHFR levels in cells. In addition, patients carrying the MTHFR rs868014 TC or CC genotypes were associated with accumulation of serum tHcy and a poor ischemic stroke outcome. Linkage disequilibrium analysis indicated that the newly identified SNP rs868014 was strongly linked with the MTHFR A1298C polymorphism. Conclusion: This study demonstrates that the MTHFR rs868014 SNP is associated with increased risk in developing ischemic stroke, miR-1203 binding, low MTHFR levels in cells, and poor shot term outcome of patients.

Association of &lt;em&gt;MTHFR&lt;/em&gt; C677T and A1298C polymorphisms with oral cancer susceptibility: evidence from a meta-analysis

Methylenetetrahydrofolate reductase (MTHFR) is a central enzyme involved in folate metabolism and plays an important role in DNA synthesis and methylation. Several studies have been conducted to illustrate the associations between MTHFR C677T and A1298C polymorphisms with oral cancer susceptibility; however, the results are inconsistent. Therefore, we conducted an updated meta-analysis to obtain a more reliable estimation of the associations. We retrieved eligible studies from PubMed, EMBASE, and CBM databases through September 2016. Ultimately, pooled analyses involved 10 studies with 1443 cases and 1640 controls for the C677T polymorphism, as well as five studies with 973 cases and 1024 controls for the A1298C polymorphism. Risk estimates were presented as odds ratios (ORs) and 95% confidence intervals (95% CIs). Pooled results indicated that neither C677T nor A1298C polymorphism was associated with oral cancer susceptibility. However, a borderline significant association was detected between MTHFR C677T polymorphism and a decreased oral cancer risk (homozygous model: OR=0.71, 95% CI=0.50–1.00) in hospital-based studies. Our results suggested that MTHFR C677T and A1298C polymorphisms might not be associated with oral cancer risk. However, more evidence is needed to further confirm these findings in the future.

Methylenetetrahydrofolate Reductase Polymorphisms and Risk of Recurrent Pregnancy Loss: a Case-Control Study.

The balance between coagulation and fibrinolysis is an essential part in early pregnancy. Mutations in methylenetetrahydrofolate reductase (MTHFR) gene lead to decreased activity of the enzyme and hyperhomocysteinemia, which then induces platelet aggregation by promoting endothelial oxidative damage, possibly resulting in adverse effect on maintenance of pregnancy. We investigated the role of MTHFR single nucleotide polymorphisms (SNPs), C677T and A1298C, in Korean patients with recurrent pregnancy loss (RPL). We conducted a prospective case-control study in the Korean population. Subjects included 302 women with 2 or more consecutive, unexplained, spontaneous miscarriages before 20 weeks of gestation and 315 control women without a history of recurrent miscarriages. The genotyping for C677T and A1298C polymorphisms was performed using the TaqMan assay. Continuous variables were compared using Student's t-test, and χ2 test was used to evaluate differences in the genotype distributions between the RPL and the controls. The genotype distribution of both polymorphisms in the RPL group did not differ from those of the controls. For further analysis, if RPL patients were divided according to the numbers of pregnancy losses (≥ 2 and ≥ 3) neither group was significantly different compared with controls. MTHFR gene C677T and A1298C polymorphisms are not associated with idiopathic RPL in Korean women, suggesting that those may not be susceptible allelic variants or be deficient to cause RPL.

Combined genotype and haplotype distributions of MTHFR C677T and A1298C polymorphisms: A cross-sectional descriptive study of 13,473 Chinese adult women.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are, independently and/or in combination, associated with many disorders. However, data on the combined genotype and haplotype distributions of the 2 polymorphisms in Chinese population were limited.We recruited 13,473 adult women from 9 Chinese provinces, collected buccal cell samples, and determined genotypes, to estimate the combined genotype and haplotype distributions of the MTHFR C677T and A1298C polymorphisms.In the total sample, the 6 common combined genotypes were CT/AA (29.5%), TT/AA (21.9%), CC/AA (15.4%), CC/AC (14.9%), CT/AC (13.7%), and CC/CC (3.4%); the 3 frequent haplotypes were 677T-1298A (43.6%), 677C-1298A (37.9%), and 677C-1298C (17.6%). Importantly, we observed that there were 51 (0.4%) individuals with the CT/CC genotype, 92 (0.7%) with the TT/AC genotype, 17 (0.1%) with the TT/CC genotype, and that the frequency of the 677T-1298C haplotype was 0.9%. In addition, the prevalence of some combined genotypes and haplotypes varied among populations residing in different areas and even showed apparent geographical gradients. Further linkage disequilibrium analysis showed that the D’ and r2 values were 0.883 and 0.143, respectively.In summary, the findings of our study provide further strong evidence that the MTHFR C677T and A1298C polymorphisms are usually in trans and occasionally in cis configurations. The frequencies of mutant genotype combinations were relatively higher in Chinese population than other populations, and showed geographical variations. These baseline data would be useful for future related studies and for developing health management programs.

The Association of MTHFR C677T and A1298C Polymorphisms with Methotrexate Response and Toxicity in Psoriasis

Background : Methotrexate (MTX) is used to treat psoriasis with various side effects and responsiveness. No predictive indicator of responsiveness or toxicity is available. Objective : To study the association of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase ( MTHFR) gene with the responsiveness and side effects of MTX in psoriatic Thai patients. Methods : The polymorphisms were identified from 86 MTX-treated patients in three hospitals located in southern Thailand using allele-specific PCR. The patients were monitored for the effectiveness and toxicity of the MTX. Results : The C677T genotype frequencies for C/C, C/T, and T/T were 70.9, 26.8, and 2.3%, respectively, and those of the A1298C genotypes for A/A, A/C, and C/C were 57, 32.5, and 10.5%, respectively. Seventy-three patients (87.9%) responded to MTX. The non-responders had higher combined frequencies of C/T and T/T of the C677T (50%) than the responders (24.7%) with no statistical significance ( p = 0.131), but had a lower frequency of CC genotype of the A1298C, although not statistically different ( p =0.691). Eleven patients (12.8%) suffered toxicity. No association of these polymorphisms and MTX toxicity was found. Conclusion : The study did not show an association between these MTHFR polymorphisms with MTX response and toxicity in these patients.

The effect of methylenetetrahydrofolate reductase polymorphisms on susceptibility to human papilloma virus infection and cervical cancer

Cervical cancer is the third most common cancer among women worldwide. Several factors lead to cervical cancer, among which human papilloma virus (HPV) infection has a prominent role. Methylenetetrahydrofolate reductase (MTHFR) is crucial in folate metabolic pathway and plays an important role in DNA synthesis and DNA methylation. MTHFR gene polymorphisms, including C677T and A1298C, lead to reduced enzyme activity. This case-control study aims to illustrate the association between MTHFR gene polymorphisms and the risk of cervical cancer.This study was conducted on 196 samples, which included 96 cervical biopsy samples compared to 100 Pap smear samples of normal healthy women without HPV infection. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for the MTHFR polymorphism detection, followed by fluorescent amplification-based specific hybridization PCR method to detect HPV16 and HPV18.The results show that the MTHFR 677TT genotype plays a protective role in cervical cancer (P=0.0030) (OR=0.21, 95% confidence interval [CI]: 0.07–0.59). Furthermore, there was a strong significant association between MTHFR 1298CC genotype and the risk of cervical cancer (OR=10.69; 95% CI: 4.28–26.71, P=0.0001).It can be concluded that A1298C polymorphism is a genetic risk factor for cervical cancer in the assessed Iranian population group. It seems that MTHFR 1298CC genotype is more susceptible to HPV 16 infection. Combination analysis of MTHFR C677T and A1298C polymorphisms revealed that combined MTHFR 677CC and 1298CC are strongly associated with a risk of cervical cancer.

Heterogenous Distribution of MTHFR Gene Variants among Mestizos and Diverse Amerindian Groups from Mexico.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Folate deficiency has been related to several conditions, including neural tube defects (NTDs) and cardiovascular diseases. Hence, MTHFR genetic variants have been studied worldwide, particularly the C677T and A1298C. We genotyped the C677T and A1298C MTHFR polymorphisms in Mexican Amerindians (MAs), from the largest sample included in a genetic study (n = 2026, from 62 ethnic groups), and in a geographically-matched Mexican Mestizo population (MEZ, n = 638). The 677T allele was most frequent in Mexican individuals, particularly in MAs. The frequency of this allele in both MAs and MEZs was clearly enriched in the South region of the country, followed by the Central East and South East regions. In contrast, the frequency of the 1298C risk allele in Mexicans was one of the lowest in the world. Both in MAs and MEZs the variants 677T and 1298C displayed opposite allele frequency gradients from southern to northern Mexico. Our findings suggest that in Mestizos the 677T allele was derived from Amerindians while the 1298C allele was a European contribution. Some subgroups showed an allele frequency distribution that highlighted their genetic diversity. Notably, the distribution of the frequency of the 677T allele was consistent with that of the high incidence of NTDs reported in MEZ.

Plasma homocysteine levels, methylene tetrahydrofolate reductase A1298C gene polymorphism and risk of retinal vein thrombosis.

There are limited data regarding the role of methylene tetrahydrofolate reductase (MTHFR) A1298C polymorphism and hyperhomocysteinemia as risk factors for retinal vein thrombosis (RVT) in Iranians. This study aimed to examine a possible association between fasting plasma total homocysteine (tHcy) levels, MTHFR A1298C polymorphism and RVT development in Iranian patients. Our study population consisted of 73 patients with a diagnosis of RVT (52.7 ± 16.2 years) and 73 age and sex-matched healthy controls (49.1 ± 14.6 years). Genotyping for the MTHFR A1298Cpolymorphism was conducted by PCR-RFLP technique and plasma tHcy levels were measured by an enzyme immunoassay method. Fasting plasma tHcy levels were 20.29 ± 8.5 μmol/l in RVT patients and 10.9 ± 3.1 μmol/l in control subjects. The number of cases with abnormal tHcy values (hyperhomocysteinemia) was significantly higher in the RVT patients than control subjects (P = 0.0001). The prevalence of MTHFR 1298CC homozygote genotype was similar in RVT patients and controls (17.8 vs.15.1%, P = 0.45). There were no significant differences in genotype distribution of MTHFR A1298C polymorphism between males and females in both RVT patients and controls (P > 0.05). The frequency of the 1298C allele was 39.1 and 35.6% in patients and controls, respectively, and did not differ significantly between them (P = 0.23). Moreover, heterozygote and homozygote genotypes in the RVT patients had significantly higher abnormal tHcy values than corresponding genotypes in control subjects (P < 0.001). Our study demonstrated that hyperhomocysteinemia but not homozygosity for MTHFR A1298C polymorphism is a significant risk factor for RVT in the Iranian population.

ASSOCIATION OF MTHFR A1298C POLYMORPHISM WITH BREAST CANCER AND/OR OVARIAN CANCER RISK: AN UPDATED META-ANALYSIS.

Background:Recent years have witnessed the discovery of similar gene variations between breast cancer and ovarian cancer, inherited breast and ovarian cancer in particular. A large number of case-control studies have been conducted to explore the association of Methylenetetrahydrofolate Reductase (MTHFR) A1298C polymorphism with breast cancer and/or ovarian cancer risk. However, the results are still inconsistent and inconclusive. Consequently, we performed a meta-analysis to evaluate the association between MTHFR A1298C polymorphism and breast, ovarian cancer risk.Materials and Methods:A comprehensive retrieval was conducted in the electronic database of PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) until June 2015 to identify eligible studies. A total of 35 studies which examined the association of MTHFR A1298C polymorphism with breast cancer and/or ovarian cancer were identified. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the effect of gene polymorphism. And allele model, homozygous model, co-dominant model, dominant model, recessive model were applied.Result:In the overall analysis, significantly increased breast cancer and/or ovarian cancer risk was found (for allele model A VS C OR = 1.05, CI: 1.02-1.08, P = 4χ10-3; for homozygous model AA VS CC OR = 1.11, CI: 1.03-1.19, P = 5χ10-3; for recessive model (AC +AA) VS CC: OR = 1.10, CI: 1.03-1.18, P = 7χ10-3).Conclusion:In the subgroup analysis, significantly increased breast cancer risk was identified among Caucasians. MTHFR A1298C polymorphism might contribute to an increased risk of breast cancer and/or ovarian cancer susceptibility. In addition, MTHFR A1298C polymorphism had a significant association with breast cancer in Caucasians.

Associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with genetic susceptibility to rheumatoid arthritis: a meta-analysis.

The aim of our study was to conduct a meta-analysis to assess whether combined evidence shows associations between C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and genetic susceptibility to rheumatoid arthritis (RA). A total of 11 articles involving 20 comparisons were included, containing 12 comparisons for the MTHFR C677T polymorphism and 8 comparisons for the MTHFR A1298C polymorphism. Significant evidence was detected for the association of RA susceptibility with the MTHFR C677T polymorphism T allele under allelic contrast and dominant model in Asians (T versus C, OR=1.300, 95% CI=1.104-1.531, p=0.002; TT + CT versus CC, OR=1.495, 95% CI=1.187-1.882, p=0.001). Significant association between RA susceptibility and the MTHFR A1298C polymorphism A allele under recessive model was found in the overall meta-analysis (AA versus AC + CC, OR=1.281, 95% CI=1.048-1.565, p=0.016). Our meta-analysis results demonstrate that the MTHFR C677T polymorphism is involved in the genetic susceptibility of RA in Asians, and the MTHFR A1298C polymorphism is associated with genetic susceptibility to RA in the overall population. Given the paucity of studies, especially in non-Asian populations, further studies with larger sample sizes are required to elucidate the role of MTHFR polymorphisms in the genetic basis of RA in different ethnic populations.

46 MTHFR gene polymorphism A1298C and development of pre-eclampsia

Introduction Pre-eclampsia (PE) is a pregnancy-specific disease diagnosed by hypertension and proteinuria after 20th week of pregnancy. The methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme for folate and homocysteine metabolism. The A1298C (rs1801131) is a common polymorphism of MTHFR gene and has also been suspected as a contributor of altered serum homocysteine levels. Hyperhomocysteinemia has been associated with pregnancy complications such as pre-eclampsia. Objective Determine wheter MTHFR A1298C polymorphism is associated with PE susceptibility. Methods In this case-control study, a total of 53 preeclamptic pregnant women were recruited from Departament of Obstetrics and Gynecology of Clinical Hospital, of Triangulo Mineiro Federal University, Uberaba, Brazil. PE was defined according clinical findings, including increased blood pressure ( ⩾ 140 mmHg systolic or ⩾ 90 mmHg diastolic on 2 or more measurements at least 6 h apart) and proteinuria ⩾ 0.3 g/24 h or ⩾ +1 on a urine dipstick after 20 weeks of gestation. The control group included 179 normal pregnant women. None of PE patients and healthy controls had hypertension history. Genomic DNA was extracted from EDTA-treated whole blood by standard procedure of phenol–chloroform. Polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) was performed for MTHFR A1298C (rs1801131) genotyping and subsequent digestion of PCR products with MboII restriction enzyme. Differences in the distribution of genotypes and alleles between groups and deviations from the Hardy-Weinberg equilibrium were tested using the chi-square test. Results No deviation from the Hardy–Weinberg equilibrium was observed for MTHFR A1298C polymorphism either in PE patients or in healthy controls (p = 0.81 and p = 0.21 respectively). The frequency of 1298C allele in PE patients and controls was 28% and 20% and was not statistically different. The frequency of AA genotype was 54.2% and 62.3%, AC genotype was 36.3 and 33.9% and CC genotype was 9.5 and 3.8% in PE patients and controls, respectively, which was not significantly different (p = 0.337). Conclusion The MTHFR A1298C (rs1801131) polymorphism is not associated with risk of developing pre-eclampsia. Conflict of interest The authors declare that they have no conflicts of interest.