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Sample records for 10-metilentetrahidrofolato reductasa mthfr

  1. MTHFR — EDRN Public Portal

    Cancer.gov

    The MTHFR gene product catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. This gene is involved in susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia.

  2. Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

    SciTech Connect

    Wlodarczyk, Bogdan J. Zhu, Huiping; Finnell, Richard H.

    2014-02-15

    Background: In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity varies widely and depends on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model. Methods: Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5. Results: When the dams in Mthfr{sup +/−} × Mthfr{sup +/−} matings were treated with 7.2 mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr{sup +/+} × Mthfr{sup +/−}, Mthfr{sup +/−} × Mthfr{sup +/−} and Mthfr{sup −/−} × {sup Mthfr+/−}) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote × wild-type versus wild-type × nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights. Conclusions: Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure. - Highlights: • An interaction between Mthfr genotype and arsenic embryotoxicity is presented. • Maternal Mthfr genotype

  3. Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

    PubMed Central

    Wlodarczyk, Bogdan J.; Zhu, Huiping; Finnell, Richard H.

    2014-01-01

    Background In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity vary widely and depend on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model. Methods Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5. Results When the dams in Mthfr+/− x Mthfr+/− matings were treated with 7.2mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr+/+ x Mthfr+/−, Mthfr+/− x Mthfr+/− and Mthfr−/− x Mthfr+/−) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote x wild-type versus wild-type x nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights. Conclusions Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure. PMID:24384392

  4. Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection.

    PubMed

    Fodil-Cornu, N; Kozij, N; Wu, Q; Rozen, R; Vidal, S M

    2009-10-01

    Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism in the MTHFR gene (677C --> T) results in reduced enzymatic activity, and is associated with an increased risk for neural tube defects and cardiovascular disease. The high prevalence of this polymorphism suggests that it may have experienced a selective advantage under environmental pressure, possibly an infectious agent. To test the hypothesis that methylenetetrahydrofolate reductase (MTHFR) genotype influences the outcome of infectious disease, we examined the response of Mthfr-deficient mice against mouse cytomegalovirus (MCMV) infection. Acute MCMV infection of Mthfr(-/-) mice resulted in early control of cytokine secretion, decreased viral titer and preservation of spleen immune cells, in contrast to Mthfr wild-type littermates. The phenotype was abolished in MTHFR transgenic mice carrying an extra copy of the gene. Infection of primary fibroblasts with MCMV showed a decrease in viral replication and in the number of productively infected cells in Mthfr(+/-) fibroblasts compared with wild-type cells. These results indicate that Mthfr deficiency protects against MCMV infection in vivo and in vitro, suggesting that human genetic variants may provide an advantage in the host response against certain pathogens.

  5. Role of methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism in pediatric cerebrovascular disorders.

    PubMed

    Alsayouf, Hamza; Zamel, Khaled M; Heyer, Geoffrey L; Khuhro, A Latif; Kahwash, Samir B; de los Reyes, Emily C

    2011-03-01

    Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation (MTHFR TT) has been linked to an increased risk for stroke, coronary artery disease, and migraine headaches. The authors analyzed the potential link between MTHFR 677C>T homozygosity and childhood stroke. A true association might facilitate screening, recurrence risk stratification, and treatment in patients with cerebrovascular disease. They performed a retrospective chart review of children tested for the MTHFR 677C>/T mutation; 533 patients underwent MTHFR testing, and 8% were homozygous for the MTHFR 677C>T mutation. There was no difference in the cohort compared with the prevalence in the general population. This suggests that the MTHFR 677 C>T polymorphism played a minimal role or no role in stroke risk. However, the data suggest that the MTHFR TT genotype may influence migraine susceptibility in children because there was a higher proportion of migraine patients (28.6%) with the MTHFR TT homozygous genotype.

  6. Increased MTHFR promoter methylation in mothers of Down syndrome individuals.

    PubMed

    Coppedè, Fabio; Denaro, Maria; Tannorella, Pierpaola; Migliore, Lucia

    2016-05-01

    Despite that advanced maternal age at conception represents the major risk factor for the birth of a child with Down syndrome (DS), most of DS babies are born from women aging less than 35 years. Studies performed in peripheral lymphocytes of those women revealed several markers of global genome instability, including an increased frequency of micronuclei, shorter telomeres and impaired global DNA methylation. Furthermore, young mothers of DS individuals (MDS) are at increased risk to develop dementia later in life, suggesting that they might be "biologically older" than mothers of euploid babies of similar age. Mutations in folate pathway genes, and particularly in the methylenetetrahydrofolate reductase (MTHFR) one, have been often associated with maternal risk for a DS birth as well as with risk of dementia in the elderly. Recent studies pointed out that also changes in MTHFR methylation levels can contribute to human disease, but nothing is known about MTHFR methylation in MDS tissues. We investigated MTHFR promoter methylation in DNA extracted from perypheral lymphocytes of 40 MDS and 44 matched control women that coinceived their children before 35 years of age, observing a significantly increased MTHFR promoter methylation in the first group (33.3 ± 8.1% vs. 28.3 ± 5.8%; p=0.001). In addition, the frequency of micronucleated lymphocytes was available from the women included in the study, was higher in MDS than control mothers (16.1 ± 8.6‰ vs. 10.5 ± 4.3‰; p=0.0004), and correlated with MTHFR promoter methylation levels (r=0.33; p=0.006). Present data suggest that MTHFR epimutations are likely to contribute to the increased genomic instability observed in cells from MDS, and could play a role in the risk of birth of a child with DS as well as in the onset of age related diseases in those women.

  7. B-vitamins, methylenetetrahydrofolate reductase (MTHFR) and hypertension.

    PubMed

    Ward, Mary; Wilson, Carol P; Strain, J J; Horigan, Geraldine; Scott, John M; McNulty, Helene

    2011-07-01

    Hypertension is a leading risk factor for cardiovascular disease (CVD) and stroke. A common polymorphism in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR), previously identified as the main genetic determinant of elevated homocysteine concentration and also recognized as a risk factor for CVD, appears to be independently associated with hypertension. The B-vitamin riboflavin is required as a cofactor by MTHFR and recent evidence suggests it may have a role in modulating blood pressure, specifically in those with the homozygous mutant MTHFR 677 TT genotype. If studies confirm that this genetic predisposition to hypertension is correctable by low-dose riboflavin, the findings could have important implications for the management of hypertension given that the frequency of this polymorphism ranges from 3 to 32 % worldwide.

  8. Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice.

    PubMed

    Levav-Rabkin, Tamar; Blumkin, Elinor; Galron, Dalia; Golan, Hava M

    2011-01-20

    The methylenetetrahydrofolate reductase (Mthfr) gene and/or abnormal homocysteine-folate metabolism are associated with increased risk for birth defects and neuropsychiatric diseases. In addition, disturbances of the GABAergic system in the brain as well as Mthfr polymorphism are associated with neurodevelopmental disorders such as schizophrenia and autism. In the present study we performed behavioral phenotyping of male and female Mthfr mice (wild type and their heterozygous littermates). The present study addresses two main questions: (1) genetic susceptibility, as examined by effects of Mthfr deficiency on behavior (Experiment 1) and (2) possible gene-drug interactions as expressed by behavioral phenotyping of Mthfr-deficient mice neonatally exposed to the GABA potentiating drug GVG (Experiment 2). Newborn development was slightly influenced by Mthfr genotype per se (Experiment 1); however the gene-drug interaction similarly affected reflex development in both male and female offspring (Experiment 2). Hyperactivity was demonstrated in Mthfr heterozygous male mice (Experiment 1) and due to GVG treatment in both Wt and Mthfr+/- male and female mice (Experiment 2). The gene-environment interaction did not affect anxiety-related behavior of male mice (Experiment 2). In female mice, gene-treatment interactions abolished the reduced anxiety observed due to GVG treatment and Mthfr genotype (Experiment 2). Finally, recognition memory of adult mice was impaired due to genotype, treatment and the gene-treatment combination in a sex-independent manner (Experiment 2). Overall, Mthfr deficiency and/or GABA potentiation differentially affect a spectrum of behaviors in male and female mice. This study is the first to describe behavioral phenotypes due to Mthfr genotype, GVG treatment and the interaction between these two factors. The behavioral outcomes suggest that Mthfr deficiency modulates the effects of GABA potentiating drugs. These findings suggest that future treatment

  9. Stability of DNA methylation patterns in mouse spermatogonia under conditions of MTHFR deficiency and methionine supplementation.

    PubMed

    Garner, Justine L; Niles, Kirsten M; McGraw, Serge; Yeh, Jonathan R; Cushnie, Duncan W; Hermo, Louis; Nagano, Makoto C; Trasler, Jacquetta M

    2013-11-01

    Little is known about the conditions contributing to the stability of DNA methylation patterns in male germ cells. Altered folate pathway enzyme activity and methyl donor supply are two clinically significant factors that can affect the methylation of DNA. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme involved in providing methyl groups from dietary folate for DNA methylation. Mice heterozygous for a targeted mutation in the Mthfr gene (Mthfr(+/-)) are a good model for humans homozygous for the MTHFR 677C>T polymorphism, which is found in 10% of the population and is associated with decreased MTHFR activity and infertility. High-dose folic acid is administered as an empirical treatment for male infertility. Here, we examined MTHFR expression in developing male germ cells and evaluated DNA methylation patterns and effects of a range of methionine concentrations in spermatogonia from Mthfr(+/-) as compared to wild-type, Mthfr(+/+) mice. MTHFR was expressed in prospermatogonia and spermatogonia at times of DNA methylation acquisition in the male germline; its expression was also found in early spermatocytes and Sertoli cells. DNA methylation patterns were similar at imprinted genes and intergenic sites across chromosome 9 in neonatal Mthfr(+/+) and Mthfr(+/-) spermatogonia. Using spermatogonia from Mthfr(+/+) and Mthfr(+/-) mice in the spermatogonial stem cell (SSC) culture system, we examined the stability of DNA methylation patterns and determined effects of low or high methionine concentrations. No differences were detected between early and late passages, suggesting that DNA methylation patterns are generally stable in culture. Twenty-fold normal concentrations of methionine resulted in an overall increase in the levels of DNA methylation across chromosome 9, suggesting that DNA methylation can be perturbed in culture. Mthfr(+/-) cells showed a significantly increased variance of DNA methylation at multiple loci across chromosome

  10. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders

    PubMed Central

    Oztop, Didem Behice; Ozkul, Yusuf

    2014-01-01

    Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. PMID:25431675

  11. MTHFR Gene Polymorphism-Mutations and Air Pollution as Risk Factors for Breast Cancer

    PubMed Central

    Gonzales, Mildred C.; Yu, Pojui; Shiao, S. Pamela K.

    2017-01-01

    Background The methylenetetrahydrofolate reductase gene (MTHFR) is one of the most investigated genes associated with breast cancer for its role in epigenetic pathways. Objectives The objectives of this metaprediction study were to examine the polymorphism-mutation risk subtypes of MTHFR and air pollution as contributing factors for breast cancer. Methods For triangulation purposes in metapredictive analyses, we used a recursive partition tree, nonlinear association curve fit, and heat maps for data visualization, in addition to the conventional comparison procedure and pooled analyses. Results We included 36,683 breast cancer cases and 40,689 controls across 82 studies for MTHFR 677 and 23,252 cases and 27,094 controls across 50 studies for MTHFR 1298. MTHFR 677 TT was a risk genotype for breast cancer (p = .0004) and in the East Asian subgroup (p = .005). On global maps, the most polymorphism-mutations on MTHFR 677 TT were found in the Middle East, Europe, Asia, and the Americas, whereas the most mutations on MTHFR 1298 CC were located in Europe and the Middle East for the control group. The geographic information system maps further revealed that MTHFR 677 TT mutations yielded a higher risk of breast cancer for Australia, East Asia, the Middle East, South Europe, Morocco, and the Americas and that MTHFR 1298 CC mutations yielded a higher risk in Asia, the Middle East, South Europe, and South America. Metapredictive analysis revealed that air pollution level was significantly associated with MTHFR 677 TT polymorphism-mutation genotype. Discussion We present the most comprehensive analyses to date of MTHFR polymorphism-mutations and breast cancer risk. Future nursing studies are needed to investigate the health impact on breast cancer of epigenetics and air pollution across populations. PMID:28114181

  12. Methylenetetrahydrofolate reductase (MTHFR) genotype, smoking habit, metastasis and oral cancer in Taiwan.

    PubMed

    Tsai, Chia-Wen; Hsu, Chia-Fang; Tsai, Ming-Hsui; Tsou, Yung-An; Hua, Chun-Hung; Chang, Wen-Shin; Lin, Cheng-Chieh; Bau, Da-Tian

    2011-06-01

    The aim of this study was to evaluate the association and interaction of genotypic polymorphism in methylenetetrahydrofolate reductase (MTHFR) with smoking habits and oral cancer in Taiwan. Two well-known polymorphic variants of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed in association with oral cancer risk, and their joint effects with individual smoking habits on oral cancer risk are discussed. In total, 620 oral cancer patients and 620 non-cancer controls in central Taiwan were recruited and genotyped. The MTHFR C677T genotype, but not the A1298C, was differently distributed between the oral cancer and control groups. The T allele of MTHFR C677T was significantly more frequently found in controls than in oral cancer patients. Joint effects of smoking and MTHFR C677T genotype significantly affected oral cancer susceptibility. The MTHFR C677T CT and TT genotypes in association with smoking conferred lower odds ratios of 0.66 and 0.54 (95% confidence interval=0.49-0.82 and 0.39-0.86), respectively. Those patients with MTHFR C677T CT and TT genotypes also had a lower risk of oral cancer metastasis. MTHFR C677T genotype may have joint effects with smoking on oral carcinogenesis, and may be a useful biomarker for prediction and prognosis of oral cancer.

  13. Increased resistance to malaria in mice with methylenetetrahydrofolate reductase (Mthfr) deficiency suggests a mechanism for selection of the MTHFR 677C>T (c.665C>T) variant.

    PubMed

    Meadows, Danielle N; Pyzik, Michal; Wu, Qing; Torre, Sabrina; Gros, Philippe; Vidal, Silvia M; Rozen, Rima

    2014-05-01

    The polymorphism 677C>T (NM_005957.4:c.665C>T/p.Ala222Val, rs1801133:C>T) in methylenetetrahydrofolate reductase (MTHFR) results in mild enzymatic deficiency and increased risk for several complex traits including adverse reproductive outcomes, birth defects, and heart disease. Despite these deleterious effects, homozygosity is high (5%-15%) in many populations, and among the highest in Mediterranean regions, where malaria was historically endemic and may have conferred a selective advantage for other mutations. We infected Mthfr-deficient (Mthfr(+) (/-) ) and MTHFR overexpressing (MTHFR(Tg) ) mice with Plasmodium berghei ANKA to induce cerebral malaria. Mthfr(+/-) mice survived longer (P < 0.02, log-rank test), and MTHFR(Tg) mice died earlier (P < 0.05, log-rank test) after infection compared with wild-type littermates. Flow cytometry revealed increased lymphocyte populations and increased CCR4(+) NK cells in spleen of Mthfr(+) (/-) mice; MTHFR(Tg) animals had decreased numbers of these NK cells. Interferon-γ and interleukin-10 immunoreactive proteins were increased and decreased, respectively, in brain of Mthfr(+/-) mice compared with wild-type. We suggest that mild MTHFR deficiency protects against malarial infection and that this phenomenon may have led to the high frequency of the 677C>T/c.665C>T variant in human populations.

  14. MTHFR C677T, MTHFR A1298C, and OPG A163G Polymorphisms in Mexican Patients with Rheumatoid Arthritis and Osteoporosis

    PubMed Central

    Brambila-Tapia, Aniel Jessica Leticia; Durán-González, Jorge; Sandoval-Ramírez, Lucila; Mena, Juan Pablo; Salazar-Páramo, Mario; Gámez-Nava, Jorge Iván; González-López, Laura; Lazalde-Medina B, Brissia; Dávalos, Nory Omayra; Peralta-Leal, Valeria; del Mercado, Mónica Vázquez; Beltrán-Miranda, Claudia Patricia; Dávalos, Ingrid Patricia

    2012-01-01

    MTHFR polymorphisms C677T and A1298C are associated with reduced MTHFR enzyme activity and hyperhomocysteinemia, which has been associated with osteoporosis. The A163G polymorphism in osteoprotegerin (OPG) has been studied in osteoporosis with controversial results. The objective of the present study was to investigate the association(s) among MTHFR C677T, MTHFR A1298C, and OPG A163G polymorphisms in Mexican patients with rheumatoid arthritis and osteoporosis. The femoral neck and lumbar spine bone mineral densities (BMDs) were measured in 71 RA patients, and genotyping for the three polymorphisms was performed via restriction fragment length polymorphism analysis. Patients with osteoporosis/osteopenia exhibited statistically significant differences in the genotype frequencies of MTHFR C677T as well as an association with femoral neck BMD; TT homozygotes had lower BMDs than patients with the CT genotype, and both of these groups had lower BMDs than patients with the CC genotype. The associations of the MTHFR C677T polymorphism with osteoporosis/osteopenia and femoral neck BMD suggest that these polymorphisms confer a risk of developing osteoporosis in patients with rheumatoid arthritis, a risk that may be reduced with folate and B complex supplementation. PMID:22377704

  15. Thermolabile MTHFR genotype and retinal vascular occlusive disease

    PubMed Central

    Cahill, M; Karabatzaki, M; Donoghue, C; Meleady, R; Mynett-Johnson, L; Mooney, D; Graham, I; Whitehead, A; Shields, D

    2001-01-01

    BACKGROUND—Raised levels of total plasma homocysteine (tHcy) are associated with an increased risk of retinal vascular occlusive disease. A thermolabile form of a pivotal enzyme in homocysteine metabolism, methylenetetrahydrofolate reductase (MTHFR), has been associated with vascular occlusive disease and raised tHcy levels. The relation between thermolabile MTHFR genotype, tHcy, and retinal vascular occlusive disease has not been determined.
METHODS—A retrospective case-control study involving hospital based controls and cases with retinal vascular occlusions in whom tHcy levels had been determined was undertaken. Genotyping for the MTHFR 677 C-T mutation that specifies the thermolabile form of the enzyme was performed by established methods in all subjects. The relation between homozygosity for thermolabile MTHFR genotype (TT), raised tHcy levels, and risk of retinal vascular occlusive disease was examined.
RESULTS—87 cases of retinal vascular occlusive disease (mean age 68.7 years) comprising 26 cases of retinal artery occlusion and 61 of retinal vein occlusion were compared with 87 controls (mean age 70.2 years). The TT genotype did not confer a significantly increased risk of retinal vascular occlusive disease. The mean tHcy level was significantly higher in the cases than in the controls (p<0.0001). Overall, and in both the cases and controls, the frequency of the TT genotype was higher in those with normal tHcy levels than in those with increased levels of tHcy. However, the TT genotype did not significantly alter the risk of increased tHcy levels in these patients.
CONCLUSIONS—The TT genotype is not associated with an increased risk of retinal vascular occlusive disease or increased tHcy levels in this group of elderly patients. In older patients, nutritional rather than genetic factors may be more important in increasing tHcy levels, a known risk factor for retinal vascular occlusive disease.

 PMID:11133719

  16. Genetic Variation of Methylenetetrahydrofolate Reductase (MTHFR) and Thymidylate Synthase (TS) Genes Is Associated with Idiopathic Recurrent Implantation Failure

    PubMed Central

    Shim, Sung Han; Lee, Yubin; Kim, Ji Hyang; Jeon, Young Joo; Ko, Jung Jae; Lee, Woo Sik; Kim, Nam Keun

    2016-01-01

    The one-carbon metabolism pathway disorder was important role in successful pregnancy. The MTHFR and TS protein were crucial factor in one-carbon metabolism. To investigate the association between recurrent implantation failure (RIF) and enzymes in the one-carbon metabolism pathway. A total of 120 women diagnosed with RIF and 125 control subjects were genotyped for MTHFR 677C>T, 1298A>C, TSER 2R/3R and TS 1494del/ins by a polymerase chain reaction-restriction fragment length polymorphism assay. According to the gene-gene combination analysis, the MTHFR 677/MTHFR 1298 (TT/AA) and MTHFR 677/TS 1494 (TT/6bp6bp) genetic combinations were associated with relatively higher risks [adjusted odds ratio (AOR), 2.764; 95% CI, 1.065–7.174; P = 0.037 and AOR, 3.186; 95% CI, 1.241–8.178; P = 0.016] in RIF patients compared to the CC/AA (MTHFR 677/MTHFR 1298) and TT/6bp6bp (MTHFR 677/TS 1494) combinations, respectively. The results suggested that the combined MTHFR 677/MTHFR 1298 genotype might be associated with increased risk of RIF. To the best of our knowledge, this study is the first to elucidate the potential association of MTHFR, TS and TSER polymorphisms with RIF risk in Korean patients. PMID:27560137

  17. Retinal Ganglion Cell Loss and Mild Vasculopathy in Methylene Tetrahydrofolate Reductase (Mthfr)-Deficient Mice: A Model of Mild Hyperhomocysteinemia

    PubMed Central

    Markand, Shanu; Saul, Alan; Roon, Penny; Prasad, Puttur; Martin, Pamela; Rozen, Rima; Ganapathy, Vadivel; Smith, Sylvia B.

    2015-01-01

    Purpose. Methylenetetrahydrofolate reductase (Mthfr) is a key enzyme in homocysteine-methionine metabolism. We investigated Mthfr expression in retina and asked whether mild hyperhomocysteinemia, due to Mthfr deficiency, alters retinal neurovascular structure and function. Methods. Expression of Mthfr was investigated at the gene and protein level using quantitative (q) RT-PCR, in situ hybridization, immunoblotting, and immunohistochemistry (IHC). The Mthfr+/+ and Mthfr+/− mice were subjected to comprehensive evaluation using ERG, funduscopy, fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), HPLC, and morphometric and IHC analysis of glial fibrillary acidic protein (GFAP) at 8 to 24 weeks. Results. Gene and protein analyses disclosed widespread retinal expression of Mthfr. Electroretinography (ERG) revealed a significant decrease in positive scotopic threshold response in retinas of Mthfr+/− mice at 24 weeks. Fundus examination in mice from both groups was normal; FA revealed areas of focal vascular leakage in 20% of Mthfr+/− mice at 12 to 16 weeks and 60% by 24 weeks. The SD-OCT revealed a significant decrease in nerve fiber layer (NFL) thickness at 24 weeks in Mthfr+/− compared to Mthfr+/+ mice. There was a 2-fold elevation in retinal hcy at 24 weeks in Mthfr+/− mice by HPLC and IHC. Morphometric analysis revealed an approximately 20% reduction in cells in the ganglion cell layer of Mthfr+/− mice at 24 weeks. The IHC indicated significantly increased GFAP labeling suggestive of Müller cell activation. Conclusions. Mildly hyperhomocysteinemic Mthfr+/− mice demonstrate reduced ganglion cell function, thinner NFL, and mild vasculopathy by 24 weeks. The retinal phenotype is similar to that of hyperhomocysteinemic mice with deficiency of cystathionine-β-synthase (Cbs) reported earlier. The data support the hypothesis that hyperhomocysteinemia may be causative in certain retinal neurovasculopathies. PMID:25766590

  18. Genetic variants in 3'-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans.

    PubMed

    Jeon, Young Joo; Kim, Jong Woo; Park, Hye Mi; Kim, Jung O; Jang, Hyo Geun; Oh, Jisu; Hwang, Seong Gyu; Kwon, Sung Won; Oh, Doyeun; Kim, Nam Keun

    2015-06-05

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3'-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3'-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3'-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention.

  19. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and susceptibility to ischemic stroke: a meta-analysis.

    PubMed

    Li, Pingping; Qin, Chao

    2014-02-10

    Associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and ischemic stroke have been reported (Ariyaratnam et al., 2007; Banerjee et al., 2007; Casas et al., 2004), but the results of these studies are inconsistent. To investigate the possible associations between the MTHFR gene polymorphism and ischemic stroke, we performed a meta-analysis. Nineteen case-control studies associated with MTHFR gene C667T involving 2223 cases and 2936 controls were included. Heterogeneity among studies was evaluated with I(2) and Egger's test and an inverted funnel plot was used to assess publication bias. Odds ratio (OR) was observed to identify the associations. Statistically significant association with ischemic stroke was identified for allele T polymorphism of MTHFR [fixed-effects OR=1.28, 95% confidence interval (95% CI): 1.17-1.40, P<0.00001] and marginally significant association was detected with genotype CT of MTHFR (fixed-effects OR=1.13, 95% CI: 1.01-127, P=0.04) and genotype TT of MTHFR (fixed-effects OR=1.43, 95% CI: 1.20-1.70, P<0.001). The results suggested that the MTHFR C667T genetic polymorphism was significantly associated with increased risk of ischemic stroke.

  20. MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family.

    PubMed

    Del Balzo, Francesca; Spalice, Alberto; Perla, Massimo; Properzi, Enrico; Iannetti, Paola

    2009-01-01

    Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members.

  1. MTHFR C677 T gene polymorphism in lymphoproliferative diseases.

    PubMed

    Deligezer, Ugur; Akisik, Ebru E; Yaman, Fulya; Erten, Nilgün; Dalay, Nejat

    2006-01-01

    Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, has been implicated in cancer risk. In the present study we used a melting curve analysis to investigate the association of the common MTHFR C677 T polymorphism with lymphoproliferative diseases. Patients (n=117) were compared with age- and sex-matched control subjects (n=154). Our results indicate that the 677 T variant occurred less frequently in patients (26%) than in the control group (33.7%; P=0.05). Investigation of the variant allele (677 T) frequency in the subgroups with Hodgkin's lymphoma (HL) and B-cell neoplasms (BCNs) revealed that this difference was a result of the significantly lower distribution of the variant allele in patients with HL (20.5%; P=0.01). This was accompanied by a significantly higher frequency of the homozygote normal genotype (677CC) among the patients with HL. In patients with BCNs the distribution of the variant allele (30.3%) was comparable to that in the control group (P=0.47). However, the difference between HL (20.5%) and BCNs (30.3%) did not reach statistical significance (P=0.09). Our results suggest that the distribution of the C677 T polymorphism may vary among lymphoproliferative diseases.

  2. MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

    PubMed Central

    Umerez, Maitane; Gutierrez-Camino, Ángela; Muñoz-Maldonado, Carmen; Martin-Guerrero, Idoia; Garcia-Orad, Africa

    2017-01-01

    Methotrexate (MTX) is an important component in the therapy used to treat childhood acute lymphoblastic leukemia (ALL). Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for MTX pharmacokinetics. Two single-nucleotide polymorphisms in MTHFR gene, C677T and A1298C, affecting MTHFR activity, have been widely studied as potential markers of MTX toxicity and/or outcome in pediatric ALL. In this review, we show that the majority of published reports do not find association or present opposite effect. Therefore, MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL. The efforts should be focused on other genes, such as transporter genes or microRNA-related genes. PMID:28392709

  3. MTHFR Gene Mutations: A Potential Marker of Late-Onset Alzheimer's Disease?

    PubMed

    Román, Gustavo C

    2015-01-01

    Recent epigenome-wide association studies have confirmed the importance of epigenetic effects mediated by DNA methylation in late-onset Alzheimer's disease (LOAD). Metabolic folate pathways and methyl donor reactions facilitated by B-group vitamins may be critical in the pathogenesis of LOAD. Methylenetetrahydrofolate reductase (MTHFR) gene mutations were studied in consecutive Alzheimer's Disease & Memory Clinic patients up to December 2014. DNA analyses of MTHFR-C667T and - A1298C homozygous and heterozygous polymorphisms in 93 consecutive elderly patients revealed high prevalence of MTHFR mutations (92.5%). Findings require confirmation in a larger series, but MTHFR mutations may become a LOAD marker, opening novel possibilities for prevention and treatment.

  4. Methylenetetrahydrofolate reductase (MTHFR) polymorphism susceptibility to schizophrenia and bipolar disorder: an updated meta-analysis.

    PubMed

    Hu, Cai-Yun; Qian, Zhen-Zhong; Gong, Feng-Feng; Lu, Shan-Shan; Feng, Fang; Wu, Yi-Le; Yang, Hui-Yun; Sun, Ye-Huan

    2015-02-01

    Previous studies examining the possible role of the methylenetetrahydrofolate reductase (MTHFR) polymorphisms in the development of schizophrenia (SZ) and bipolar disorder (BPD) have provided inconclusive findings, this meta-analysis was therefore designed to get a more reliable assessment. A total of 38 articles were identified through a search of electronic databases, up to 27 February 2014. Odds ratios (ORs) with 95% confidence interval (CIs) were calculated using random effects models. Meta-analysis showed that MTHFR C677T was significantly associated with SZ, the highest OR was found for the recessive model (for TT vs. CT + CC: OR = 1.34, 95% CI: 1.18-1.53); a marginal association of MTHFR C677T with increased risk of BPD has also been found for the recessive model (OR = 1.26, 95% CI: 1.00-1.59). Subgroup analysis by ethnicity indicated that the significant association with SZ and BPD existed among Asian and African populations, but not for the white. MTHFR A1298C was significant associated with SZ, the highest OR for the dominant model (OR = 1.13, 95% CI: 1.03-1.24). Subgroup analysis indicated a significant association with SZ existed in Asian populations, not among the white populations and no significant association was detected between the MTHFR A1298C and BPD in all groups. We conclude that MTHFR polymorphism is associated with SZ and BPD among Asian, African populations, but not the white.

  5. Variants in maternal COMT and MTHFR genes and risk of neural tube defects in offspring.

    PubMed

    Liu, Jufen; Zhang, Yali; Jin, Lei; Li, Guoxing; Wang, Linlin; Bao, Yanping; Fu, Yunting; Li, Zhiwen; Zhang, Le; Ye, Rongwei; Ren, Aiguo

    2015-04-01

    Methylenetetrahydrofolate reductase (MTHFR) C677T and catechol-O-Methyltransferase (COMT) G158A are associated with a risk of neural tube defects (NTDs) in offspring. This study examined the effect of a MTHFR × COMT interaction on the risk of NTDs in a Chinese population with a high prevalence of NTDs. A total of 576 fetuses or newborns with NTDs and 594 controls were genotyped for MTHFRrs1801133, MTHFRrs1801131, and COMTrs4680 and COMTrs737865. Information on maternal sociodemographic characteristics, reproductive history, and related behavior was collected through face-to-face interviews. Possible interactions between genetic variants of MTHFR and COMT were examined. MTHFR C677T homozygous TT was associated with an elevated risk of total NTDs (odds ratio [OR] = 1.37, 95 % confidence interval [CI] = 0.93-2.03) and of anencephaly (OR = 1.67, 95 % CI = 0.98-2.84) compared with the CC genotype. There was a COMT rs737865 CC × MTHFR rs1801133 TT interaction for total NTDs (OR = 3.02, 95 % CI = 1.00-9.14) and for anencephaly (OR = 3.39, 95 % CI = 0.94-12.18). No interaction was found between COMT rs4680 AA/AG and MTHFR CT/TT genotypes for total NTDs or any subtype of NTD. The interaction of COMT rs737865 and MTHFR C677T was associated with an increased risk of NTDs, especially anencephaly, in a Chinese population with a high prevalence of NTDs.

  6. Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics.

    PubMed

    Abhinand, P A; Shaikh, Faraz; Bhakat, Soumendranath; Radadiya, Ashish; Bhaskar, L V K S; Shah, Anamik; Ragunath, P K

    2016-01-01

    Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of -10.3983 (kcal mol(-1)). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.

  7. Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients.

    PubMed

    Spellicy, Catherine J; Northrup, Hope; Fletcher, Jack M; Cirino, Paul T; Dennis, Maureen; Morrison, Alanna C; Martinez, Carla A; Au, Kit Sing

    2012-01-01

    The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD) in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR), are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs) in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype.

  8. Is methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism related with varicocele risk?

    PubMed

    Ucar, V B; Nami, B; Acar, H; Kilinç, M

    2015-02-01

    Varicocele is one of the main reasons for male infertility the exact aetiology of which remains unclear. Methylenetetrahydrofolate reductase (MTHFR) is important for DNA synthesis and methylation, which has a key role during spermatogenesis. Numerous literature suggests that the MTHFR polymorphism may be genetic risk factors for male infertility. In this study, we evaluated C677T and A1298C MTHFR gene polymorphism frequency in patients with varicocele and normal men. A total of 107 varicocele patients and 109 fertile healthy individuals were included. Genotyping of the MTHFR gene in C677T and A1298C base pairs carried out by using real-time PCR technique and afterwards, the statistical analysis accomplished. There is a statistical difference for the frequency of 1298AA genotype in patients with varicocele compared with normal controls (P = 0.0051, OR = 2.2750). Instead, subsequently, 1298/A allel frequency in patient group was significantly higher in comparison with control group (P = 0.0174). According to our results, 1298AA genotype in MTHFR gene raises the risk of varicocele approximately 2.3 times more compared with men carrying other genotypes. The results show that genetic factors have an important role in the molecular basis of varicocele.

  9. Folic acid rivals methylenetetrahydrofolate reductase (MTHFR) gene-silencing effect on MEPM cell proliferation and apoptosis.

    PubMed

    Xiao, Wen-Lin; Wu, Min; Shi, Bing

    2006-11-01

    It's clear that environmental factors play a role in the aetiology of orofacial clefting (OFC) and an important area of future research will be to unravel interactions that occur between candidate genes and environmental factors during early development of the embryo. Periconceptional folic acid supplementation may reduce the risk of OFC. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5-methylenetetrahydrofolate, the predominant circulating form of folic acid. To determine the effect of MTHFR gene mutation on murine embryonic palatal mesenchymal (MEPM) cells and the interaction with folic acid supplement, we used RNAi study in the primary cultures of MEPM cells. The cells of MTHFR gene silencing grew slower and the apoptosis cell number was more than the cells of control. Supplement with 20 microg/ml folic acid was the best to preventing teratogenic effect of MTHFR gene silencing. By flow cytometry analysis of cell cycle, results were shown that the MEPM cells were retarded in G(0)/G(1) after MTHFR gene silencing. While using 20 microg/ml folic acid supplements could make cell transit the G(1)/S restriction point and the cells growth was close to normal level.

  10. C677T (RS1801133 ) MTHFR gene polymorphism frequency in a colombian population

    PubMed Central

    Gómez-Gutierrez, Alberto; Gómez, Piedad Elena; Casas-Gomez, Maria Consuelo; Briceño, Ignacio

    2015-01-01

    Introduction: Abnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy. Objective: To establish the frequency of the C> T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. Methods: Data from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics®). The frequency of the C> T MTHFR rs1801133 marker polymorphism was analyzed. Results: Microarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T / T (p= 0.0001). Conclusions: Results for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies. PMID:26309343

  11. Variants in MTHFR gene and neural tube defects susceptibility in China.

    PubMed

    Wang, Yongxin; Liu, Yuan; Ji, Wenyu; Qin, Hu; Wu, Hao; Xu, Danshu; Turtuohut, Tukebai; Wang, Zengliang

    2015-08-01

    Neural tube defect (NTD) is a severe congenital birth abnormalities involving incomplete neural tube closure. 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene plays key role in folate cycle and methylation cycle, which could affect the DNA synthesis, repair and methylation. In this study, we aim to investigate the correlation between MTHFR polymorphisms and NTD-affected pregnancy. There were 444 participants involved in our study. Tag-SNPs were identified in HapMap Databases. Blood samples were collected from all subjects to further extract the genomic DNAs by TaqMan Blood DNA kits. We also carried out a meta-analysis based on previous published studies to further examine the association between MTHFR polymorphisms and NTD. In case-control study analysis, two SNPs were identified to be associated with NTD risk. The 677 C > T genetic variant was correlated with increased risk of NTD-affected pregnancy. However, the 1298 A > C polymorphism was shown to lower the risk of NTD-affected pregnancy. The protective role of 1298 A > C polymorphisms was further supported by the result of meta-analysis. Our study revealed that the SNPs of 677C > T and 1298A > C in MTHFR were associated with NTD-affected pregnancy, in which 677C > T was a risk factor and in contrast 1298A > C was protective factor against NTD. Our results of meta-analysis also revealed the 1298A > C MTHFR polymorphism play protective role in NTD.

  12. Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three la...

  13. Evaluation of High Resolution Melting for MTHFR C677T Genotyping in Congenital Heart Disease

    PubMed Central

    Yue, Shuying; Zhang, Kun; Wang, Hui; Dong, Rui; Yang, Xiaomeng; Liu, Yi; Ma, Yanhui

    2016-01-01

    Background High resolution melting (HRM) is a simple, flexible and low-cost mutation screening technique. The methylenetetrahydrofolate reductase (MTHFR) gene encoding a critical enzyme, potentially affects susceptibility to some congenital defects like congenital heart disease (CHD). We evaluate the performance of HRM for genotyping of the MTHFR gene C677T locus in CHD cases and healthy controls of Chinese Han population. Methods A total of 315 blood samples from 147 CHD patients (male72, female 75) and 168 healthy controls (male 92, female 76) were enrolled in the study. HRM was utilized to genotype MTHFR C677T locus of all the samples. The results were compared to that of PCR-RFLP and Sanger sequencing. The association of the MTHFR C677T genotypes and the risk of CHD was analyzed using odds ratio with their 95% confidence interval (CIs) from unconditional logistic regression. Results All the samples were successfully genotyped by HRM within 1 hour and 30 minutes while at least 6 hours were needed for PCR-RFLP and sequencing. The genotypes of MTHFR C677T CC, CT, and TT were 9.52%, 49.66%, and 40.82% in CHD group but 29.17%, 50% and 20.83% in control group, which were identical using both methods of HRM and PCR-RFLP, demonstrating the sensitivity and specificity of HRM were all 100%. Conclusion MTHFR C677T is a potential risk factor for CHD in our local residents of Shandong province in China. HRM is a fast, sensitive, specific and reliable method for clinical application of genotyping. PMID:26990189

  14. Association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with ischemic stroke in the Eastern Chinese Han population.

    PubMed

    Lv, Q-Q; Lu, J; Sun, H; Zhang, J-S

    2015-04-27

    The association between the MTHFR genetic polymorphism and ischemic stroke has been reported by a number of investigators. However, the results have been controversial and conflicting. The aim of this study was to explore the association between the MTHFR variants C677T and A1298C and the risk of ischemic stroke in an Eastern Chinese Han population. A total of 199 patients with ischemic stroke and 241 controls were recruited. Genotyping of the MTHFR C677T and A1298C polymorphisms was carried out using the Taqman 7900HT Sequence Detection System. The overall estimates (odds ratio: OR) for the allele (C) and genotype (AC+CC) of the A1298C polymorphism were 1.57 [95% confidence interval (CI) = 1.16-2.10], and 2.36 (95%CI = 1.39-4.00), respectively, establishing significant association of the MTHFR A1298C polymorphism with ischemic stroke. In contrast, there were no statistically significant differences compared to controls between MTHFR C677T polymorphic variants in the association ischemic stroke risk. Furthermore, haplotype-based analysis demonstrated that compared with the C-677-A-1298 haplotype, the C-677-C-1298 and T-677-C-1298 haplotypes showed significant increased risk of ischemic stroke (OR = 1.56; 95%CI = 1.07- 2.2; P = 0.02; OR = 1.76; 95%CI = 1.17-2.65; P < 0.01, respectively). We concluded that the A1298C polymorphism and the haplotypes C-677-C-1298 and T-677-C-1298 in MTHFR might modulate the risk of ischemic stroke in the Eastern Chinese Han population.

  15. Analysis of MTHFR, CBS, Glutathione, Taurine, and Hydrogen Sulfide Levels in Retinas of Hyperhomocysteinemic Mice

    PubMed Central

    Cui, Xuezhi; Navneet, Soumya; Wang, Jing; Roon, Penny; Chen, Wei; Xian, Ming; Smith, Sylvia B.

    2017-01-01

    Purpose Hyperhomocysteinemia (Hhcy) is implicated in certain retinal neurovascular diseases, although whether it is causative remains uncertain. In isolated ganglion cells (GCs), mild Hhcy induces profound death, whereas retinal phenotypes in Hhcy mice caused by mutations in remethylation (methylene tetrahydrofolatereductase [Mthfr+/−]) or transsulfuration pathways (cystathionine β-synthase [Cbs+/−]) demonstrate mild GC loss and mild vasculopathy. The current work investigated compensation in vivo of one pathway for the other, and, because the transsulfuration pathway yields cysteine necessary for formation of glutathione (GSH), taurine, and hydrogen sulfide (H2S), they were analyzed also. Methods Retinas isolated from wild-type (WT), Mthfr+/−, and Cbs+/− mice (12 and 22 weeks) were analyzed for methylene tetrahydrofolate reductase (MTHFR), cystathionine-β-synthase (CBS), and cystathionase (CTH) RNA/protein levels. Retinas were evaluated for levels of reduced:oxidized GSH (GSH:GSSG), Slc7a11 (xCT), taurine, taurine transporter (TAUT), and H2S. Results Aside from decreased CBS RNA/protein levels in Cbs+/− retinas, there were minimal alterations in remethylation/transsulfuration pathways in the two mutant mice strains. Glutathione and taurine levels in Mthfr+/− and Cbs+/− retinas were similar to WT, which may be due to robust levels of xCT and TAUT in mutant retinas. Interestingly, levels of H2S were markedly increased in retinas of Mthfr+/− and Cbs+/− mice compared with WT. Conclusions Ganglion cell loss and vasculopathy observed in Mthfr+/− and Cbs+/− mouse retinas may be milder than expected, not because of compensatory increases of enzymes in remethylation/transsulfuration pathways, but because downstream transsulfuration pathway products GSH, taurine, and H2S are maintained at robust levels. Elevation of H2S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter. PMID:28384716

  16. Increased risk of the abdominal aortic aneurysm in carriers of the MTHFR 677T allele.

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Gabriel, Marcin; Zapalski, Stanisław; Pawlak, Andrzej L

    2003-01-01

    Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Several genetic, biochemical and environmental factors are recognized as relevant for the pathogenesis of AAA. We determined the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (C677T) in 63 patients with AAA and compared it to that in 75 subjects of the population sample. The frequencies of the C/C, C/T and T/T genotypes were 65%, 27%, and 8% in the population sample and 33%, 60%, and 6% in the patients. This corresponds to a 4.4-fold greater risk of AAA in subjects who have the 677C/T variant of MTHFR, as compared with those who are 677C/C (p < 0.0001; 95% CI=2.11-9.34). The frequency of allele MTHFR 677T in patients (0.37) was higher than in the population sample (0.21; p < 0.007). This association between the common allele of the MTHFR gene--MTHFR 677T--and the development of AAA suggests that elevated homocysteine (Hcy) may disturb the function of the aortic wall. The disturbance may involve enhancement of elastin degradation, the process enhanced by mild hyperhomocysteinemia in minipigs. The magnitude of this effect, which refers to the AAA patients unselected for familial occurrence, indicates that the disturbance of aortic wall physiology caused by the presence of the MTHFR 677T allele is greater than the effect of the earlier described allele disequilibrium at the polymorphic alleles of the PAI1 (plasminogen activator inhibitor 1) gene seen only in familial cases of AAA.

  17. Renal cell carcinoma risk is associated with the interactions of APOE, VHL and MTHFR gene polymorphisms

    PubMed Central

    Lv, Cai; Bai, Zhiming; Liu, Zhenxiang; Luo, Pengcheng; Zhang, Jie

    2015-01-01

    Objective: The study was designed to explore the association of renal cell carcinoma (RCC) with VHL (rs779805), MTHFR (rs1801133) and APOE (rs8106822 and rs405509) polymorphisms, investigate the interactions among the single nucleotide polymorphisms (SNPs), and explore roles of the interactions in the pathogenesis of RCC in Chinese Han population. Methods: 81 RCC patients and 80 healthy controls were included in the study. Polymerase chain reaction (PCR) and direct sequencing methods were used in the analysis on the genotypes of APOE, VHL and MTHFR gene polymorphisms. Multifactor dimensionality reduction (MDR) method was adopted to conduct gene-gene interaction analysis. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to evaluate the correlation between gene-gene interactions and RCC risk. Results: Significant correlations were found between RCC risk and 3 SNPs (rs8106822, rs779805 and rs1801133). Genotype AA and allele A of APOE rs8106822 were significantly associated with RCC susceptibility (OR=2.65, 95% CI=1.05-6.69). Meanwhile, we found that the frequencies of genotype GG and allele G were much higher in case group, compared with controls (P<0.05 for both) and they appeared to be risk factors for RCC (OR=2.90, 95% CI=1.22-6.87; OR=1.78, 95% CI=1.14-2.27). While, allele T of MTHFR rs1801133 could decrease the risk of RCC (OR=0.62, 95% CI=0.40-0.97). MDR analysis showed that gene-gene interactions among APOE, VHL and MTHFR SNPs were closely related with RCC susceptibility. Conclusion: APOE, VHL and MTHFR gene polymorphisms were related to the risk of RCC. The interactions among APOE, VHL and MTHFR genes could increase the risk of RCC. PMID:26191297

  18. Meta-Prediction of MTHFR Gene Polymorphism Mutations and Associated Risk for Colorectal Cancer

    PubMed Central

    Yu, C. H.

    2016-01-01

    The methylenetetrahydrofolate reductase (MTHFR) gene is one of the most investigated of the genes associated with chronic human diseases because of its associations with hyperhomocysteinemia and toxicity. It has been proposed as a prototype gene for the prevention of colorectal cancer (CRC). The major objectives of this meta-analysis were to examine the polymorphism-mutation patterns of MTHFR and their associations with risk for CRC as well as potential contributing factors for mutations and disease risks. This analysis included 33,626 CRC cases and 48,688 controls across 92 studies for MTHFR 677 and 16,367 cases and 24,874 controls across 54 studies for MTHFR 1298, comprising data for various racial and ethnic groups, both genders, and multiple cancer sites. MTHFR 677 homozygous TT genotype was protective (p < .05) for CRC for all included populations; however, with heterogeneity across various racial–ethnic groups and opposing findings, it was a risk genotype for the subgroup of Hispanics (p < .01). Additional countries for which subgroup analyses resulted in 677 TT as a risk genotype included Turkey, Romania, Croatia, Hungary, Portugal, Mexico, Brazil, U.S. Hawai’i, Taiwan, India, and Egypt. Countries with the highest mutation rates and risks for both MTHFR 677 and 1298 genotypes are presented using global maps to visualize the grouping patterns. Meta-predictive analyses revealed that air pollution levels were associated with gene polymorphisms for both genotypes. Future nursing research should be conducted to develop proactive measures to protect populations in cities where air pollution causes more deaths. PMID:26858257

  19. Association between dietary intake of folate and MTHFR and MTR genotype with risk of breast cancer.

    PubMed

    He, J M; Pu, Y D; Wu, Y J; Qin, R; Zhang, Q J; Sun, Y S; Zheng, W W; Chen, L P

    2014-10-31

    We investigated the association between dietary intake of folate, vitamin B6, and the 5,10-methylenetetrahydrofolate reductase (MTHFR) genotype with breast cancer. A matched case-control study was conducted, and 413 patients with newly diagnosed and histologically confirmed breast cancer and 436 controls were recruited. Folate intake, vitamin B6, and vitamin B12 levels were calculated, and the MTHFR C677T and A1298C and MTR A2756G polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Breast cancer cases were generally older, older at first live birth, and younger at menarche, had a higher body mass index, were smokers, had higher energy intake, and more first-degree relatives with breast cancer as well as more live births compared to controls. With respect to energy intake, we found that higher energy intake were more likely to increase the risk of breast cancer. The MTHFR 667TT genotype was associated with a moderately increased risk of breast cancer when compared with the CC genotype, and a significant odds ratio (OR; 95% confidence interval, CI) was found (OR = 1.70, 95%CI = 1.06-2.73). Individuals carrying T allele were associated with higher risk of breast cancer when compared with C allele (OR = 1.34, 95%CI = 1.06-1.70). We did not find a significant effect of the MTHFR A1298C and MTR A2756G on the risk of breast cancer. We did not find any association between folate intake and MTHFR C677T polymorphisms. In conclusion, we found that the MTHFR C667T polymorphism is associated with the risk of breast cancer, indicating that this genotype plays a role in breast cancer development.

  20. Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population

    PubMed Central

    Yakub, Mohsin; Moti, Naushad; Parveen, Siddiqa; Chaudhry, Bushra; Azam, Iqbal; Iqbal, Mohammad Perwaiz

    2012-01-01

    Background Hyperhomocysteinemia (>15 µmol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-β-synthase (CBS; T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population. Methodology/Principal Findings In a cross-sectional survey, 872 healthy adults (355 males and 517 females; age 18–60 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine; folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length- polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [β(SE β), 2.01(0.63) and 16.19(1.8) µmol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [β(SE β), −0.56(0.58) and −0.83(0.99) µmol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was −1.88(0.81) µmol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p value <0.001). Odds of having hyperhomocysteinemia with MTHFR 677TT genotype was 10-fold compared to MTHFR 677CC genotype [OR (95%CI); 10.17(3.6–28.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.34–0.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in

  1. A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews.

    PubMed

    Ben-Shachar, Shay; Zvi, Tal; Rolfs, Arndt; Breda Klobus, Andrea; Yaron, Yuval; Bar-Shira, Anat; Orr-Urtreger, Avi

    2012-11-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis.

  2. A study on the correlation between MTHFR promoter methylation and diabetic nephropathy

    PubMed Central

    Yang, Xiao-Hui; Cao, Ren-Fang; Yu, Yang; Sui, Miao; Zhang, Tao; Xu, Jing-Yi; Wang, Xiao-Mei

    2016-01-01

    Objective: In order to observe the relationship between MTHFR promoter and DN, the determinations on MTHFR promoter methylation level and expression of HCY from DN patients have been carried out. Methods: According to the Diabetes diagnosis and classification standard from WHO in 1999, 85 patients with DM diagnosed by Endocrinology and 30 healthy participants from our medical examination center were chosen as control specimen to study in this paper. All this specimen were divided into A, B, C and D four groups , which are corresponding simple diabetes mellitus group (SDM), early diabetic nephropathy group (EDN), clinical diabetic nephropathy group (CDN) and normal control group. And then, all common materials and clinical experiments data have been collected respectively. (1) Extracted the peripheral blood DNA of each group and determinate the methylation status of MTHFR gene promoter by PCR (MSP). (2) Determinated the serum HCY protein expression of each group. Results: (1) The MTHFR promoter methylation of SDM and diabetic nephropathy group are wear off comparied with normal control group. And MTHFR promoter was in demethylation state in normal control group, a slightly weak in SDN, a obviously weak in early diabetic nephropathy group; the MTHFR promoter was in methylation state in clinical diabetic nephropathy group. (2) The HCY protein of simple diabetes mellitus group, early diabetic nephropathy group and clinical diabetic nephropathy group are Pitch with normal control group. HCY protein level of each group are as 7.41±1.61 umol/L, 10.34±2.89 umol/L, 10.95±5.89 umol/L and 13.03±6.14 umol/L corresponding normal control group, simple diabetes mellitus group, early diabetic nephropathy group and clinical diabetic nephropathy group. And there is no statistical significance about the differences among four groups. Conclusion: The demethylation state of MTHFR promoter was obviously weaker in clinical diabetic nephropathy group than in SDM. The level of serum

  3. Isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations.

    PubMed

    Cinemre, Hakan; Bilir, Cemil; Akdemir, Nermin

    2010-12-01

    Isolated renal vein thrombosis is very rare without the presence of nephrotic syndrome. It is more common in the newborns and infants. Whereas major risk factors in adults are the procoagulant states such as protein C or S deficiency, factor V Leiden mutation, primary or secondary antiphospholipid syndrome, severe hypothyroidism, and trauma. Here, we report a case of isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations. It should be noted that the presence of MTHFR-1298 and PAI-1 4G gene mutations together might be one of the examples of genetic mutation combinations that increase the likelihood of a thrombotic event.

  4. Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population.

    PubMed

    Sameer, A S; Shah, Z A; Nissar, S; Mudassar, S; Siddiqi, M A

    2011-06-21

    Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C→T and 1298 A→C, have been shown to impact various diseases, including cancer. The 677 C→T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population.

  5. The association of the MTHFR C677T polymorphism with inflammatory bowel diseases in the Israeli Jewish population

    PubMed Central

    Karban, Amir; Feldman, Tzah; Waterman, Matti; Leiba, Ronit; Efrati, Edna

    2016-01-01

    Abstract MTHFR C677T is a common gene polymorphism that has been shown to be associated with hyperhomocysteinemia. Studies on the role of MTHFR in inflammatory bowel diseases (IBD) have yielded conflicting results, perhaps due in part to genetic heterogeneity. The prevalence of the MTHFR C677T variant allele varies according to Jewish subpopulations: Ashkenazi vs non-Ashkenazi. The aim of this study was to examine the association between MTHFR C677T genotype and IBD in the different Jewish populations. DNA samples were assessed for the presence of the MTHFR C677T variant allele in 445 Jewish Israeli IBD patients: 338 with Crohn's disease [CD] (214 Ashkenazi and 124 non-Ashkenazi Jews) and 107 with ulcerative colitis [UC] (73 Ashkenazi and 34 non-Ashkenazi Jews), and in 347 healthy controls: 173 Ashkenazi and 174 Non-Ashkenazi Jews. Possible genotype–phenotype associations were investigated. We showed a significantly higher frequency of MTHFR 677T variant genotypes in non-Ashkenazi CD patients: Odds ratio of 1.86 for heterozygotes (CT) and 2.89 for homozygotes (TT) compared to non-Ashkenazi healthy controls. No significant association was found for UC in non-Ashkenazi patients or for CD or UC in Ashkenazi patients. Our findings suggest that the MTHFR 677T variant may contribute to the risk of CD in non-Ashkenazi but not Ashkenazi Jews. This may result from genetic heterogeneity and highlights the complexity of the genetic etiology of IBD. PMID:28002332

  6. Association of MTHFR C677T polymorphism with loneliness but not depression in cognitively normal elderly males.

    PubMed

    Lan, Wen-Hsuan; Yang, Albert C; Hwang, Jen-Ping; Hong, Chen-Jee; Liou, Ying-Jay; Yeh, Heng-Liang; Liu, Mu-En; Tsai, Shih-Jen

    2012-07-11

    Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is involved in folate and homocysteine metabolism, and has been associated with geriatric disorders, including dementia and late-life depression. The present work aimed to investigate the effect of MTHFR C677T polymorphism on the presence of depression and loneliness in cognitively normal male subjects. A total of 323 cognitively normal male subjects were included in this study (mean age=80.6; SD=5.3). Depression was assessed by the Geriatric Depression Scale-Short Form (GDS-SF) and loneliness by UCLA loneliness scales. Analysis of variance (ANOVA) was used to test the between MTHFR genotype difference in depression and loneliness. Multiple regression was used to test the effect of MTHFR polymorphism on the loneliness, controlling for age, education, cognitive function, and depression. ANOVA showed a significant between-genotype difference in loneliness scores (P=0.015), and post hoc comparisons showed that subjects with C/C genotype had significantly higher loneliness ratings, compared to those with C/T or T/T genotype. Regression analysis indicated that the effect of MTHFR polymorphism on loneliness was independent of age, education, cognitive function, and depression. Our findings suggest that MTHFR C677T polymorphism may be linked more to loneliness than depression in the cognitively normal elderly males, and may be implicated in the pathophysiology of late-life depression in relation to MTHFR genes.

  7. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency.

    PubMed

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-08-10

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28-75 were enrolled in this study from September 2005-December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk.

  8. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

    PubMed Central

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-01-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

  9. Population- and Family-Based Studies Associate the "MTHFR" Gene with Idiopathic Autism in Simplex Families

    ERIC Educational Resources Information Center

    Liu, Xudong; Solehdin, Fatima; Cohen, Ira L.; Gonzalez, Maripaz G.; Jenkins, Edmund C.; Lewis, M. E. Suzanne; Holden, Jeanette J. A.

    2011-01-01

    Two methylenetetrahydrofolate reductase gene ("MTHFR") functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the…

  10. Thrombosis Related ABO, F5, MTHFR, and FGG Gene Polymorphisms in Morbidly Obese Patients

    PubMed Central

    Kupcinskiene, Kristina; Murnikovaite, Martyna; Varkalaite, Greta; Juzenas, Simonas; Trepenaitis, Darius; Petereit, Ruta; Maleckas, Almantas

    2016-01-01

    Objective. Obesity is a well-known risk factor for thrombotic complications. The aim of the present study was to determine the frequency of thrombosis related ABO, F5, MTHFR, and FGG gene polymorphisms in morbidly obese patients and compare them with the group of nonobese individuals. Methods. Gene polymorphisms were analyzed in 320 morbidly obese patients (BMI > 40 kg/m2) and 303 control individuals (BMI < 30 kg/m2) of European descent. ABO C>T (rs505922), F5 C>G (rs6427196), MTHFR C>T (rs1801133), and FGG C>T (rs6536024) SNPs were genotyped by RT-PCR. Results. We observed a tendency for MTHFR rs1801133 TT genotype to be linked with morbid obesity when compared to CC genotype; however, the difference did not reach the significant P value (OR 1.84, 95% CI 0.83–4.05, P = 0.129). Overall, the genotypes and alleles of rs505922, rs6427196, rs1801133, and rs6536024 SNPs had similar distribution between morbidly obese and nonobese control individuals. Distribution of height and weight means among individuals carrying different rs505922, rs6427196, rs1801133, and rs6536024 genotypes did not differ significantly. Conclusions. Gene polymorphisms ABO C>T (rs505922), F5 C>G (rs6427196), MTHFR C>T (rs1801133), and FGG C>T (rs6536024) were not associated with height, weight, or morbid obesity among European subjects. PMID:27999448

  11. Dietary consumption of B vitamins, maternal MTHFR polymorphisms and risk for spontaneous abortion

    PubMed Central

    Rodríguez-Guillén, María del Rosario; Torres-Sánchez, Luisa; Chen, Jia; Galván-Portillo, Marcia; Silva-Zolezzi, Irma; Blanco-Muñoz, Julia; Hernández-Valero, María A.; López-Carrillo, Lizbeth

    2010-01-01

    Objective To asses he association between intake of folate and B vitamins and the incidence of spontaneous abortion (SA) according to the maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677 C>T and 1298 A>C). Material and Methods We conducted a nested case-control study within a perinatal cohort of women recruited in the state of Morelos, Mexico. Twenty-three women with SA were compared to 74 women whose pregnancy survived beyond week 20th. Intake of folate and B vitamins respectively, was estimated using a validated food frequency questionnaire. Maternal MTHFR polymorphisms were determined by PCR-RFLP and serum homocysteine levels by HPLC. Results Carriers of MTHFR 677TT and 1298AC genotypes respectively showed an increased risk of SA (OR 677TT vs. CC/CT=5.0; 95% CI: 1.2, 20.9 and OR 1298 AC vs. AA=5.5; 95% CI: 1.1, 26.6). Conclusions Our results support the role of MTHFR polymorphisms as a risk factor for SA, regardless of dietary intake of B vitamins. PMID:19180309

  12. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo.

    PubMed

    Yasar, Ali; Gunduz, Kamer; Onur, Ece; Calkan, Mehmet

    2012-01-01

    The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo.

  13. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.

    PubMed

    Liew, Siaw-Cheok; Gupta, Esha Das

    2015-01-01

    The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally.

  14. Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Alzheimer Disease Risk: a Meta-Analysis.

    PubMed

    Rai, Vandana

    2017-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is key enzyme of folate/homocysteine pathway. Case control association studies on MTHFR C677T polymorphism and Alzheimer's disease (AD) have been repeatedly performed over the last two decades, but the results are inconclusive. The aim of the present study was to assess the risk of MTHFR C677T polymorphism for AD. Forty-one studies were identified by a search of PubMed, Google Scholar, Elsevier, and Springer Link databases, up to January 2015. Odds ratios (ORs) with corresponding 95 % confidence interval (CI) were calculated using fixed effect model or random effect model. The subgroup analyses based on ethnicity were performed. MTHFR C677T polymorphism had a significant association with susceptibility to AD in all genetic models (for T vs C OR = 1.29, 95 % CI = 1.07-1.56, p = 0.003; for TT + CT vs CC OR = 1.29, 95 % CI = 1.19-1.40, p = 0.0004; for TT vs CC OR = 1.31, 95 % CI = 1.16-1.48, p = 0.001; for CT vs CC OR = 1.24, 95 % CI = 1.13-1.35, p < 0.004; and for TT vs CT + CC OR = 1.13, 95 % CI = 1.00-1.28, p = 0.02). Results of present meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of AD.

  15. Gene-specific DNA methylation of DNMT3B and MTHFR and colorectal adenoma risk.

    PubMed

    Ho, Vikki; Ashbury, Janet E; Taylor, Sherryl; Vanner, Stephen; King, Will D

    2015-12-01

    DNA methyltransferase 3B (DNMT3B) and methylenetetrahydrofolate reductase (MTHFR) are genes which encode enzymes critical to one-carbon metabolism. Polymorphisms in these genes have been implicated in colorectal cancer etiology; however, epigenetic modifications such as gene-specific DNA methylation also affect gene expression. DNA methylation of DNMT3B and MTHFR was quantified in blood leukocytes using Sequenom EpiTYPER® among 272 participants undergoing a screening colonoscopy. DNA methylation was quantified in 66 and 28CpG sites of DNMT3B and MTHFR respectively, and conceptualized using two approaches. First, measures representing average methylation across all CpG sites were created. Second, unsupervised principal component (PC) analysis was used to identify summary variables representing methylation around the transcription start site and in the gene-coding area for both DNMT3B and MTHFR. Logistic regression was used to compare methylation levels between participants diagnosed with colorectal adenoma(s) versus those with a normal colonoscopy via the estimation of odds ratios (ORs) and 95% confidence intervals (95% CIs) for the risk of colorectal adenomas. No association was observed between average DNA methylation of either DNMT3B or MTHFR and colorectal adenoma risk. For DNMT3B, increasing DNA methylation of CpG sites in the gene-coding area was associated with a higher risk of colorectal adenomas (OR=1.34; 95% CI: 1.01-1.79 per SD). This research provides preliminary evidence that methylation of DNMT3B may have functional significance with respect to colorectal adenomas, precursors to the vast majority of colorectal cancers.

  16. Effect of MTHFR polymorphisms on hyperhomocysteinemia in levodopa-treated Parkinsonian patients.

    PubMed

    Caccamo, D; Gorgone, G; Currò, M; Parisi, G; Di Iorio, W; Menichetti, C; Belcastro, V; Parnetti, L; Rossi, A; Pisani, F; Ientile, R; Calabresi, P

    2007-01-01

    High plasma homocysteine levels have been observed in Parkinson's disease (PD) patients treated with levodopa. In this study, we investigated the effects of C677T and A1298C MTHFR polymorphisms, in association with L-DOPA daily dose and vitamin status, on hyperhomocysteinemia development in PD patients. Plasma homocysteine and folate/vitamin B12 levels were assayed in 49 L-DOPA-treated PD patients, and compared with those of 86 healthy subjects. Genotyping for MTHFR polymorphisms was carried out by DG-DGGE. Homocysteine levels were significantly higher in patients than in controls (16.3 +/- 5.7 vs. 11.7 +/- 2.7 micromol/l, P < 0.01). No significant differences were found between patients and controls with regard to folate/vitamin B12 levels, and MTHFR allele distribution. The TT+AA genotype was significantly more frequent in PD patients than in controls (32.5% vs. 17.4%, P < 0.05), but not associated with an increased risk for PD (OR = 2.3, CI = 1.0-5.2). Further, patients carrier of this genotype exhibited a mild hyperhomocysteinemia (22.1 +/- 4.9 micromol/l), while a protective effect was observed in patients having the CC+AA genotype (11.2 +/- 1.6 micromol/l; OR = 0.19, CI = 0.06-0.59). Interestingly, homocysteine levels were also moderately increased in patients with CT heterozygous genotype, in the context of either AA or AC (14.5 +/- 3.6 micromol/l), in comparison to subjects with the CC + AA genotype. Finally, we did not find any significant association of combined C677T and A1298C MTHFR polymorphisms with an increased risk for hyperhomocysteinemia in PD patients. A better understanding of the role of homocysteine and MTHFR genotypes in PD is needed to reveal novel approaches for disease management.

  17. Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia.

    PubMed

    Hill, Lori D; York, Timothy P; Kusanovic, Juan P; Gomez, Ricardo; Eaves, Lindon J; Romero, Roberto; Strauss, Jerome F

    2011-01-31

    Preeclampsia is a leading cause of perinatal morbidity and mortality. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease. One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction. Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2-ME inhibits Hypoxia Inducible Factor 1α, a transcription factor mediating hypoxic responses. COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor. Variations in MTHFR have been associated with preeclampsia. By accounting for allelic variation in both genes, the role of COMT has been clarified. COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity. We tested for association between COMT haplotypes and the MTHFR 677 C → T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0.004), and that risk increased linearly from low to high activity haplotypes (P = 0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor "T" allele interact to increase preeclampsia risk (p = 0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0.052) and the fetal risk alleles in combination with a maternal balancing allele (P<0.001). This non-random distribution was not observed in controls (P = 0.341 and P = 0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia

  18. The MTHFR C677T Variant is Associated with Responsiveness to Disulfiram Treatment for Cocaine Dependency

    PubMed Central

    Spellicy, Catherine J.; Kosten, Thomas R.; Hamon, Sara C.; Harding, Mark J.; Nielsen, David A.

    2013-01-01

    Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2 weeks and then randomized into disulfiram (250 mg/day, N = 32) and placebo groups (N = 35) for 10 weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10 weeks of the study (N = 56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT or TT MTHFR genotype group (N = 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N = 24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81–69% (p = 0.007). Conclusion: This study indicates that a patient’s MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630. PMID:23335901

  19. Regulation of Folate-Mediated One-Carbon Metabolism by Glycine N-Methyltransferase (GNMT) and Methylenetetrahydrofolate Reductase (MTHFR).

    PubMed

    Wang, Yi-Cheng; Wu, Ming-Tsung; Lin, Yan-Jun; Tang, Feng-Yao; Ko, Hsin-An; Chiang, En-Pei

    2015-01-01

    Folate-mediated one-carbon metabolism is an important therapeutic target of human diseases. We extensively investigated how gene-nutrient interactions may modulate human cancer risk in 2 major folate metabolic genes, MTHFR and GNMT. The biochemical impacts of MTHFR and GNMT on methyl group supply, global DNA methylation, nucleotide biosynthesis, DNA damage, and partitioning of the folate dependent 1-carbon group were carefully studied. The distinct model systems used included: EB virus-transformed lymphoblasts expressing human MTHFR polymorphic genotypes; liver-derived GNMT-null cell-lines with and without GNMT overexpression; and HepG2 cells with stabilized inhibition of MTHFR using shRNA, GNMT wildtype, heterozygotous (GNMT(het)) and knockout (GNMT(nul)) mice. We discovered that the MTHFR TT genotype significantly reduces folate-dependent remethylation under folate restriction, but it assists purine synthesis when folate is adequate. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in human hematological malignancies. GNMT affects transmethylation kinetics and S-adenosylmethionine (adoMet) synthesis, and facilitates the conservation of methyl groups by limiting homocysteine remethylation fluxes. Restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. The systematic series of studies gives new insights into the underlying mechanisms by which MTHFR and GNMT may participate in human tumor prevention.

  20. Gender-Specific Effect of Mthfr Genotype and Neonatal Vigabatrin Interaction on Synaptic Proteins in Mouse Cortex

    PubMed Central

    Blumkin, Elinor; Levav-Rabkin, Tamar; Melamed, Osnat; Galron, Dalia; Golan, Hava M

    2011-01-01

    The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of Mthfr deficiency and neonatal exposure to the GABA potentiating drug vigabatrin (GVG) in mice has been shown to have gender-dependent effects on mice anxiety and to have memory impairment effects in a gender-independent manner. Here we show that Mthfr deficiency interacts with neonatal GABA potentiation to alter social behavior in female, but not male, mice. This impairment was associated with a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the female cortex. Reelin and fragile X mental retardation 1 protein (FMRP) levels and membrane GluR1/GluR2 ratios were elevated in wild-type mice treated neonatally with GVG and in Mthfr+/− mice treated with saline, but not in Mthfr+/− mice treated with GVG, compared with control groups (wild type treated with saline). A minor influence on the levels of these proteins was observed in male mice cortices, possibly due to high basal protein levels. Interaction between gender, genotype, and treatment was also observed in the GABA pathway. In female mice, GABA Aα2/gephyrin ratios were suppressed in all test groups; in male mice, a genotype-specific enhancement of GABA Aα2/gephyrin was observed. The lack of an effect on either reln or Fmr1 transcription suggests post-transcriptional regulation of these genes. Taken together, these findings suggest that Mthfr deficiency may interact with neonatal GABA potentiation in a gender-dependent manner to interrupt synaptic function. This may illustrate a possible mechanism for the epigenetic involvement of Mthfr

  1. Gender-specific effect of Mthfr genotype and neonatal vigabatrin interaction on synaptic proteins in mouse cortex.

    PubMed

    Blumkin, Elinor; Levav-Rabkin, Tamar; Melamed, Osnat; Galron, Dalia; Golan, Hava M

    2011-07-01

    The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of Mthfr deficiency and neonatal exposure to the GABA potentiating drug vigabatrin (GVG) in mice has been shown to have gender-dependent effects on mice anxiety and to have memory impairment effects in a gender-independent manner. Here we show that Mthfr deficiency interacts with neonatal GABA potentiation to alter social behavior in female, but not male, mice. This impairment was associated with a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the female cortex. Reelin and fragile X mental retardation 1 protein (FMRP) levels and membrane GluR1/GluR2 ratios were elevated in wild-type mice treated neonatally with GVG and in Mthfr+/- mice treated with saline, but not in Mthfr+/- mice treated with GVG, compared with control groups (wild type treated with saline). A minor influence on the levels of these proteins was observed in male mice cortices, possibly due to high basal protein levels. Interaction between gender, genotype, and treatment was also observed in the GABA pathway. In female mice, GABA Aα2/gephyrin ratios were suppressed in all test groups; in male mice, a genotype-specific enhancement of GABA Aα2/gephyrin was observed. The lack of an effect on either reln or Fmr1 transcription suggests post-transcriptional regulation of these genes. Taken together, these findings suggest that Mthfr deficiency may interact with neonatal GABA potentiation in a gender-dependent manner to interrupt synaptic function. This may illustrate a possible mechanism for the epigenetic involvement of Mthfr

  2. Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk

    PubMed Central

    Weiwei, Zheng; Liping, Chen; Dequan, Li

    2014-01-01

    Objective: we conducted a case-control study to investigate the association between dietary folate, vitamin B6 and vitamin B12 intake, MTHFR and MTR genotype, and breast cancer risk. Methods: Genotyping for MTHFR C677T and A1298C and MTR A2756G polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) method. The intake of folate, vitamin B6 and vitamin B12 were calculated by each food item from questionnaire. Results: Subjects with breast cancer tended to have more first-degree relatives (χ2=30.77, P<0.001) and have high intake of folate (t=2.42, P=0.008) and Vitamin B6 (t=2.94, P=0.002). Compared to the reference group, women with MTHFR 677 TT genotype and T allele had a significantly increased risk of breast cancer, with ORs (95%CI) of 1.8(1.08-2.27) and 1.39(1.02-1.92), respectively. For those who had folate intake<450 ug/day, MTHFR 667TT genotype was associated with a higher risk of breast cancer (OR=2.45, 95% CI=1.09-5.82, P=0.02). Similarly, subjects with Vitamin B6 intake<0.84 mg/day and MTHFR 667T allele genotype was correlated with a marginally increased risk of breast cancer. A significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer (P for interaction was 0.025). Conclusion: This case-control study found a significant association between MTHFR C667T polymorphism, folate intake and vitamin B6 and breast cancer risk, and a significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer. PMID:24639841

  3. MTHFR Functional Polymorphism C677T and Genomic Instability in the Etiology of Idiopathic Autism in Simplex Families. Revision

    DTIC Science & Technology

    2013-10-01

    leads to increase global DNA hypomethylation and consequently results in increased generation of de novo CNVs bringing about a higher risk for...association of of MTHFR 677T allele with increased level of global hypomethylation; and 3) the association of level of global hypomethylation with increased...MTHFR 677T allele leads to increase global DNA hypomethylation and consequently results in increased generation of de novo CNVs bringing about a

  4. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and promoter methylation in cervical oncogenic lesions and cancer.

    PubMed

    Botezatu, Anca; Socolov, Demetra; Iancu, Iulia V; Huica, Irina; Plesa, Adriana; Ungureanu, Carmen; Anton, Gabriela

    2013-04-01

    The aim of this study was to investigate the role of methylenetetrahydrofolate reductase (MTHFR) polymorphisms and MTHFR methylation pattern in cervical lesions development among women from Romania, a country with high prevalence of human papillomavirus (HPV) cervical infections. To achieve this goal, blood samples and cervical cytology specimens (n = 77)/tumour tissue specimens (n = 23) were investigated. As control, blood and negative cytological smears (n = 50) were used. A statistically significant association was found between T allele of C677T polymorphism and cervical lesions, heterozygote women presenting a threefold increased risk (normal/cervical lesions and tumours: wild homozygote 34/41 (0.68/0.41), heterozygote 14/51 (0.28/0.51), mutant homozygote 2/8 (0.04/0.08); OR = 3.081, P = 0.0035). Using χ square test for the control group, the HPV-negative and HPV-positive patients with cervix lesions, a significant correlation between viral infection and T allele of C677T polymorphism (P = 0.0287) was found. The MTHFR promoter was methylated in all HGSIL and tumour samples, significant differences being noted between HPV-positive samples, control group and cases of cervical dysplastic lesions without HPV DNA (P < 0. 0001) and between samples from patients with high-risk (hr)HPV versus low-risk (lr)HPV (P = 0.0026). No correlations between polymorphisms and methylation were observed. In Romania, individuals carrying T allele are susceptible for cervical lesions. MTHFR promoter methylation is associated with cervical severity lesions and with hrHPV.

  5. Riboflavin status, MTHFR genotype and blood pressure: current evidence and implications for personalised nutrition.

    PubMed

    McAuley, E; McNulty, H; Hughes, C; Strain, J J; Ward, M

    2016-08-01

    Clinical deficiency of the B-vitamin riboflavin (vitamin B2) is largely confined to developing countries; however accumulating evidence indicates that suboptimal riboflavin status is a widespread problem across the developed world. Few international data are available on riboflavin status as measured by the functional biomarker, erythrocyte glutathione reductase activation coefficient, considered to be the gold standard index. One important role of riboflavin in the form of flavin dinucleotide is as a co-factor for the folate-metabolising enzyme methylenetetrahydrofolate reductase (MTHFR). Homozygosity for the common C677T polymorphism in MTHFR, affecting over 10 % of the UK and Irish populations and up to 32 % of other populations worldwide, has been associated with an increased risk of CVD, and more recently with hypertension. This review will explore available studies reporting riboflavin status worldwide, the interaction of riboflavin with the MTHFR C677T polymorphism and the potential role of riboflavin in personalised nutrition. Evidence is accumulating for a novel role of riboflavin as an important modulator of blood pressure (BP) specifically in individuals with the MTHFR 677TT genotype, with results from a number of recent randomised controlled trials demonstrating that riboflavin supplementation can significantly reduce systolic BP by 5-13 mmHg in these genetically at risk adults. Studies are however required to investigate the BP-lowering effect of riboflavin in different populations and in response to doses higher than 1·6 mg/d. Furthermore, work focusing on the translation of this research to health professionals and patients is also required.

  6. Meta-analysis of the association of MTHFR polymorphisms with multiple myeloma risk

    PubMed Central

    Ma, Li-Min; Ruan, Lin-Hai; Yang, Hai-Ping

    2015-01-01

    The association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with multiple myeloma (MM) risk has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensively estimate. The case-control studies about MTHFR C677T and A1298C polymorphisms with MM risk were collected by searching PubMed, Elsevier, China National Knowledge Infrastructure and Wanfang Databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to assess the strength of association. Overall, no significant association was found between MTHFR A1298C polymorphism and MM risk under all four genetic models (AC vs. AA, OR = 0.99, 95%CI = 0.82-1.20; CC vs. AA, OR = 1.14, 95%CI = 0.77-1.68; recessive model, OR = 1.10, 95%CI = 0.76-1.59; dominant model, OR = 1.01, 95%CI = 0.84-1.22). The risk was also not significantly altered for C677T polymorphism and MM in overall comparisons (CT vs. CC, OR = 1.04, 95%CI = 0.93-1.17; TT vs. CC, OR = 1.16, 95%CI = 0.98-1.37; recessive model, OR = 1.13, 95%CI = 0.98-1.32; dominant model, OR = 1.07, 95%CI = 0.96-1.20). In subgroup analyses by ethnicity, no significant association was observed in both Caucasians and Asians. This meta-analysis suggested that MTHFR polymorphisms were not associated with MM risk. PMID:26022785

  7. DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR.

    PubMed

    Tao, Meng Hua; Shields, Peter G; Nie, Jing; Marian, Catalin; Ambrosone, Christine B; McCann, Susan E; Platek, Mary; Krishnan, Shiva S; Xie, Bin; Edge, Stephen B; Winston, Janet; Vito, Dominica; Trevisan, Maurizio; Freudenheim, Jo L

    2009-03-01

    Aberrant promoter methylation is recognized as an important feature of breast carcinogenesis. We hypothesized that genetic variation of genes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR), two critical enzymes in the one-carbon metabolism, may alter DNA methylation levels and thus influence DNA methylation in breast cancer. We evaluated case-control association of MTHFR C677T, A1298C, and MTR A2756G polymorphisms for cases strata-defined by promoter methylation status for each of three genes, E-cadherin, p16, and RAR-beta2 in breast cancer; in addition, we evaluated case-case comparisons of the likelihood of promoter methylation in relation to genotypes using a population-based case-control study conducted in Western New York State. Methylation was evaluated with real-time methylation-specific PCRs for 803 paraffin-embedded breast tumor tissues from women with primary, incident breast cancer. We applied unordered polytomous regression and unconditional logistic regression to derive adjusted odds ratios and 95% confidence intervals. We did not find any association of MTHFR and MTR polymorphisms with breast cancer risk stratified by methylation status nor between polymorphisms and likelihood of promoter methylation of any of the genes. There was no evidence of difference within strata defined by menopausal status, estrogen receptor status, folate intake, and lifetime alcohol consumption. Overall, we found no evidence that these common polymorphisms of the MTHFR and MTR genes are associated with promoter methylation of E-cadherin, p16, and RAR-beta2 genes in breast cancer.

  8. Alcohol consumption and genetic variation in MTHFR and MTR in relation to breast cancer risk

    PubMed Central

    Platek, Mary E.; Shields, Peter G.; Marian, Catalin; McCann, Susan E.; Bonner, Matthew R.; Nie, Jing; Ambrosone, Christine B.; Millen, Amy E.; Ochs-Balcom, Heather M.; Quick, Sylvia K.; Trevisan, Maurizio; Russell, Marcia; Nochajski, Thomas H.; Edge, Stephen B.; Freudenheim, Jo L.

    2010-01-01

    It has been hypothesized that effects of alcohol consumption on one-carbon metabolism may explain, in part, the association of alcohol consumption with breast cancer risk. The methylenetetrahydrofolate reductase (MTHFR) and 5-methyltetrahydrofolate-homocysteine methyltransferease (MTR) genes express key enzymes in this pathway. We investigated the association of polymorphisms in MTHFR (rs1801133 and rs1801131) and MTR (rs1805087) with breast cancer risk and their interaction with alcohol consumption in a case-control study, the Western New York Exposures and Breast Cancer (WEB) study. Cases (n=1063) were women with primary, incident breast cancer and controls (n= 1890) were frequency matched to cases on age and race. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression. We found no association of MTHFR or MTR genotype with risk of breast cancer. In the original case control study, there was a nonsignificant increased odds of breast cancer among women with higher lifetime drinking. In the current study, there was no evidence of an interaction of genotype and alcohol in premenopausal women. However, among postmenopausal women there was an increase in breast cancer risk for women who were homozygote TT for MTHFR C677T and had high lifetime alcohol intake (≥1161.84 ounces) (OR=1.92, CI=1.13–3.28) and for those who had a high number of drinks per drinking day (> 1.91 drinks/day) (OR=1.80, CI=1.03–3.28) compared to nondrinkers who were homozygote CC. Our findings indicate that among postmenopausal women, increased breast cancer risk with alcohol consumption may be as a result of effects on one-carbon metabolism. PMID:19706843

  9. DNA promoter methylation in breast tumors: No association with genetic polymorphisms in MTHFR and MTR

    PubMed Central

    Tao, Meng Hua; Shields, Peter G.; Nie, Jing; Marian, Catalin; Ambrosone, Christine B.; McCann, Susan E.; Platek, Mary; Krishnan, Shiva S.; Xie, Bin; Edge, Stephen B.; Winston, Janet; Vito, Dominica; Trevisan, Maurizio; Freudenheim, Jo L.

    2013-01-01

    Aberrant promoter methylation is recognized as an important feature of breast carcinogenesis. We hypothesized that genetic variation of genes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR), two critical enzymes in one-carbon metabolism, may alter DNA methylation levels, and thus influence DNA methylation in breast cancer. We evaluated case-control association of MTHFR C677T, A1298C, and MTR A2756G polymorphisms for cases strata defined by promoter methylation status for each of three genes, E- cadherin, p16, and RAR-β2 in breast cancer; in addition, we evaluated case-case comparisons of likelihood of promoter methylation in relation to genotypes using a population-based case-control study conducted in Western New York State. Methylation was evaluated with real time methylation-specific PCRs for 803 paraffin embedded breast tumor tissues from women with primary, incident breast cancer. We applied unordered polytomous regression and unconditional logistic regression to derive adjusted odds ratios (OR) and 95% confidence intervals (CI). We did not find any association of MTHFR and MTR polymorphisms with breast cancer risk stratified by methylation status nor between polymorphisms and likelihood of promoter methylation of any of the genes. There was no evidence of difference within strata defined by menopausal status, ER status, folate intake and lifetime alcohol consumption. Overall, we found no evidence that these common polymorphisms of the MTHFR and MTR genes are associated with promoter methylation of E- cadherin, p16, and RAR-β2 genes in breast cancer. PMID:19240236

  10. Association of MTHFR (C677T) Gene Polymorphism With Breast Cancer in North India

    PubMed Central

    Waseem, Mohammad; Hussain, Syed Rizwan; Kumar, Shashank; Serajuddin, Mohammad; Mahdi, Farzana; Sonkar, Satyendra Kumar; Bansal, Cherry; Ahmad, Mohammad Kaleem

    2016-01-01

    BACKGROUND Breast cancer is one of the most common malignancies in women and is associated with a variety of risk factors. The functional single-nucleotide polymorphism (SNP) C677T in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) may lead to decreased enzyme activity and affect the chemosensitivity of tumor cells. This study was designed to investigate the association of MTHFR gene polymorphism (SNP) in the pathogenesis of breast cancer among the North Indian women population. MATERIALS AND METHODS Genotyping was performed by polymerase chain reaction (PCR) using genomic DNA, extracted from the peripheral blood of subjects with (275 cases) or without (275 controls) breast cancer. Restriction fragment length polymorphism was used to study C677T polymorphism in the study groups. RESULTS The distribution of MTHFR (C677T) genotype frequencies, ie, CC, TT, and CT, among the patients was 64.7%, 2.18%, and 33.09%, respectively. In the healthy control group, the CC, TT, and CT frequencies were 78.91%, 1.09%, and 20.1%, respectively. The frequencies of C and T alleles were 81.2% and 18.7%, respectively, in the patient subjects, while they were 88.9% and 11.09%, respectively, among the healthy control group. Frequencies of the CT genotype and the T allele were significantly different (P = 0.007 and P = 0.005, respectively) between the control and the case subjects. CONCLUSION This study shows an association of the CT genotype and the T allele of the MTHFR (C667T) gene with increased genetic risk for breast cancer among Indian women. PMID:27721657

  11. Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers

    NASA Astrophysics Data System (ADS)

    Husna, M. Z.; Endom, I.; Ibrahim, S.; Selvi, N. Amaramalar; Fakhrurazi, H.; Htwe, R. Ohnmar; Kanehaswari, Y.; Halim, A. R. Abdul; Wong, S. W.; Subashini, K.; Syahira, O. Nur; Aishah, S.

    2013-11-01

    Mechanism underlying the beneficial effect of folic acid supplementation in reducing the risk of neural tube defect is still not well understood. Current evidences show the involvement of folic acid metabolic gene's polymorphism as contributing factors that regulate this pathway. Therefore, the objective of this research was to determine the presence of C677T polymorphism for methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR-19 bp deletion) genes between mother-children pairs of case and control. With the approval of UKMMC ethic committee, genomic DNA was extracted from one hundred and forty consented bloods. Polymerase chain reaction (PCR), PCR-RFLP (Restriction Fragment Length Polymorphism) and sequencing were employed to verify each nucleotide change. Our result shows that mutant MTHFR and DHFR alleles are present in all Malaysian sub-ethnic groups, case and control. Even though mutant MTHFR are found to be slightly higher in the case groups, 75% of the affected child is a non carrier for this allele and 62.5% of the mothers with an affected child are genotypically normal. For DHFR, almost all (87.5-100%) investigated samples are a carrier or having a double DHFR deletion be it a case or control pairs. However, strong maternal inheritance shown by the deleted allele might be due to a cascade effect of lacks of folate consumption or maternal uniparental disomy. In conclusion, the use of MTHFR and DHFR as markers in determining the risk of having spina bifida baby is uninformative and plays a small indirect role as the genetic causes of spina bifida. Therefore, spina bifida remains etiologically unknown polygenic and quantitative developmental trait whereby the searches for positive genetic marker need to be continued.

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

    PubMed Central

    Contreras-Cubas, Cecilia; Sánchez-Hernández, Beatríz E.; García-Ortiz, Humberto; Martínez-Hernández, Angélica; Barajas-Olmos, Francisco; Cid, Miguel; Mendoza-Caamal, Elvia C.; Centeno-Cruz, Federico; Ortiz-Cruz, Gabriela; Jiménez-López, José Concepción; Córdova, Emilio J.; Salas-Bautista, Eva Gabriela; Saldaña-Alvarez, Yolanda; Fernández-López, Juan Carlos; Mutchinick, Osvaldo M.

    2016-01-01

    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. PMID:27649570

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

    PubMed

    Contreras-Cubas, Cecilia; Sánchez-Hernández, Beatríz E; García-Ortiz, Humberto; Martínez-Hernández, Angélica; Barajas-Olmos, Francisco; Cid, Miguel; Mendoza-Caamal, Elvia C; Centeno-Cruz, Federico; Ortiz-Cruz, Gabriela; Jiménez-López, José Concepción; Córdova, Emilio J; Salas-Bautista, Eva Gabriela; Saldaña-Alvarez, Yolanda; Fernández-López, Juan Carlos; Mutchinick, Osvaldo M; Orozco, Lorena

    2016-01-01

    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.

  14. Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in depressed versus nondepressed patients.

    PubMed

    Lizer, Mitsi H; Bogdan, Renee L; Kidd, Robert S

    2011-11-01

    Numerous studies have found an association between low serum folate levels and incidence of depression. Folic acid supplementation has been successfully used as an adjunct to treat depression in these patients. However, some individuals have a genetic deficiency in the methylene tetrahydrofolate reductase (MTHFR) gene that limits conversion of folic acid to its biologically active form, L-methylfolate. Several studies have identified a higher frequency of genetic variations in the MTHFR gene in depressed patients than in nondepressed controls. This study evaluated the frequency of the most common genetic variation MTHFR C667T in a group of depressed U.S. Caucasians and compared results with those of a control group of nondepressed U.S. Caucasians. Subjects were recruited from a psychiatric practice, an ambulatory care clinic, and the community. Informed consent and a cheek swab sample were obtained from each subject for analysis using real-time polymerase chain reaction (PCR). Allele and genotype frequencies were compared using Pearson X2 analysis. Complete data were obtained for 156 subjects. No significant differences were found in frequency of the MTHFR C667T T allele (0.415 vs 0.365; p=0.408) or the MTHFR C667T TT genotype (20.7% vs 17.6%; p=0.619) between the depressed and non-depressed controls, respectively. Therefore, use of L-methylfolate without an additional indication of need does not appear to be warranted in this group of U.S. Caucasians. Some patients may benefit from L-methylfolate, but an evidence-based approach, such as MTHFR genotyping, should be used to identify these specific patients. Additional research is also needed to confirm the benefit of L-methylfolate in specific patient populations (e.g., MTHFR TT genotype).

  15. Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy risk: a meta-analysis.

    PubMed

    Zhang, Jie; Xiao, Yan; Zhang, Xian-Wen; Gao, Zhi-Qing; Han, Jing-Hui

    2014-07-01

    Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy (T2DN) risk is still unclear. This study was performed to evaluate if there is an association between the MTHFR A1298C gene polymorphism and T2DN risk using meta-analysis. The relevant reports were searched and identified from PubMed, Cochrane Library on 1 October 2013, and eligible studies were included and synthesized. Eight reports were recruited into this meta-analysis for the association of the MTHFR A1298C gene polymorphism with T2DN risk. The MTHFR A1298C C allele or CC genotype was shown to be not associated with T2DN risk (C allele: OR = 0.76, 95% CI: 0.43-1.34, p = 0.34; CC genotype: OR = 1.18, 95% CI: 0.63-2.22, p = 0.60). Interestingly, AA genotype was associated with the T2DN risk (OR = 0.68, 95% CI: 0.49-0.96, p = 0.03). In the sensitivity analysis according to the Hardy-Weinberg equilibrium (HWE), the results were consistent with those in non-sensitivity analysis. However, in the sensitivity analysis according to the control source from hospital, sample size of case (≥ 100), sample size of case (<100), the MTHFR A1298C gene polymorphism was not associated with T2DN risk. In conclusion, the MTHFR A1298C gene polymorphism was not associated with T2DN risk. However, additional studies are required to firmly establish a correlation between the MTHFR A1298C gene polymorphism and T2DN risk.

  16. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and tumor risk: evidence from 134 case-control studies.

    PubMed

    Tang, Min; Wang, Shang-Qian; Liu, Bian-Jiang; Cao, Qiang; Li, Bing-Jie; Li, Peng-Chao; Li, Yong-Fei; Qin, Chao; Zhang, Wei

    2014-07-01

    Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, which is essential for DNA synthesis and methylation. Genetic variations in the MTHFR gene seem to contribute to a decreased activity of MTHFR, ultimately confer increased susceptibility to cancer. As the most extensively studied polymorphism, MTHFR C677T polymorphism was shown to contribute to cancer susceptibility but the results were inconsistent. The authors performed a meta-analysis including 134 studies (46,207 cases and 69,160 controls) to address the issue. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the association. Overall, a significant elevated risk of cancer was associated with the MTHFR C677T polymorphism in T-allele versus C-allele comparison (OR = 1.06, 95% CI 1.02-1.11, P(heterogeneity) < 0.001), homozygote model (OR = 1.08, 95% CI 1.01-1.17, P(heterogeneity) < 0.001) and dominant model (OR = 1.05, 95% CI 1.00-1.10, P(heterogeneity) < 0.001). In the stratified analyses, significantly increased cancer risks were indicated among Asians in all genetic models except for heterozygote model. Further analysis revealed that C677T was significantly associated with an increased risk of esophageal and stomach cancer. This meta-analysis supports an association between the MTHFR C677T polymorphism and increased risk of esophageal and stomach cancer, especially among Asians. Additionally, more high-quality studies and that the covariates responsible for heterogeneity should be controlled to obtain a more conclusive response about the function of MTHFR C677T in cancer.

  17. Factor V Leiden, Prothrombin and MTHFR Mutation in Patients with Preeclamsia, Intrauterine Growth Restriction and Placental Abruption

    PubMed Central

    Livrinova, Vesna; Lega, Marija Hadzi; Dimcheva, Anita Hristova; Samardziski, Igor; Isjanovska, Rozalinda

    2015-01-01

    BACKGROUND: Factor V Leiden, Prothrombin and MTHFR gene mutation, could have an influence in pregnancy with adverse outcome Preeclamsia, IUGR and Placental abruption. AIM: The aim of this study is to investigate the presence of above mentioned inherited thrombophilias and its statistical significance, distribution among the complicated and normal pregnancy, and relative risk for carrier of mutation to develop preeclampsia, IUGR and placental abruption. MATERIAL AND METHODS: Prospective cohort study is implemented at University Clinic for Obstetric and Gynecology in Skopje, Republic of Macedonia. The study included 109 delivered patients: 40 with preeclapmsia, 22 with IUGR, 17 with placental abruption and 30 as control group with normal pregnancy. The amount of 3 ml venous blood has been used for detection of these point mutations using ThromboStrip -Opegen, QIAGEN kit manufactured for thrombotic risk. RESULTS: The highest frequency was found: in the group with preeclampsia 35% were MTHFR homozygous, IUGR -MTHFR heterozygous 45%, Placental abruption- 52.9% MTHFR heterozygous, and in the control group without thrombophilia 56.7%. There were combined thrombophilia in 3 patients. There aren`t statistical significance in presence of thrombophilia among groups (p > 0.05). Statistical significance (p < 0.05) was found between carriers of MTHFR homozygous in preeclampsia and group with placental abruption and control group. Relative risk in IUGR group for MTHFR homozygous was 5.54 (1.37MTHFR homozygous could increase the risk for development of IUGR and mutation of Factor V Leiden for placental abruption. Further investigations with more patients are warranted. PMID:27275292

  18. Quantification of gene-specific methylation of DNMT3B and MTHFR using sequenom EpiTYPER®.

    PubMed

    Ho, Vikki; Ashbury, Janet E; Taylor, Sherryl; Vanner, Stephen; King, Will D

    2016-03-01

    Among 272 patients undergoing a screening colonoscopy, DNA methylation of DNMT3B and MTHFR, genes encoding enzymes critical to one-carbon metabolism, was quantified in blood leukocytes using Sequenom EpiTYPER®. DNA methylation was quantified in 66 and 28 CpG sites of DNMT3B and MTHFR respectively, and conceptualized using two approaches. First, measures representing average methylation across all CpG sites were created. Second, unsupervised principal component (PC) analysis was used as a pattern derivation and data-reduction approach, to develop two summary variables (PC1 and PC2). These two summary variables represented methylation around the transcription start site (PC1) and in the gene-coding area (PC2) for both DNMT3B and MTHFR. The data contained in this article presents the variation of methylation levels for individual CpG sites within the DNMT3B and MTHFR genes and possible correlations uncovered using PC analysis. The data are related to the research article "Gene-specific DNA methylation of DNMT3B and MTHFR and colorectal adenoma risk" in Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis.

  19. A Study on MTHFR C677T Gene Polymorphism and Alcohol Dependence among Meiteis of Manipur, India.

    PubMed

    Singh, Huidrom Suraj; Salam, Kabita; Saraswathy, Kallur Nava

    2014-01-01

    Chronic alcohol consumption is reported to be associated with increase in plasma homocysteine levels which is further influenced by the polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene. The present study aims to understand the extent of the MTHFR C677T polymorphism in alcohol dependent (AD) cases of Meiteis of Manipur, a Mendelian population of India. MTHFR C677T polymorphism was screened in 313 controls and 139 alcohol dependent (AD) cases who all met DSM-IV criteria for alcohol dependence. Both AD cases and controls were unrelated up to 1st cousin. Among the control group, different drinking patterns like abstainer/nondrinkers (NDs), occasional drinkers (ODs), and moderate drinkers (MDs) are included. Both the groups were found to be in Hardy-Weinberg equilibrium (P > 0.05). Genotypic and allelic frequency distribution of MTHFR C677T polymorphism did not differ significantly between AD cases and controls (P > 0.05). However, individuals carrying mutant (T) allele show more than 1-fold increased risk for AD though not significant (OR = 1.43; 95% CI 0.41-5.01, P > 0.05). In conclusion, MTHFR C677T polymorphism is not found to be risk marker for AD in present studied population. However, higher prevalence of the mutant T allele may exacerbate deleterious health risk in future especially among alcohol drinkers.

  20. Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico.

    PubMed

    Ruiz-Argüelles, Guillermo J; Coconi-Linares, Lucia Nancy; Garcés-Eisele, Javier; Reyes-Núñez, Virginia

    2007-10-01

    Methylenetetrahydrofolate reductase (MTHFR) has two common variants with reduced activity due to polymorphisms at nucleotides 677 and 1298. Both affect folate metabolism and thus remethylation of homocysteine, but are also thought to affect nucleotide synthesis and DNA methylation. Methotrexate (MTX), which interrupts folate metabolism, is used in the treatment of a variety of diseases including acute lymphoblastic leukemia (ALL), but exerts in some patients toxic effects on fast dividing tissues such as mucosal epithelia. The enhanced toxicity may be due to cooperative effects between MTX and MTHFR variants. Accordingly, it has been reported that carrying the 677T allele of the MTHFR is a risk factor for MTX-associated mucositis. As in the Mexican population, which is characterized by a high prevalence of the 677T MTHFR variant, several of its commonly associated defects have not been observed, we investigated the relationship between MTX toxicity and the 677T allele. Out of 28 patients with ALL (CC: 2, CT: 10, TT: 16), 16 had episodes of MTX-associated mucositis (CC: 0, CT: 6, TT: 10). Neither at the gene level nor at the genotype level was a significant association with mucositis found. It may be postulated that the risk of higher MTX toxicity in patients with decreased MTHFR activity could be neutralized by the normally folate rich diet in Mexico.

  1. Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice

    PubMed Central

    Sontag, Jean-Marie; Wasek, Brandi; Taleski, Goce; Smith, Josephine; Arning, Erland; Sontag, Estelle; Bottiglieri, Teodoro

    2014-01-01

    Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of complex disorders, including developmental, vascular, and neurological diseases. MTHFR deficiency is associated with elevation of homocysteine levels and alterations in the methylation cycle. Here, using young and aged Mthfr knockout mouse models, we show that mild MTHFR deficiency can lead to brain-region specific impairment of the methylation of Ser/Thr protein phosphatase 2A (PP2A). Relative to wild-type controls, decreased expression levels of PP2A and leucine carboxyl methyltransferase (LCMT1) were primarily observed in the hippocampus and cerebellum, and to a lesser extent in the cortex of young null Mthfr−/− and aged heterozygous Mthfr+/− mice. A marked down regulation of LCMT1 correlated with the loss of PP2A/Bα holoenzymes. Dietary folate deficiency significantly decreased LCMT1, methylated PP2A and PP2A/Bα levels in all brain regions examined from aged Mthfr+/+ mice, and further exacerbated the regional effects of MTHFR deficiency in aged Mthfr+/− mice. In turn, the down regulation of PP2A/Bα was associated with enhanced phosphorylation of Tau, a neuropathological hallmark of Alzheimer’s disease (AD). Our findings identify hypomethylation of PP2A enzymes, which are major CNS phosphatases, as a novel mechanism by which MTHFR deficiency and Mthfr gene-diet interactions could lead to disruption of neuronal homeostasis, and increase the risk for a variety of neuropsychiatric disorders, including age-related diseases like sporadic AD. PMID:25202269

  2. Population distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C risk alleles for methotrexate toxicity in Israel.

    PubMed

    Efrati, Edna; Elkin, Hela; Nahum, Sagi; Krivoy, Norberto

    2013-04-01

    Methylenetetrahydrofolate reductase (MTHFR) is a central regulatory enzyme in the folate pathway. Two non-synonymous single nucleotide polymorphisms in MTHFR, C677T (rs1801133) and A1298C (rs1801131) have been associated with reduced MTHFR enzyme activity. These polymorphisms, especially C677T, appear to be linked with methotrexate-related toxicity, particularly hepatotoxicity; thus, pretreatment identification of individuals carrying these polymorphisms may be of clinical relevance. The purpose of this study was to determine the frequency and distribution of MTHFR polymorphic variants, known to functionally impair MTHFR activity, in the highly heterogeneous Israeli population. MTHFR genotyping was carried out in the representatives of three major demographic groups in Israel by PCR-restriction fragment length polymorphism and high-resolution melting. The relative distribution of variant alleles 677T and 1298C was found to be similar in individuals of Jewish, Druze and Arab Moslem descent (p = 0.09). However, Ashkenazi Jews displayed a 1.9-fold higher frequency of variant 677T and a 1.8-fold lower frequency of variant 1298C compared to non-Ashkenazi Jews (p < 0.001). Distinct differences in the relative frequencies of both polymorphisms were also found between Ashkenazi Jews and Druze (p < 0.01 for C677T, p < 0.01 for A1298C) or Ashkenazi Jews and Arab Moslem (p < 0.01 for C677T, p < 0.05 for A1298C). These data underscore the importance of geographic genetic analysis for a better understanding of human pharmacotherapy and personalized medicine.

  3. Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis.

    PubMed

    Yang, Lin; Hu, Xin; Xu, Luhang

    2012-10-01

    The associations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and methotrexate (MTX)-induced toxicities in patients with acute lymphoblastic leukemia (ALL) have been evaluated in various populations, with the results remained conflicting. Therefore, we conducted a meta-analysis by combining available data to derive a more precise estimation of the association. PubMed, Embase, and China National Knowledge Infrastructure were searched until 21 September 2011 to identify eligible studies. A total of 14 studies were included, with all studies investigating MTHFR C677T polymorphism while nine of them investigating MTHFR A1298C polymorphism only. Results suggested that MTHFR C677T polymorphism was associated with significantly increased risk of MTX-induced toxicity, specifically liver toxicity (TT/CT vs. CC: odds ratio (OR) = 1.70, 95 % confidence interval (CI) = 1.05-2.75), myelosuppression (TT vs. CT/CC: OR = 2.82, 95 %CI = 1.25-6.34), oral mucositis (TT/CT vs. CC: OR = 3.68, 95 %CI = 1.73-7.85), gastrointestinal toxicity (TT/CT vs. CC: OR = 2.36, 95 %CI = 1.36-4.11), and skin toxicity (T vs. C: OR = 2.26, 95 %CI = 1.07-4.74). MTHFR A1298C polymorphism was found to be associated with decreased risk of skin toxicity (CC/AC vs. AA: OR = 0.11, 95 %CI = 0.01-0.85). Genotyping of MTHFR polymorphism, C677T particularly, prior to treatment for ALL is likely to be useful with the aim of tailoring MTX therapy and thus reducing the MTX-related toxicities. However, further studies with larger data set and well-designed models are required to validate our findings.

  4. Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians.

    PubMed

    Naushad, Shaik Mohammad; Krishnaprasad, Chintakindi; Devi, Akella Radha Rama

    2014-05-01

    Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism shows considerable heterogeneity in its distribution in humans worldwide. The current study was conducted to investigate whether this polymorphism exhibited adaptive developmental plasticity in the control of the TT-genotype frequency. We screened 1,818 South Indian subjects (895 males and 923 females) for MTHFR C677T polymorphism using PCR-restriction fragment length polymorphism approach. MTHFR 677T-allele frequency in males and females was 9.1 and 11.0%, respectively. Compared to females, males had lower frequency of TT-genotype [odds ratio 0.31, 95% confidence interval (CI) 0.08-1.01]. The frequency of MTHFR 677T-allele was highest in the age group of 20-40 years and it gradually decreased from 40-60 to 60-80 years (P trend<0.0001). MTHFR 677TT-genotype was associated with 7.02-folds (95% CI: 2.12-25.63, P<0.0001) cumulative risk for recurrent pregnancy loss (RPL), neural tube defects (NTDs) and deep vein thrombosis (DVT). Linear regression model suggested that male gender exhibited increased homocysteine levels by 9.35 μmol/L while each MTHFR 677T-allele contributed to 4.63 μmol/L increase in homocysteine. Plasma homocysteine showed inverse correlation with dietary folate (r=-0.17, P<0.0001), B2 (r=-0.14, P<0.0001) and B6 (r=-0.07, P=0.03). Examination of the spontaneously aborted fetuses (n=35) showed no significant association of fetal genotype on its in utero viability. From the current study, it was concluded that C677T seemed to have acquired adaptive developmental plasticity among South Indians due to environmental influences thus contributing to hyperhomocysteinemia and its associated complications such as RPL, NTDs, DVT, etc.

  5. Polymorphisms in the MTHFR gene are associated with recurrence risk in lymph node-positive breast cancer patients

    PubMed Central

    Suner, Ali; Buyukhatipoglu, Hakan; Aktas, Gokmen; Kus, Tulay; Ulasli, Mustafa; Oztuzcu, Serdar; Kalender, Mehmet Emin; Sevinc, Alper; Kul, Seval; Camci, Celaletdin

    2016-01-01

    Purpose The aim of this study is to clarify the relationship between recurrence risk of breast cancer and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms. Patients and methods Breast cancer patients who had undergone surgery in Gaziantep University Oncology Hospital between June 2005 and June 2012 were followed-up and retrospectively enrolled in this study. Blood samples were collected from all patients to assess MTHFR C677T polymorphisms. Stage according to tumor–node–metastasis system, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 status, grade of disease, menopausal status, and administered chemotherapy or hormonal therapy were recorded. Effects of these parameters on recurrence risk were evaluated using univariate analysis and multivariate binary logistic regression model. Results Association of MTHFR C677T polymorphisms with recurrence risk was evaluated in 298 patients whose median age was 47 years (range: 21–79 years). In all patients, age (odds ratio [OR] =0.953, P=0.005) and N3 lymph node status (OR =6.293, P=0.001) were found to affect the recurrence risk. While MTHFR homozygote genotype did not have an effect on recurrence risk in all patients, increased risk was observed in lymph node-positive subgroup (OR =4.271; 95% CI 1.515–12.023; P=0.006). Adjusting for age, tumor size (T), and node status (N), MTHFR homozygote genotype had more statistically significant risk for recurrence (OR =3.255; 95% CI 1.047–10.125; P=0.041). Conclusion MTHFR TT genotype was found to be associated with increased recurrence risk in patients with lymph node-positive breast cancer. PMID:27672331

  6. Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis.

    PubMed

    Wu, Shuai; Han, Yan; Hu, Qiang; Zhang, Xiaojie; Cui, Guangcheng; Li, Zezhi; Guan, Yangtai

    2017-05-01

    Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) 677 C>T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C>T and ACE I/D polymorphisms and DPN found in various types of electronic databases. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (ORs) and its corresponding 95 % confidence interval (95 % CI) were calculated. We used STATA statistical software (version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D>I mutation (OR = 1.43, 95 % CI 1.12-1.83, P = 0.004) and MTHFR 677 C>T mutation (OR = 1.43, 95 % CI 1.08-1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P < 0.05). Subgroup analysis by country indicated that the MTHFR 677 C>T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D>I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta-analyses support the view that the MTHFR and ACE genes might play an important role in the development of DPN.

  7. Hyperhomocysteinaemia, low folate concentrations and MTHFR C677T mutation in abdominal aortic aneurysm.

    PubMed

    Cao, Hui; Hu, Xinhua; Zhang, Qiang; Li, Jun; Liu, Bing; Wang, Junpeng; Shao, Yang; Zhang, Zhishen; Liu, Chengwei; Hu, Haidi; Zhang, Jian; Xin, Shijie

    2014-05-01

    Hintergrund: Homocystein (Hcy) wurde mit dem Bauchaortenaneurysma (AAA) in Verbindung gebracht. Allerdings wurde der Zusammenhang von Hcy, Vitamin B12 und Folsäure bei Patienten mit AAA bislang nicht in unserer Population untersucht. Patienten und Methoden: 463 Patienten mit einem AAA wurden in die Studie eingeschlossen. 463 Probanden waren nach Alter und Geschlecht mit den Patienten abgestimmt. Wir untersuchten bei allen den Plasmaspiegel von Hcy, Vitamin B12, Folsäure und die Verteilung der C677T Methylentetrahydrofolat Reduktase (MTHFR) Gen-Mutation. Ergebnisse: Die mittlere Plasma- Hcy Konzentrationen waren bei Patienten mit AAA im Vergleich zur Kontrollgruppe signifikant höher (18,37 ± 6,97 vs 12,89 ± 4,08 umol/l, P < 0,001). Die Häufigkeit des homozygoten (TT) Genotyps der MTHFR C677T Mutation war bei Patienten mit AAA signifikant höher als in der Kontrollgruppe (19,4 % vs 11,9 %, P = 0,002). Nüchtern Hcy korrelierte negativ mit Folsäure (AAA: r = - 0,311, P < 0,01; Kontrolle: r = - 0,348, P < 0,01). Die Aneurysmen waren signifikant größer (p < 0,001) bei Patienten mit Hyperhomocysteinämie als bei Patienten mit normalen Hcy Plasmaspiegel. Die Größe des AAA korrelierte linear mit dem Plasma- Hcy Spiegel (r = 0,286, p < 0,001). Schlussfolgerungen: Serum Folsäuremangel und Hyperhomocysteinämie waren mit einem erhöhten Risiko von AAA assoziiert. Der homozygote (TT) Genotyp des MTHFR Genmutation kann ein entscheidender erblicher Risikofaktor für AAA sein.

  8. The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia

    PubMed Central

    Thomsen, Liv Cecilie V.; McCarthy, Nina S.; Melton, Phillip E.; Cadby, Gemma; Austgulen, Rigmor; Nygård, Ottar K.; Johnson, Matthew P.; Brennecke, Shaun; Moses, Eric K.; Bjørge, Line; Iversen, Ann-Charlotte

    2017-01-01

    Objective: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia. Methods: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. Results: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83–1.32, minor allele frequency = 0.15). Conclusion: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a

  9. Combined genotype and haplotype distributions of MTHFR C677T and A1298C polymorphisms

    PubMed Central

    Fan, Shujun; Yang, Boyi; Zhi, Xueyuan; Wang, Yanxun; Zheng, Quanmei; Sun, Guifan

    2016-01-01

    Abstract 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. PMID:27902594

  10. Genetic and epigenetic variation in the DNMT3B and MTHFR genes and colorectal adenoma risk.

    PubMed

    Ho, Vikki; Ashbury, Janet E; Taylor, Sherryl; Vanner, Stephen; King, Will D

    2016-05-01

    Polymorphisms in DNMT3B and MTHFR have been implicated in cancer etiology; however, it is increasingly clear that gene-specific DNA methylation also affects gene expression. A cross-sectional study (N = 272) investigated the main and joint effects of polymorphisms and DNA methylation in DNMT3B and MTHFR on colorectal adenoma risk. Polymorphisms examined included DNMT3B c.-6-1045G > T, and MTHFR c.665C > T and c.1286A > C. DNA methylation of 66 and 28 CpG sites in DNMT3B and MTHFR, respectively, was quantified in blood leukocytes using Sequenom EpiTYPER®. DNA methylation was conceptualized using two approaches: (1) average methylation and (2) unsupervised principal component analysis to identify variables that represented methylation around the transcription start site and the gene coding area of both genes. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associated with the main and joint effects of polymorphisms and DNA methylation. DNA methyltransferase 3B (DNMT3B) TT versus GG/GT genotypes was associated with increased colorectal adenoma risk (OR = 2.12; 95% CI: 1.03-4.34). In addition, increasing DNA methylation in the gene-coding area of DNMT3B was associated with higher risk of colorectal adenomas (OR = 1.34; 95% CI: 1.01-1.79 per SD). In joint effect analyses, synergistic effects were observed among those with both the DNMT3B TT genotype and higher DNMT3B methylation levels compared to those with GT/GG genotypes and lower methylation levels (OR = 4.19; 95% CI: 1.45-12.13 for average methylation; OR = 4.26; 95%CI: 1.31-13.87 for methylation in the transcription start site). This research provides novel evidence that genetic and epigenetic variations contribute to colorectal adenoma risk, precursor to the majority of colorectal cancer (CRC).

  11. Folate Levels and Polymorphisms in the Genes MTHFR, MTR, and TS in Colorectal Cancer

    PubMed Central

    Taflin, Helena; Wettergren, Yvonne; Odin, Elisabeth; Carlsson, Göran; Derwinger, Kristoffer

    2014-01-01

    AIM The aim of the study was to explore and describe the effect of polymorphisms in folate-associated genes regarding the levels of different folate forms and their distribution in tumors and mucosa in patients with colorectal cancer. MATERIALS AND METHODS Tumor and mucosa tissues from 53 patients with colorectal cancer were analyzed. The concentrations of tetrahydrofolate (THF), 5-methylTHF, and 5,10-methyleneTHF were measured by liquid chromatography—mass spectrometry. Genotyping of polymorphisms in the folate-associated genes methylenetetrahydrofolate reductase (MTHFR, C677T), methionine synthase (MTR, A2756G), and thymidylate synthase (TS, 5′-TSER 28 bp tandem repeat and 3′-TSUTR 6 bp deletion/insertion), were done by real-time polymerase chain reaction. Folate levels and distributions were determined in the total patient cohort and after subgrouping by genotypes. RESULTS The total folate level, as well as the THF and 5,10-methyleneTHF levels, were significantly higher in the tumor compared with mucosa tissue (P = 0.030, 0.031, and 0.015, respectively). The individual variation in folate levels in both tumor and mucosa were larger than the variation found when the patients were subgrouped by the gene polymorphisms. No significant differences in the mean concentration of any folate in the mucosa or tumor tissue were found in relation to the analyzed polymorphisms. The percentage level of 5,10-methyleneTHF in tumors was highest in patients with the MTHFR 677 CC genotype, and lowest in patients with the TT genotype (P = 0.033). A significantly lower percentage level of the 5,10-methyleneTHF level was found in tumors of patients with the 5′-TSER 3R/3R genotype (P = 0.0031). CONCLUSION A significant difference was found between the percentage level of 5,10-methyleneTHF in tumor tissues in relation to the MTHFR C677T and 5′-TSER 28 bp repeat polymorphisms. However, no differences were found in the actual tissue folate levels, or in their distribution, in

  12. Gene-wide association study between the methylenetetrahydrofolate reductase gene (MTHFR) and schizophrenia in the Japanese population, with an updated meta-analysis on currently available data.

    PubMed

    Yoshimi, Akira; Aleksic, Branko; Kawamura, Yukiko; Takahashi, Nagahide; Yamada, Shinnosuke; Usui, Hinako; Saito, Shinichi; Ito, Yoshihito; Iwata, Nakao; Inada, Toshiya; Noda, Yukihiro; Yamada, Kiyofumi; Ozaki, Norio

    2010-12-01

    Methylenetetrahydrofolate reductase (MTHFR) is a critical molecule for single-carbon transfer reactions. Recent evidence suggests that polymorphisms of MTHFR are related to neural tube deficits and the pathogenesis of schizophrenia. While several studies have demonstrated associations between the gene encoding the MTHFR (MTHFR) polymorphisms and schizophrenia, these studies lack consistency. Therefore, we conducted a gene-wide association study (patients with schizophrenia = 696, control subjects = 747) and performed imputation analysis. Additionally, we performed meta-analysis on currently available data from 18 studies for two common functional polymorphisms (rs1801131 and rs1801133). There were no significant associations with schizophrenia in the single marker analysis for the seven tagging SNPs of MTHFR. In the haplotypic analysis, a nominally significant association was observed between the haplotypes, which included four SNPs (rs1801133, rs17421511, rs17037396, and rs9651118) and the schizophrenic patients. Additionally, the imputation analysis demonstrated there were several associated markers on the MTHFR chromosomal region. However, confirmatory analyses of three tagging SNPs (rs1801133, rs17037396, and rs9651118) and the top SNP (rs17421511) for the imputation results (patients with schizophrenia = 797, control subjects = 1025) failed to replicate the haplotypic analysis and the imputation results. These findings suggest that MTHFR polymorphisms are unlikely to be related to the development of schizophrenia in the Japanese population. However, since our meta-analysis results demonstrated strong support for association of rs1801133 with schizophrenia, further replication studies based on a gene-wide approach need to be considered.

  13. Associations of MTHFR C677T and MTRR A66G Gene Polymorphisms with Metabolic Syndrome: A Case-Control Study in Northern China

    PubMed Central

    Yang, Boyi; Fan, Shujun; Zhi, Xueyuan; Wang, Da; Li, Yongfang; Wang, Yinuo; Wang, Yanxun; Wei, Jian; Zheng, Quanmei; Sun, Guifan

    2014-01-01

    Prior evidence indicates that homocysteine plays a role in the development of metabolic syndrome (MetS). Methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms are common genetic determinants of homocysteine levels. To investigate the associations of the MTHFR C677T and MTRR A66G polymorphisms with MetS, 692 Chinese Han subjects with MetS and 878 controls were recruited. The component traits of MetS and the MTHFR C677T and MTRR A66G genotypes were determined. A significant association was observed between the MTHFR 677T allele and increased risk of MetS, high fasting blood glucose, high waist circumference, and increasing number of MetS components. The MTRR A66G polymorphism was associated with an increased risk of MetS when combined with the MTHFR 677TT genotype, although there was no association found between MetS and MTRR A66G alone. Furthermore, the MTRR 66GG genotype was associated with high fasting blood glucose and triglycerides. Our data suggest that the MTHFR 677T allele may contribute to an increased risk of MetS in the northern Chinese Han population. The MTRR A66G polymorphism is not associated with MetS. However, it may exacerbate the effect of the MTHFR C677T variant alone. Further large prospective population-based studies are required to confirm our findings. PMID:25429430

  14. HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women.

    PubMed

    Batschauer, Anna P; Cruz, Nathalia G; Oliveira, Vanessa C; Coelho, Fernanda F; Santos, Izabela R; Alves, Michelle T; Fernandes, Ana P; Carvalho, Maria G; Gomes, Karina B

    2011-11-01

    Genetic factors related to cancer have been extensively studied and several polymorphisms have been associated to breast cancer. The FGFR4, MTHFR, and HFE genes have been associated with neoplastic diseases development. The current report outlines the analysis of the polymorphisms G388A (FGFR4), C677T (MTHFR), C282Y, and H63D (HFE) in Brazilian breast cancer patients. We studied 68 patients with invasive ductal and operable breast carcinoma and 85 women as a control group. The polymorphism frequencies in the breast cancer and control groups were analyzed, but no significant difference was observed by comparing the two groups. The presence of each polymorphism was analyzed according to the clinical features and markers already established as prognostic in the breast cancer group. The C677T, H63D, and G388A polymorphisms were not associated to histological grade, age of diagnosis, expression of HER2 receptor, or estrogen and progesterone receptor. The H63D polymorphism showed a significant association (P = 0.02) with the presence of p53 mutations, and C667T showed association to lymph node involvement (P = 0.05). Lymph node involvement, G388A polymorphism, and histological grade were independently associated to metastasis/death. Our data suggests that the polymorphisms G388A, C677T, and H63D are not useful in breast cancer diagnosis, but they may be significant additional prognostic markers related to breast cancer survival.

  15. Haplotype analysis of the folate-related genes MTHFR, MTRR, and MTR and migraine with aura

    PubMed Central

    Roecklein, Kathryn A.; Scher, Ann I.; Smith, Albert; Harris, Tamara; Eiriksdottir, Gudny; Garcia, Melissa; Gudnason, Villi; Launer, Lenore J.

    2014-01-01

    Aims The C677T variant in the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include Methionine synthase (MTR; EC 2.1.1.13), and Methionine synthase reductase (MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR. Methods Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache (n=367), migraine without aura (n=85), migraine with aura (n=167), and no headache (n=1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNPs and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing Results Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing. Conclusions These results suggest that MTRR variants may protect against migraine with aura in an older population. PMID:23430981

  16. Does the MTHFR A1298C Polymorphism Modulate the Cardiorespiratory Response to Training?

    PubMed

    Cięszczyk, Paweł; Zarębska, Aleksandra; Jastrzębski, Zbigniew; Sawczyn, Michał; Kozakiewicz-Drobnik, Izabela; Leońska-Duniec, Agata; Kaczmarczyk, Mariusz; Maciejewska-Skrendo, Agnieszka; Żmijewski, Piotr; Trybek, Grzegorz; Smółka, Wojciech; Pilch, Jan; Leźnicka, Katarzyna; Lulińska-Kuklik, Ewelina; Sawczuk, Marek; Massidda, Myosotis

    2016-12-01

    The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphic variant is a candidate to explain the individual differences in trainability and response to exercise training. Therefore, the aim of the study was to verify whether the A1298C polymorphism influenced the aerobic and anaerobic performance as well as body and mass composition in young Polish women following low-high impact aerobic exercise training. Two hundred and one women aged 21 ± 1 years (range 19-24) were included in the study. All of them completed a 12-week exercise training program and were measured for selected somatic features, aerobic capacity and cardiorespiratory fitness indices as well as peak anaerobic power and anaerobic capacity, before and after the intervention. A mixed 2 x 2 ANOVA for 20 dependent variables grouped in three categories was conducted. No significant interaction of the genotype with training for body mass and body composition variables was observed. Although, there were three significant genotype x training interactions for maximal oxygen uptake variables, regardless of body mass i.e.: for VO2max (p < 0.05), HRmax (p < 0.0001) and HRAT/HRmax (p < 0.0001). Significantly greater improvement in VO2max was gained by the CC+AC group compared to the AA genotype group. The present results support the hypothesis that individual differences in trainability are at least in part determined by the genetic component and MTHFR A1298C seems to be one of the many polymorphisms involved.

  17. Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population

    ERIC Educational Resources Information Center

    Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

    2012-01-01

    The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

  18. Spectrum of MTHFR gene SNPs C677T and A1298C: a study among 23 population groups of India.

    PubMed

    Saraswathy, Kallur Nava; Asghar, Mohammad; Samtani, Ratika; Murry, Benrithung; Mondal, Prakash Ranjan; Ghosh, Pradeep Kumar; Sachdeva, Mohinder Pal

    2012-04-01

    Elevated homocysteine is a risk factor for many complex disorders. The role of methylenetetrahydrofolate reductase (MTHFR) gene in methylation of homocysteine makes it one of the most important candidate genes for these disorders. Considering the heterogeneity in its distribution in world populations, we screened MTHFR C677T and A1298C single nucleotide polymorphisms in a total of 23 Indian caste, tribal and religious population groups from five geographical regions of India and belonging to four major linguistic groups. The frequencies of MTHFR 677T and 1298C alleles were found to be 10.08 and 20.66%, respectively. MTHFR homozygous genotype 677TT was absent in eight population groups and homozygous 1298CC was absent in two population groups. 677T allele was found to be highest among north Indian populations with Indo-European tongue and 1298C was high among Dravidian-speaking tribes of east India and south India. The less common mutant haplotype 677T-1298C was observed among seven population groups and overall the frequency of this haplotype was 0.008, which is similar to that of African populations. cis configuration of 677T and 1298C was 0.94%. However, we could not find any individual with four mutant alleles which supports the earlier observation that presence of more than two mutant alleles may decrease the viability of foetus and possibly be a selective disadvantage in the population.

  19. Association of the MTHFR C677T (rs1801133) polymorphism with idiopathic male infertility in a local Pakistani population

    PubMed Central

    Ismail, M; Azhar Beg, M; Shabbir, A; Rashid Kayani, A; Kaukab Raja, G

    2016-01-01

    Abstract The present study determined an association between idiopathic sperm disorders in a local Pakistani infertile male population and the MTHFR C677T polymorphism. After ruling out non genetic factors, a total of 437 idiopathic infertile men including 57 azoospermic, 66 oligospermic, 44 asthenozoospermic, 29 teratozoospermic, 20 oligoasthenospermic and 221 infertile normospermic men were recruited. Furthermore, 218 normospermic fertile men, who had two children (or more) were included as controls. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to determine MTHFR C677T (rs1801133) polymorphism. A significant association of the minor MTHFR 677T allele with male infertility was observed (p <0.05). In addition, men with MTHFR 677 CT and TT genotypes were at a greater risk [odds ratio (OR): 1.81, 95% confidence interval (95% CI): 1.17-2.80, p = 0.008 and OR: 9.24, 95% CI: 1.20-70.92, p = 0.032, respectively] of infertility. All the subgroups of male infertility (azoospermic, oligospermic, asthenospermic, oligoasthenoteratospermic (OAT) and normospermic infertile) had significantly (p <0.05) higher frequencies of CT and TT genotypes when compared to fertile men. The combined genotypes (CT + TT) were also found significantly (OR: 2.01, 95% CI: 1.31-3.08, p <0.001) associated with male infertility. The results suggest that the polymorphism might be a factor of male infertility in the Pakistani population. PMID:27785408

  20. MTHFR gene C677T mutation and ACE gene I/D polymorphism in Turkish patients with osteoarthritis.

    PubMed

    Inanir, Ahmet; Yigit, Serbulent; Tural, Sengul; Cecen, Osman; Yildirim, Eren

    2013-01-01

    Osteoarthritis is a degenerative joint disorder resulting in destruction of articular cartilage, osteophyte formation, and subchondral bone sclerosis. In recent years, numerous genetic factors have been identified and implicated in osteoarthritis. The aim of the current study was to examine the influence of methylenetetrahydrofolate reductase (MTHFR) gene C677T mutation and angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) variations on the risk of osteoarthritis. Genomic DNA is obtained from 421 persons (221 patients with osteoarthritis and 200 healthy controls). ACE gene I/D polymorphism genotypes were determined using polymerase chain reaction using I and D allele-specific primers. The MTHFR C677T mutation was analyzed by polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) methods. We found significant difference between the groups with respect to both ACE and MTHFR genotype distributions (p< 0.001, p< 0.001 respectively). Our study suggests that ACE gene DD genotype and MTHFR gene CC genotype could be used as genetic markers in osteoarthritis in Turkish study populations.

  1. 5,10-Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) gene polymorphisms and adult meningioma risk.

    PubMed

    Zhang, Jun; Zhou, Yan-Wen; Shi, Hua-Ping; Wang, Yan-Zhong; Li, Gui-Ling; Yu, Hai-Tao; Xie, Xin-You

    2013-11-01

    The causes of meningiomas are not well understood. Folate metabolism gene polymorphisms have been shown to be associated with various human cancers. It is still controversial and ambiguous between the functional polymorphisms of folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) and risk of adult meningioma. A population-based case–control study involving 600 meningioma patients (World Health Organization [WHO] Grade I, 391 cases; WHO Grade II, 167 cases; WHO Grade III, 42 cases) and 600 controls was done for the MTHFR C677T and A1298C, MTRR A66G, and MTR A2756G variants in Chinese Han population. The folate metabolism gene polymorphisms were determined by using a polymerase chain reaction–restriction fragment length polymorphism assay. Meningioma cases had a significantly lower frequency of MTHFR 677 TT genotype [odds ratio (OR) = 0.49, 95 % confidence interval (CI) 0.33–0.74; P = 0.001] and T allele (OR = 0.80, 95 % CI 0.67–0.95; P = 0.01) than controls. A significant association between risk of meningioma and MTRR 66 GG (OR = 1.41, 95 % CI 1.02–1.96; P = 0.04) was also observed. When stratifying by the WHO grade of meningioma, no association was found. Our study suggested that MTHFR C677T and MTRR A66G variants may affect the risk of adult meningioma in Chinese Han population.

  2. Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome

    ERIC Educational Resources Information Center

    Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

    2008-01-01

    Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study…

  3. Methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus.

    PubMed

    Zhou, Tian-Biao; Drummen, Gregor P C; Jiang, Zong-Pei; Li, Hong-Yan

    2015-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme that regulates nucleotide synthesis and DNA methylation. The MTHFR C677T gene polymorphism (rs1801133), a C → T transition at nucleotide 677 in exon 4, is a common gene variant of MTHFR and has been implicated in diabetic nephropathy, albeit with inconsistent results. Here, we performed a meta-analysis to assess the common effect size of this polymorphism on DN susceptibility. Case-control studies on the association of the MTHFR C677T gene polymorphism with DN risk were retrieved from databases up to August 1, 2013, and eligible studies were recruited into the meta-analysis and further analyzed. Of 132 studies, 33 were identified as suitable for this analysis. The results showed that T allele and TT genotype were distinctly associated with DN susceptibility in the overall population and Asians, and might be a risk factor in Caucasians and Africans (T allele: Overall population: p < 0.00001, Asians: p = 0.0002, Caucasians: p = 0.02, Africans: p < 0.00001; TT genotype: Overall population: p < 0.00001, Asians: p = 0.0003, Caucasians: p = 0.008, Africans: p = 0.0003). Furthermore, the analysis suggested that the CC genotype might play a protective role against DN onset in patients with type 2 diabetes for the overall population, Asians, Caucasian and Africans. However, due to the limited sample size in the African population, these results should be interpreted with care. In conclusion, the MTHFR C677T T allele or TT genotype might be a significant genetic molecular marker to determine the risk of DN in patients with type 2 diabetes and help to develop suitable disease prevention and management strategies.

  4. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene and susceptibility to depression in Asian population: a systematic meta-analysis.

    PubMed

    Rai, V

    2014-01-01

    Genetic association studies on MTHFR C677 T polymorphism and depression have been repeatedly performed over the last two decades and results are generally inconsistent. The aim of the present study was to assess the risk of MTHFR C677T polymorphism for depression in Asian population. The author performed a meta-analysis and pooled data from individual case-control studies that examined the association between C677T polymorphism and depression (meta-analysis: 13 studies, 1,120 cases and 1,688 controls).The pooled Odd Ratios (OR) were estimated by both fixed effects and random effects models. Overall, there was an association between MTHFR C677T polymorphism and increased risk of depression under five genetic models (OR T vs. C=1.44, 95% CI= 1.56-1.78, P=0.001; OR TT vs. CC= 1.78, 95% CI 1.17– 2.69, P=0.006; OR CT vs CC=1.102, 95% CI=0.91-1.32,P=0.31; OR TT vs. CT+CC=1.73, 95% CI= 0.87-3.41, P=0.11; OR TT+CT vs. CC=1.26, 95% CI=0.96-1.64, P=0.08). Sensitivity analysis suggested exclusion of any single study did not alter the overall pooled Ors. In conclusion results of present meta-analysis supports that there is a significant association between MTHFR C677T polymorphism and depression risk, and MTHFR 677T allele contributes to increased risk of depression in Asian individuals.

  5. Role of 677C→T polymorphism a single substitution in methylenetetrahydrofolate reductase (MTHFR) gene in North Indian infertile men.

    PubMed

    Naqvi, Hena; Hussain, Syed Rizwan; Ahmad, Mohammad Kaleem; Mahdi, Farzana; Jaiswar, Shyam Pyari; Shankhwar, Satya Narayain; Mahdi, Abbas Ali

    2014-02-01

    Failure or severe difficulty in conceiving a child is surprisingly common, worldwide problem. Half of these cases are due to male factors with defects in sperm (1 in 15 men) being the single most common cause. Also about 60-75 % of male infertility cases are idiopathic, since the molecular mechanisms underlying the defects remain unknown. DNA methylation is crucial for spermatogenesis and high methylenetetrahydrofolate reductase (MTHFR) activity in adult testis than other organs in mouse, signifies its critical role in spermatogenesis. According to recent findings there is a correlation of epigenetic regulation of several imprinted genes with disturbed spermatogenesis and fertility. Consequently any change in the MTHFR gene sequence can modify the spermatogenesis including transmission of infertility to the carriers. The aim of the study is to analyze the distribution of the single nucleotide polymorphism C677T in the MTHFR gene in 637 North Indian infertile patients and 364 fertile North Indian men as controls by using PCR-RFLP technique and Chi Square test for statistical analysis. The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total infertile men were 70.17, 24.17, 5.65 % in infertile men and 75.27, 21.7, 2.74 % in controls, respectively. The average frequency of the MTHFR 677T allele was 17.73 % in infertile men as compared to 13.59 % in controls. The statistical difference was significant. Disease risk was found 2.27-folds increased in patients who were carrying T allele. We found an association of C677T polymorphism with male infertility and that it may be a genetic risk factor for male infertility in North Indian population.

  6. Association between MTHFR C677T polymorphism and depression: a meta-analysis in the Chinese population.

    PubMed

    Jiang, Wei; Xu, Jun; Lu, Xiao-Jie; Sun, Yang

    2016-09-01

    Depression is a worldwide public health issue, and its prevalence increases each year. Although a number of studies have been conducted on the association between MTHFR C677T polymorphism and depression in China, this association remains elusive and controversial. To clarify the impact of MTHFR C677T polymorphism on the risk of depression, a meta-analysis was performed in the Chinese population. Relevant studies were identified using PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure and Chinese Biology Medicine through May 5, 2015. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. A total of 13 case-control studies including 1895 patients and 1913 controls were involved in this meta-analysis. Overall, T variant of MTHFR C677T gene polymorphism was significantly associated with an increased risk of depression in the Chinese population (T vs. C: OR = 1.52, 95% CI = 1.24-1.85; TT + CT vs. CC: OR = 1.64, 95% CI = 1.16-2.30; TT vs. CC: OR = 2.19, 95% CI = 1.49-3.24; TT vs. CC + CT: OR = 1.80, 95% CI = 1.31-2.46). In subgroup analyses stratified by geographic area and source of controls, the significant results were found in population-based studies, in hospital-based studies, in North and South China. The risk conferred by MTHFR C677T polymorphism is higher in North China than in South China. In conclusion, this meta-analysis suggests that MTHFR C677T polymorphism is associated with depression in the Chinese population, but these associations vary in different geographic locations.

  7. C677T and A1298C Polymorphisms of MTHFR Gene and Their Relation to Homocysteine Levels in Turner Syndrome

    PubMed Central

    Oliveira, Kelly C.; Verreschi, Ieda T.N.; Sugawara, Eduardo K.; Silva, Vanessa C.; Galera, Bianca B.; Galera, Marcial Francis; Bianco, Bianca

    2012-01-01

    Aims: To determine the frequency of C677T and A1298C polymorphisms of the MTHFR gene and correlate them with homocysteine serum levels in patients with Turner syndrome (TS) and controls. Methods: This case–control study included 78 women with TS and a control group of 372 healthy individuals without personal or family history of cardiovascular disease and cancer. C677T (rs1801133) and A1298C (rs1801131) polymorphisms were detected by polymerase chain reaction–restriction fragment-length polymorphism and the TaqMan system, respectively. Homocysteine serum levels were determined by high-performance liquid chromatography. The results were analyzed statistically, and p<0.05 was considered to represent a significant difference. Results: The homocysteine levels change was 13.9+3.3 nM in patients with TS and 8.8+3.2 nM in the control group. No significant difference between groups was found (p=0.348). Single-marker analysis revealed no association between MTHFR C677T polymorphism and TS when genotype (p=0.063) or allelic (p=0.277) distribution was considered. Regarding MTHFR A1298C polymorphism, a statistical difference was found between the TS group and the control group, for both genotype (p<0.0001) and allele (p<0.0001) distribution. Haplotype analysis of 2 MTHFR polymorphisms identified 2 haplotypes—CC and TC—associated with TS (p<0.001 and p=0.0165, respectively). However, homocysteine levels were not higher in patients with haplotype risk. Conclusion: The results suggest that the C677T and A1298C polymorphisms of the MTHFR gene are not related to homocysteine levels in Brazilian patients with TS, despite the differential distribution of the mutated allele C (A1298C) in these patients. Further studies are needed to investigate the possible genetic interaction with homocysteine levels in TS. PMID:22283972

  8. A Meta-Analysis of Association between Methylenetetrahydrofolate Reductase Gene (MTHFR) 677C/T Polymorphism and Diabetic Retinopathy

    PubMed Central

    Luo, Shasha; Wang, Furu; Shi, Chao; Wu, Zhifeng

    2016-01-01

    Aims: To shed light on the conflicting findings of the association between the methylenetetrahydrofolate reductase gene (MTHFR) 677C/T polymorphism and the risk of diabetic retinopathy (DR), a meta-analysis was conducted. Methods: A predefined search was performed on 1747 DR cases and 3146 controls from 18 published studies by searching electronic databases and reference lists of relevant articles. A random-effects or fixed-effects model was used to estimate the sizes of overall and stratification effects of the MTHFR 677C/T polymorphism on the risk of DR, as appropriate. Results: Risks were evaluated by odds ratios (OR) with 95% confidence intervals (95% CI). We found a significant association between the MTHFR 677C/T polymorphism and the risk of DR for each genetic model (recessive model: OR = 1.67; 95% CI: 1.19–2.40 and dominant model: OR = 1.71; 95% CI: 1.28–2.28; respectively). In stratified analysis; we further found that the Asian group with both types of diabetes mellitus (DM) showed a significant association with genetic models (recessive model: OR = 2.16; 95% CI: 1.75–2.60 and dominant model: OR = 1.98; 95% CI: 1.42–2.76; respectively). Conclusions: Our study suggested that the MTHFR 677C/T polymorphism may contribute to DR development, especially in Asian populations. Prospective and additional genome-wide association studies (GWAS) are needed to clarify the real role of the MTHFR gene in determining susceptibility to DR. PMID:27517946

  9. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age at onset of schizophrenia: no consistent evidence for an association in the Nordic population.

    PubMed

    Saetre, Peter; Grove, Jakob; Børglum, Anders D; Mors, Ole; Werge, Thomas; Andreassen, Ole A; Vares, Maria; Agartz, Ingrid; Terenius, Lars; Jönsson, Erik G

    2012-12-01

    Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes a common polymorphism (rs1801133 or C677T), which is associated with enzyme activity. The T-allele of the C677T polymorphism has been associated with earlier age at onset of schizophrenia in a Scandinavian population, although no association was found in replication attempts in other populations. Extending the study to five Nordic samples consisting of 2,198 patients with schizophrenia, including the original Scandinavian samples, there was no significant association between MTHFR C677T polymorphism and age at onset in schizophrenia. The present results do not suggest that the investigated MTHFR polymorphism has any significant influence on age at onset of schizophrenia in the Nordic population.

  10. Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C.

    PubMed

    Sazci, Ali; Ergul, Emel; Tuncer, Nese; Akpinar, Gurler; Kara, Ihsan

    2006-12-11

    Hyperhomocysteinemia is an independent risk factor for ischemic stroke. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a critical role in modulating the levels of plasma homocysteine. Two polymorphisms in the MTHFR gene, C677T, A1298C result in reduced enzyme activity. The mechanisms of ischemic and hemorrhagic stroke are not well understood. Although controversial, previous studies have shown evidence of causality of both stroke subtypes in patients with methylenetetrahydrofolate reductase gene polymorphisms. Therefore, we examined whether the C677T and A1298C polymorphisms of MTHFR gene are genetic risk factors for both ischemic and hemorrhagic stroke in a Turkish Caucasian population. In a case-control study, 120 total unrelated stroke patients (92 ischemic stroke, 28 hemorrhagic stroke), and 259 healthy controls were genotyped for C677T and A1298C polymorphisms of the MTHFR gene using a PCR-RFLP based-method. The MTHFR 1298C allele (chi(2)=8.589; P=0.014), C1298C genotype (OR=2.544; P=0.004), and C677C/C1298C compound genotype (OR=3.020; P=0.001) were associated with overall stroke. The MTHFR 1298C allele (chi(2)=11.166; P=0.004), C1298C genotype (OR=2.950; P=0.001), and C677C/C1298C compound genotype (OR=3.463, P=0.0001) were strongly associated with ischemic stroke. Interestingly however, the MTHFR 677T allele (chi(2)=6.033; P=0.049), T677T genotype (OR=3.120; P=0.014), and T677T/A1298A compound genotype (OR=4.211; P=0.002) were associated with hemorrhagic stroke. In conclusion, the C677T and A1298C polymorphisms of the MTHFR gene are genetic risk factors for hamorrhagic and ischemic stroke respectively, independent of other atherothrombotic risk factors.

  11. Interaction of MTHFR C677T and A1298C, and MTR A2756G gene polymorphisms in breast cancer risk in a population in Northeast Brazil.

    PubMed

    de Cássia Carvalho Barbosa, Rita; da Costa, Débora Menezes; Cordeiro, Denise Ellen Francelino; Vieira, Ana Patricia Freitas; Rabenhorst, Silvia Helena Barem

    2012-11-01

    Polymorphisms in genes encoding enzymes of folate metabolism are a focus of breast cancer risk studies due of the role of these enzymes in DNA methylation, synthesis, and repair. MTHFR, encoding for 5,10-methylenetetrahydrofolate reductase, is one of the most studied genes in this regard, but findings are controversial, and the majority of studies have analyzed polymorphisms individually. In this case control study, we examined the combination of the polymorphisms MTHFR C677T and A1298C with MTR A2756G, where MTR, methionine synthase, is an important enzyme of the folate cycle in the methylation pathway. One hundred and forty-two patients with breast cancer and controls were included and the genotypes were determined using PCR-RFLP. In the population studied, individuals carrying the polymorphic allele in the heterozygous state for both enzymes, MTHFR C677T and MTR A2756G, had an increased risk [odds ratio, OR=2.77 (95% confidence interval, CI=1.19-6.52)] for disease, compared to those with the wild genotype. In addition, individuals carrying the MTR 2756 genotype AG had an increased risk when this was combined with the MTHFR 1298 genotype CC [OR=5.13 (95% CI=0.87-38.82)]. No significant results were found from the analyses associating the MTHFR C677T and A1298C genotypes. However, when stratifying the patients by age (50 years old as the cut-off), patients over 50 years old had greater risk, with the presence of both MTHFR polymorphisms in the heterozygous state [OR=5.33 (95% CI=1.42-21.03)]. This study points out the importance of the interactions between the MTHFR C677T, MTHFR A1298C and MTR A2756G polymorphisms, and also highlights the relevance of the MTR A2756G polymorphism and age in breast cancer risk.

  12. Does the MTHFR A1298C Polymorphism Modulate the Cardiorespiratory Response to Training?

    PubMed Central

    Zarębska, Aleksandra; Jastrzębski, Zbigniew; Sawczyn, Michał; Kozakiewicz-Drobnik, Izabela; Leońska-Duniec, Agata; Kaczmarczyk, Mariusz; Maciejewska-Skrendo, Agnieszka; Żmijewski, Piotr; Trybek, Grzegorz; Smółka, Wojciech; Pilch, Jan; Leźnicka, Katarzyna; Lulińska-Kuklik, Ewelina; Sawczuk, Marek; Massidda, Myosotis

    2016-01-01

    Abstract The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphic variant is a candidate to explain the individual differences in trainability and response to exercise training. Therefore, the aim of the study was to verify whether the A1298C polymorphism influenced the aerobic and anaerobic performance as well as body and mass composition in young Polish women following low-high impact aerobic exercise training. Two hundred and one women aged 21 ± 1 years (range 19–24) were included in the study. All of them completed a 12-week exercise training program and were measured for selected somatic features, aerobic capacity and cardiorespiratory fitness indices as well as peak anaerobic power and anaerobic capacity, before and after the intervention. A mixed 2 x 2 ANOVA for 20 dependent variables grouped in three categories was conducted. No significant interaction of the genotype with training for body mass and body composition variables was observed. Although, there were three significant genotype x training interactions for maximal oxygen uptake variables, regardless of body mass i.e.: for VO2max (p < 0.05), HRmax (p < 0.0001) and HRAT/HRmax (p < 0.0001). Significantly greater improvement in VO2max was gained by the CC+AC group compared to the AA genotype group. The present results support the hypothesis that individual differences in trainability are at least in part determined by the genetic component and MTHFR A1298C seems to be one of the many polymorphisms involved. PMID:28031756

  13. MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population.

    PubMed

    Nair, Rohini R; Khanna, Anuradha; Singh, Kiran

    2012-02-01

    Recurrent early pregnancy loss (REPL) is a multifactorial disorder as both genetic and environmental factors contribute to the development of disease. Folate metabolism is an important mechanism to ensure proper fetal growth. Hyperhomocysteinemia leads to a number of disorders and REPL is one of them. In a case-control study DNA from 106 cases with the history of 3 or more REPL and 140 healthy fertile controls with successful pregnancy outcomes were genotyped for C677T single-nucleotide polymorphism (SNP) of the MTHFR (methylenetetrahydrofolate reductase) gene through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), which was further confirmed by sequencing. Allele frequencies of REPL cases were compared with healthy controls and a statistically significant association was found between REPL and the mutant T allele (χ² = 8.786, odds ratio [OR] = 2.20, 95% confidence interval [CI] = 1.323-3.9658, P = .003). The genotype frequencies of SNP C677T also differ significantly between these 2 groups (χ² = 8.237, P = .016). The OR for heterozygous CT in the REPL versus controls is 1.9591 (95% CI = 1.0285-3.7318, P = .04). The OR for TT homozygous is 6.3009 (95% CI = 1.2065, P = .02). Combined odds ratio of CT and TT against the control has been calculated as 2.2194 (95% CI = 1.2029-4.0952, P = .02) which is also significant. Thus the present study clearly indicates that homozygosity and heterozygosity for the MTHFR C677T polymorphism confer a 6.3009- and 1.9591-fold increased risk of idiopathic REPL, respectively.

  14. The methylenetetrahydrofolate reductase (MTHFR) 677 C>T polymorphism increases the risk of developing chronic myeloid leukemia-a case-control study.

    PubMed

    Bănescu, Claudia; Iancu, Mihaela; Trifa, Adrian P; Macarie, Ioan; Dima, Delia; Dobreanu, Minodora

    2015-04-01

    The methylenetetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C polymorphisms are associated with variations in folate levels, a phenomenon linked to the development of various malignancies. The aim of this study was to investigate the influence of the 677 C>T and 1298 A>C polymorphisms in the MTHFR gene on the risk of developing chronic myeloid leukemia (CML). Our study included 151 patients with CML and 305 controls. The MTHFR 677 C>T and 1298 A>C polymorphisms were investigated by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and allele-specific PCR techniques. The CT and TT genotypes of the MTHFR 677 C>T polymorphism were associated with an increased risk of developing CML (odds ratio (OR) = 1.556, 95% confidence interval (CI) = 1.017-2.381, p value = 0.041, and OR = 1.897, 95% CI = 1.046-3.44, p value = 0.035, respectively). No association was observed between the prognostic factors (blasts, basophils, additional chromosomal abnormalities, EUTOS score, Sokal and Hasford risk groups) and the MTHFR 677 C>T and 1298 A>C variant genotypes in CML patients. Our study shows that the MTHFR 677 C>T polymorphism is significantly associated with the risk of CML in Romanian patients.

  15. MTHFR c.677C>T Inhibits Cell Proliferation and Decreases Prostate Cancer Susceptibility in the Han Chinese Population in Shanghai

    PubMed Central

    Wu, Jun-Long; Zhou, Shu-Xian; Zhao, Rui; Zhang, Xuan; Chang, Kun; Gu, Cheng-Yuan; Gan, Hua-Lei; Dai, Bo; Zhu, Yao; Zhang, Hai-Liang; Shi, Guo-Hai; Qu, Yuan-Yuan; Zhao, Jian-Yuan; Ye, Ding-Wei

    2016-01-01

    Methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C variants were known to be associated with prostate cancer (PCa) risk with conflicting results, because of MTHFR and nutrient status interaction in the prostate development. In this large-scale, hospital-based, case-control study of 1817 PCa cases and 2026 cancer-free controls, we aimed to clarify the association between these two MTHFR variants and PCa risk in Shanghai and to explore the underlying molecular mechanisms. We found that both the heterozygous CT (adjusted OR = 0.78, 95% CI: 0.67–0.92) and the homozygous TT genotypes (adjusted OR = 0.68, 95% CI: 0.55–0.83) of c.677C>T were associated with a significantly decreased risk of PCa compared with homozygous wild-type CC genotype, respectively, using multivariate logistic regression. Furthermore, we confirmed that MTHFR c.677T allele was related to an increased serum homocysteine level in the Han Chinese population in Shanghai. In the cultured PCa cell lines, we observed that MTHFR c.677T could elevate the cellular homocysteine level and cause DNA damage, thus increasing cell apoptosis and finally inhibiting cell proliferation. In conclusion, MTHFR c.677T was a protective factor of PCa risk in ethnic Han Chinese males by inducing DNA damage and cell apoptosis. PMID:27819322

  16. Prevalence of hyperhomocysteinemia and the MTHFR C677T polymorphism in patients with arterial and venous thrombosis from North Western Russia.

    PubMed

    Shmeleva, Veronika M; Kapustin, Sergey I; Papayan, Ludmila P; Sobczyńska-Malefora, Agata; Harrington, Dominic J; Savidge, Geoffrey F

    2003-01-01

    Conflicting data from Western European and USA population studies led us to investigate hyperhomocysteinemia (HHcy), the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and thrombotic disease in North Western Russia. Plasma total homocysteine (tHcy) levels, MTHFR C677T genotype, selected life style determinants and haemostatic factor activity were determined in patients with arterial (n = 33), venous (n = 40), arterial + venous (n = 11) thrombosis and healthy controls (n = 30). We found raised median tHcy levels in all patient groups vs. controls (p < 0.05), with odds ratios (95% CI) for vascular disease among patients with HHcy (defined as > 15 micromol/l) of 3.9 (0.6 - 14.3), 4.8 (1.2 - 18.8) and 15.8 (2.8 - 87.3) respectively. tHcy levels were a function of MTHFR C677T genotype, and all patients with tHcy levels > 30 micromol/l had the MTHFR C677T homozygous substitution. Elevated tHcy levels (p < 0.05) were identified in smokers and coffee drinkers, with the degree of elevation dependent on MTHFR C677T genotype. Of the studied haemostatic parameters increased factor VIII activity and vWF antigen and activity was observed in HHcy subjects. We conclude that HHcy and MTHFR C677T genotype are positively associated with arterial and venous thrombotic disease in the population of North Western Russia.

  17. Associations between Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Non-Alcoholic Fatty Liver Disease (NAFLD) Risk: A Meta-Analysis

    PubMed Central

    Sun, Man-Yi; Zhang, Li; Shi, Song-Li; Lin, Jing-Na

    2016-01-01

    Background C677T and A1298C are the most common allelic variants of Methylenetetrahydrofolate Reductase (MTHFR) gene. The association between MTHFR polymorphisms and the occurrence of non-alcoholic fatty liver disease (NAFLD) remains controversial. This study was thus performed to examine whether MTHFR mutations are associated with the susceptibility to NAFLD. Methods A first meta-analysis on the association between the MTHFR polymorphisms and NAFLD risks was carried out via Review Manager 5.0 and Stata/SE 12.0 software. The on-line databases, such as PubMed, EMBASE, CENTRAL, WOS, Scopus and EBSCOhost (updated to April 1st, 2016), were searched for eligible case-control studies. The odd radio (OR), 95% confidence interval (CI) and P value were calculated through Mantel-Haenszel statistics under random- or fixed-effect model. Results Eight articles (785 cases and 1188 controls) contributed data to the current meta-analysis. For C677T, increased NAFLD risks were observed in case group under homozygote model (T/T vs C/C, OR = 1.49, 95% CI = 1.03~2.15, P = 0.04) and recessive model (T/T vs C/C+C/T, OR = 1.42, 95% CI = 1.07~1.88, P = 0.02), but not the other genetics models, compared with control group. For A1298C, significantly increased NAFLD risks were detected in allele model (C vs A, OR = 1.53, 95% CI = 1.13~2.07, P = 0.006), homozygote model (C/C vs A/A, OR = 2.81, 95% CI = 1.63~4.85, P = 0.0002), dominant model (A/C+C/C vs A/A, OR = 1.60, 95% CI = 1.06~2.41, P = 0.03) and recessive model (C/C vs A/A+A/C, OR = 2.08, 95% CI = 1.45~3.00, P<0.0001), but not heterozygote model. Conclusion T/T genotype of MTHFR C677T polymorphism and C/C genotype of MTHFR A1298C are more likely to be associated with the susceptibility to NAFLD. PMID:27128842

  18. Genetic risk factors for arterial ischemic stroke in children: a possible MTHFR and eNOS gene-gene interplay?

    PubMed

    Djordjevic, Valentina; Stankovic, Marija; Brankovic-Sreckovic, Vesna; Rakicevic, Ljiljana; Radojkovic, Dragica

    2009-07-01

    In order to investigate the influence of genetic factors in childhood stroke, we compared the distributions of mutations/ polymorphisms affecting hemostasis and/or endothelial function (factor V [FV] Leiden, factor II [FII] G20210A, methylenetetrahydrofolate reductase [MTHFR] C677T, angiotensin-converting enzyme [ACE] insertion/deletion [ID], and endothelial nitric oxide synthase [eNOS] G894T) among children with stroke and controls. A total number of 26 children with arterial ischemic stroke and a control group of 50 healthy children were included in the study. No statistically significant differences in allelic and genotypic distribution were detected in comparisons between groups. However, when combined genotypes were analyzed, statistical significance was observed for the association of MTHFR CT and eNOS TT gene variants. The results of our study suggest that this genotype combination represents a risk factor of 7.2 (P = .017) for arterial ischemic stroke in children.

  19. Life-threatening methylenetetrahydrofolate reductase (MTHFR) deficiency with extremely early onset: characterization of two novel mutations in compound heterozygous patients.

    PubMed

    Forges, Thierry; Chery, Céline; Audonnet, Sandra; Feillet, François; Gueant, Jean-Louis

    2010-06-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzymatic component of the folate cycle, converting 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the methyl donor for remethylation of homocysteine into methionine. Severe MTHFR deficiency is a rare recessive disease leading to major hyperhomocysteinemia, homocystinuria, and progressive neurological distress within the two first decades of life. More than 50 mutations have been reported so far in affected patients but only a few cases with very early onset of symptoms during the first weeks have been described, most of them showing a particular severe clinical course. We detected two novel mutations by direct sequencing of MTHFR in compound heterozygous patients with extremely low or undetectable enzyme activity; one of them had clinical onset during the first week of life and fatal issue at the age of six weeks. Prenatal diagnosis of his sibling allowed for early treatment with B vitamins and betaine and a favorable outcome. One of these mutations (c.523G>A) led to an Ala>Thr transition in the catalytic domain of the enzyme, the other (c.1166G>A) induced alternative splicing of exon 7 at the junction of the catalytic and regulatory domains. Both parents carried only one of these mutations and presented with moderate and intermediate hyperhomocysteinemia, respectively, without neurological symptoms. Severe MTHFR deficiency thus has to be taken into consideration when investigating neurological distress even in the newborn, regarding the need for an earliest possible treatment. Characterization of the relatives further allows for preventive measure to limit the risks of chronic hyperhomocysteinemia.

  20. Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype

    PubMed Central

    Traylor, Matthew; Adib-Samii, Poneh; Thijs, Vincent; Sudlow, Cathie; Rothwell, Peter M.; Boncoraglio, Giorgio; Dichgans, Martin; Meschia, James; Maguire, Jane; Levi, Christopher; Rost, Natalia S.; Rosand, Jonathan; Hassan, Ahamad; Bevan, Steve; Markus, Hugh S.

    2016-01-01

    Background and Purpose— Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels–associated genetic variant MTHFR C677T for association with magnetic resonance imaging–confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods— We included 1359 magnetic resonance imaging–confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results— MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions— MTHFR C677T was associated with magnetic resonance imaging–confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes. PMID:26839351

  1. MTHFR Functional Polymorphism C677T and Genomic Instability in the Etiology of Idiopathic Autism in Simplex Families

    DTIC Science & Technology

    2014-12-01

    AWARD NUMBER: W81XWH-12-1-0298 TITLE: MTHFR Functional Polymorphism C677T and Genomic Instability in the Etiology of Idiopathic Autism in... Autism in Simplex Families 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0298 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Xudong Liu, PhD 5d...DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Autism Spectrum Disorder (ASD

  2. Role of MTHFR C677T and MTR A2756G polymorphisms in thyroid and breast cancer development.

    PubMed

    Zara-Lopes, T; Gimenez-Martins, A P A; Nascimento-Filho, C H V; Castanhole-Nunes, M M U; Galbiatti-Dias, A L S; Padovani-Júnior, J A; Maniglia, J V; Francisco, J L E; Pavarino, E C; Goloni-Bertollo, E M

    2016-05-09

    Folate metabolism is essential for DNA synthesis and repair. Alterations in genes that participate in folate metabolism can be associated with several types of malignant neoplasms, including thyroid and breast cancer. In the present case-control study, we examined the association between methylenetetrahydrofolate reductase (MTHFR C677T, rs1801133) and methionine synthase (MTR A2756G, rs1805087) polymorphisms and risk for thyroid and breast cancer. Polymerase chain reaction-restriction fragment length technique was used to determine the specific genotypes in the genes of interest. Statistical analysis was performed by multiple logistic regression test. We found an association between MTHFR C677T polymorphism and risks to both thyroid (OR = 2.50; 95%CI = 1.15-5.46; P = 0.02) and breast cancer (OR = 2.53; 95%CI = 1.08-5.93; P = 0.03). Tobacco consumption and high body mass index were also associated with thyroid cancer. In addition, increased age (≥50 years) and alcohol consumption were found to be associated with breast cancer. Our results indicated that MTHFR C677T is significantly associated with thyroid and breast cancer risks. Thus, these factors may be used as potential prognostic markers for thyroid and breast cancers.

  3. Functional variants in CYP1B1, KRAS and MTHFR genes are associated with shorter telomere length in postmenopausal women.

    PubMed

    Cerne, Jasmina Z; Pohar-Perme, Maja; Cerkovnik, Petra; Gersak, Ksenija; Novakovic, Srdjan

    2015-07-01

    Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length.

  4. Preferential transmission of the MTHFR 677 T allele to infants with Down syndrome: implications for a survival advantage.

    PubMed

    Hobbs, Charlotte A; Cleves, Mario A; Lauer, Ronald M; Burns, Trudy L; James, S Jill

    2002-11-15

    We have examined the transmission frequencies of the methylenetetrahydrofolate reductase (MTHFR) 677 T and C alleles from heterozygous parents to children with Down syndrome (trisomy 21) in 202 Caucasian families. Our results indicated that the MTHFR 677T allele was transmitted to children with Down syndrome at a significantly higher rate than would be expected based on Mendelian inheritance patterns, and the C allele was transmitted at a significantly lower rate (P < 0.009). Transmission frequencies were also examined independently for maternally and paternally transmitted alleles to assess potential parent-of-origin effects. Because the vast majority of conceptions with trisomy 21 end in pregnancy loss, we questioned whether the observed preferential transmission of the T allele to this population of liveborn infants with Down syndrome could reflect a survival advantage. A plausible biochemical interpretation of these results is presented based on a maternal-fetal MTHFR 677T allele interaction in the context of the constitutive overexpression of three copies of the cystathionine beta synthase gene in the trisomy 21 fetus. Published 2002 Wiley-Liss, Inc.

  5. Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

    PubMed Central

    Zou, Peng; Ji, Guixiang; Gu, Aihua; Zhao, Peng

    2012-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs. Methods An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis. Results A significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR  = 2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR  = 1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR  = 1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR  = 1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls. Conclusion The results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted. PMID:23056169

  6. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to diabetic nephropathy in Chinese type 2 diabetic patients: a meta-analysis.

    PubMed

    Chang, Wei-wei; Zhang, Liu; Yao, Ying-shui; Su, Hong; Jin, Yue-long; Chen, Yan

    2013-08-01

    The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and diabetic nephropathy (DN) or diabetes mellitus (DM) risk has been widely reported, but the results are still debatable. To investigate the role of MTHFR C677T polymorphism on DM or DN, 13 separate studies in the Chinese population on the relation between MTHFR C677T polymorphism and DM or DN were analyzed by a meta-analysis. Five genetic models were used to estimate the association between MTHFR C677T polymorphism and the risk of DM or DN. Overall, our meta-analysis for DN versus healthy controls produced significant results for all genetic contrasts except for the co-dominant model (allele contrast: OR = 2.24, 95%CI: 1.88-2.65, p < 0.00001, Pheterogeneity = 0.49). However, the meta-analysis for DM versus healthy controls produced non-significant results for all contrasts (allele contrast: OR = 1.12, 95%CI: 0.92-1.35, p = 0.25, Pheterogeneity = 0.07). In addition, the meta-analysis for DM versus DN produced significant results for all contrasts (allele contrast: OR = 1.88, 95%CI: 1.65-2.15, p < 0.00001, Pheterogeneity = 0.83). The current meta-analysis suggested that MTHFR C677T polymorphism might influence DN risk, but not for DM in the Chinese population.

  7. Methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism is associated with antipsychotic-induced weight gain in first-episode schizophrenia.

    PubMed

    Srisawat, Umarat; Reynolds, Gavin P; Zhang, Zhi Jun; Zhang, Xiang Rong; Arranz, Belen; San, Luis; Dalton, Caroline F

    2014-03-01

    Genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism may be important predictors of antipsychotic drug-induced weight gain (AIWG). We tested whether two functional MTHFR polymorphisms are related to AIWG. Weight gain was studied in two cohorts of first-episode, initially drug-naive schizophrenia patients; Chinese Han (n = 182) and Spanish Caucasians (n = 72) receiving antipsychotics for 10 wk and 3 months respectively. Blood DNA was genotyped for 677C/T and 1298A/C MTHFR polymorphisms. Patients with the 677 CC genotype had a significantly greater increase in BMI compared to T-allele carriers in both Chinese (p = 0.012) and Spanish (p = 0.017) samples. The 677C/T MTHFR polymorphism showed an additive effect, but no significant interaction, with the -759C/T HTR2C polymorphism previously associated with AIWG. These results suggest that the 677C/T MTHFR polymorphism might, along with the -759C/T HTR2C polymorphism and other genetic factors, provide a useful marker for the important and limiting side effect of AIWG.

  8. The effect of MTHFR C677T polymorphism on type 2 diabetes mellitus with vascular complications in Chinese Han population: a meta-analysis.

    PubMed

    Zhang, Dan; Zhou, Yijun; Han, Lingling; Ji, Hongmei; Li, Jia

    2014-01-01

    Methylenetetrahydrofolate reductase plays an important role in folate metabolism. Individuals who are type 2 diabetes mellitus have greatest risk for the development of vascular complications. The results of studies which assessed the association between MTHFR C677T polymorphism and T2DM with vascular complications were inconsistent in the Chinese Han population. The purpose of this meta-analysis was to assess the associations between MTHFR C677T polymorphism and T2DM with vascular complications in the Chinese Han population. We collected all relevant articles on MTHFR C677T polymorphisms and T2DM with vascular complications in the Chinese Han population in multiple electronic databases which were searched to December 2013. Fixed-effects and random-effects meta-analyses were performed to assess the odds ratios (ORs). Stratified Analysis, sensitivity Analysis and publication bias were examined. A total of 1984 diabetic patients with vascular complications and 1703 single diabetic patients were found in meta-analysis. There was a significant association between MTHFR C677T polymorphisms and T2DM with vascular complications under recessive genetic model, dominant genetic model, homozygous genetic model, heterozygous genetic model and allele comparison. Sensitivity analysis indicated that the overall result was dependable. Our meta-analysis suggests the MTHFR C677T polymorphisms is associated with T2DM with vascular complications in the Chinese Han population.

  9. High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.

    PubMed

    Bahous, Renata H; Jadavji, Nafisa M; Deng, Liyuan; Cosín-Tomás, Marta; Lu, Jessica; Malysheva, Olga; Leung, Kit-Yi; Ho, Ming-Kai; Pallàs, Mercè; Kaliman, Perla; Greene, Nicholas DE; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

    2017-01-09

    Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C>T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex.Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR 3 deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.

  10. MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study

    PubMed Central

    Tiwari, Diptika; Bose, Purabi Deka; Das, Somdatta; Das, Chandana Ray; Datta, Ratul; Bose, Sujoy

    2015-01-01

    Preterm delivery (PTD) is one of the most significant contributors to neonatal mortality, morbidity, and long-term adverse consequences for health; with highest prevalence reported from India. The incidence of PTD is alarmingly very high in Northeast India. The objective of the present study is to evaluate the associative role of MTHFR gene polymorphism and progesterone receptor (PR) gene mutation (PROGINS) in susceptibility to PTD, negative pregnancy outcome and low birth weights (LBW) in Northeast Indian population. Methods A total of 209 PTD cases {extreme preterm (< 28 weeks of gestation, n = 22), very preterm (28–32 weeks of gestation, n = 43) and moderate preterm (32–37 weeks of gestation, n = 144) and 194 term delivery cases were studied for MTHFR C677T polymorphism and PR (PROGINS) gene mutation. Statistical analysis was performed using SPSS software. Results Distribution of MTHFR and PR mutation was higher in PTD cases. Presence of MTHFR C677T polymorphism was significantly associated and resulted in the increased risk of PTD (p < 0.001), negative pregnancy outcome (p < 0.001) and LBW (p = 0.001); more significantly in extreme and very preterm cases. Presence of PR mutation (PROGINS) also resulted in increased risk of PTD and negative pregnancy outcome; but importantly was found to increase the risk of LBW significantly in case of very preterm (p < 0.001) and moderately preterm (p < 0.001) delivery cases. Conclusions Both MTHFR C677T polymorphism and PR (PROGINS) mutation are evident genetic risk factors associated with the susceptibility of PTD, negative pregnancy outcome and LBW. MTHFR C677T may be used as a prognostic marker to stratify subpopulation of pregnancy cases predisposed to PTD; thereby controlling the risks associated with PTD. PMID:25709895

  11. Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure.

    PubMed

    Zuckerman, Chava; Blumkin, Elinor; Melamed, Osnat; Golan, Hava M

    2015-10-01

    The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII α and γ, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII α, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior. Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry.

  12. MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis.

    PubMed

    Nikzad, Hossein; Karimian, Mohammad; Sareban, Kobra; Khoshsokhan, Maryam; Hosseinzadeh Colagar, Abasalt

    2015-11-01

    Methylenetetrahydrofolate reductase (MTHFR) functions as a main regulatory enzyme in folate metabolism. The association of MTHFR gene Ala222Val polymorphism with male infertility in an Iranian population was investigated by undertaking a meta-analysis and in-silico approach. A genetic association study included 497 men; 242 had unexplained infertility and 255 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism was used for genotyping MTHFR-Ala222Val. OpenMeta[Analyst] software was used to conduct the analysis; 22 studies were identified by searching PubMed and the currently reported genetic association study. A novel in-silico approach was used to analyse the effects of Ala222Val substitution on the structure of mRNA and protein. Genetic association study revealed a significant association of MTHFR-222Val/Val genotype with oligozoospermia (OR 2.32; 95% CI, 1.12 to 4.78; P = 0.0451) and azoospermia (OR 2.59; 95% CI 1.09 to 6.17; P = 0.0314). Meta-analysis for allelic, dominant and codominant models showed a significant association between Ala222Val polymorphism and the risk of male infertility (P < 0.001). In silico-analysis showed MTHFR-Ala222Val affects enzyme structure and could also change the mRNA properties (P = 0.1641; P < 0.2 is significant). The meta-analysis suggested significant association of MTHFR-Ala222Val with risk of male infertility, especially in Asian populations.

  13. Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies.

    PubMed

    Lee, Jung Eun; Wei, Esther K; Fuchs, Charles S; Hunter, David J; Lee, I-Min; Selhub, Jacob; Stampfer, Meir J; Willett, Walter C; Ma, Jing; Giovannucci, Edward

    2012-04-01

    Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three large prospective studies: the Nurses' Health Study, the Health Professionals Follow-up Study, and the Physicians' Health Study. A total of 602 incident cases were identified and individually matched to controls who provided blood specimens. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI) and then pooled the estimates using a random effects model. We found a lower risk of colorectal cancer among participants with low plasma folate levels: compared with the lowest quartile, RRs (95% CIs) for each successively higher quartile of plasma folate levels were 1.55 (1.14-2.11), 1.37 (1.00-1.88), and 1.47 (1.07-2.01; P for trend = 0.10). For the MTHFR polymorphisms, RRs (95% CIs) were 0.62 (0.44-0.90) for 677TT versus CC/CT and 0.68 (0.31-1.51) for 1298CC versus AC/AA, and these lower-risk genotypes were associated with lower circulating plasma folate levels. When we partitioned the variation in plasma folate levels, variation due to folate intake was not positively associated with colorectal cancer risk. We found that low plasma folate levels were associated with lower risk of colorectal cancer. The reasons underlying a lower risk of colorectal cancer with low plasma folate levels require elucidation because plasma folate levels can reflect dietary intake, genetic influences, and other factors.

  14. Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: An updated meta-analysis.

    PubMed

    Yadav, Upendra; Kumar, Pradeep; Gupta, Sanjay; Rai, Vandana

    2016-04-01

    Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme of folate/homocysteine metabolic pathway. C677T polymorphism of MTHFR gene was reported as risk factor for congenital defects, metabolic and neuropsychiatric disorders. Numerous case-control studies investigated C677T polymorphism as risk factor for schizophrenia but results of these studies were contradictory. To draw a conclusion, a meta-analysis of all available case-control studies was performed. PubMed, Google Scholar, Springer Link and Elsevier databases were searched for eligible case-control studies. Pooled odds ratio with 95%CI was used as an association measure and all statistical analyses were performed by Open Meta-Analyst and MIX software. Total 38 studies with 10,069 cases and 13,372 controls were included in the present meta-analysis. Results of meta-analysis showed significant associated between C677T polymorphism and risk of schizophrenia (ORTvsC=1.18, 95%CI=1.10-1.27, p=<0.001; ORCTvsCC=1.10, 95%CI=1.04-1.17, p=<0.001; ORTTvsCC=1.40, 95%CI=1.20-1.64, p=<0.001; ORTT+CTvsCC=1.19, 95%CI=1.09-1.30, p=<0.001). We also performed subgroup and sensitivity analyses. Subgroup analysis was done according to ethnicity and significant association was found between C677T polymorphism and risk of schizophrenia in all three ethnic populations-African (OR=2.51; 95%CI=1.86-3.40; p=<0.001), Asian (OR=1.21; 95%CI=1.10-1.33; p=<0.001) and Caucasian (OR=1.07; 95%CI=1.01-1.14; p=0.01). In conclusion the results of the present meta-analysis suggested that the MTHFR C677T polymorphism is a risk factor for schizophrenia.

  15. The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations.

    PubMed

    Goin-Kochel, Robin P; Porter, Anne E; Peters, Sarika U; Shinawi, Marwan; Sahoo, Trilochan; Beaudet, Arthur L

    2009-04-01

    New evidence suggests that autism may be associated with (a) varied behavioral responses to folate therapy and (b) metabolic anomalies, including those in folate metabolism, that contribute to hypomethylation of DNA. We hypothesized that children with autism who are homozygous for the MTHFR 677 T allele (TT) and, to a lesser extent those with the CT variant, would exhibit more behavioral problems and/or more severe problematic behaviors than homozygous wild-type (CC) individuals because of difficulties in effectively converting 5,10-MTHF to 5-MTHF. Data from the Autism Genetic Resource Exchange (AGRE) collection were analyzed for all children who met strict criteria for autism per the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) and who had been genotyped for the 677 C to T MTHFR polymorphism (n=147). Chi-square tests, logistic regression, and one-way ANOVAs were used to determine whether differences existed among MTHFR genotypes for specific behaviors on the ADI-R and indices for level of functioning. Exploratory results indicated four behaviors from the ADI-R that were more common and problematic (95% CI) among those with at least one copy of the T allele as compared to homozygous wild-type individuals: direct gaze, current complex body movements, a history of self-injurious behavior, and current overactivity (ORs=2.72, 2.33, 2.12, 2.47, respectively). No differences existed among genotypes for level of functioning as measured with the Peabody Picture Vocabulary Test-Third Edition, Ravens Colored Progressive Matrices, or the Vineland Adaptive Behavior Scales. Findings call for further investigation of the relationship between folate metabolism and problem behaviors among children with autism.

  16. Coenzyme Q10, hyperhomocysteinemia and MTHFR C677T polymorphism in levodopa-treated Parkinson's disease patients.

    PubMed

    Gorgone, Gaetano; Currò, Monica; Ferlazzo, Nadia; Parisi, Giulia; Parnetti, Lucilla; Belcastro, Vincenzo; Tambasco, Nicola; Rossi, Aroldo; Pisani, Francesco; Calabresi, Paolo; Ientile, Riccardo; Caccamo, Daniela

    2012-03-01

    There is evidence that increased homocysteine (Hcy) levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects. Homocysteine neurotoxicity mainly relies on redox state alterations. The present work was aimed at investigating the relationships between plasma Hcy concentrations and percent content of oxidized versus total Coenzyme Q10 (%CoQ10) in 60 PD patients and 82 healthy subjects. Both groups were screened for plasma levels of Hcy, vitamin B12, folate, %CoQ10 and C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism. The MTHFR TT677 mutated genotype was found more frequently in patients than in controls (p = 0.01). In a multivariate analysis, Hcy levels and %CoQ10 were associated with the case/control category (p < 0.0001), MTHFR genotype (p < 0.0001) and their interaction term (p = 0.0015), even after adjusting for age, sex, folate and vitamin B12. Patients carrying the TT677 genotype exhibited the highest values of Hcy and %CoQ10 (p < 0.0001). Structural equation modelling evidenced that the TT677 genotype and levodopa daily dose were independently and directly correlated with Hcy (p < 0.0001, and p = 0.003, respectively), which, in turn, showed a significant correlation (p < 0.0001) with the %CoQ10 in PD patients. Our results suggest that increased Hcy levels act as mediator of the systemic oxidative stress occurring in PD, and %CoQ10 determination might be regarded as a predictor of toxic Hcy effects.

  17. The C677T variant in MTHFR modulates associations between blood-based and cerebrospinal fluid biomarkers of neurodegeneration

    PubMed Central

    Roussotte, Florence F.; Narr, Katherine L.; Small, Gary W.

    2016-01-01

    The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene results in reduced enzymatic activity and elevated blood levels of homocysteine. Plasma levels of apolipoprotein E (ApoE) are negatively correlated with cerebral amyloid burden, but plasma homocysteine concentrations are associated with increased amyloid-β (Aβ) deposition in the brain. Here, we sought to determine whether associations between low plasma ApoE levels and elevated in-vivo amyloid burden were modulated by carrying the C677T variant. We tested this hypothesis in a large sample of elderly participants from the Alzheimer’s Disease Neuroimaging Initiative. We used general linear models to examine associations between plasma homocysteine concentrations, circulating ApoE levels, cerebrospinal fluid concentrations of Aβ, and their modulation by MTHFR and ApoE genotype. Age, sex, and dementia status were included as covariates in all analyses. Higher circulating levels of ApoE predicted increased cerebrospinal fluid concentrations of Aβ, indicating lower in-vivo burden, in C-allele carriers, but not in homozygotes at the C677T variant, who showed significant elevations in plasma homocysteine levels. This modulation by the MTHFR genotype did not remain significant after controlling for ApoE genotype. In T-homozygotes who do not carry the ApoE-ε4 allele, the relationship between low plasma ApoE levels and an increased risk of dementia is likely obscured by the presence of elevated plasma homocysteine. This report suggests the value of genotyping patients at the C677T functional variant when using plasma ApoE levels as a preclinical biomarker for Alzheimer’s disease. PMID:27380243

  18. Association of OGG1 and MTHFR polymorphisms with age-related cataract: A systematic review and meta-analysis

    PubMed Central

    Liu, Yizhi

    2017-01-01

    Purpose To discern and confirm genetic biomarkers that help identify populations at high risk for age-related cataract (ARC). Methods A literature search was performed in the PubMed, Web of Science and China National Knowledge Internet databases for genetic association studies published before June 26, 2016 regarding ARC susceptibility. All genetic polymorphisms reported were systematically reviewed, followed by extraction of candidate genes/loci with sufficient genotype data in ≥3 studies for the meta-analysis. A random/fixed-effects model was used to calculate the pooled odds ratios and 95% confidence intervals to evaluate the associations considering multiple genetic models. Sensitivity analysis was also performed. Results A total of 144 polymorphisms in 36 genes were reported in the 61 previous genetic association studies. Thereby, three polymorphisms of two genes (8-oxoguanine DNA glycosylase-1 [OGG1]; methylenetetrahydrofolate reductase NADPH [MTHFR]) in eight studies were included in the meta-analysis. Regarding the OGG1-rs1052133, the GG (OR = 1.925; 95%CI, 1.181–3.136; p = 0.009) and CG (OR = 1.384; 95%CI, 1.171–1.636; p<0.001) genotypes indicated higher risk of ARC. For the MTHFR gene, the CC+TT genotype of rs1801133 might be protective (OR, 0.838; 95%CI, 0.710–0.989; p = 0.036), whereas the AA+CC genotype of rs1801131 indicated increased risk for the mixed subtype (OR = 1.517; 95%CI, 1.113–2.067; p = 0.008). Conclusions Polymorphisms of OGG1 and MTHFR genes are associated with ARC susceptibility and may help identify populations at high risk for ARC. PMID:28253266

  19. Association of MTHFR, SLC19A1 Genetic Polymorphism, Serum Folate, Vitamin B12 and Hcy Status with Cognitive Functions in Chinese Adults

    PubMed Central

    Cai, Can; Xiao, Rong; Van Halm-Lutterodt, Nicholas; Zhen, Jie; Huang, Xiaochen; Xu, Yao; Chen, Shuying; Yuan, Linhong

    2016-01-01

    Background/Aim: Studies have indicated a relationship between either gene polymorphism or in vivo B vitamins’ nutritional status with cognition in the elderly. However, the combined effects of MTHFR and SLC19A1gene polymorphism with serum folate and vitamin B12 levels on cognition in Chinese adult population remain unclear. Methods: Demographic information of 426 Chinese adults aged from 55 to 90 were collected by a well designed self-administered questionnaire. The Montreal Cognitive Assessment test was utilized to evaluate the cognition status of the participants. MTHFR and SLC19A1 genotyping was analyzed using polymerase chain reaction-ligase detection reaction (PCR- LDR) method. Serum folate, vitamin B12 and homocysteine (Hcy) levels were detected by commercial assay kits. Pearson’s correlation was used for data analyses and statistical significance was set at p < 0.05. Results: Serum Hcylevels demonstrated a negative correlation with serum folate (r = −0.301) and vitamin B12 (r = −0.292) levels. The negative correlation found between serum Hcy levels and attention ability was observed in all 426 studied subjects (r = −0.122). Subjects with MTHFR 677 T/T and 1298 A/A genotypes demonstrated a higher serum Hcy levels (p < 0.05). Carriers of MTHFR (1298 A/C + C/C and 1793 G/A) and SLC19A1 80 G/G genotypes showed lower abstraction and delayed memory ability, respectively (p < 0.05). Subjects with MTHFR 1793 G/A genotype along with low serum folate concentration demonstrated the lowest name and orientation abilities. The effects of MTHFR 1793 G/A genotype on cognitive performance were dependent on the status of serum vitamin B12. Conclusion: Cognition of adults was associated with MTHFR, SLC19A1 gene polymorphism and serum Hcy levels. This study clearly establishes a combined effect of MTHFR gene polymorphism and serum B vitamins levels on cognition in Chinese adults. PMID:27783031

  20. Human genetic selection on the MTHFR 677C>T polymorphism

    PubMed Central

    Mayor-Olea, Álvaro; Callejón, Gonzalo; Palomares, Arturo R; Jiménez, Ana J; Gaitán, María Jesús; Rodríguez, Alfonso; Ruiz, Maximiliano; Reyes-Engel, Armando

    2008-01-01

    Background The prevalence of genotypes of the 677C>T polymorphism for the MTHFR gene varies among humans. In previous studies, we found changes in the genotypic frequencies of this polymorphism in populations of different ages, suggesting that this could be caused by an increase in the intake of folate and multivitamins by women during the periconceptional period. The aim was to analyze changes in the allelic frequencies of this polymorphism in a Spanish population, including samples from spontaneous abortions (SA). Methods A total of 1305 subjects born in the 20th century were genotyped for the 677C>T polymorphism using allele specific real-time PCR with Taqman® probes. A section of our population (n = 276) born in 1980–1989 was compared with fetal samples (n = 344) from SA of unknown etiology from the same period. Results An increase in the frequency of the T allele (0.38 vs 0.47; p < 0.001) and of the TT genotype (0.14 vs 0.24; p < 0.001) in subjects born in the last quarter of the century was observed. In the 1980–1989 period, the results show that the frequency of the wild type genotype (CC) is about tenfold lower in the SA samples than in the controls (0.03 vs 0.33; p < 0.001) and that the frequency of the TT genotype increases in the controls (0.19 to 0.27) and in the SA samples (0.20 to 0.33 (p < 0.01)); r = 0.98. Conclusion Selection in favor of the T allele has been detected. This selection could be due to the increased fetal viability in early stages of embryonic development, as is deduced by the increase of mutants in both living and SA populations. PMID:19040733

  1. Meta-analysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity

    PubMed Central

    Fisher, Mark C.; Cronstein, Bruce N.

    2008-01-01

    Objective Methotrexate is an effective therapy for Rheumatoid Arthritis (RA) but is also associated with toxicity. Pharmacogenetics is the systematic evaluation of the role of genetic differences in the efficacy and toxicity of therapeutic interventions. Because the results of small pharmacogenetic studies are often misleading, we undertook a meta-analysis of published studies to determine the role of polymorphisms in the therapeutic efficacy and toxicity of methotrexate. Methods A search of PUBMED produced 55 publications which were then reviewed for relevance to methotrexate toxicity and efficacy in patients with RA. To ensure that no studies were missed, each polymorphism found was then entered as an independent search string and all results were again reviewed. Results Only 2 polymorphisms (C677T and A1298C in methylenetetrahydrofolate reductase, MTHFR, total: 8 studies) relevant to methotrexate metabolism and efficacy had sufficient data to perform a meta-analysis of their association with toxicity; there was no polymorphism with sufficient data to perform a meta-analysis of efficacy. In a fixed effects model, the C677T polymorphism was associated with increased toxicity (OR 1.71, CI 1.32 – 2.21, p<0.001). The A1298C polymorphism was not associated with increased toxicity (OR 1.12, CI 0.79 – 1.6, p=0.626). Conclusions As pharmacogenetics evolves, more data are needed to assess the role of various polymorphisms for drug efficacy and toxicity. These results illustrate the paucity of reliable pharmacogenetic data on a commonly used anti-rheumatic drug and the potential role of pharmacogenetics in tailoring drug therapy for an individual patient. PMID:19208607

  2. Genetic Analysis of BDNF, GNB3, MTHFR, ACE and APOE Variants in Major and Recurrent Depressive Disorders in Russia

    PubMed Central

    Bondarenko, EA; Shadrina, MI; Grishkina, MN; Druzhkova, TA; Akzhigitov, RG; Gulyaeva, NV; Guekht, AB; Slominsky, PA

    2016-01-01

    This study was conducted to explore the possibility of association between the single-nucleotide polymorphisms rs6264 of BDNF, rs5443 of GNB3, and rs1801133 of MTHFR; the In/Del polymorphism of ACE; and the ε2 allele of APOE and major depressive disorder (MDD) and recurrent depressive disorder (RDD) in an East Slavic population. Generalized multifactor dimensionality reduction (GMDR) method was applied to detect gene-gene interactions. One hundred fifty patients with RDD (101 females and 49 males) and 208 patients with MDD (115 females and 93 males) were included in the study. The comparison group consisted of 200 unrelated individuals. There was no significant difference in genotype distributions or allele frequencies between the controls and any of the diagnostic groups. Nevertheless, the frequency of the G allele of rs1801133 of MTHFR was higher in the RDD group and the frequency of the C allele of rs6264 of BDNF was higher in the MDD group. The difference between the controls and specific disease groups almost reached statistical significance (P = 0.08). A GMDR did not reveal optimal two- and three-dimensional models with significant prediction accuracies (P ˃ 0.05) for the MDD or RDD groups. PMID:27994504

  3. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and thymidylate synthase (TYMS) in multiple myeloma risk.

    PubMed

    Lima, Carmen S P; Ortega, Manoela M; Ozelo, Margareth C; Araujo, Renato C; De Souza, Cármino A; Lorand-Metze, Irene; Annichino-Bizzacchi, Joyce M; Costa, Fernando F

    2008-03-01

    We tested whether the polymorphisms of the methylenetetrahydrofolate reductase gene, MTHFR C677T and A1298C, the methionine synthase gene, MTR A2756G, the methionine synthase reductase gene, MTRR A66G, and the thymidylate synthase gene, TYMS 2R-->3R, involved in folate and methionine metabolism, altered the risk for multiple myeloma (MM). Genomic DNA from 123MM patients and 188 controls was analysed by polymerase chain reaction and restriction digestion for the polymorphism analyses. The frequency of the MTR 2756 AG plus GG genotype was higher in patients than in controls (39.8% versus 23.4%, P=0.001). Individual carriers of the variant allele G had a 2.31 (95% CI: 1.38-3.87)-fold increased risk for MM compared with others. In contrast, similar frequencies of the MTHFR, the MTRR and the TYMS genotypes were seen in patients and controls. These results suggest, for the first time, a role for the MTR A2756G polymorphism in MM risk in our country, but should be confirmed by large-scale epidemiological studies with patients and controls age matched.

  4. Folate supplementation, MTHFR gene polymorphism and neural tube defects: a community based case control study in North India.

    PubMed

    Deb, Roumi; Arora, Jyoti; Meitei, Sanjenbam Yaiphaba; Gupta, Sangeeta; Verma, Vanita; Saraswathy, Kallur Nava; Saran, Sunil; Kalla, Aloke Kumar

    2011-09-01

    The present study analyses the potential role of MTHFR gene polymorphism, folate supplementation and dietary pattern among the mothers of NTD neonates and controls in heterogeneous populations of North India, with the special focus on their ethnic labels. Results indicated significant increased risk for neural tube defects with respect to low folic acid supplementation and vegetarian diet in univariate and multivariate analyses. There was no significant difference in the genotypic or allelic distribution of MTHFR C677T polymorphism, however, high frequency of CT genotype, as observed, among controls suggests heterozygous advantage probably due to supplementary folate. Among the two communities, Muslim NTD mothers had higher TT genotype showing increased risk for neural tube defects (adjusted OR: 12.9; 95% CI: 1.21-136.8) and lower folic acid supplementation (adjusted OR: 3.5; 95% CI: 1.18-10.22). Whereas, marginal increased risk for NTDs with vegetarian diet was observed among Hindus. Cultural and ethnic variation in the risk factors for neural tube defects is highlighted in the study.

  5. The Genetic Diversity and Structure of Linkage Disequilibrium of the MTHFR Gene in Populations of Northern Eurasia

    PubMed Central

    Trifonova, E.A.; Eremina, E.R.; Urnov, F.D.; Stepanov, V.A.

    2012-01-01

    The structure of the haplotypes and linkage disequilibrium (LD) of the methylenetetrahydrofolate reductase gene (MTHFR) in 9 population groups from Northern Eurasia and populations of the international HapMap project was investigated in the present study. The data suggest that the architecture of LD in the human genome is largely determined by the evolutionary history of populations; however, the results of phylogenetic and haplotype analyses seems to suggest that in fact there may be a common “old” mechanism for the formation of certain patterns of LD. Variability in the structure of LD and the level of diversity of MTHFRhaplotypes cause a certain set of tagSNPs with an established prognostic significance for each population. In our opinion, the results obtained in the present study are of considerable interest for understanding multiple genetic phenomena: namely, the association of interpopulation differences in the patterns of LD with structures possessing a genetic susceptibility to complex diseases, and the functional significance of the pleiotropicMTHFR gene effect. Summarizing the results of this study, a conclusion can be made that the genetic variability analysis with emphasis on the structure of LD in human populations is a powerful tool that can make a significant contribution to such areas of biomedical science as human evolutionary biology, functional genomics, genetics of complex diseases, and pharmacogenomics. PMID:22708063

  6. MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring.

    PubMed

    Jadavji, N M; Deng, L; Malysheva, O; Caudill, M A; Rozen, R

    2015-08-06

    Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3weeks of age. Short-term memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory

  7. Association of neural tube defects in children of mothers with MTHFR 677TT genotype and abnormal carbohydrate metabolism risk: a case-control study.

    PubMed

    Cadenas-Benitez, N M; Yanes-Sosa, F; Gonzalez-Meneses, A; Cerrillos, L; Acosta, D; Praena-Fernandez, J M; Neth, O; Gomez de Terreros, I; Ybot-González, P

    2014-03-26

    Abnormalities in maternal folate and carbohydrate metabolism have both been shown to induce neural tube defects (NTD) in humans and animal models. However, the relationship between these two factors in the development of NTDs remains unclear. Data from mothers of children with spina bifida seen at the Unidad de Espina Bífida del Hospital Infantil Virgen del Rocío (case group) were compared to mothers of healthy children with no NTD (control group) who were randomly selected from patients seen at the outpatient ward in the same hospital. There were 25 individuals in the case group and 41 in the control group. Analysis of genotypes for the methylenetetrahydrofolate reductase (MTHFR) 677CT polymorphism in women with or without risk factors for abnormal carbohydrate metabolism revealed that mothers who were homozygous for the MTHFR 677TT polymorphism and at risk of abnormal carbohydrate metabolism were more likely to have offspring with spina bifida and high levels of homocysteine, compared to the control group. The increased incidence of NTDs in mothers homozygous for the MTHFR 677TT polymorphism and at risk of abnormal carbohydrate metabolism stresses the need for careful metabolic screening in pregnant women, and, if necessary, determination of the MTHFR 677CT genotype in those mothers at risk of developing abnormal carbohydrate metabolism.

  8. The 844ins68 cystathionine beta-synthase and C677T MTHFR gene polymorphism and the vaso-occlusive event risk in sickle cell disease

    PubMed Central

    Alves Jacob, Maza; da Cunha Bastos, Celso; Regina Bonini-Domingos, Claudia

    2011-01-01

    Introduction Sickle cell disease (SCD) is an inflammatory condition with an increase in the adhesion of sickled erythrocytes, and it is a potential cause of vaso-occlusive episodes, an event related to clinical manifestations, morbidity and mortality. The cystathionine beta-synthase enzyme gene (CBS) and the methylenetetrahydrofolate reductase enzyme gene (MTHFR) are risk factors for thromboembolic disorders. This study evaluated the frequency of the 844ins68 CBS and C677T MTHFR gene polymorphisms and their possibility to be risk factors for vaso-occlusive crises. Material and methods In total 91 blood samples from SCD patients were studied by PCR-RFLP and PCR-allele-specific, for the SCD genotype confirmation and polymorphism identification. Results The presence of clinical manifestations related to vaso-occlusive crises were more frequent among patients with the Hb SS genotype (p = 0.007). The CBS enzyme gene was three times more frequent (p = 0.011) among patients with vaso-occlusive complications. The MTHFR gene mutation frequency showed no increased risk for vaso-occlusive crises in SCD patients (p = 0.193). The interaction between the two polymorphisms was evaluated in 12.08% of the SCD patients and doubled the vaso-occlusive disease risk (relative risk: 2.16). Conclusions We conclude that the presence of 844ins68 CBS and C677T MTHFR gene polymorphism was a risk factor for vaso-occlusive episodes in the SCD patients evaluated. PMID:22291740

  9. Homocysteine and the C677T Gene Polymorphism of Its Key Metabolic Enzyme MTHFR Are Risk Factors of Early Renal Damage in Hypertension in a Chinese Han Population

    PubMed Central

    Yun, Lin; Xu, Rui; Li, Guohua; Yao, Yucai; Li, Jiamin; Cong, Dehong; Xu, Xingshun; Zhang, Lihua

    2015-01-01

    Abstract The combined hyperhomocysteinemia condition is a feature of the Chinese hypertensive population. This study used the case-control method to investigate the association between plasma homocysteine and the C677T gene polymorphism of its key metabolic enzyme, 5, 10-methylenetetrahydrofolate reductase (MTHFR), and early renal damage in a hypertensive Chinese Han population. A total of 379 adult essential hypertensive patients were selected as the study subjects. The personal information, clinical indicators, and the C677T gene polymorphism of MTHFR were texted. This study used the urine microalbumin/urine creatinine ratio (UACR) as a grouping basis: the hypertension without renal damage group (NRD group) and the hypertension combined with early renal damage group (ERD group). Early renal damage in the Chinese hypertensive population was associated with body weight, systolic pressure, diastolic pressure, urea nitrogen, serum creatinine, cystatin C, uric acid, aldosterone, and glomerular filtration rate. The homocysteine level and the UACR in the TT genotype group were higher than those in the CC genotype group. The binary logistic regression analysis results showed that after sex and age were adjusted, the MTHFR C677T gene polymorphism was correlated with early renal damage in hypertension in both the recessive model and in the additive model. Plasma homocysteine and the C677T gene polymorphism of its key metabolic enzyme MTHFR might be independent risk factors of early renal damage in the hypertensive Chinese Han population. PMID:26717388

  10. The 677C>T mutation of the MTHFR gene increases the risk of venous thromboembolism in Koreans and a meta-analysis from Asian population.

    PubMed

    Jang, Moon Ju; Jeon, Young Joo; Choi, Won-Il; Choi, Yi Seul; Kim, Su Yeoun; Chong, So Young; Oh, Doyeun; Kim, Nam Keun

    2013-06-01

    The frequency of methylenetetrahydrofolate reductase (MTHFR) mutations varies between racial and ethnic groups, and there are also conflicting data regarding MTHFR gene mutations in Asian patients with venous thromboembolism (VTE). The aim of this study was to examine the association between common MTHFR gene mutations (677C>T and 1298A>C) and risk of VTE in Koreans. This study was a retrospective case-control study. We enrolled 203 patients with VTE and 403 controls. For the 677C>T polymorphism, there was no difference in the frequency of the CT genotype and TT genotype between the patients with VTE and the controls. However, in the recessive analysis (CC + CT vs TT), the frequency of the TT genotype was significantly higher in VTE than in controls (odds ratio = 1.700; 95% confidence interval = 1.108-2.607, P = .015). In conclusion, the TT genotype of MTHFR 677C>T increases the risk of VTE in Koreans. This finding was supported by meta-analysis of previous Asian studies.

  11. Association between MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Meta-Analysis Based on 51 Case-Control Studies

    PubMed Central

    Li, Su-yi; Ye, Jie-yu; Liang, En-yu; Zhou, Li-xia; Yang, Mo

    2015-01-01

    Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material/Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79–1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80–1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84–1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73–1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81–1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility. PMID:25761797

  12. Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. We screened 224 subjects (52% female, mean age 39 +/- 11 years) with SCID-diagnosed major...

  13. Association of MTHFR C677T and A1298C polymorphisms with oral cancer susceptibility: evidence from a meta-analysis

    PubMed Central

    Jiang, Sui; Xu, Jin-Dong; Zhuo, Zhen-Jian; Hua, Zhu-Ming

    2017-01-01

    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. PMID:28138253

  14. MTHFR C677T polymorphism and breast, ovarian cancer risk: a meta-analysis of 19,260 patients and 26,364 controls

    PubMed Central

    He, Lilin; Shen, Yongxiang

    2017-01-01

    Objective Previous studies have found that many gene variations can be detected in both breast cancer and ovarian cancer, which is beneficial for the elaboration of the molecular origin of breast and ovarian cancer. Furthermore, many studies have explored the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with the risk of breast cancer and/or ovarian cancer; however, the results remained inconclusive. Therefore, this study conducted a systematic review and meta-analysis to evaluate the association between MTHFR C677T polymorphism and the risk of breast and ovarian cancer. Materials and methods A total of 50 studies with 19,260 cases and 26,364 controls including 39 studies for breast cancer and 8 studies for ovarian cancer were identified on searching through PubMed, Embase, Web of Science, China National Knowledge Infrastructure, WanFang, and Database of Chinese Scientific and Technical Periodicals (VIP). Allele model, dominant model, recessive model, homozygous model, and co-dominant model were applied to evaluate the association of MTHFR C677T polymorphism with breast cancer and/or ovarian cancer risk. Moreover, the odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association between MTHFR C677T polymorphism and breast and ovarian cancer risk. Results A significantly increased breast cancer risk was observed in the overall analysis (for C vs T, OR =1.19, CI: 1.12–1.28, P<0.05; for CC vs TT, OR =1.20, CI: 1.10–1.23, P<0.05; for (CT+CC) vs TT, OR =1.19, CI: 1.11–1.27, P<0.05; for CC vs (CT+TT), OR =1.19, CI: 1.79–1.95, P<0.05), while no significantly increased ovarian cancer risk was detected. In the subgroup analysis based on ethnicity, a significant association of breast cancer and/or ovarian cancer risk with MTHFR C677T polymorphism was observed in Asians. Interestingly, there was no significant association between MTHFR C677T polymorphism and ovarian cancer risk in

  15. Sodium arsenite alters cell cycle and MTHFR, MT1/2, and c-Myc protein levels in MCF-7 cells

    SciTech Connect

    Ruiz-Ramos, Ruben; Lopez-Carrillo, Lizbeth; Albores, Arnulfo; Hernandez-Ramirez, Raul U.; Cebrian, Mariano E.

    2009-12-15

    There is limited available information on the effects of arsenic on enzymes participating in the folate cycle. Therefore, our aim was to evaluate the effects of sodium arsenite on the protein levels of methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) and its further relationship with the expression MT1/2 and c-myc in MCF-7 cells. Arsenite treatment (0-10 muM) for 4 h decreased MTHFR levels in a concentration-dependent fashion without significant effects on DHFR. The effects on MTHFR were observed at arsenite concentrations not significantly affecting cell viability. We also observed an increase in S-phase recruitment at all concentrations probed. Lower concentrations (< 5 muM) induced cell proliferation, showing a high proportion of BrdU-stained cells, indicating a higher DNA synthesis rate. However, higher concentrations (>= 5 muM) or longer treatment periods induced apoptosis. Arsenite also induced dose-dependent increases in MT1/2 and c-Myc protein levels. The levels of MTHFR were inversely correlated to MT1/2 and c-Myc overexpression and increased S-phase recruitment. Our findings indicate that breast epithelial cells are responsive to arsenite and suggest that exposure may pose a risk for breast cancer. The reductions in MTHFR protein levels contribute to understand the mechanisms underlying the induction of genes influencing growth regulation, such as c-myc and MT1/2. However, further research is needed to ascertain if the effects here reported following short-time and high-dose exposure are relevant for human populations chronically exposed to low arsenic concentrations.

  16. Meta-analysis of Methylenetetrahydrofolate reductase maternal gene in Down syndrome: increased susceptibility in women carriers of the MTHFR 677T allele.

    PubMed

    Victorino, D B; Godoy, M F; Goloni-Bertollo, E M; Pavarino, E C

    2014-08-01

    Because a number of data studies include some controversial results about Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Down syndrome (DS), we performed a meta-analysis to determine a more precise estimation of this association. Studies were searched on PubMed, EMBASE and Lilacs-Scielo, up to April 2013, and they were eligible if they included case mothers (DSM) that have gave birth to children with DS, and controls mothers (CM) that have gave birth to healthy children without chromosomal abnormality, syndrome or malformation. The combined odds ratio with 95% confidence intervals was calculated by fixed or random effects models to assess the strength of associations. Potential sources of heterogeneity between studies were evaluated using Q test and the I(2). Publication bias was estimated using Begg's test and Egger's linear regression test. Sensitivity analyses were performed by using allelic, dominant, recessive and codominant genetic models, Hardy-Weinberg equilibrium (HWE) and ethnicity. Twenty-two studies with 2,223 DSM and 2,807 CM were included for MTHFR C677T and 15 studies with 1,601 DSM and 1,849 CM were included for MTHFR A1298C. Overall analysis suggests an association of the MTHFR C677T polymorphism with maternal risk for DS. Moreover, no association between the MTHFR A1298C polymorphism and maternal risk for DS was found. There is also evidence of higher heterogeneity, with I(2) test values ranging from 8 to 89%. No evidence of publication bias was found. Taken together, our meta-analysis implied that the T allele carriers might carry an increased maternal risk for DS.

  17. Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia.

    PubMed

    Nishi, Akira; Numata, Shusuke; Tajima, Atsushi; Kinoshita, Makoto; Kikuchi, Kumiko; Shimodera, Shinji; Tomotake, Masahito; Ohi, Kazutaka; Hashimoto, Ryota; Imoto, Issei; Takeda, Masatoshi; Ohmori, Tetsuro

    2014-09-01

    Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia.

  18. Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases.

    PubMed

    Dorszewska, Jolanta; Florczak, Jolanta; Rozycka, Agata; Kempisty, Bartosz; Jaroszewska-Kolecka, Joanna; Chojnacka, Katarzyna; Trzeciak, Wiesław H; Kozubski, Wojciech

    2007-01-01

    Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are accompanied by increased levels of 8-oxo-2'-deoxyguanosine (8-oxo2dG) and alterations in levels of homocysteine (Hcy), methionine (Met), and cysteine (Cys). Hcy may undergo remethylation due to involvement of MTHFR, MTR and MTHFD1 proteins. Present studies are aimed at determination of 8-oxo2dG, Hcy, Met, and Cys in AD and PD patients as well as in control groups, using HPLC/EC/UV, as well as estimation, by restriction analysis, frequency of following gene polymorphisms: MTHFR (C677T, A1298C, G1793A), MTHFD1 (G1958A), and MTR (A2756G). In AD there were significant differences of the levels of only Cys (GG, MTHFR, G1793A) and Met/Hcy (AA, MTHFD1, G1958A) whereas in PD there were more significant differences of the levels of thiols: Hcy [MTHFR: CT (C677T) and GG (G1793A); MTR, AG (A2756G)], Met [MTR, AA (A2756G)], Cys [MTR, AG (A2756G)], and Met/Hcy [MTHFR: CC, CT (C677T) and AA (A1298C), and GG (G1793A); MTHFD1 AA(G1958A); MTR AA(A2756G)]. Significant differences in the levels of Cys/Hcy, MTHFD1 GA (G1958) were varied between AD and PD groups. The results indicate that of the enzymes studied only polymorphisms of folate-dependent enzyme MTHFD1 have pointed to significant differences in intensity of turnover of circulating thiols between AD and PD patients.

  19. MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline123

    PubMed Central

    Yan, Jian; Wang, Wei; Gregory, Jesse F; Malysheva, Olga; Brenna, J Thomas; Stabler, Sally P; Allen, Robert H; Caudill, Marie A

    2011-01-01

    Background: Homozygosity for the variant 677T allele in the methylenetetrahydrofolate reductase (MTHFR) gene increases the requirement for folate and may alter the metabolic use of choline. The choline adequate intake is 550 mg/d for men, although the metabolic consequences of consuming extra choline are unclear. Objective: Deuterium-labeled choline (d9-choline) as tracer was used to determine the differential effects of the MTHFR C677T genotype and the effect of various choline intakes on the isotopic enrichment of choline derivatives in folate-compromised men. Design: Mexican American men with the MTHFR 677CC or 677TT genotype consumed a diet providing 300 mg choline/d plus supplemental choline chloride for total choline intakes of 550 (n = 11; 4 with 677CC and 7 with 677TT) or 1100 (n = 12; 4 with 677CC and 8 with 677TT) mg/d for 12 wk. During the last 3 wk, 15% of the total choline intake was provided as d9-choline. Results: Low but measurable enrichments of the choline metabolites were achieved, including that of d3-phosphatidylcholine (d3-PtdCho)—a metabolite produced in the de novo pathway via choline-derived methyl groups. Men with the MTHFR 677TT genotype had a higher urinary enrichment ratio of betaine to choline (P = 0.041), a higher urinary enrichment of sarcosine (P = 0.041), and a greater plasma enrichment ratio of d9-betaine to d9-PtdCho with the 1100 mg choline/d intake (P = 0.033). Conclusion: These data show for the first time in humans that choline itself is a source of methyl groups for de novo PtdCho biosynthesis and indicate that the MTHFR 677TT genotype favors the use of choline as a methyl donor. PMID:21123458

  20. Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts.

    PubMed

    Chevrier, Cécile; Perret, Claire; Bahuau, Michel; Zhu, Huiping; Nelva, Agnès; Herman, Christine; Francannet, Christine; Robert-Gnansia, Elisabeth; Finnell, Richard H; Cordier, Sylvaine

    2007-02-01

    The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.

  1. Screening for C677T and A1298C MTHFR polymorphisms in patients with epilepsy and risk of hyperhomocysteinemia.

    PubMed

    Caccamo, D; Condello, S; Gorgone, G; Crisafulli, G; Belcastro, V; Gennaro, S; Striano, P; Pisani, F; Ientile, R

    2004-01-01

    Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic polymorphisms andor inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar between cases and controls (46.3% vs 42.3%), whereas that of C1298 allele was significantly higher in patients (30.5% vs 19.4%, p < 0.05). Significant differences between the two groups were also found for the frequencies of genotypes AA1298 (46.3% in cases vs 67.3% in controls, p < 0.01) and AC1298 (46.3% in cases vs 26.6% in controls, p < 0.01). Other genotype frequencies did not show any statistically significant differences. Haplotype frequencies significantly differed between the two groups. The CT677/AC1298 diplotype was significantly more frequent in epileptic patients than in controls (32.6% vs 18.4%, p < 0.05). Patients treated with enzyme-inducing antiepileptic drugs, having this diplotype and concomitant low folate concentration (i.e., < 3.4 nmol/L), exhibited plasma homocysteine levels significantly higher than normal values (27.1 +/- 2.44 micromol/L, p < 0.001). This increase, however, was lower than that observed in folate-deficient patients with diplotype TT677/AA1298 (41.3 +/- 3.41 micromol/L, p < 0.001). Indeed, these two diplotypes could be regarded as risk factors for hyperhomocysteinemia. Conversely, we found that the CC677/AA1298 diplotype was significantly more frequent in controls (p < 0.01), suggesting a protective role. Our study suggests that both C677T and A1298C MTHFR polymorphisms should be examined when assessing genetic risk factors of hyperhomocysteinemia in epilepsy.

  2. Genetic polymorphism of MTHFR C677T and premature coronary artery disease susceptibility: A meta-analysis.

    PubMed

    Hou, Xiaowen; Chen, Xin; Shi, Jingpu

    2015-07-01

    The association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and premature coronary artery disease (PCAD) is controversial. To explore a more precise estimation of the association, a meta-analysis was conducted in the present study. The relevant studies were identified by searching PubMed, EMBASE, the Web of Science, Cochrane Collaboration Database, Chinese National Knowledge Infrastructure, Wanfang Database and China Biological Medicine up to November, 2014. The meta-analysis was performed by STATA 11. 21 studies with a total of 6912 subjects, including 2972 PCAD patients and 3940 controls. The pooled analysis showed that MTHFR C677T gene polymorphism was probably associated with PCAD (CT vs. CC: OR=1.13, 95% CI=1.01-1.27; dominant model: OR=1.16, 95% CI=1.04-1.29; recessive model: OR=1.19, 95% CI=1.00-1.40; allele analysis: OR=1.17, 95% CI=1.01-1.34). Subgroup analysis by plasma homocysteine concentration showed a significant association in the homocysteine >15μmol/L subgroup (CT vs. CC: OR=1.44, 95% CI=1.10-1.88; TT vs. CC: OR=2.51, 95% CI=1.12-5.63; dominant model: OR=1.51, 95% CI=1.16-1.96; recessive model: OR=2.33, 95% CI=1.05-5.20; allele analysis: OR=1.48, 95% CI=1.18-1.87). Subgroup analysis by continent displayed a significant association among the Asian population (CT vs. CC: OR=1.51, 95% CI=1.23-1.86; TT vs. CC: OR=2.81, 95% CI=1.87-4.23; dominant model: OR=1.65, 95% CI=1.35-2.01; recessive model: OR=2.22, 95% CI=1.53-3.21; allele analysis: OR=1.61, 95% CI=1.37-1.89). The statistical stability and reliability was demonstrated by sensitivity analysis and publication bias outcomes. In conclusion, the meta-analysis suggests that MTHFR C677T gene polymorphism may be associated with PCAD.

  3. The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women.

    PubMed

    Tong, Seo-Yun; Lee, Jong-Min; Song, Eun-Seop; Lee, Kwang-Beom; Kim, Mi-Kyung; Yun, Young Mi; Lee, Jae-Kwan; Son, Sung-Kyong; Lee, Jung-Pil; Kim, Jae-Hoon; Hur, Soo-Young; Kwon, Yong-Il

    2010-01-01

    The purpose of the study was to investigate the association between cervical cancer risk and single-nucleotide polymorphisms (SNPs) in three one-carbon metabolism genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) in Korean women. Twelve SNPs were identified in MTHFR, MTR, and MTRR in the 927 case-control samples, which included 165 cervical intraepithelial neoplasia 1 (CIN1), 167 cervical intraepithelial neoplasia 2 and 3 (CIN2/3), 155 cervical cancer patients, and 440 normal controls. The frequencies of the genotypes and haplotypes were assessed in the controls, CINs, and cervical cancers. Individual carriers of the variant allele C of MTHFR A1298C (rs1801131) had a 0.64-fold [95% confidence interval (CI): 0.42-0.98] decreased risk for CIN2/3 compared with common homozygotes. However, no significant association was found between most other variants and cervical cancer risk. The results also identified an increased CIN1 risk in carriers with at least one copy of haplotype 3 in the MTHFR gene (odds ratio, 1.88; 95% CI: 1.03-3.42). In conclusion, there was no significant association between most SNPs in MTHFR, MTR, or MTRR and the risk of CIN and cervical cancer in Korean women. In addition, there was no significant association of MTHFR haplotypes with risk of CIN2/3 and cervical cancer.

  4. Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men.

    PubMed

    Safarinejad, Mohammad Reza; Shafiei, Nayyer; Safarinejad, Shiva

    2011-12-01

    We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different

  5. Plasminogen activator inhibitor-1 4G/5G and the MTHFR 677C/T polymorphisms and susceptibility to polycystic ovary syndrome: a meta-analysis.

    PubMed

    Lee, Young Ho; Song, Gwan Gyu

    2014-04-01

    The aim of this study was to explore whether the plasminogen activator inhibitor-1 (PAI-1) 4G/5G and the methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphisms are associated with susceptibility to polycystic ovary syndrome (PCOS). Meta-analyses were conducted to determine the association between the PAI-1 4G/5G and MTHFR 677C/T polymorphisms and PCOS using: (1) allele contrast (2) homozygote contrast, (3) recessive, and (4) dominant models. For meta-analysis, nine studies of the PAI-1 4G/5G polymorphism with 2384 subjects (PCOS, 1615; controls, 769) and eight studies of the MTHFR 677C/T polymorphism with 1270 study subjects were included. Meta-analysis of all study subjects showed no association between PCOS and the PAI-1 4G allele (OR=0.949, 95% CI=0.671-1.343, p=0.767). Stratification by ethnicity, however, indicated a significant association between the PAI-1 4G allele and PCOS in Turkish and Asian populations (OR=0.776, 95% CI=0.602-0.999, p=0.049; OR=1.749, 95% CI=1.297-2.359, p=2.5×10(-5) respectively). In addition, meta-analysis indicated an association between PCOS and the PAI-1 4G4G+4G5G genotype in Europeans (OR=1.406, 95% CI=1.025-1.928, p=0.035). However, meta-analysis of all study subjects showed no association between PCOS and the MTHFR 677T allele (OR=0.998, 95% CI=0.762-1.307, p=0.989), including Europeans (OR=0.806, 95% CI=0.610-1.063, p=0.126). Meta-analysis showed no association between PCOS and the MTHFR 677C/T polymorphism using homozygote contrast, and recessive and dominant models. In conclusion, meta-analysis suggests the PAI-1 4G/5G polymorphism is associated with susceptibility to PCOS in European, Turkish, and Asian populations, but the MTHFR 677C/T polymorphism is not associated with susceptibility to PCOS in Europeans.

  6. Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: A five-year prospective cohort study of primary care attendees.

    PubMed

    Bousman, Chad A; Potiriadis, Maria; Everall, Ian P; Gunn, Jane M

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) genetic variation has been associated with the diagnosis of major depressive disorder (MDD) but no study to date has examined the effect MTHFR variation has on MDD prognosis. We sought to examine the prospective effects of two common MTHFR variants (C677T and A1298C) as well as seven haplotype-tagging single nucleotide polymorphisms (htSNPs) on MDD prognosis over a 5-year (60-month) period. Participants were 147 depressed primary care attendees enrolled in the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) prospective cohort study. Prognosis of MDD was measured using three methods: (1) DSM-IV criteria, (2) Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9), and (3) Center for Epidemiologic Studies Depression Scale (CESD). DSM-IV criteria for MDD was assessed using the Composite International Diagnostic Interview at baseline and 24, 36, 48, and 60 months post-baseline; whereas, PHQ-9 and CESD measures were employed at baseline and 12, 24, 36, 48, and 60 months post-baseline. Repeated measures analysis of variance showed that PHQ-9 symptom severity trajectories differed by C677T genotype (F = 3.34, df = 2,144, P = 0.038), with 677CC genotype showing the most severe symptom severity course over the 60 months of observation. Neither the A1298C polymorphism nor any of the htSNPs were associated with MDD prognosis regardless of measure used. Our results suggest that the MTHFR C677T polymorphism may serve as a marker for MDD prognosis pending independent replication.

  7. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene Ala222Val and susceptibility to ovary cancer: a systematic review and meta-analysis.

    PubMed

    Pan, Xinwei; Lu, Yan; Long, Ying; Yao, Desheng

    2014-03-01

    Many studies have reported the role of methylenetetrahydrofolate reductase (MTHFR) gene Ala222Val polymorphism with ovary cancer risk, but the results remained controversial. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR Ala222Val polymorphism and ovary cancer risk. A total of 8 studies including 3,723 cases and 4,001 controls were also involved in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, no significant association between ovary cancer risk and MTHFR Ala222Val polymorphism was found in all genetic models [codominant model: OR = 0.980, 95% CI = 0.756-1.270, P h = 0.088, P = 0.877; dominant model: OR = 1.022, 95% CI = 0.864-1.208, P h = 0.033, P = 0.803; recessive model: OR = 1.050, 95% CI = 0.803-1.373, P h = 0.032, P = 0.723; allele comparison model: OR = 1.028, 95% CI = 0.898-1.178, P h = 0.012, P = 0.685]. In the stratified analysis by ethnicity, no evidence of any associations of this polymorphism with ovary cancer was found in the Caucasian populations. Our meta-analysis supports that the MTHFR Ala222Val polymorphism is not contributed to the risk of ovary cancer from currently available evidence.

  8. Additive Interaction of MTHFR C677T and MTRR A66G Polymorphisms with Being Overweight/Obesity on the Risk of Type 2 Diabetes

    PubMed Central

    Zhi, Xueyuan; Yang, Boyi; Fan, Shujun; Li, Yongfang; He, Miao; Wang, Da; Wang, Yanxun; Wei, Jian; Zheng, Quanmei; Sun, Guifan

    2016-01-01

    Although both methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms have been associated with type 2 diabetes (T2D), their interactions with being overweight/obesity on T2D risk remain unclear. To evaluate the associations of the two polymorphisms with T2D and their interactions with being overweight/obesity on T2D risk, a case-control study of 180 T2D patients and 350 healthy controls was conducted in northern China. Additive interaction was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S). After adjustments for age and gender, borderline significant associations of the MTHFR C677T and MTRR A66G polymorphisms with T2D were observed under recessive (OR = 1.43, 95% CI: 0.98–2.10) and dominant (OR = 1.43, 95% CI: 1.00–2.06) models, respectively. There was a significant interaction between the MTHFR 677TT genotype and being overweight/obesity on T2D risk (AP = 0.404, 95% CI: 0.047–0.761), in addition to the MTRR 66AG/GG genotypes (RERI = 1.703, 95% CI: 0.401–3.004; AP = 0.528, 95% CI: 0.223–0.834). Our findings suggest that individuals with the MTHFR 677TT or MTRR 66AG/GG genotypes are more susceptible to the detrimental effect of being overweight/obesity on T2D. Further large-scale studies are still needed to confirm our findings. PMID:27983710

  9. Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in gastric cancer

    PubMed Central

    Song, Binbin; Ai, Jiang; Kong, Xianghong; Liu, Dexin; Li, Jun

    2013-01-01

    Objective: We aimed to explore the association of P16, MGMT and HMLH1 with gastric cancer and their relation with Methylenetetrahydrofolate reductase (MTHFR). Methods: 322 gastric patients who were confirmed with pathological diagnosis were included in our study. Aberrant DNA methylation of P16, MGMT and HMLH1 and polymorphisms of MTHFR C677T and A1298C were detected using PCR-RFLP. Results: The proportions of DNA hypermethylation in P16, MGMT and hMLH1 genes in gastric cancer tissues were 75.2% (242/322), 27.6% (89/322) and 5.3% (17/322), respectively. In the remote normal-appearing tissues, 29.5% (95/322) and 16.1%(52/322) showed hypermethylation in P16 and MGMT genes, respectively. We found a significantly higher proportion of DNA hypermethylation of P16 in patients with N1 TNM stage in cancer tissues and remote normal-appearing tissues (P<0.05). Similarly, we found DNA hypermethylation of MGMT had significantly higher proportion in N1 and M1 TNM stage (P<0.05). Individuals with homozygotes (TT) of MTHFR C677T had significant risk of DNA hypermethylation of MGMT in cancer tissues [OR (95% CI)=4.27(1.76-7.84)], and a significant risk was also found in those carrying MTHFR 677CT/TT genotype [OR (95% CI)= 3.27(1.21-4.77)]. Conclusion: We found the aberrant hypermethylation of cancer-related genes, such as P16, MGMT and HMLH1, could be predictive biomarkers for detection of gastric cancer. PMID:24550949

  10. Haplotypes of the MTHFR gene are associated with an increased risk of breast cancer in a Han Chinese population in Gansu province.

    PubMed

    Song, Ailing; Zhao, Lei; Li, Yumin; Wu, Li; Li, Yu; Liu, Xiaokang; Lan, Shen

    2016-07-01

    Elevated homocysteine levels are a risk factor for breast cancer, although the mechanism underlying this effect is unknown. Genome-wide association studies were used to systematically identify genetic variants which were significantly associated with the circulating homocysteine concentration. To examine the role of homocysteine-related variants in the occurrence of breast cancer, we investigated the association between these variants and breast cancer in a Han Chinese population. Five variants of genome-wide significant homocysteine-related genes were selected for the analysis in a case-control study, with a total of 487 patients with breast cancer and 605 controls. We found that none of the studied polymorphisms were related to the altered breast cancer risk. In the haplotypic analysis, the 5,10-methylenetetrahydrofolate reductase (MTHFR) haplotypes rs12085006A/rs1999594G/rs1801133C (OR = 3.44, 95% CI = 1.58-7.50, P = 0.0019) and rs12085006A/rs1999594G/rs1801133T (OR = 16.21, 95% CI = 2.19- 120.32, P = 0.0065) were significantly associated with an increased breast cancer risk when compared with the wild-type haplotype. Both of the risky MTHFR haplotypes were correlated with decreased MTHFR gene expression and elevated homocysteine concentrations, indicating a genetic component for hyperhomocysteinemia. The MTHFR haplotypes reconstructed with homocysteine-related variants were associated with the occurrence of breast cancer. This finding further emphasizes the importance of homocysteine metabolism genes in breast carcinogenesis and highlights the interplay of diet, genetics, and human cancers. © 2016 IUBMB Life, 68(7):526-534, 2016.

  11. Association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma susceptibility: Evidence from a meta-analysis

    PubMed Central

    He, Jing; Liao, Xiao-Yu; Zhu, Jin-Hong; Xue, Wen-Qiong; Shen, Guo-Ping; Huang, Shao-Yi; Chen, Wei; Jia, Wei-Hua

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies. PMID:25146845

  12. [Allele polymorphism analysis in coagulation factors F2, F5 and folate metabolism gene MTHFR by using microchip-based multiplex real time PCR].

    PubMed

    Bogdanov, K V; Nikitin, M M; Slyadnev, M N

    2015-01-01

    Single nucleotide polymorphism (SNP) genotyping methods are widely used for the detection of hereditary thrombophilias caused by genetic defects in the coagulation system. The hereditary thrombophilias are frequently associated with higher incidences of point mutations in hemostasis (F2 20210G>A, F5 1691G>A) and folate metabolism (MTHFR 677C>Т, MTHFR 1298A>C) genes. Moreover, the combination of gene abnormalities in F2 or/and MTHFR with F5 Leiden mutation leads to increased risk of developing thrombosis. Thus, simultaneous detection of the multiple gene mutations in a sample has important clinical relevance. The microchip-based multiplex real time PCR for estimation of allele specific polymorphism in hemostatic and folate metabolism genes presented here has a high efficiency and may be used for laboratory diagnosis. The optimized protocol for estimation of 4 different types of genetic polymorphisms allowed PCR to be performed with minimal quantity of DNA template and PCR reagents including Taq polymerase and a short-term thermocycling.

  13. Incidence Assessment of MTHFR C677T and A1298C Polymorphisms in Iranian Non-syndromic Cleft Lip and/or Palate Patients

    PubMed Central

    Ebadifar, Asghar; Ameli, Nazila; Khorramkhorshid, Hamid Reza; Salehi Zeinabadi4, Mehdi; Kamali, Kourosh; Khoshbakht, Tayyebeh

    2015-01-01

    Background and aims. The aim of the present study is to determine the incidence of MTHFR C677 T and A1298C muta-tions in Iranian patients with cleft lip and/or cleft palate. Materials and methods. We screened 61 Iranian patients with cleft lip and/or cleft palate for mutations in the two alleles of MTHFR gene associated with cleft lip and/or palate: A1298C and C677T, using Polymerase Chain Reaction following by RFLP. Results. The 677T and 1298C homozygote genotypes showed a frequency of 36.1% and 11.4%, respectively. Combined genotype frequencies in newborns having oral clefts showed that the highest genotype was 677TT/1298AA (22.9%) and 677TT/1298CC genotypes were not observed. Conclusion. The results showed that 65.6% of all patients had at least one T mutant allele in C677T and 58.9% C mutant allele for A1298C. According to the frequencies of homozygosity of mutant alleles, it could be said that MTHFR genotype of 677TT shows a greater role in having oral clefts. PMID:26236436

  14. Synergistic Effect of the MTHFR C677T and EPHX2 G860A Polymorphism on the Increased Risk of Ischemic Stroke in Chinese Type 2 Diabetic Patients

    PubMed Central

    Ma, Liang; Kong, Xiaomu; Yan, Meihua; Zhao, Tingting; Zhao, Hailing; Liu, Qian

    2017-01-01

    The aim of this study was to investigate the relationship between the combined effect of MTHFR C677T (rs1801133) and EPHX2 G860A (rs751141) polymorphism and ischemic stroke in Chinese T2DM patients. This case-control study included a total of 626 Chinese T2DM patients (236 T2DM patients with ischemic stroke and 390 T2DM patients without ischemic stroke). The rs1801133 and rs751141 were genotyped using real-time polymerase chain reaction. Statistical analysis was performed with SPSS 17.0. Results showed that the combined effect of MTHFR TT and EPHX2 GG or GA + AA genotype has a higher risk of ischemic stroke compared with the control group (combined effect of MTHFR CC and EPHX2 GA + AA genotypes; OR = 3.46 and OR = 3.42, resp.; P = .001 and P = .002, resp.). The A allele showed marked association with a lower risk of ischemic stroke in patients with the lowest Hcy levels under additive, recessive, and dominant genetic models (OR = 0.45, OR = 0.11, and OR = 0.44, resp.; P = .002, P = .035, and P = .008, resp.), which was not observed in medium or high Hcy level groups. In conclusion, the T allele of rs1801133 and the G allele of rs751141 may be risk factors of ischemic stroke in the Chinese T2DM population.

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

    PubMed Central

    Yang, Bo; Fang, Kun; Ren, Shangqing; Liao, Jian; Liu, Shengzhuo; Liu, Liangren; Peng, Zhufeng; Dong, Qiang

    2017-01-01

    Background Methylenetetrahydrofolate 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. Methods We 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. Results A 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. Conclusion This study suggests that the MTHFR C667T polymorphism may contribute to the genetic

  16. Influence of food groups on plasma total homocysteine for specific MTHFR C677T genotypes in Chinese population

    PubMed Central

    Li, Fan; Xiang, Tianyuan; Wang, Weimin; Ma, Cong; Yang, Chao; Chen, Haixu

    2016-01-01

    1 Scope It has been demonstrated that a mutation of MTHFR C677T increases plasma total homocysteine (Hcy) concentration and decreases folate. Natural foods can improve Hcy levels, but the effect of certain foods remains undetermined. The aim of this study was to investigate the association between food groups and Hcy, and to explore the correlations between Hcy and dietary folate/vitamin (Vit) B12 for genotype‐specific population. 2 Methods and results A total of 4507 adults were enrolled in this study, all of whom underwent physical examinations and genotyping. A dietary recall questionnaire, which assessed the frequency (F) and quantity (Q) of food consumption, was completed by all. For the male CC group, after adjustment for age and BMI, fish (F) was negatively correlated with Hcy; for the male CT group, fish (F) and eggs (F) were negatively associated with Hcy, whereas cereal/wheat (Q) were positively correlated with Hcy; for the male TT group, fish (F), meat (Q), milk (F), and fruits/vegetables (Q) were negatively associated with Hcy, whereas sugar (Q) and salt (Q) were positively associated with Hcy. For the female CC group, fruits/vegetables (Q), eggs (F) and meat (F) were negatively correlated with Hcy, but soy (F) was positively correlated with Hcy; for the female CT group, eggs (F) and meat (Q) were negatively correlated with Hcy, whereas soy (F), fried foods (F) and salt (Q) were positively correlated with Hcy; for the female TT group, fish(F), eggs (F), and fruits/vegetables (F) were negatively associated with Hcy. Furthermore, we found that Hcy was more closely correlated with folate than with Vit B12 for males (CC, CT and TT) and female TT genotype. However, the correlation between Hcy and Vit B12 was stronger for the female CT/CC groups. 3 Conclusion Hcy levels were influenced by food groups to varying degrees, which were based on gender and MTHFR C677T genotypes. Hcy levels were more closely correlated with folate for males (CC, CT and TT) and the

  17. [The normotensive carriers of the MTHFR 677T allele, displaying the increased risk of development of the abdominal aortic aneurysm (AAA), occur at the highest frequency among the smoking patients].

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Pawlak, Andrzej L

    2004-01-01

    Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Smoking, hypertension and several genetic factors are recognized as relevant for the pathogenesis of AAA. We studied association between the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (677C>T) and the occurrence of hypertension and smoking status in the group of 74 male patients with AAA. In the patients group, the smoking hypertensive persons represented the largest subgroup (43%). We determined the the MTHFR 677C>T polymorphism in AAA patients and compared it to that in 71 healthy normotensive males. The frequencies of the 677T allele and MTHFR 677C>T genotypes were similar in both groups, but the subgroup of normotensive AAA patients (n=29) displayed significantly increased frequencies of 677T allele (0.4) and of 677CT and TT genotypes (69%), as compared to those in the control group (0.28 and 46%, respectively). This corresponds to the 3.3-fold greater risk of AAA in normotensive subjects with the 677T allele of MTHFR, as compared to the homo-zygotes 677CC (p<0.03; 95% CI=1.2-9.2). The highest frequencies of MTHFR 677T allele (0.43) and 677CT and TT genotypes (73%) were found in the subgroup of normotensive smoking patients (n=22).

  18. Development and characterization of reference materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 genetic testing.

    PubMed

    Barker, Shannon D; Bale, Sherri; Booker, Jessica; Buller, Arlene; Das, Soma; Friedman, Kenneth; Godwin, Andrew K; Grody, Wayne W; Highsmith, Edward; Kant, Jeffery A; Lyon, Elaine; Mao, Rong; Monaghan, Kristin G; Payne, Deborah A; Pratt, Victoria M; Schrijver, Iris; Shrimpton, Antony E; Spector, Elaine; Telatar, Milhan; Toji, Lorraine; Weck, Karen; Zehnbauer, Barbara; Kalman, Lisa V

    2009-11-01

    Well-characterized reference materials (RMs) are integral in maintaining clinical laboratory quality assurance for genetic testing. These RMs can be used for quality control, monitoring of test performance, test validation, and proficiency testing of DNA-based genetic tests. To address the need for such materials, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Coordination Program (GeT-RM), which works with the genetics community to improve public availability of characterized RMs for genetic testing. To date, the GeT-RM program has coordinated the characterization of publicly available genomic DNA RMs for a number of disorders, including cystic fibrosis, Huntington disease, fragile X, and several genetic conditions with relatively high prevalence in the Ashkenazi Jewish population. Genotypic information about a number of other cell lines has been collected and is also available. The present study includes the development and commutability/genotype characterization of 10 DNA samples for clinically relevant mutations or sequence variants in the following genes: MTHFR; SERPINA1; RET; BRCA1; and BRCA2. DNA samples were analyzed by 19 clinical genetic laboratories using a variety of assays and technology platforms. Concordance was 100% for all samples, with no differences observed between laboratories using different methods. All DNA samples are available from Coriell Cell Repositories and characterization information can be found on the GeT-RM website.

  19. [Investigation of detoxification polymorphisms genes, methylenetetrahydrofolate-reductase (MTHFR) and P53 in the radiosensitive human cells].

    PubMed

    Shagirova, Zh M; Ushenkova, L N; Mikhaĭlov, V F; Kurbatova, L A; Kuz'mina, N S; Semiachkina, A N; Vasil'eva, I M; Mazurik, V K; Zasukhina, G D

    2010-01-01

    The genes of detoxication, MTHFR and p53 were studied in Down' and Ehlers-Danlos syndrome cells. The frequency GSTM1(0/0) genotype in Down syndrome patients was in 1.5 times higher than in control cells (p < 0.069). Opposite the frequency GSTM1(0/0) genotype in Ehlers-Danlos syndrome was 23.3% 2 times lower than in control cells (p < 0.034). This indication was in 2 times lower in women cells than in men cells and in 3 times lower than in control cells (p < 0.026). The mutations of p53 gene (7th exon) were detected in 4 from 11 Down patients (36.7%; in 2 cases af women and men), in Ehlers-Danlos patients--in 5 cases and only in men (29.4% among all the observed patients). The observations 24 healthy donors weren't revealed any mutations (p < 0.013-0.001). The hypothesis about the connection between gene polymorphisms which take a part in genome stability and radiosensitivity in Down and Ehlers-Danlos patients was developed.

  20. Genetic Variants in MTHFR Gene Predict ≥ 2 Radiation Pneumonitis in Esophageal Squamous Cell Carcinoma Patients Treated with Thoracic Radiotherapy

    PubMed Central

    Zhang, Jian; Li, Hongsheng; Qiao, Yumei; Huang, Chengsuo; Li, Baosheng

    2017-01-01

    Reactive oxygen species (ROS), formed as an indirect production of radiotherapy (RT), could cause DNA damage of normal tissues. Meanwhile, our body possesses the ability to restore the damage by DNA repair pathways. The imbalance between the two systems could finally result in radiation injury. Therefore, in this prospective cohort study, we explored the association of genetic variants in ROS metabolism and DNA repair pathway-related genes with radiation pneumonitis (RP). A total of 265 locally advanced esophageal squamous cell carcinoma (ESCC) patients receiving RT in Chinese Han population were enrolled. Five functional single nucleotide polymorphisms (SNPs) (rs1695 in GSTP1; rs4880 in SOD2; rs3957356 in GSTA1; and rs1801131, rs1801133 in MTHFR) were genotyped using the MassArray system, and rs1801131 was found to be a predictor of ≥ 2 RP. Our results showed that, compared with TT genotype, patients with GG/GT genotypes of rs1801131 had a notably lower risk of developing ≥ 2 RP (HR = 0.339, 95% CI = 0.137–0.839, P = 0.019). Further independent studies are required to confirm this findings. PMID:28046029

  1. Thrombophilic genetic factors PAI-1 4G-4G and MTHFR 677TT as risk factors of alcohol, cryptogenic liver cirrhosis and portal vein thrombosis, in a Caucasian population.

    PubMed

    D'Amico, Mario; Pasta, Francesca; Pasta, Linda

    2015-08-15

    The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and Prothrombin 20210A, were studied as risk factors in 865 Caucasian patients with liver cirrhosis, consecutively enrolled from June 2008 to January 2014. A total of 582 HCV, 80 HBV, 94 alcohol, (82 with more than one etiologic factor) and 191 cryptogenic patients with liver cirrhosis had been consecutively enrolled; 243 patients showed portal vein thrombosis (PVT). At least one of the above THRGFs was present in 339/865 patients (39.2%). PAI-1 4G-4G and MTHFR 677TT were the most frequent THRGFs, statistically significant in patients with alcohol, cryptogenic liver cirrhosis, and PVT: respectively 24 and 28, 50 and 73, and 65 and 83 (all chi-square tests>3.84, and p values<0.05). Two logistic regression analysis, using PAI-1 4G-4G and MTHFR 677TT, as dependent variable, confirmed the independent significant relationship of these THRGFs with alcohol, cryptogenic liver cirrhosis and PVT. PAI 1 and MTHFR 677 genotypes, deviated from those expected in populations in Hardy-Weinberg equilibrium (all p values<0.05), in the subgroups of patients with alcohol, cryptogenic liver cirrhosis and presence of PVT. Our study shows the pivotal role of PAI-1 4G-4G and MTHFR 677TT in patients with alcohol, cryptogenic liver cirrhosis, and PVT, in a Caucasian population. In conclusion, thrombo and fibro-genetic mechanisms of PAI-1 4G-4G and MTHFR 677TT, could have a role in the development of liver cirrhosis, mainly in patients without HCV and HBV, and PVT.

  2. Association between C677T and A1298C polymorphisms of the MTHFR gene and risk of male infertility: a meta-analysis.

    PubMed

    Yang, Y; Luo, Y Y; Wu, S; Tang, Y D; Rao, X D; Xiong, L; Tan, M; Deng, M Z; Liu, H

    2016-04-26

    Published studies on the association between the C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and male infertility risk are controversial. To obtain a more precise evaluation, we performed a meta-analysis based on published case-control studies. We conducted an electronic search of PubMed, EMBASE, the Cochrane Library, the Web of Science, and the China Knowledge Resource Integrated Database for papers on MTHFR gene C677T and A1298C polymorphisms and male infertility risk. Pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were used to assess the strength of association in homozygote, heterozygote, dominant, recessive, and additive models. Statistical heterogeneity, test of publication bias, and sensitivity analysis were carried out using the STATA software (Version 13.0). Overall, 21 studies of C677T (4505 cases and 4024 controls) and 13 studies of A1298C (2785 cases and 3094 controls) were included in this meta-analysis. For C677T, the homozygote comparison results were OR = 1.629, 95%CI (1.215- 2.184), and the recessive model results were OR = 1.462 (1.155- 1.850). For A1298C, the homozygote comparison results were OR = 1.289 (1.029-1.616), and the recessive model results were OR = 1.288 (1.034-1.604). In conclusion, the current meta-analysis showed that the MTHFR C677T polymorphism was associated with a significantly increased male infertility risk in the Asian and overall populations, but not in the Caucasian population, and there was a significant association between the A1298C polymorphism and male infertility risk in the Asian, Caucasian, and overall groups.

  3. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism.

    PubMed

    Cook, Fiona J; Mumm, Steven; Whyte, Michael P; Wenkert, Deborah

    2014-04-01

    Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this

  4. MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults

    PubMed Central

    2012-01-01

    Background This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults. Methods A total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks. Results After 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989). Conclusions This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation. PMID:22230384

  5. Effect of polymorphisms of the MTHFR and APOE genes on susceptibility to diabetes and severity of diabetic retinopathy in Brazilian patients.

    PubMed

    Errera, F I V; Silva, M E R; Yeh, E; Maranduba, C M C; Folco, B; Takahashi, W; Pereira, A C; Krieger, J E; Passos-Bueno, M R

    2006-07-01

    Diabetes mellitus (DM) is a highly prevalent complex genetic disorder. There has been a worldwide effort in the identification of susceptibility genes for DM and its complications, and the 5-10-methylenetetrahydrofolate reductase (MTHFR) and apolipoprotein-E (APOE) genes have been considered good candidate susceptibility genes to this condition. The objectives of the present study were to determine if the 677T MTHFR and epsilon2/epsilon3/epsilon4 APOE alleles are risk factors for DM and for severity of diabetic retinopathy (DR). A total of 248 individuals were studied: 107 healthy individuals and 141 diabetic patients (46 with type 1 diabetes and 95 with type 2 diabetes), who also had DR (81 with non-proliferative DR and 60 with proliferative DR). The polymorphisms were analyzed by PCR followed by digestion with restriction enzyme or the single-nucleotide primer extension method. No evidence of association between the 677TT genotype of MTHFR gene and DM [cases: TT = 10/95 (10.6%); controls: TT = 14/107 (13%)] or with severity of DR was observed [cases: TT = 5/60 (8.5%); controls: TT = 9/81 (11.1%); P > 0.05]. We also did not find evidence of an association between APOE alleles and proliferative DR (epsilon2, epsilon3 and epsilon4 in cases: 9, 76, and 15%, and in controls: 5, 88, and 12%, respectively) but the carriers of epsilon2 allele were more frequent among patients with type 2 DM and DR than in controls [cases: 15/95 (15.8%); controls: 7/107 (6.5%); P < 0.05]. Therefore, our results suggest that the epsilon2 allele/APOE might be a risk factor for diabetes in the Brazilian population.

  6. MTHFR 677 TT genotype in a mother and her child with Down syndrome, atrioventricular canal and exstrophy of the bladder: implications of a mutual genetic risk factor?

    PubMed

    Reutter, Heiko; Betz, Regina C; Ludwig, Michael; Boemers, Thomas M

    2006-08-01

    Apart from Husmann and Vandersteen [in: Gearhart JP, Matthews R (eds) The Epispadias-Exstrophy Complex. Kluwer, New York, pp 199-206, 1999], we report only the second case of Down syndrome (DS) associated with exstrophy of the bladder (EB). Besides the appearance of DS, the newborn exhibited a complete atrioventricular canal (CAVC) and classical EB, including diastases of the symphysis, an epispadic penis and an open bladder plate. Despite current recommendations, the mother had not supplemented her intake of folic acid during the periconceptional period. In a comparable case, Al-Gazali et al. (Am J Med Genet 103:128-132, 2001) found the homozygous 677T allele of the methylenetetrahydrofolate (MTHFR) gene 677C-->T polymorphism in a mother and her child with DS and cervical meningomyelocele. They found that the mother, who also had not supplemented her folic acid intake, had a secondarily altered folate status with an increased homocysteine level, suggesting that the homozygous TT mutation in the MTHFR gene in both mother and her child had contributed to the presentation of DS and a neural tube defect. The combined clinical findings of the present case and the observations of Al-Gazali et al. led us to investigate the 677C-->T polymorphism in our mother-child pair. Likewise we found that mother and child were homozygous for the mutant 677T allele. Our findings support the suggestion of Al-Gazali et al. that the MTHFR 677TT could be a mutual genetic risk factor for the co-occurrence of trisomy 21 and midline defects, the risk of which may be reduced by periconceptional folic acid supplementation.

  7. Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

    PubMed Central

    Li, Chao; Ni, Juan; Liu, Yao-Xian; Wang, Han; Liang, Zi-Qing; Wang, Xu

    2017-01-01

    Background/Aims Folic acid (FA) is a core micronutrient involved in DNA synthesis/methylation, and the metabolism of FA is responsible for genomic stability. MicroRNAs may affect gene expression during folate metabolism when cellular homeostasis is changed. This study aimed to reveal the relationship between FA deficiency and the expression of miR-22-p/miR-149-5p and the targeted regulation of miR-22-3p/miR-149-5p on the key folate metabolic gene Methylenetetrahydrofolate reductase (MTHFR). Methods Normal (HL-7702 cells) and cancerous (QGY-7703 cells) human hepatocytes were intervened in modified RPMI 1640 with FA deficiency for 21 days. The interaction between MTHFR and the tested miRNAs was verified by Dual-Luciferase Reporter Assays. The changes in the expression of miR-22-3p/miR-149-5p in response to FA deficiency were detected by Poly (A) Tailing RT-qPCR, and the expression of MTHFR at both the transcriptional and translational levels was determined by RT-qPCR and Western blotting, respectively. Result MiR-22-3p/miR-149-5p directly targeted the 3’UTR sequence of the MTHFR gene. FA deficiency led to an upregulation of miR-22-3p/miR-149-5p expression in QGY-7703/HL-7702 cells, while the transcription of MTHFR was decreased in QGY-7703 cells but elevated in HL-7702 cells. Western blotting showed that FA deficiency resulted in a decline of the MTHFR protein in QGY-7703 cells, whereas in HL-7702 cells, the MTHFR protein level remained constant. Conclusion The results suggested that miR-22-3p/miR-149-5p exert different post-transcriptional effects on MTHFR under conditions of FA deficiency in normal and cancerous human hepatocytes. The results also implied that miR-22-3p/miR-149-5p might exert anticancer effects in cases of long-term FA deficiency. PMID:28045918

  8. MTHFR Glu429Ala and ERCC5 His46His Polymorphisms Are Associated with Prognosis in Colorectal Cancer Patients: Analysis of Two Independent Cohorts from Newfoundland

    PubMed Central

    Negandhi, Amit A.; Hyde, Angela; Dicks, Elizabeth; Pollett, William; Younghusband, Banfield H.; Parfrey, Patrick; Green, Roger C.; Savas, Sevtap

    2013-01-01

    Introduction In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland. Methods The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort. Results When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04–2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15–2.76, p = 0.01), SERPINE1 −675indelG (HR: 0.52, 95%CI: 0.32–0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03–1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18–2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04–2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11–2.94, p = 0.018). Conclusions In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two

  9. Geographical Distribution of MTHFR C677T, A1298C and MTRR A66G Gene Polymorphisms in China: Findings from 15357 Adults of Han Nationality

    PubMed Central

    Yang, Boyi; Liu, Yuyan; Li, Yongfang; Fan, Shujun; Zhi, Xueyuan; Lu, Xiangxiang; Wang, Da; Zheng, Quanmei; Wang, Yinuo; Wang, Yanxun; Sun, Guifan

    2013-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms are important genetic determinants for homocysteine (Hcy) levels, and are associated with several disorders. These polymorphisms are heterogeneously distributed worldwide. Our objective was to explore the geographical distributions of these polymorphisms in China. Methodologies 15357 healthy adults were recruited from 10 regions. Buccal samples were collected and genomic DNA was isolated. Genotyping was performed using the fluorogenic 5′-nuclease assay. Principal Findings The prevalence of the three polymorphisms among different populations from China varied significantly and showed apparent geographical gradients. For MTHFR C677T, the frequencies of the 677T allele and the 677TT genotype were significantly higher among northern populations and ranged from the lowest values (24.0% and 6.4%, respectively) in Hainan (southern) to the highest values (63.1% and 40.8%, respectively) in Shandong (northern). For MTHFR A1298C, the 1298C allele and the 1298CC genotype frequencies were significantly higher among southern populations and increased from low values (13.1% and 1.4%, respectively) in Shandong to high values (25.7% and 6.7%, respectively) in Hainan. For A66G, the 66G allele and the 66GG genotype frequencies increased from lower values (23.7% and 5.4%, respectively) in Shandong to higher values (29.2% and 8.6%, respectively) in Hainan. The overall frequency of the 677T allele, 677TT genotype, 1298C allele, 1298CC genotype, 66G allele and 66GG genotype in the Chinese Han population was 45.2%, 23.2%, 18.6%, 3.9%, 25.7%, and 6.6%, respectively. No gender differences were found in the prevalence of both the MTHFR C677T and MTRR A66G polymorphisms. Conclusions This study indicates that there are marked geographical variations in the prevalence of the three polymorphisms among Chinese Han populations. Our baseline data may be useful for

  10. Relationship of MTHFR Gene 677C→T Polymorphism, Homocysteine, and Estimated Glomerular Filtration Rate Levels With the Risk of New-Onset Diabetes

    PubMed Central

    Qin, Xianhui; Li, Youbao; Yuan, Hui; Xie, Di; Tang, Genfu; Wang, Binyan; Wang, Xiaobin; Xu, Xin; Xu, Xiping; Hou, Fanfan

    2015-01-01

    Abstract East Asian patients with diabetes have a higher risk for renal complications and strokes than Europeans. We aimed to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) gene 677C→T polymorphism, which was associated with a higher stroke risk and was common in the Chinese population, as well as homocysteine and estimated glomerular filtration rate (eGFR) levels on the risk of new-onset diabetes (NOD). A total of 2422 subjects without diabetes were followed-up for 7 years. NOD was defined as fasting plasma glucose ≥7.0 mmol/L or self-reported physician diagnosis of diabetes. Compared with subjects with MTHFR 677CC genotype, those with TT genotype had a higher risk of NOD in females (odds ratio 2.78, 95% confidence interval 1.39–5.56) but not in males (0.80, 0.40–1.61, P for interaction = 0.008). Furthermore, MTHFR 677C→T polymorphism was more strongly associated with the risk of NOD among females with higher body mass index (BMI, ≥23 vs <23 kg/m2, P for interaction = 0.009) or lower high-density lipoprotein-cholesterol (HDL-C, <1.3 vs ≥1.3 mmol/L, P for interaction = 0.015) levels. Hyperhomocysteinemia (≥16 vs <10 μmol/L) was not significantly associated with NOD in males (0.88, 0.42–1.85) or females (1.52, 0.65–3.57). However, mildly decreased eGFR (<90 vs 90–120 mL/min/1.73 m2) was associated with NOD mainly in males (1.96, 1.01–3.78; females, 0.74, 0.32–1.72, P for interaction = 0.134). Females with MTHFR 677TT genotype had a significantly higher risk of NOD, particularly those with higher BMI or low HDL-C levels. The higher risk of NOD associated with mildly decreased eGFR also warrants more investigation. Our results provide insights into the ethnic differences of diabetic complications between East Asian patients and Europeans. PMID:25700330

  11. Association between MTHFR C677T polymorphism and diabetic nephropathy in the Chinese population: An updated meta-analysis and review.

    PubMed

    Xiong, Xuan; Lin, Xiao-Kun; Xiao, Xiao; Qin, Dan-Ping; Zhou, Dao-Yuan; Hu, Jian-Guang; Liu, Yan; Zhong, Xiao-Shi

    2016-01-01

    To clarify the effects of MTHFR C677T polymorphism on the risk of diabetic nephropathy (DN) in the Chinese population, an updated meta-analysis was performed. Related studies were identified from PubMed, Springer Link, Ovid and Chinese Databases up to 24 February 2015. A total of 15 studies including 1227 DN cases, 586 healthy controls and 1277 diabetes mellitus (DM) controls were involved in this meta-analysis. Overall, a significantly elevated risk of DN was associated with all variants of MTHFR C677T when compared with the healthy group (T vs C, odds ratio (OR) = 2.22, 95% confidence interval (CI) = 1.88-2.61; TT vs CC, OR = 4.22, 95% CI = 3.02-5.90; TT + CT vs CC, OR = 2.62, 95% CI = 2.07-3.31; TT vs CC + CT, OR = 2.81, 95% CI = 2.08-3.81) or DM (T vs C, OR = 1.78, 95% CI = 1.59-2.00; TT vs CC, OR = 2.95, 95% CI = 2.33-3.73; TT + CT vs CC, OR = 1.93, 95% CI = 1.63-2.29; TT vs CC + CT, OR = 2.31, 95% CI = 1.87-2.84). In subgroup analyses stratified by ethnicity and geographic areas, it revealed the significant results in Chinese Han, in North and South China. The risk conferred by MTHFR C677T polymorphism is higher in North China than in South China. This meta-analysis showed that the MTHFR C677T variants may influence DN risk in Chinese, and further studies with gene-gene and gene-environment interactions are required for definite conclusions.

  12. A novel lateral flow assay based on GoldMag nanoparticles and its clinical applications for genotyping of MTHFR C677T polymorphisms

    NASA Astrophysics Data System (ADS)

    Hui, Wenli; Zhang, Sinong; Zhang, Chao; Wan, Yinsheng; Zhu, Juanli; Zhao, Gang; Wu, Songdi; Xi, Dujuan; Zhang, Qinlu; Li, Ningning; Cui, Yali

    2016-02-01

    Current techniques for single nucleotide polymorphism (SNP) detection require tedious experimental procedures and expensive and sophisticated instruments. In this study, a visual genotyping method has been successfully established via combining ARMS-PCR with gold magnetic nanoparticle (GoldMag)-based lateral flow assay (LFA) and applied to the genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T. C677T substitution of the gene MTHFR leads to an increased risk of diseases. The genotyping result is easily achievable by visual observation within 5 minutes after loading of the PCR products onto the LFA device. The system is able to accurately assess a broad detection range of initial starting genomic DNA amounts from 5 ng to 1200 ng per test sample. The limit of detection reaches 5 ng. Furthermore, our PCR-LFA system was applied to clinical trials for screening 1721 individuals for the C677T genotypes. The concordance rate of the genotyping results detected by PCR-LFA was up to 99.6% when compared with the sequencing results. Collectively, our PCR-LFA has been proven to be rapid, accurate, sensitive, and inexpensive. This new method is highly applicable for C677T SNP screening in laboratories and clinical practices. More promisingly, it could also be extended to the detection of SNPs of other genes.

  13. Genotype prevalence and allele frequencies of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation in two caste groups of India.

    PubMed

    Rai, V; Yadav, U; Kumar, P

    2012-06-15

    The aim of the present study was to investigate the distribution of 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism in two caste group populations of eastern Uttar Pradesh. This mutation has been suggested to be positively associated with the risk of several congenital and multifactorial disorders. Frequency of mutant T allele differs in various ethnic and geographical populations of the world. MTHFR C677T mutation analysis was carried out by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) method and the samples studied were randomly selected from the healthy individuals belonging to two caste populations. In Brahmin samples, genotype frequencies of CC, CT and TT were 0.727, 0.25 and 0.023 respectively whereas in Rajput samples, CC genotype was observed in 88 samples, CT genotype in 25 and TT genotype was found in 2 samples. Frequency of mutant T allele was found to be 0.147 in Brahmin and 0.126 in Rajput populations. The percentage of CT genotype and C allele were high in both the populations.

  14. Genetic effect of MTHFR C677T polymorphism on the structural covariance network and white-matter integrity in Alzheimer's disease.

    PubMed

    Chang, Yu-Tzu; Hsu, Shih-Wei; Tsai, Shih-Jen; Chang, Ya-Ting; Huang, Chi-Wei; Liu, Mu-En; Chen, Nai-Ching; Chang, Wen-Neng; Hsu, Jung-Lung; Lee, Chen-Chang; Chang, Chiung-Chih

    2017-03-25

    The 677 C to T transition in the MTHFR gene is a genetic determinant for hyperhomocysteinemia. We investigated whether this polymorphism modulates gray matter (GM) structural covariance networks independently of white-matter integrity in patients with Alzheimer's disease (AD). GM structural covariance networks were constructed by 3D T1-magnetic resonance imaging and seed-based analysis. The patients were divided into two genotype groups: C homozygotes (n = 73) and T carriers (n = 62). Using diffusion tensor imaging and white-matter parcellation, 11 fiber bundle integrities were compared between the two genotype groups. Cognitive test scores were the major outcome factors. The T carriers had higher homocysteine levels, lower posterior cingulate cortex GM volume, and more clusters in the dorsal medial lobe subsystem showing stronger covariance strength. Both posterior cingulate cortex seed and interconnected peak cluster volumes predicted cognitive test scores, especially in the T carriers. There were no between-group differences in fiber tract diffusion parameters. The MTHFR 677T polymorphism modulates posterior cingulate cortex-anchored structural covariance strength independently of white matter integrities. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

  15. A new and improved method based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the determination of A1298C mutation in the methylenetetrahydrofolate reductase (MTHFR) gene.

    PubMed

    Machnik, Grzegorz; Zapala, Malgorzata; Pelc, Ewa; Gasecka-Czapla, Monika; Kaczmarczyk, Grzegorz; Okopien, Boguslaw

    2013-01-01

    Intracellular folate homeostasis and metabolism is regulated by numerous genes. Among them, 5,10-methylenetetrahydrofolate reductase (MTHFR) is of special interest because of its involvement in regulation of the homocysteine level in the body as a result of folate metabolism. Moreover, some studies demonstrated that the homocysteine plasma level in individuals may be influenced by polymorphisms present in the MTHFR gene. Two common, clinically relevant mutations have been described: MTHFR C677T and MTHFR A1298C. Although several laboratory techniques allow genotyping of both polymorphisms, PCR-RFLP analysis is simple to perform, relatively cheap, and thus one of the most utilized. In the case of A1298C, the PCR-RFLP technique that utilizes MboII endonuclease class II requires an acrylamide gel electrophoresis, since agarose gel electrophoresis is unable to resolve short deoxyribonucleic acid (DNA) fragments after restriction digestion. Agarose gel electrophoresis is commonly preferred over that of acrylamide. To resolve this inconvenience, a novel PCR-RFLP, AjuI-based method to genotype A1298C alleles has been developed that can be performed on standard agarose gel.

  16. Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC)

    PubMed Central

    Salem, Rany M.; Lipkowitz, Michael S.; Bhatnagar, Vibha; Pandey, Braj; Schork, Nicholas J.; O’Connor, Daniel T.

    2012-01-01

    Background. Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. Methods. We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ∼4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ∼4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. Results. In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. Conclusion. We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association. PMID:21613384

  17. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials

    PubMed Central

    Holmes, Michael V; Newcombe, Paul; Hubacek, Jaroslav A; Sofat, Reecha; Ricketts, Sally L; Cooper, Jackie; Breteler, Monique MB; Bautista, Leonelo E; Sharma, Pankaj; Whittaker, John C; Smeeth, Liam; Fowkes, F Gerald R; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A; Singleton, Andrew B; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B; Rich, Stephen S; Matarin, Mar; Norman, Paul E; Flicker, Leon; Almeida, Osvaldo P; van Bockxmeer, Frank M; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J; Bobak, Martin; Sterne, Jonathan AC; Smith, George Davey; Talmud, Philippa J; van Duijn, Cornelia; Humphries, Steve E; Price, Jackie F; Ebrahim, Shah; Lawlor, Debbie A; Hankey, Graeme J; Meschia, James F; Sandhu, Manjinder S; Hingorani, Aroon D; Casas, Juan P

    2011-01-01

    Summary Background The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. Methods We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks). Findings The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, −0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar

  18. MTHFR 677C>T Polymorphism and the Risk of Breast Cancer: Evidence from an Original Study and Pooled Data for 28031 Cases and 31880 Controls

    PubMed Central

    Sekhar, Deepa; Francis, Amirtharaj; Gupta, Nishi; Konwar, Rituraj; Kumar, Sandeep; Kumar, Surender; Thangaraj, Kumarasamy; Rajender, Singh

    2015-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) acts at an important metabolic point in the regulation of cellular methylation reaction. It assists in the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter aids in remethylation of homocysteine to de novo methionine that is required for DNA synthesis. The objective of this study was to examine the effect of MTHFR 677 C>T polymorphism on the risk of breast cancer in the Indian sub-continent. Methods and Results We genotyped 677 C>T locus in 1096 individuals that were classified into cases (N=588) and controls (N=508). Genotype data were analyzed using chi-square test. No significant difference was observed in the distribution of genotypes between cases and controls in north Indian (P = 0.932), south Indian (P = 0.865), and pooled data (P = 0.680). To develop a consensus regarding the impact of 677C>T polymorphism on breast cancer risk, we also conducted a meta-analysis on 28031 cases and 31880 controls that were pooled from sixty one studies. The overall summary estimate upon meta-analysis suggested no significant correlation between the 677C>T substitution and breast cancer in the dominant model (Fixed effect model: OR = 0.97, P=0.072, Random effects model: OR = 0.96, P = 0.084) or the recessive model (Fixed effect model: OR = 1.05, P = 0.089; Random effects model: OR= 1.08, P= 0.067). Conclusion 677 C>T substitution does not affect breast cancer risk in the Indo-European and Dravidian populations of India. Analysis on pooled data further ruled out association between the 677 C>T polymorphism and breast cancer. Therefore, 677 C>T substitution does not appear to influence the risk of breast cancer. PMID:25803740

  19. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression

    PubMed Central

    Eszlari, N; Kovacs, D; Petschner, P; Pap, D; Gonda, X; Elliott, R; Anderson, I M; Deakin, J F W; Bagdy, G; Juhasz, G

    2016-01-01

    Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development. PMID:26926881

  20. High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism

    PubMed Central

    Aarabi, Mahmoud; San Gabriel, Maria C.; Chan, Donovan; Behan, Nathalie A.; Caron, Maxime; Pastinen, Tomi; Bourque, Guillaume; MacFarlane, Amanda J.; Zini, Armand; Trasler, Jacquetta

    2015-01-01

    Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR. PMID:26307085

  1. MTHFR, MTR, and MTRR Polymorphisms in Relation to p16INK4A Hypermethylation in Mucosa of Patients with Colorectal Cancer

    PubMed Central

    Wettergren, Yvonne; Odin, Elisabeth; Carlsson, Göran; Gustavsson, Bengt

    2010-01-01

    We recently analyzed the hypermethylation status of the p16INK4a (p16) gene promoter in normal-appearing mucosa obtained from patients with colorectal cancer. Hypermethylation of p16 was associated with reduced survival of these patients. In the present study, germ line polymorphisms in the folate- and methyl-associated genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR), were analyzed in the same patient cohort to find a possible link between these genetic variants and p16 hypermethylation. Genomic DNA was extracted from blood of patients (n = 181) and controls (n = 300). Genotype analyses were run on an ABI PRISM® 7900HT sequence-detection system (Applied Biosystems), using real-time polymerase chain reaction and TaqMan chemistry. The results showed that the genotype distributions of the patient and control groups were similar. No significant differences in cancer-specific or disease-free survival of stage I–III patients according to polymorphic variants were detected, nor were any differences in cancer-specific or disease-free survival detected when patients were subgrouped according to the MTHFR or MTR genotype groups and dichotomized by p16 hypermethylation status in mucosa. However, patients with the MTRR 66 AA/AG genotypes were found to have a significantly worse cancer-specific survival when the mucosa were positive, compared with negative, for p16 hypermethylation (hazard ratio 2.7; 95% confidence interval 1.2–6.4; P = 0.023). In contrast, there was no difference in survival among patients with the MTRR 66 GG genotype stratified by p16 hypermethylation status. These results indicate a relationship between genetic germ-line variants of the MTRR gene and p16 hypermethylation in mucosa, which may affect the clinical outcome of patients with colorectal cancer. PMID:20549016

  2. Role of C677T and A1298C MTHFR, A2756G MTR and -786 C/T eNOS Gene Polymorphisms in Atrial Fibrillation Susceptibility

    PubMed Central

    Giusti, Betti; Gori, Anna Maria; Marcucci, Rossella; Sestini, Ilaria; Saracini, Claudia; Sticchi, Elena; Gensini, Francesca; Fatini, Cinzia; Abbate, Rosanna; Gensini, Gian Franco

    2007-01-01

    Background Hyperhomocysteinemia has been suggested to play a role in the NonValvular Atrial Fibrillation (NVAF) pathogenesis. Polymorphisms in genes coding for homocysteine (Hcy) metabolism enzymes may be associated with hyperhomocysteinemia and NVAF. Methodologies 456 NVAF patients and 912 matched controls were genotyped by an electronic microchip technology for C677T and A1298C MTHFR, A2756G MTR, and -786C/T eNOS gene polymorphisms. Hcy was determined by an immunoassay method. Principal Findings The genotype distribution of the four polymorphisms as well as genotype combinations did not differ in patients and controls. Hcy was higher in patients than in controls (15.2, 95%CI 14.7–15.7 vs 11.3, 95%CI 11.0–11.6 µmol/L; p<0.0001). In both populations, a genotype-phenotype association (p<0.0001) between Hcy and C677T MTHFR polymorphism was observed; in controls a significant (p = 0.029) association between tHcy and −786C/T eNOS polymorphism was also observed. At the multivariate analysis the NVAF risk significantly increased in the upper quartiles of Hcy compared to the lowest: OR from 2.8 (1.68–4.54 95%CI) in Q2 to 12.9 (7.96–21.06 95%CI) in Q4. Conclusions Our data demonstrated the four polymorphisms, although able, at least in part, to affect Hcy, were not associated with an increased risk of NVAF per se or in combination. PMID:17551576

  3. Maternal Supplementary Folate Intake, Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms and the Risk of Orofacial Cleft in Iranian Children

    PubMed Central

    Ebadifar, Asghar; KhorramKhorshid, Hamid Reza; Kamali, Koorosh; Salehi Zeinabadi, Mehdi; Khoshbakht, Tayyebeh; Ameli, Nazila

    2015-01-01

    Background: The purpose of this study was to describe the association of MTHFR gene single nucleotide polymorphisms (C677T and A1298C) and maternal supplementary folate intake with orofacial clefts in the Iranian population. Methods: In this case-control study, peripheral venous blood was taken from 65 patients with orofacial clefts and 215 unaffected controls for DNA extraction and kept in EDTA for further analysis. The genotyping was carried out using Polymerase Chain Reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) and gel electrophoresis. Data were analyzed using Chi square test and logistic regression tests. Results: Genotype frequencies of 677TT were reported to be 13.5 and 36.1% in controls and CL/P patients, respectively, which showed a significant difference compared to CC as reference (OR=4.118; 95% CI=1.997–8.492; p=0.001). Conversely, 1298CC with frequencies of 10.8 and 12.7% in controls and patients, respectively, showed no significant difference compared to AA (OR=2.359; 95% CI=0.792–7.023; p=0.123). Comparing patients whose mothers did not report the folate supplement intake during pregnancy, to controls, it was observed that lack of folate intake was a predisposing factor for having a child with oral clefts (OR=5/718, p=0.000). Conclusion: Children carrying the 677TT variant of the MTHFR gene may have an increased risk of CL/P. In addition, the finding that the risk associated with this allele was obviously higher when the mothers didn’t use folic acid, supports the hypothesis that folic acid may play a role in the etiology of CL/P. PMID:26140186

  4. Glucose Tolerance, MTHFR C677T and NOS3 G894T Polymorphisms, and Global DNA Methylation in Mixed Ancestry African Individuals

    PubMed Central

    Mutize, Tinashe; Erasmus, Rajiv T.

    2016-01-01

    The aim of this study is to quantify global DNA methylation and investigate the relationship with diabetes status and polymorphisms in MTHFR C677T and NOS3 G894T genes in mixed ancestry subjects from South Africa. Global DNA methylation was measured, and MTHFR rs1801133 and NOS3 rs1799983 polymorphisms were genotyped using high throughput real-time polymerase chain reaction and direct DNA sequencing. Of the 564 participants, 158 (28%) individuals had T2DM of which 97 (17.2%) were screen-detected cases. Another 119 (21.1%) had prediabetes, that is, impaired fasting glucose, impaired glucose tolerance, or the combination of both, and the remainder 287 (50.9%) had normal glucose tolerance. Global DNA methylation was significantly higher in prediabetes and screen-detected diabetes than in normal glucose tolerance (both p ≤ 0.033) and in screen-detected diabetes compared to known diabetes on treatment (p = 0.019). There was no difference in global DNA methylation between known diabetes on treatment and normal glucose tolerance (p > 0.999). In multivariable linear regression analysis, only NOS3 was associated with increasing global DNA methylation (β = 0.943; 95% CI: 0.286 to 1.560). The association of global DNA methylation with screen-detected diabetes but not treated diabetes suggests that glucose control agents to some extent may be reversing DNA methylation. The association between NOS3 rs1799983 polymorphisms and DNA methylation suggests gene-epigenetic mechanisms through which vascular diabetes complications develop despite adequate metabolic control. PMID:27990443

  5. A Lower Degree of PBMC L1 Methylation in Women with Lower Folate Status May Explain the MTHFR C677T Polymorphism Associated Higher Risk of CIN in the US Post Folic Acid Fortification Era

    PubMed Central

    Badiga, Suguna; Johanning, Gary L.; Macaluso, Maurizio; Azuero, Andres; Chambers, Michelle M.; Siddiqui, Nuzhat R.; Piyathilake, Chandrika J.

    2014-01-01

    Background Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. Methods The study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. Results The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017). Conclusions This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation. PMID:25302494

  6. 5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle-southern Italian adults.

    PubMed

    Zappacosta, Bruno; Graziano, Mirella; Persichilli, Silvia; Di Castelnuovo, Augusto; Mastroiacovo, Pierpaolo; Iacoviello, Licia

    2014-01-01

    Two genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) can influence the plasma homocysteine (Hcy) levels, especially in the presence of an inadequate folate status. The aim of this study was to evaluate the frequencies of C677T and of A1298C MTHFR polymorphisms and their correlation with Hcy and serum folate concentrations in a population of blood donors living in a region of middle-southern Italy (the Molise Region). One hundred ninety seven blood donors were studied for total plasma Hcy, serum folate and C677T and A1298C MTHFR genotypes. The frequency of C677T genotypes was 20.8% (CC), 49.8% (CT) and 29.4% (TT); for the A1298C genotypes: 48.7% (AA), 43.7% (AC) and 7.6% (CC). Hcy and serum folate concentrations were significantly different among genotypes of the C677T polymorphism (CC versus CT versus TT: <0.0001 both for Hcy and folate), with Hcy values increasing, and serum folate decreasing, from CC to TT subjects. Regarding to A1298C polymorphism, the difference among genotypes (AA versus AC versus CC; p: 0.026 for Hcy and 0.014 for serum folate), showed an opposite trend for both parameters, with Hcy higher in the wild-type and lower in the homozygotes and serum folate higher in CC than in AA subjects. In conclusion, we found a high frequency of MTHFR allele associated with high level of Hcy and low levels of folate in an Italian southern population.

  7. Interactions among methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) polymorphisms - a cross-sectional study: multiple heterozygosis as a risk factor for higher homocysteine levels and vaso-occlusive episodes.

    PubMed

    Amaral, F M; Miranda-Vilela, A L; Lordelo, G S; Ribeiro, I F; Daldegan, M B; Grisolia, C K

    2017-02-23

    High plasma homocysteine (Hcy) ​​levels may be responsible for vaso-occlusive episodes and may have acquired and/or genetic causes. This cross-sectional study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C) and cystathionine-β-synthase (CBS; T833C/844ins68, G919A) polymorphisms in serum levels of folic acid, vitamin B12 and Hcy, and to verify a possible association between these polymorphisms and the clinical variability. Blood samples of Brazilian patients with a diagnosis of thrombosis were submitted to genotyping by PCR-based methods and serum dosages of folic acid, vitamin B12 and Hcy. Except for the CBS G919A polymorphism, all other genetic markers were in Hardy-Weinberg equilibrium. An increased risk for venous thrombosis was found for the MTHFR 1298CC carriers (OR = 1.688; 95%CI = 0.839-3.398, P = 0.018) and those homozygously mutant for the CBS haplotype 844ins68/T833C (OR = 2.488; 95%CI = 0.501-12.363, P = 0.031), while heterozygous for this CBS haplotype showed an increased risk for higher Hcy levels (OR = 5.900; 95%CI = 1.003-34.691, P = 0.030). Significant interactions were observed among the MTHFR C677T, MTHFR A1298C and CBS haplotype 844ins68/T833C polymorphisms in the results for Hcy levels (P = 0.000), where heterozygous had higher values. Interactions among these polymorphisms can affect serum Hcy levels, where multiple heterozygosis could be a risk factor for vaso-occlusive episodes.

  8. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

    PubMed Central

    Jakubowska, A; Rozkrut, D; Antoniou, A; Hamann, U; Scott, R J; McGuffog, L; Healy, S; Sinilnikova, O M; Rennert, G; Lejbkowicz, F; Flugelman, A; Andrulis, I L; Glendon, G; Ozcelik, H; Thomassen, M; Paligo, M; Aretini, P; Kantala, J; Aroer, B; von Wachenfeldt, A; Liljegren, A; Loman, N; Herbst, K; Kristoffersson, U; Rosenquist, R; Karlsson, P; Stenmark-Askmalm, M; Melin, B; Nathanson, K L; Domchek, S M; Byrski, T; Huzarski, T; Gronwald, J; Menkiszak, J; Cybulski, C; Serrano, P; Osorio, A; Cajal, T R; Tsitlaidou, M; Benítez, J; Gilbert, M; Rookus, M; Aalfs, C M; Kluijt, I; Boessenkool-Pape, J L; Meijers-Heijboer, H E J; Oosterwijk, J C; van Asperen, C J; Blok, M J; Nelen, M R; van den Ouweland, A M W; Seynaeve, C; van der Luijt, R B; Devilee, P; Easton, D F; Peock, S; Frost, D; Platte, R; Ellis, S D; Fineberg, E; Evans, D G; Lalloo, F; Eeles, R; Jacobs, C; Adlard, J; Davidson, R; Eccles, D; Cole, T; Cook, J; Godwin, A; Bove, B; Stoppa-Lyonnet, D; Caux-Moncoutier, V; Belotti, M; Tirapo, C; Mazoyer, S; Barjhoux, L; Boutry-Kryza, N; Pujol, P; Coupier, I; Peyrat, J-P; Vennin, P; Muller, D; Fricker, J-P; Venat-Bouvet, L; Johannsson, O Th; Isaacs, C; Schmutzler, R; Wappenschmidt, B; Meindl, A; Arnold, N; Varon-Mateeva, R; Niederacher, D; Sutter, C; Deissler, H; Preisler-Adams, S; Simard, J; Soucy, P; Durocher, F; Chenevix-Trench, G; Beesley, J; Chen, X; Rebbeck, T; Couch, F; Wang, X; Lindor, N; Fredericksen, Z; Pankratz, V S; Peterlongo, P; Bonanni, B; Fortuzzi, S; Peissel, B; Szabo, C; Mai, P L; Loud, J T; Lubinski, J

    2012-01-01

    Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. PMID:22669161

  9. Analysis of Polymorphisms in Genes (AGT, MTHFR, GPIIIa, and GSTP1) Associated with Hypertension, Thrombophilia and Oxidative Stress in Mestizo and Amerindian Populations of México

    PubMed Central

    Juárez-Velázquez, Rocio; Canto, Patricia; Canto-Cetina, Thelma; Rangel-Villalobos, Hector; Rosas-Vargas, Haydee; Rodríguez, Maricela; Canizales-Quinteros, Samuel; Velázquez Wong, Ana Claudia; Ordoñez-Razo, Rosa María; Vilchis-Dorantes, Guadalupe; Coral-Vázquez, Ramón Mauricio

    2010-01-01

    Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1) polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele and genotype frequencies were compared using χ2 tests. All populations followed the Hardy Weinberg equilibrium for assay markers with the exception of the Triki, whose were in Hardy Weinberg dysequilibrium for the glutathione S-transferase P1 polymorphism. Interestingly, according to all the analyzed single nucleotide polymorphisms (SNPs), the Triki population was the most differentiated and homogeneous group of the six populations analyzed. A comparison of our data with those previously published for some Caucasian, Asian and Black populations showed quite significant differences. These differences were remarkable with all the Mexican populations having a lower frequency of the 105V allele of the glutathione S-transferase P1 and reduced occurrence of the 222A allele of the 5,10 methylenetetrahydrofolate reductase. Our results show the genetic diversity among different Mexican populations and with other racial groups. PMID:20592457

  10. Whole genome sequencing identifies ANXA3 and MTHFR mutations in a large family with an unknown equinus deformity associated genetic disorder.

    PubMed

    Zhang, Zhiqun; Kong, Zhuqing; Zhu, Miao; Lu, Wenxiang; Ni, Lei; Bai, Yunfei; Lou, Yue

    2016-10-01

    The aim of this study was to characterize a previously uncharacterized genetic disorder associated with equinus deformity in a large Chinese family at the genetic level. Blood samples were obtained and whole genome sequencing was performed. Differential gene variants were identified and potential impacts on protein structure were predicted. Based on the control sample, several diseases associated variants were identified and selected for further validation. One of the potential variants identified was a ANXA3 gene [chr4, c.C820T(p.R274*)] variant. Further bioinformatic analysis showed that the observed mutation could lead to a three-dimensional conformational change. Moreover, a MTHFR variant that is different from variants associated with clubfoot was also identified. Bioinformatic analysis showed that this mutation could alter the protein binding region. These findings imply that this uncharacterized genetic disorder is not clubfoot, despite sharing some similar symptoms. Furthermore, specific CNV profiles were identified in association with the diseased samples, thus further speaking to the complexity of this multigenerational disorder. This study examined a previously uncharacterized genetic disorder appearing similar to clubfoot and yet having distinct features. Following whole genome sequencing and comparative analysis, several differential gene variants were identified to enable a further distinction from clubfoot. It is hoped that these findings will provide further insight into this disorder and other similar disorders.

  11. Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment.

    PubMed

    Rozycka, Agata; Jagodzinski, Pawel P; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2013-12-01

    An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease.

  12. Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment

    PubMed Central

    Rozycka, Agata; Jagodzinski, Pawel P.; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2013-01-01

    An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease. PMID:24532985

  13. A cross-sectional study to find out the relationship of methylenetetrahydrofolate reductase (MTHFR) C677T genotype with plasma levels of folate and total homocysteine by daily folate intake in Japanese.

    PubMed

    Fukuda, Nana; Hamajima, Nobuyuki; Wakai, Kenji; Suzuki, Koji

    2014-01-01

    In those with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, enzyme activity is lowered. Therefore, these individuals might require an increased intake of folate to maintain or control blood levels of plasma folate or total homocysteine (tHcy). We examined associations of dietary folate intake with fasting plasma folate and total homocysteine (tHcy) according to genotype among 554 Japanese (207 men and 347 women aged 39-89 y) recruited in 2009. Intake of folate was estimated with a food frequency questionnaire. The MTHFR polymorphism was genotyped by a polymerase chain reaction with confronting two-pair primers. The log-transformed concentration of folate or tHcy was regressed on energy-adjusted folate intake in a linear regression analysis. Higher folate intake was associated with higher plasma folate among those with the CC (β=0.165, p=0.066) or CT (β=0.248, p<0.001) genotypes, and with lower tHcy levels only among those with the CC (β=-0.141, p=0.013) genotype. Plasma folate was significantly and inversely associated with tHcy, irrespective of MTHFR genotype. When the analysis was restricted to those with tHcy levels higher than the reference range (≥13.5 nmol/mL, n=20), these significant associations were not found. The interaction between folate intake or plasma folate and genotype was not significant in any analysis. In conclusion, dietary folate intake was positively associated with plasma folate among those with the CC or CT genotypes and inversely associated with tHcy among those with the CC genotype, but the associations were not clear among those with higher levels of tHcy.

  14. Breast cancer risk associated with gene expression and genotype polymorphisms of the folate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population.

    PubMed

    López-Cortés, Andrés; Echeverría, Carolina; Oña-Cisneros, Fabián; Sánchez, María Eugenia; Herrera, Camilo; Cabrera-Andrade, Alejandro; Rosales, Felipe; Ortiz, Malena; Paz-Y-Miño, César

    2015-08-01

    Breast cancer (BC) is the leading cause of cancer-related death among women in 2014. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and MTR reductase (MTRR) are enzymes that play an important role in folate metabolism. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G, and MTRR A66G, alter plasmatic folate and homocysteine concentrations, causing problems during the repairment, synthesis, and methylation of the genetic material. Therefore, it is essential to know how BC risk is associated with histopathological and immunohistochemical characteristics, genotype polymorphisms, and gene expression in a high altitude Ecuadorian mestizo population. DNA was extracted from 195 healthy and 114 affected women. Genotypes were determined by restriction enzymes and genomic sequencing. mRNA was extracted from 26 glandular breast tissue samples, both from cancerous tissue and healthy tissue adjacent to the tumor. Relative gene expression was determined with the comparative Livak method (2(-ΔΔCT)). We found significant association between the rs1801133 (A222V) genotypes and an increased risk of BC development: C/T (odds ratio [OR] = 1.8; 95 % confidence interval [CI] = 1.1-3.2; P = 0.039), T/T (OR = 2.9; 95 % CI = 1.2-7.2; P = 0.025), and C/T + T/T (OR = 1.9; 95 % CI = 1.1-3.3; P = 0.019). Regarding relative gene expression, we found significant mRNA subexpression between the combined genotypes C/T + T/T (rs1801133) and triple negative breast cancer (TNBC) (P = 0.034). In brief, the MTHFR gene and its protein could act as potential predictive biomarkers of BC, especially TNBC among the high altitude Ecuadorian mestizo population.

  15. [The different genotypes of MTHFR 1298A>C and PON1 -108C>T polymorphisms confer the increased risk of the abdominal aortic aneurysm in the smoking and nonsmoking persons].

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Pawlak, Andrzej L

    2005-01-01

    In abdominal aortic aneurysm (AAA) both the etiology and the pathogenesis are of the multifactorial character. The genetic component in the determination of this disease is proven by its familial occurrence. Smoking represents the best recognized risk factor of the AAA development. Increased concentrations of homocysteine (Hcy) in plasma are the common finding in these patients. It is assumed that the Hcy thiolactone, the most reactive metabolite of Hcy, may participate in the aortic wall destruction in AAA. The polymorphic variants of the methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C) influence tissue concentrations of the Hcy. Paraoxonase (PON1), the enzyme associated in plasma with the HDL fraction, as lactonase detoxicates the Hcy thiolactone. The promotor polymorphism of PON1 - 108C>T gene may determine the lower activity of this enzyme. In the case-control study of 106 patients with AAA and 97 healthy persons, the effects of selected genetic and nongenetic risk factors on development of AAA were assessed, considering the possibilities of interaction between them. It was found, that the arterial hypertension, cigarette smoking and the lower HDL fraction are independent risk factors of AAA. The arterial hypertension was a risk factor both in the smoking and the nonsmoking males, whereas the lower HDL fraction has been the risk factor only for the smoking men. By the multivariate analysis in the nonsmoking males the MTHFR 1298 AC and CC genotypes increased the risk of AAA development 4,8-fold in relation to the MTHFR 1298 AA nonsmoking males. In reference to the genotypes of the expected high impact on the metabolism of Hcy and of Hcy thiolactone, the genotypes of MTHFR 677TT and PON1 -108CT and TT were more frequent in smoking ones, but the difference was not significant. This observation fits with the assumption that the influence of smoking on the occurrence of AAA prevails over that of genetic variability. When the patients age was considered

  16. Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study.

    PubMed

    Abrahamsen, Bo; Madsen, Jonna Skov; Tofteng, Charlotte Landbo; Stilgren, Lis; Bladbjerg, Else Marie; Kristensen, Søren Risom; Brixen, Kim; Mosekilde, Leif

    2005-03-01

    We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to some extent explain why this polymorphism is associated with low BMD or fracture in some study populations and not in others. It would also indicate that fractures associated with the TT genotype could be preventable by vitamin B supplementation. We have, therefore, reviewed baseline food record data from our original study to determine if BMD and fracture associations with the MTHFR genotype depended on the intake of folate, riboflavin, or other members of the vitamin B complex, associated with homocysteine metabolism. We analyzed genotype, BMD, and dietary records from 1700 healthy postmenopausal women who participated in the DOPS study. For the assessment of fracture risk, we used longitudinal observations from 854 women in the control group who remained compliant with their initial allocation of no treatment. Riboflavin intake was significantly correlated with femoral neck (FN) BMD in women with the TT genotype (r = 0.24, P < 0.01). FN and lumbar spine (LS) BMD were only associated with the MTHFR genotype in the lowest quartile of riboflavin intake. At the FN, similar threshold effects were shown for folate, vitamin B12, and vitamin B6. Among these vitamin B complex members, stepwise regression analysis identified riboflavin as the only significant predictor of FN BMD in the TT genotype. In conclusion, we confirm reports that BMD in the MTHFR TT genotype is only significantly reduced in the lowest quartile of riboflavin, B12, B6, and folate intake, at least at the time of menopause. Vitamin B supplementation would only be expected to benefit BMD in about 2% of the population, i

  17. Ethnic variation of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase (MTHFR) gene in southwestern Mexico.

    PubMed

    Antonio-Véjar, V; Del Moral-Hernández, O; Alarcón-Romero, L C; Flores-Alfaro, E; Leyva-Vázquez, M A; Hernández-Sotelo, D; Illades-Aguiar, B

    2014-09-29

    In this study, we examined the distribution of genotype and allele frequencies of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase gene (MTHFR) in two ethnic groups in the State of Guerrero, Mexico, which were compared with those of the Mestizo population of the region. A comparative study was conducted on 455 women from two ethnic groups and a group of Mestizo women of the State of Guerrero, Mexico: 135 Nahuas, 124 Mixtecas, and 196 Mestizas. Genotyping of both polymorphisms were performed by using polymerase chain reaction-restriction fragment length polymorphism methods. We found that the 677TT genotype was more frequent in Nahua and Mixteca women compared to Mestiza women (P = 0.008), and the most prevalent genotype in both ethnic groups was the 1298AA genotype (P < 0.001). We also compared the 677T allele frequency obtained from the groups studied with the frequencies reported in other ethnic groups of Mexico (Huichol, Tarahumara, and Purepecha). There were significant differences between the three ethnic groups compared to Nahuas (Huicholes, P = 0.004; Tarahumaras, P < 0.001; Purepechas, P = 0.042). Our results indicated significant differences in the frequencies of the C677T and A1298C polymorphisms between the two ethnic groups and the Mestizo population of the State of Guerrero. In addition, we found strong differences with other ethnic groups in Mexico. These results could be useful for future studies investigating diseases related to folate metabolism, and could help the government to design specific nutrition programs for different ethnic groups.

  18. Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

    PubMed Central

    Mischoulon, David; Lamon-Fava, Stefania; Selhub, Jacob; Katz, Judith; Papakostas, George I.; Iosifescu, Dan V.; Yeung, Albert S.; Dording, Christina M.; Farabaugh, Amy H.; Clain, Alisabet J.; Baer, Lee; Alpert, Jonathan E.; Nierenberg, Andrew A.; Fava, Maurizio

    2014-01-01

    Objective To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. Methods We screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined. Results Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C=41%, C/T=47%, T/T=11%, A/A=66%, A/G=29%, G/G=4%). In the fluoxetine-treated subsample (n=49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response. Conclusion The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples. PMID:22789065

  19. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, intakes of folate and related B vitamins and colorectal cancer: a case-control study in a population with relatively low folate intake.

    PubMed

    Sharp, Linda; Little, Julian; Brockton, Nigel T; Cotton, Seonaidh C; Masson, Lindsey F; Haites, Neva E; Cassidy, Jim

    2008-02-01

    Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case-control study of folate intake, related dietary factors and MTHFR polymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12 or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CT v. CC = 0.77 (95 % CI 0.52, 1.16); OR for TT v. CC = 0.62 (95 % CI 0.31, 1.24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0.81 (95 % CI 0.45, 1.49)). There were significant interactions between total folate and C677T (P = 0.029) and A1298C (P = 0.025), and total vitamin B6 and both polymorphisms (C677T, P = 0.016; A1298C, P = 0.033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.

  20. Role of polymorphisms in factor V (FV Leiden), prothrombin, plasminogen activator inhibitor type-1 (PAI-1), methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) genes as risk factors for thrombophilias.

    PubMed

    Miranda-Vilela, A L

    2012-09-01

    Thrombophilias are defined as a predisposition to thrombosis due to hematological changes which induce blood hypercoagulability; they can be inherited or acquired. They are individually characterized by a large phenotypic variability, even when they occur within the same family. Hereditary thrombophilias are, in most cases, due to changes related to physiological coagulation inhibitors or mutations in the genes of coagulation factors. High levels of plasma homocysteine may also be responsible for vaso-occlusive episodes and may have acquired (nutritional deficiencies of folate and vitamins B6 and B12) and/or genetic causes (mutations in the genes responsible for expression of enzymes involved in the intracellular metabolism of homocysteine). Considering that: (1) thromboses are events of multigenic and multifactorial etiopathology; (2) the presence of mutations in several genes significantly increases the risk of their occurrence; (3) the vascular territory (venous and/or arterial) affected involves different pathophysiological mechanisms and treatments, knowledge of genetic variants that may contribute to the risk and variability of the phenotypic manifestations of these diseases is extremely important. This understanding may provide support for a more individualized and therefore more effective treatment for thrombophilia carriers. Thus, this mini-review aims to address a comprehensive summary of thrombophilias and thrombosis, and discuss the role of polymorphisms in Factor V (FV Leiden), Prothrombin, Plasminogen activator inhibitor type-1 (PAI-1), Methylenetetrahydrofolate reductase (MTHFR) and Cystathionine β-synthase (CBS) genes as risk factors for thrombophilias.

  1. Prevalence of metilentetrahidrofolate reductase C677T polymorphism, consumption of vitamins B6, B9, B12 and determination of lipidic hydroperoxides in obese and normal weight Mexican population.

    PubMed

    Hernández-Guerrero, César; Romo-Palafox, Inés; Díaz-Gutiérrez, Mary Carmen; Iturbe-García, Mariana; Texcahua-Salazar, Alejandra; Pérez-Lizaur, Ana Bertha

    2013-11-01

    Introducción. El estrés oxidativo es un factor clave en el inicio y el desarrollo de las comorbilidades de la obesidad. La enzima metiltetrahidrofolato reductasa (MTHFR) participa en el metabolismo del folato con la acción de las vitaminas B9 y B12. El gen MTHFR puede presentar un polimorfismo de un solo nucleótido (SNP) en la posición 677 (C677T), que puede promover homocisteinemia asociada a la producción de radicales libres. Objetivo. Determinar la frecuencia del SNP C677T de la MTHFR, evaluar el consumo de vitaminas B6, B9, B12 y determinar la concentración de hidroperóxidos lipídicos (LOOH) en plasma en un grupo de obesos y testigo. Métodos. Se clasificaron 128 mexicanos mestizos de acuerdo a su índice de masa corporal en normopeso (Nw; n=75) y obesidad (ObeI-III; n=53). Se identificó el SNP C677T de la MTHFR mediante la técnica de PCR-RFLP. El consumo de vitaminas B6, B9 y B12 se evaluó mediante una encuesta validada. Se determinaron LOOH como un indicador de estrés oxidativo periférico. Resultados. No hubo diferencia estadística significativa en la frecuencia del polimorfismo C677T entre homocigotos TT en Nw (0.19) y ObeI-III (0.25). La frecuencia del alelo T en Nw fue de 0.45, y 0.51 en el grupo ObeI-III. Los LOOH mostraron diferencia estadística significativa (p.

  2. MTHFR and ACE Gene Polymorphisms and Risk of Vascular and Degenerative Dementias in the Elderly

    ERIC Educational Resources Information Center

    Pandey, Pratima; Pradhan, Sunil; Modi, Dinesh Raj; Mittal, Balraj

    2009-01-01

    Focal lacunar infarctions due to cerebral small vessel atherosclerosis or single/multiple large cortical infarcts lead to vascular dementia, and different genes and environmental factors have been implicated in causation or aggravation of the disease. Previous reports suggest that some of the risk factors may be common to both vascular as well as…

  3. Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2R, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Using linear regression models, we studied the main and two-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma homocysteine normalized by red blood cell...

  4. One-Carbon Metabolism and Breast Cancer Survival in a Population-Based Study

    DTIC Science & Technology

    2005-06-01

    1. All genotype distributions at these three loci were in agreement with Hardy-Weinberg Equilibrium. In addition, genotyping for the MTHFR 677C>T...95%CI 1.04-2.06). MTHFR 677 C-- > T GENOTYPF AND BC SURV’,[VAL HR: 1.46 (1.04 -- 2.06) MTHFR 677 C->T Genotype------ TT or CT CC Overall survival ofthe...BC cases in the LIBCSP affected by MTHFR 677 C-.T genotypes: CC versus TT or CT c. Study associations of one-carbon metabolism (diet and polymorphism

  5. Methylenetetrahydrofolate Reductase C677T: Hypoplastic Left Heart and Thrombosis.

    PubMed

    Spronk, Kimberly J; Olivero, Anthony D; Haw, Marcus P; Vettukattil, Joseph J

    2015-10-01

    The incidence of congenital heart defects is higher in infants with mutation of methylenetetrahydrofolate reductase (MTHFR) gene. The MTHFR C677T gene decreases the bioavailability of folate and increases plasma homocysteine, a risk factor for thrombosis. There have been no reported cases in the literature on the clinical implications of this procoagulable state in the setting of cyanotic heart disease, which itself has prothrombotic predisposition. Two patients with hypoplastic left heart syndrome developed postoperative thrombotic complications, both were homozygous for MTHFR C677T. We present these cases and highlight the implications of MTHFR mutation in the management of complex congenital heart disease.

  6. Folate and Breast Cancer: Role of Intake, Blood Levels, and Metabolic Gene Polymorphisms

    DTIC Science & Technology

    2004-06-01

    intake is associated with a decreased breast cancer risk particularly among those with MTHFR , MTR, and MTRR polymorphisms. The specific aims are 1...misincorporation in breast cancer risk. To date, the major results are the MTHFR 677TT genotype and low folate intake is associated with an increased risk of

  7. Folate and Breast Cancer: Role of Intake, Blood Levels and Metabolic Gene Polymorphisms

    DTIC Science & Technology

    2003-06-01

    those with MTHFR , MTR, and MTRR polymorphisms. The specific aims of this postdoctoral training proposal are 1) further methodological training in the...analysis of gene-gene and gene-environment interactions by studying folate intake and folate metabolic gene polymorphisms ( MTHFR , MTR, MTRR) using data

  8. Polymorphisms in folate-related enzyme genes in idiopathic infertile Brazilian men.

    PubMed

    Gava, Marcello M; Kayaki, Erika A; Bianco, Bianca; Teles, Juliana S; Christofolini, Denise M; Pompeo, Antonio C L; Glina, Sidney; Barbosa, Caio P

    2011-12-01

    The aim of the study was to analyze the distribution of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and methionine synthase (MTR) polymorphisms in idiopathic infertile Brazilian men and fertile men. Case-control study comprising 133 idiopathic infertile Brazilian men with nonobstructive azoospermia ([NOA] n = 55) or severe oligozoospermia ([SO] n = 78) and 173 fertile men as controls. MTHFR C677T, A1298C, and G1793A; MTRR A66G; and MTR A2756G polymorphisms were studied by quantitative polymerase chain reaction (qPCR). The results were analyzed statistically and a P value <.05 was considered significant. Single-marker analysis revealed a significant association among MTHFR C677T polymorphism and both NOA group (P = .018) and SO group (P < .001). Considering the MTHFR A1298C, MTHFR G1793A, and MTRR A66G polymorphisms, no difference was found between NOA group and SO group. Regarding the MTR A2756G polymorphism, a significant difference was found between NOA and controls, P = .017. However, statistical analysis revealed no association between SO group and controls. Combined genotypes of 3 MTHFR polymorphisms did not identify a haplotype associated with idiopathic infertility. The combinatory analysis of the 3 polymorphisms MTHFR, MTRR, and MTR did not show difference between cases and controls. The findings suggest the MTHFR C677T and MTR A2756G polymorphisms could be an important genetic factor predisposing to idiopathic infertility in Brazilian men.

  9. Status of vitamin B-12 and B-6 but not of folate, homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene differs in frequency in different ethnic groups which have differing prevalence of age-related cognitive impairments. We used a battery of neuropsychological tests to examine association of the MTHFR C677T polymorphism w...

  10. Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes.

    PubMed

    Lawrance, Andrea K; Racine, Julie; Deng, Liyuan; Wang, Xiaoling; Lachapelle, Pierre; Rozen, Rima

    2011-02-01

    Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with homocystinuria can result in early demise or later-onset neurological impairment, including developmental delay, motor dysfunction, and seizures. We previously characterized BALB/c Mthfr (-/-)mice as a model for this disorder and have recently backcrossed the disrupted allele onto the C57Bl/6 background to examine the variable phenotypes in MTHFR deficiency. Compared with BALB/c Mthfr (-/-)mice, C57Bl/6 Mthfr (-/-)mice have enhanced survival rates (81% vs 26.5%). Four-day-old BALB/c mutant pups had lower body, brain, and spleen weights relative to their wild-type counterparts compared with C57Bl/6 mutants. Pregnant BALB/c Mthfr (+/-)mice had increased resorptions and embryonic delays compared with wild-type littermates, whereas these outcomes in C57Bl/6 c Mthfr (+/-)mice were similar to those of wild-type C57Bl/6 mice. BALB/c-mutant pups had altered hematological profiles (higher hematocrit, hemoglobin, and white blood cell counts, with lower platelet counts) compared with C57Bl/6 mutants. Mutants of both strains had similar degrees of hepatic steatosis, hepatic activity of betaine:homocysteine methyltransferase, and altered cerebellar histology. Electroretinograms (ERG) in C57Bl/6 Mthfr (-/-)mice revealed decreased amplitude of scotopic and photopic waves in 6-week-old mice, with normalized ERGs at 13 weeks. Plasma homocysteine was modestly higher in C57Bl/6 compared with BALB/c mice. Our results emphasize the variable presentation of MTHFR deficiency in different genetic backgrounds and suggest that plasma homocysteine is not a predictor of severity. In addition, our novel findings of decreased spleen weights, thrombocytopenia, and impaired retinal function warrant investigation in patients with severe MTHFR deficiency or other forms of homocystinuria.

  11. The Importance of Homozygous Polymorphisms of Methylenetetrahydrofolate Reductase Gene in Romanian Patients with Idiopathic Venous Thromboembolism

    PubMed Central

    Hotoleanu, Cristina; Trifa, Adrian; Popp, Radu; Fodor, Daniela

    2013-01-01

    Background: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have recently raised the interest as a possible thrombophilic factors. Aims: We aimed to assess the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in idiopathic venous thromboembolism (VTE) in a Romanian population and the associated risk of VTE. Study Design: We performed a case-control transversal study including 90 patients diagnosed with VTE and 75 sex- and age-matched controls. Methods: MTHFR C677T and A1298C polymorphisms were detected using PCR-RFLP method. Results: The homozygous MTHFR 677TT genotype, present in 18.8% of patients with VTE versus 6.6% of controls, was significantly associated with VTE (p= 0.021, OR= 3.26, 95%CI (1.141–9.313)). The heterozygous MTHFR A1298C genotype, presenting the highest prevalence in the VTE group (34.4%) as well as in controls (37.3%), was not associated with VTE (p=0.7). No associations were found for heterozygous MTHFR C677T (with a frequency of 32.2% in VTE and 37.3% in controls, p=0.492), respective homozygous MTHFR A1298C genotype (with a frequency of 1.1% in VTE and 2.6% in controls, p=0.456). Conclusion: Among MTHFR polymorphisms, only homozygosity for MTHFR 677TT may be considered a risk factor for VTE; the MTHFR A1298C polymorphism is not significantly associated with an increased risk of VTE. PMID:25207100

  12. [Methylenetetrahydrofolate reductase deficiency-induced schizophrenia in a school-age boy].

    PubMed

    Wang, Qiao; Liu, Jing; Liu, Yu-Peng; Li, Xi-Yuan; Ma, Yan-Yan; Wu, Tong-Fei; Ding, Yuan; Song, Jin-Qing; Wang, Yu-Jie; Yang, Yan-Ling

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine.

  13. 5,10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant.

    PubMed

    Tsuji, Megumi; Takagi, Atsushi; Sameshima, Kiyoko; Iai, Mizue; Yamashita, Sumimasa; Shinbo, Hiroko; Furuya, Noritaka; Kurosawa, Kenji; Osaka, Hitoshi

    2011-06-01

    5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most prevalent inborn error of folate metabolism, and has variable clinical manifestations from asymptomatic to severe psychomotor retardation, microcephalus and seizure. In untreated infantile cases, it predominantly affects the central nervous system, which is sometimes fatal. On the other hand, peripheral nerve involvement is uncommon. We present a severe infantile case of MTHFR deficiency that manifested unilateral phrenic nerve palsy with communicating hydrocephalus, developmental delay and died at 11months of age. An enzymatic study confirmed MTHFR deficiency with residual activity of 0.75% of mean control values in cultured fibroblasts. Mutation analysis of the MTHFR gene revealed homozygous, tandem missense mutations c.[446G>T; 447C>T] in exon 3 of the MTHFR gene converting glycine to valine (Gly149Val). In MTHFR deficiency, betaine may improve the symptoms if started immediately after birth by reducing the level of serum homocysteine and increasing that of methionine. Our results show that we should be aware of possible inborn errors of folate metabolism such as MTHFR deficiency, in infants with unexplained developmental delay manifesting rapidly progressive polyneuropathy.

  14. C677T polymorphism of the methylenetetrahydrofolate reductase gene does not affect folic acid, vitamin B12, and homocysteine serum levels in Turkish children with neural tube defects.

    PubMed

    Erdogan, M O; Yildiz, S H; Solak, M; Eser, O; Cosar, E; Eser, B; Koken, R; Buyukbas, S

    2010-06-22

    Association between neural tube defects (NTDs) and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was suspected, because the MTHFR gene codes for a key enzyme in folate metabolism. Its deficiency usually leads to significant reductions in plasma concentrations of folate, vitamin B(12) and methionine, whereas homocysteine levels are increased. We examined folate, vitamin B(12) and homocysteine serum concentrations and polymorphism of the C677T MTHFR gene in Turkish children with neural tube defects. Thirty-three children with NTDs, 26 mothers and 48 healthy individuals were studied. C677T MTHFR polymorphism was determined by melting curve analyses (LightCycler). The levels of folate, vitamin B(12) and homocysteine serum concentrations in NTDs were evaluated and compared, along with information concerning alleles of the MTHFR gene. C677T allele frequencies in NTD children and their mothers were similar to those found in controls. Serum folate and vitamin B(12) concentrations were significantly higher in NTD children than that of controls. Serum homocysteine concentrations were not significantly higher in NTD children and mothers. We concluded that C677T MTHFR gene polymorphism does not affect folic acid, vitamin B(12) and homocysteine metabolism in Turkish children with NTDs. C677T polymorphism of the MTHFR gene cannot be regarded as a major risk factor for NTDs in Turkish children.

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

    PubMed

    Hajiesmaeil, Mogge; Tafvizi, Farzaneh; Sarmadi, Soheila

    2016-12-01

    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.

  16. Analysis of thrombophilic genetic mutations in patients with Sheehan's syndrome: is thrombophilia responsible for the pathogenesis of Sheehan's syndrome?

    PubMed

    Gokalp, Deniz; Tuzcu, Alpaslan; Bahceci, Mithat; Ayyildiz, Orhan; Yurt, Murat; Celik, Yusuf; Alpagat, Gulistan

    2011-06-01

    The gene mutations of Factor V R506Q (FV-Leiden), prothrombin (FII G20210A), methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C and PAI-1 4G/5G are well-established risk factors for thrombosis. We aimed to investigate the prevalence of these gene mutations and their possible impact on the development of pathogenesis in patients with Sheehan's syndrome (SS). 40 female patients with SS compared to a control group of 45 healthy women. The presence of FV-Leiden, FII G20210A, MTHFR C677T, MTHFR A1298C and PAI-1 4G/5G gene mutations were assessed by polymerase chain reaction analysis with a light cycler analyzer. An odds ratio of greater than one is considered to increase the risk of SS disease as found in Factor V Leiden, FII G20210A, MTHFR C677T, MTHFR A1298C and PAI-1 4G/5G polymorphism, as follows respectively: 1.13, 1.85, 6.00, 8.14 and 1.45. MTHFR C677T and MTHFR A1298C polymorphism were found significantly higher in SS patients than the control group (P<0.001), however FV-Leiden, FII G20210A and PAI-1 4G/5G polymorphism showed no significant difference (P>0.05). The level of plasma total homocysteine (tHcy) was significantly higher in patients with SS than in the control group (P<0.001). We suggest that the genetic mutations of FV-Leiden, FII G20210A, MTHFR C677T, MTHFR A1298C and PAI-1 4G/5G increase the risk of SS. Also, high plasma tHcy levels may be a risk factor for the development of SS.

  17. Methylenetetrahydrofolate reductase homozygous mutation in a young boy with cerebellar infarction.

    PubMed

    Spalice, Alberto; Del Balzo, Francesca; Perla, Francesco Massimo; Properzi, Enrico; Carducci, Carla; Antonozzi, Italo; Iannetti, Paola

    2009-06-08

    Posterior circulation vascular occlusive disease in children is a rare and uncommonly reported event. Among the numerous risk factors, the methylenetetrahydrofolate reductase (MTHFR) mutation is considered to be a common genetic cause of thrombosis in adults and children. Recently, a link between the MTHFR mutation and cerebrovascular disorders was reported in children. Diffusion tensor imaging (DTI) is a great improvement on magnetic resonance imaging (MRI), making the in vivo anatomical and pathological study of the brain and its fibers possible. In our patient cerebellar infarction was associated with MTHFR mutation and, in a standard neurological examination, DTI revealed normal white matter tracts.

  18. Predictive value of homocysteine for depression after acute coronary syndrome

    PubMed Central

    Kang, Hee Ju; Stewart, Robert; Bae, Kyung Yeol; Kim, Sung Wan; Shin, Il Seon; Kang, Hyuno; Moon, Won Jin; Hong, Young Joon; Ahn, Youngkeun; Jeong, Myung Ho; Yoon, Jin Sang; Kim, Jae Min

    2016-01-01

    We investigated roles of plasma homocysteine and MTHFR gene in relation to risks and treatment responses of depression in ACS. A sample of 969 patients with recent ACS were recruited and 711 followed 1 year later. In addition, of 378 baseline participants with depressive disorder, 255 were randomized to a 24-week double blind trial of escitalopram (N = 127) or placebo (N = 128). A higher homocysteine concentration was independently associated with prevalent depressive disorder at baseline irrespective of MTHFR genotype; and with both incident and persistent depressive disorder at follow-up only in the presence of TT genotype. MTHFR genotype was not itself associated with depressive disorder after ACS. No associations were found with 24-week antidepressant treatment responses. Plasma homocysteine could be a biomarker for depressive disorder particularly in the acute phase of ACS. Focused interventions for those with higher homocysteine level and MTHFR TT genotype might reduce the risk of later depressive disorder. PMID:27626182

  19. Gene polymorphisms involved in folate and methionine metabolism and increased risk of sporadic colorectal adenocarcinoma.

    PubMed

    Guimarães, José Luiz Miranda; Ayrizono, Maria de Lurdes; Coy, Cláudio Saddy Rodrigues; Lima, Carmen Silvia Passos

    2011-10-01

    This pilot study has compared the polymorphic genotype frequencies of methylenetetrahydrofolate reductase (MTHFR A1298C and C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), and thymidylate synthase (TS 2R/3R) in 113 patients with sporadic colorectal adenocarcinoma (SCA) and 188 healthy blood donors, used as matched controls. The aim was to assess the role of these genotypes in the increased risk of SCA among the southeastern Brazilian population. Carriers of genotype MTRR 66GG, or the combined variants MTHFR 1298AC + CC plus 677CT + TT, or MTHFR 677CT + TT plus MTR 2756AG + GG, or MTHFR 1298AC + CC plus 677CT + TT plus MTR 2756AG + GG, or yet, MTHFR 1298AC + CC plus 677CT + TT plus MTRR 66AG + GG, respectively, showed an increased risk of the order of 1.99-, 3.26-, 2.22-, 10.92-, and 14.88-fold of developing SCA when compared with carriers of the other studied polymorphic genotypes, whether in isolation or in combination. In addition, individuals with the MTHFR 677CT + TT or the MTR 2756AG + GG genotypes had a 2.12- and a 1.42-fold increased risks of SCA onset before 50 years of age. African-Brazilians with the MTRR 66GG genotype had a 1.98-fold increased risk of SCA while individuals with the MTR 2756AG + GG and the MTHFR 677CT + TT genotypes showed a 2.11- and a 1.62-fold increased risk of undifferentiated and advanced tumors at diagnosis, respectively. Carriers of genotype MTHFR 1298AC + CC or MTHFR 1298AC + CC plus MTRR 66AG + GG had a 1.42- and a 3.07-fold increased risk of rectal tumor, respectively. Additionally, carriers of MTHFR 677CT + TT or MTHFR 677CT + TT plus TS 2R/3R + 3R/3R had a 1.55- and a 5.39-fold increased risk for colon tumor, respectively, in comparison with carriers of the wild genotypes. These data suggest that all polymorphisms coding for folate and methionine-dependent enzymes, particularly when present in combination with

  20. Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: role of oxidative stress and PRMT-1.

    PubMed

    Savoia, Carmine; Ebrahimian, Talin; Lemarié, Catherine A; Paradis, Pierre; Iglarz, Marc; Amiri, Farhad; Javeshgani, Danesh; Schiffrin, Ernesto L

    2010-02-09

    In the present study, we tested the hypothesis that the PPARgamma (peroxisome-proliferator-activated receptor gamma) activator rosiglitazone improves vascular structure and function in aged hyperhomocysteinaemic MTHFR (methylene tetrahydrofolate reductase) gene heterozygous knockout (mthfr+/-) mice fed a HCD (high-cholesterol diet), a model of high cardiovascular risk. One-year-old mthfr+/- mice were fed or not HCD (6 mg x kg-1 of body weight x day-1) and treated or not with rosiglitazone (20 mg x kg-1 of body weight x day-1) for 90 days and compared with wild-type mice. Endothelium-dependent relaxation of carotid arteries was significantly impaired (-40%) only in rosiglitazone-treated HCD-fed mthfr+/- mice. Carotid M/L (media-to-lumen ratio) and CSA (cross-sectional area) were increased (2-fold) in mthfr+/- mice fed or not HCD compared with wild-type mice (P<0.05). Rosiglitazone reduced M/L and CSA only in mthfr+/- mice fed a normal diet. Superoxide production was increased in mthfr+/- mice fed HCD treated or not with rosiglitazone, whereas plasma nitrite was decreased by rosiglitazone in mice fed or not HCD. PRMT-1 (protein arginine methyltransferase-1), involved in synthesis of the NO (nitric oxide) synthase inhibitor ADMA (asymmetric omega-NG,NG-dimethylarginine), and ADMA were increased only in rosiglitazone-treated HCD-fed mthfr+/- mice. Rosiglitazone had both beneficial and deleterious vascular effects in this animal model of high cardiovascular risk: it prevented carotid remodelling, but impaired endothelial function in part through enhanced oxidative stress and increased ADMA production in mice at high cardiovascular risk.

  1. The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

    PubMed Central

    Chang, Wen-Shin; Ji, Hong-Xue; Hsiao, Chieh-Lun; Miao, Chia-En; Hsu, Yuan-Nian; Bau, Da-Tian

    2015-01-01

    Background Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations. Methodology/Principal Findings In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016). Conclusions Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease. PMID:25793509

  2. Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level.

    PubMed

    Weiner, Alexandra S; Boyarskikh, Uljana A; Voronina, Elena N; Mishukova, Olga V; Filipenko, Maxim L

    2014-01-01

    Methionine synthase (MTR) and methylenetetrahydrofolate reductase (MTHFR) enzymes are involved in the metabolism of methyl groups, and thus have an important role in the maintenance of proper DNA methylation level. In our study we aimed to evaluate the effect of the polymorphism A2756G (rs1805087) in the MTR gene on the level of human leukocyte genomic DNA methylation. Since the well-studied polymorphism C677T (rs1801133) in the MTHFR gene has already been shown to affect DNA methylation, we aimed to analyze the effect of MTR A2756G independently of the MTHFR C677T polymorphism. For this purpose, we collected the groups of 80 subjects with the MTR 2756AA genotype and 80 subjects with the MTR 2756GG genotype, having equal numbers of individuals with the MTHFR 677CC and the MTHFR 677TT genotypes, and determined the level of DNA methylation in each group. Individuals homozygous for the mutant MTR 2756G allele showed higher DNA methylation level than those harboring the MTR 2756AA genotype (5.061 ± 1.761% vs. 4.501 ± 1.621%, P=0.0391). Individuals with wild-type MTHFR 677СC genotype displayed higher DNA methylation level than the subjects with mutant MTHFR 677TT genotype (5.103 ± 1.767% vs. 4.323 ± 1.525%, P=0.0034). Our data provide evidence that the MTR A2756G polymorphism increases the level of DNA methylation and confirm the previous reports that the MTHFR C677T polymorphism is associated with DNA hypomethylation.

  3. Prognostic Relevance of Methylenetetrahydrofolate Reductase Polymorphisms for Prostate Cancer

    PubMed Central

    Lin, Victor C.; Lu, Te-Ling; Yin, Hsin-Ling; Yang, Sheau-Fang; Lee, Yung-Chin; Liu, Chia-Chu; Huang, Chao-Yuan; Yu, Chia-Cheng; Chang, Ta-Yuan; Huang, Shu-Pin; Bao, Bo-Ying

    2016-01-01

    Folate metabolism has been associated with cancers via alterations in nucleotide synthesis, DNA methylation, and DNA repair. We hypothesized that genetic variants in methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate metabolism, would affect the prognosis of prostate cancer. Three haplotype-tagging single-nucleotide polymorphisms (SNPs) across the MTHFR gene region were genotyped in a cohort of 458 patients with clinically localized prostate cancer treated with radical prostatectomy. One SNP, rs9651118, was associated with disease recurrence, and the association persisted after multivariate analyses adjusting for known risk factors. Public dataset analyses suggested that rs9651118 affects MTHFR expression. Quantitative real-time polymerase chain reaction analysis revealed that MTHFR expression is significantly upregulated in prostate tumor tissues when compared with adjacent normal tissues. Furthermore, overexpression of MTHFR correlates with cancer recurrence and death in two independent publicly available prostate cancer datasets. In conclusion, our data provide rationale to further validate the clinical utility of MTHFR rs9651118 as a biomarker for prognosis in prostate cancer. PMID:27916838

  4. Association between methylenetetrahydrofolate reductase C677T polymorphism and psoriasis: A meta-analysis.

    PubMed

    Wu, Dongze; Shi, Deshun; Yang, Li; Zhu, Xiaoliang

    2016-02-01

    Several studies have evaluated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and psoriasis. However, the results remain inconclusive. The objective of the present study was to conduct a qualitative and quantitative meta-analysis investigating the associations between MTHFR C677T and psoriasis. A published work search of PubMed, Embase, Web of Science and Chinese National Knowledge Infrastructure database were conducted to identify all publications concerning MTHFR C677T polymorphism and psoriasis on 1 October 2014. The principal outcome measure for evaluating the strength of the association was crude odds ratios along with their corresponding 95% confidence intervals. Data were extracted and statistical analyses were implemented using STATA version 12.0 software. A total of 1179 psoriatic cases and 937 controls from five case-control studies concentrating on the association between MTHFR C677T polymorphism and psoriasis were included in this qualitative meta-analysis. Pooled analysis revealed that there is no association between this polymorphism and susceptibility to psoriasis in dominant, recessive, allele and additive models under a random-effect model. However, a marginal significant association was found in the overdominant model under fixed-effect model. Subgroup analysis of ethnicity demonstrated that there is no association between MTHFR C677T polymorphism and either Asian or European psoriatic patients. In conclusion, MTHFR C677T polymorphism, qualitatively, is not a genetic factor for the pathogenesis of psoriasis but could quantitatively reflect the severity of psoriasis to some extent.

  5. Role of genetic mutations in folate-related enzyme genes on Male Infertility.

    PubMed

    Liu, Kang; Zhao, Ruizhe; Shen, Min; Ye, Jiaxin; Li, Xiao; Huang, Yuan; Hua, Lixin; Wang, Zengjun; Li, Jie

    2015-11-09

    Several studies showed that the genetic mutations in the folate-related enzyme genes might be associated with male infertility; however, the results were still inconsistent. We performed a meta-analysis with trial sequential analysis to investigate the associations between the MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G mutations and the MTHFR haplotype with the risk of male infertility. Overall, a total of 37 studies were selected. Our meta-analysis showed that the MTHFR C677T mutation was a risk factor for male infertility in both azoospermia and oligoasthenoteratozoospermia patients, especially in Asian population. Men carrying the MTHFR TC haplotype were most liable to suffer infertility while those with CC haplotype had lowest risk. On the other hand, the MTHFR A1298C mutation was not related to male infertility. MTR A2756G and MTRR A66G were potential candidates in the pathogenesis of male infertility, but more case-control studies were required to avoid false-positive outcomes. All of these results were confirmed by the trial sequential analysis. Finally, our meta-analysis with trial sequential analysis proved that the genetic mutations in the folate-related enzyme genes played a significant role in male infertility.

  6. Bladder exstrophy-epispadias complex and the role of methylenetetrahydrofolate reductase C677T polymorphism: A case control study

    PubMed Central

    Raman, Venkat Shankar; Bajpai, Minu; Ali, Abid

    2016-01-01

    Purpose: The Bladder Exstrophy-Epispadias Complex (BEEC) is the most serious form of midline abdominal malformation. The etiology of BEEC is unknown and is thought to be multifactorial. Methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T is strongly associated with other midline abnormalities such as neural tube defects. No proper case-control study existed comparing MTHFR polymorphism with BEEC. We sought to find an association with MTHFR polymorphism and patients with bladder exstrophy (BE). Materials and Methods: The design of the study was a case-control study, involving 50 children with BEEC and 50 normal healthy school children. Genetic analysis for MTHFR 677 polymorphism was carried out after DNA extraction and polymerase chain reaction amplification. Epidemiological analysis was done by using the birth defect questionnaire on parents of BEEC. Results: Forty-two classical BE, two cloacal exstrophies (CE), four epispadias, and two exstrophy variant patients were a part of this study. Severe variety of BE had a significant association with C667T MTHFR polymorphism as compared to the normal control population (P = 0.01). Conclusion: C677T MTHFR polymorphism has a strong association with severe variety (CE) of BEEC occurrence. PMID:26862292

  7. Role of genetic mutations in folate-related enzyme genes on Male Infertility

    PubMed Central

    Liu, Kang; Zhao, Ruizhe; Shen, Min; Ye, Jiaxin; Li, Xiao; Huang, Yuan; Hua, Lixin; Wang, Zengjun; Li, Jie

    2015-01-01

    Several studies showed that the genetic mutations in the folate-related enzyme genes might be associated with male infertility; however, the results were still inconsistent. We performed a meta-analysis with trial sequential analysis to investigate the associations between the MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G mutations and the MTHFR haplotype with the risk of male infertility. Overall, a total of 37 studies were selected. Our meta-analysis showed that the MTHFR C677T mutation was a risk factor for male infertility in both azoospermia and oligoasthenoteratozoospermia patients, especially in Asian population. Men carrying the MTHFR TC haplotype were most liable to suffer infertility while those with CC haplotype had lowest risk. On the other hand, the MTHFR A1298C mutation was not related to male infertility. MTR A2756G and MTRR A66G were potential candidates in the pathogenesis of male infertility, but more case-control studies were required to avoid false-positive outcomes. All of these results were confirmed by the trial sequential analysis. Finally, our meta-analysis with trial sequential analysis proved that the genetic mutations in the folate-related enzyme genes played a significant role in male infertility. PMID:26549413

  8. Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults.

    PubMed

    Liu, Ping; Zhang, Min; Xie, Xing; Jin, Jie; Holman, C D'Arcy J

    2016-03-01

    The 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are critical enzymes in folate metabolism. Previous studies have reported conflicting results on the associations between MTHFR/TS polymorphisms and adult leukemia risk, which may due to the lack of information on folate intake. We investigated the risks of adult leukemia with genetic polymorphisms of folate metabolic enzymes (MTHFR C677T, A1298C, and TS) and evaluated if the associations varied by dietary folate intake from a multicenter case-control study conducted in Chinese. This study comprised 442 incident adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium, and study site. Genotypes were determined by a polymerase chain reaction (PCR) or PCR-based restriction fragment length polymorphism assay. Dietary folate intake was assessed by face-to-face interviews using a validated food-frequency questionnaire. The MTHFR 677TT genotype conferred a significant higher risk of leukemia in males than in females and exhibited an increased risk of acute myeloid leukemia (AML) but a decreased risk of acute lymphoblastic leukemia (ALL). The MTHFR 1298AC genotype appeared to decrease the risks of leukemia in both genders, in AML and ALL. Stratified analysis by dietary folate intake showed the increased risks of leukemia with the MTHFR 677TT and TS 2R3R/2R2R genotypes were only significant in individuals with low folate intake. A significant interaction between TS polymorphism and dietary folate intake was observed (P = 0.03). This study suggests that dietary folate intake and gender may modify the associations between MTHFR/TS polymorphisms and adult leukemia risk.

  9. Impact of methylenetetrahydrofolate reductase polymorphisms and folate intake on the risk of gastric cancer and their association with Helicobacter pylori infection and tumor site.

    PubMed

    Chen, J; Yuan, L; Duan, Y Q; Jiang, J Q; Zhang, R; Huang, Z J; Xiao, X R

    2014-01-24

    Folic acid and methylenetetrahydrofolate reductase (MTHFR) may both affect the development of human cancer. We conducted a population-based case-control study in a Chinese population to investigate the potential role of folate intake and MTHFR gene polymorphisms in gastric cancer, and their interaction with infection by Helicobacter pylori and tumor location. A total of 767 patients with newly diagnosed gastric cancer and 775 controls were selected for this study. Genotyping of MTHFR C677T and A1298C was conducted by TaqMan assays using the ABI Prism 7911HT Sequence Detection System, and information on folate intake was collected by questionnaire. Compared with the CC genotype of MTHFR C677T, the TT genotype was significantly associated with a decreased risk of gastric cancer when the analysis was adjusted for other potential risk factors. We found a marginal significantly decreased risk of gastric cancer for individuals carrying the T allele [adjusted odds ratio (OR) = 0.83; 95% confidence interval (CI) = 0.65-1.01]. We detected an inverse relationship between folate intake and risk of gastric cancer, and the adjusted ORs (95%CI) for moderate and high folate intake were 0.97 (0.74-1.25) and 0.64 (0.49-0.87), respectively. Moreover, H. pylori infection, folate intake, and location of the tumor showed a significant interaction with the MTHFR C677T polymorphism. Our study suggests a protective role of MTHFR 677TT and high folate intake against gastric cancer, and the effect of the MTHFR C677T genotype may differ by H. pylori infection, folate consumption, and tumor site.

  10. Polymorphisms in methylenetetrahydrofolate reductase gene and risk of non-Hodgkin lymphoma in a multi-ethnic population.

    PubMed

    Suthandiram, Sujatha; Gan, Gin Gin; Zain, Shamsul Mohd; Haerian, Batoul Sadat; Bee, Ping Chong; Lian, Lay Hoong; Chang, Kian Meng; Ong, Tee Chuan; Mohamed, Zahurin

    2014-05-01

    An imbalance in folate metabolism can adversely affect DNA synthesis and methylation systems which can lead to susceptibility to non-Hodgkin lymphoma (NHL). Whether single nucleotide polymorphisms (SNPs) and their haplotypes in the methylenetetrahydrofolate reductase (MTHFR) are associated with NHL, remain inconclusive. We investigated the association between MTHFR C677T and A1298C SNPs and NHL risk in a population which is made up of Malay, Chinese and Indian ethnic subgroups. A total of 372 NHL patients and 722 controls were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects failed to demonstrate significant association between the MTHFR C677T and A1298C SNPs with NHL and its subtypes. The results were in agreement with the previous meta-analyses. In the Indian ethnic subgroup however, single locus analysis of MTHFR A1298C appears to confer risk to NHL (Odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.22-3.00, P=0.006). The risk is almost doubled in homozygous carrier of MTHFR 1298CC (OR 4.03, 95% CI 1.56-10.43, P=0.004). Haplotype analysis revealed higher frequency of CC in the Indian NHL patients compared with controls (OR 1.86, 95% CI 1.18-2.93, P=0.007). There is lack of evidence to suggest an association between MTHFR C677T and A1298C with the risk of NHL in the Malays and Chinese. In the Indians however, the MTHFR A1298C confers risk to NHL. This study suggests ethnicity modifies the relationship between polymorphisms in the folate-metabolizing gene and NHL.

  11. Homocysteine is not associated with global motor or cognitive measures in nondemented older Parkinson's disease patients.

    PubMed

    Camicioli, Richard M; Bouchard, Thomas P; Somerville, Martin J

    2009-01-30

    Levodopa (L-dopa) treatment of Parkinson's disease (PD) is associated with elevated homocysteine (Hcy). To examine the relationship between Hcy, methylenetetrahydrofolate reductase polymorphisms (MTHFR: 677C/T; 1298A/C), and B-vitamins in older PD patients and whether Hcy or MTHFR polymorphisms were associated with clinical measures. MTHFR polymorphisms, B-vitamin intake, and blood concentrations of Hcy, vitamin B12 and folate, and creatinine were determined and compared between groups (PD and controls). The relationship of Hcy to clinical measures was examined in PD. Among 51 patients [30M/21F, mean age (SD): 71.5 (4.7)] and 50 controls [29M/21F, 71.5 (4.8)], Hcy was higher in PD [13.6 (3.8); controls: 10.5 (2.5), P < 0.0005]. Hcy was associated with B-vitamin intake [F = 21.7, P < 0.0005], folate level (R = 0.31, P = 0.035), and the interaction of intake with MTHFR 677T (F = 5.2, P = 0.007), but not MTHFR 1298C genotype. Hcy did not correlate with global measures of cognition, mood, or parkinsonism in PD or with dyskinesias, fluctuations, or freezing. Higher vitamin B12 levels were associated with lower dyskinesia risk. Hcy was influenced by PD, MTHFR 677 genotype, and vitamin use, but not by the MTHFR 1298 genotype. There was no clear association with motor or cognitive measures, but dyskinesias were less likely with higher B12.

  12. The prevalence of methylenetetrahydrofolate reductase 677 C-T, factor V 1691 G-A, and prothrombin 20210 G-A mutations in healthy populations in Setif, Algeria.

    PubMed

    Bourouba, Romyla; Houcher, Bakhouche; Djabi, Farida; Egin, Yonca; Akar, Nejat

    2009-10-01

    The polymorphic mutation 677 C-T in the methylenetetrahydrofolate reductase (MTHFR) gene presents a heterogeneous worldwide distribution and is associated with different disorders such as cardiovascular disease. Its frequency shows great ethnic and geographic variations. The aim of this work is to determine the frequency of MTHFR 677 C-T and coexistence of MTHFR 677 C-T with 2 other common, hereditary thrombophilia causes-namely, factor V 1691 G-A and prothrombin (PT) 20210 G-A mutation-in the Sétif region of Algeria. The study involved 147 apparently healthy participants (82 men and 65 women). Genotyping was carried out by a real-time polymerase chain reaction. The MTHFR 677T carrier frequency was found to be 54.4% (80/147); 59 individuals were heterozygous (40.1%), and 21 were homozygous (14.3%). The frequency of MTHFR 677T was found to be 34.3%. Among the 147 individuals, 3 (2.0%) had factor V Leiden, and 5 (3.4%) had PT 20210 A mutation. Of the 80 participants with MTHFR 677T mutation, 2 had heterozygote factor V 1691 G-A gene mutation, and 4 had heterozygote PT 20210 G-A gene mutation. The results showed that MTHFR 677T prevalence is quite high: an allelic frequency of 34.3% with a genotype frequency of 14.3%. Factor V 1691 G-A and PT 20210 G-A gene mutations are rare in the healthy population of the Sétif region of Algeria.

  13. The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.

    PubMed

    Sohn, Kyoung-Jin; Jang, Hyeran; Campan, Mihaela; Weisenberger, Daniel J; Dickhout, Jeffrey; Wang, Yi-Cheng; Cho, Robert C; Yates, Zoe; Lucock, Mark; Chiang, En-Pei; Austin, Richard C; Choi, Sang-Woon; Laird, Peter W; Kim, Young-In

    2009-05-01

    The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased risk of colon cancer although it may increase the risk of breast cancer. This polymorphism is associated with changes in intracellular folate cofactors, which may affect DNA methylation and synthesis via altered one-carbon transfer reactions. We investigated the effect of this mutation on DNA methylation and uracil misincorporation and its interaction with exogenous folate in further modulating these biomarkers of one-carbon transfer reactions in an in vitro model of the MTHFR 677T mutation in HCT116 colon and MDA-MB-435 breast adenocarcinoma cells. In HCT116 cells, the MTHFR 677T mutation was associated with significantly increased genomic DNA methylation when folate supply was adequate or high; however, in the setting of folate insufficiency, this mutation was associated with significantly decreased genomic DNA methylation. In contrast, in MDA-MB-435 cells, the MTHFR 677T mutation was associated with significantly decreased genomic DNA methylation when folate supply was adequate or high and with no effect when folate supply was low. The MTHFR 677T mutation was associated with a nonsignificant trend toward decreased and increased uracil misincorporation in HCT116 and MDA-MB-435 cells, respectively. Our data demonstrate for the first time a functional consequence of changes in intracellular folate cofactors resulting from the MTHFR 677T mutation in cells derived from the target organs of interest, thus providing a plausible cellular mechanism that may partly explain the site-specific modification of colon and breast cancer risks associated with the MTHFR C677T mutation.

  14. Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer's Disease Risk.

    PubMed

    Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S Pamela K

    2017-01-11

    Background: Alzheimer's disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results: Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group (p = 0.0021-0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions: The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations.

  15. Effects of folic acid deficiency and MTHFRC677T polymorphisms on cytotoxicity in human peripheral blood lymphocytes

    SciTech Connect

    Wu Xiayu; Liang Ziqing; Zou Tianning; Wang Xu

    2009-02-13

    Apoptosis (APO) and necrosis (NEC) are two different types of cell death occurring in response to cellular stress factors. Cells with DNA damage may undergo APO or NEC. Folate is an essential micronutrient associated with DNA synthesis, repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) regulates intracellular folate metabolism. Folate deficiency and MTHFR C677T polymorphisms have been shown to be related to DNA damage. To verify the cytotoxic effects of folate deficiency on cells with different MTHFR C677T genotypes, 15 human peripheral lymphocyte cases with different MTHFR C677T genotypes were cultured in folic acid (FA)-deficient and -sufficient media for 9 days. Cytotoxicity was quantified using the frequencies of APO and NEC as endpoints, the nuclear division index (NDI), and the number of viable cells (NVC). These results showed that FA is an important factor in reducing cytotoxicity and increasing cell proliferation. Lymphocytes with the TT genotype proliferated easily under stress and exhibited different responses to FA deficiency than lymphocytes with the CC and CT genotypes. A TT individual may accumulate more cytotoxicity under cytotoxic stress, suggesting that the effects of FA deficiency on cytotoxicity are greater than the effects in individuals with the other MTHFR C677T variants.

  16. Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders.

    PubMed

    Grove, Tyler; Taylor, Stephan; Dalack, Gregory; Ellingrod, Vicki

    2015-05-01

    Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders.

  17. Methylenetetrahydrofolate reductase genetic polymorphisms and esophageal squamous cell carcinoma susceptibility: A meta-analysis of case-control studies

    PubMed Central

    Shujuan, Yang; Jianxing, Zhang; Xin-yue, Chen

    2013-01-01

    Objectives: Genetic factors and environmental factors play a role in pathogenesis of esophageal squamous cell carcinoma (ESCC). Previous studies regarding the association of folate intake and Methylenetetrahydrofolate reductase C677T polymorphism with ESCC was conflicting. We conducted a meta-analysis to investigate the association of MTHFR C677T and folate intake with esophageal cancer risk. Methodology: MEDLINE, EMBASE and the Chinese Biomedical Database were searched in our study. The quality of studies were evaluated by predefined scale, and The association of polymorphisms of MTHFR C677T and folate intake and ESCC risk was estimated by Odds ratio (ORs) with 95% confidence intervals (CIs). Results: Nineteen studies (4239 cases and 5575 controls) were included for meta-analysis. A significant association was seen between individuals with MTHFR 677 CT [OR(95%)=1.47(1.32-1.63)] and TT [OR(95%)=1.69(1.49-1.91)] genotypes and ESCC risk (p<0.05). Low intake of folate had significantly higher risk of esophageal cancer among individuals with CT/TT genotype [OR(95%)=1.65(1.1-2.49)], while high intake of folate did not find significant high risk of esophageal cancer among individuals with CT/TT genotype [OR(95%)=1.64 (0.82-3.26)]. Conclusions: Our meta-analysis indicated the folate intake and MTHFR 677CT/TT are associated with the risk of ESCC, and folate showed a significant interaction with polymorphism of MTHFR C677T. PMID:24353609

  18. The maize brown midrib2 (bm2) gene encodes a methylenetetrahydrofolate reductase that contributes to lignin accumulation.

    PubMed

    Tang, Ho Man; Liu, Sanzhen; Hill-Skinner, Sarah; Wu, Wei; Reed, Danielle; Yeh, Cheng-Ting; Nettleton, Dan; Schnable, Patrick S

    2014-02-01

    The midribs of maize brown midrib (bm) mutants exhibit a reddish-brown color associated with reductions in lignin concentration and alterations in lignin composition. Here, we report the mapping, cloning, and functional and biochemical analyses of the bm2 gene. The bm2 gene was mapped to a small region of chromosome 1 that contains a putative methylenetetrahydrofolate reductase (MTHFR) gene, which is down-regulated in bm2 mutant plants. Analyses of multiple Mu-induced bm2-Mu mutant alleles confirmed that this constitutively expressed gene is bm2. Yeast complementation experiments and a previously published biochemical characterization show that the bm2 gene encodes a functional MTHFR. Quantitative RT-PCR analyses demonstrated that the bm2 mutants accumulate substantially reduced levels of bm2 transcript. Alteration of MTHFR function is expected to influence accumulation of the methyl donor S-adenosyl-L-methionine (SAM). Because SAM is consumed by two methyltransferases in the lignin pathway (Ye et al., ), the finding that bm2 encodes a functional MTHFR is consistent with its lignin phenotype. Consistent with this functional assignment of bm2, the expression patterns of genes in a variety of SAM-dependent or -related pathways, including lignin biosynthesis, are altered in the bm2 mutant. Biochemical assays confirmed that bm2 mutants accumulate reduced levels of lignin with altered composition compared to wild-type. Hence, this study demonstrates a role for MTHFR in lignin biosynthesis.

  19. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency.

    PubMed

    Munoz, Tatiana; Patel, Jinesh; Badilla-Porras, Ramses; Kronick, Jonathan; Mercimek-Mahmutoglu, Saadet

    2015-01-01

    Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessively inherited inborn error of folate metabolism. We report a new patient with severe MTHFR deficiency who presented at age 4 months with early onset severe scoliosis associated with severe hypotonia. Markedly decreased MTHFR enzyme activity (0.3 nmoles CHO/mg protein/h; reference range>9) and compound heterozygous mutations (c. 1304T>C; p.Phe435Ser and c.1539dup; p.Glu514Argfs∗24) in the MTHFR gene confirmed the diagnosis. She was treated with vitamin B12, folic acid and betaine supplementation and showed improvements in her developmental milestones and hypotonia. To the best of our knowledge, this is the first patient with MTHFR deficiency reported with severe early onset scoliosis. Despite the late diagnosis and treatment initiation, she showed favorable short-term neurodevelopmental outcome. This case suggests that homocysteine measurement should be included in the investigations of patients with developmental delay, hypotonia and scoliosis within first year of life prior to organizing genetic investigations.

  20. Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil.

    PubMed

    Biselli, J M; Goloni-Bertollo, E M; Zampieri, B L; Haddad, R; Eberlin, M N; Pavarino-Bertelli, E C

    2008-01-22

    The aim of the present study was to investigate the effect of polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, A2756G in methionine synthase reductase (MTR) gene and A80G in reduced folate carrier 1 (RFC1) gene, and plasma homocysteine (Hcy), on the maternal risk for Down syndrome (DS). Seventy-two DS mothers and 194 mothers who had no children with DS were evaluated. The investigation of the MTHFR C677T, MTR A2756G and RFC1 A80G polymorphisms was performed by polymerase chain reaction and enzyme digestion and the MTHFR A1298C polymorphism by allele-specific polymerase chain reaction. Hcy quantification was carried out by liquid chromatography-tandem mass spectrometry. The median number of polymorphic alleles for the four loci tested was greater in DS mothers compared to the control group, and the presence of three or more polymorphic alleles increased the risk for having a child with DS 1.74 times. Elevated maternal risk for DS was also observed when plasma Hcy concentration was higher than 4.99 micromol/L. In conclusion, the presence of three or more polymorphic alleles for MTHFR C677T, MTHFR A1298C, MTR A2756G, and RFC1 A80G, and plasma Hcy concentrations higher than 4.99 micromol/L are maternal risk factors for DS.

  1. Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer’s Disease Risk

    PubMed Central

    Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S. Pamela K.

    2017-01-01

    Background: Alzheimer’s disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results: Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group (p = 0.0021–0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions: The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations. PMID:28085050

  2. One-Carbon Metabolism and Breast Cancer Survival in a Population-Based Study

    DTIC Science & Technology

    2007-06-01

    association of one-carbon metabolism polymorphisms and overall survival was different by ER/PR status for several polymorphisms, i.e. MTHFR C677T (p...survival ER/PR status Chemotheray + - yes no Gene Genotype HR HR HR HR MTHFR 0 1.00(ref) 1.00(ref) 1.00(ref) 1.00(ref) (C677T) 1 1.47 0.61 1.13...0.86 P,int 0.05 0.55 MTHFR 0 1.00(ref) 1.00(ref) 1.00(ref) 1.00(ref) (A1208C) 1 1.27 0.66 1.22 0.91 P,int 0.13 0.64 TSTR 0 1.00(ref

  3. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance.

    PubMed

    Trimmer, Elizabeth E

    2013-01-01

    Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydofolate (CH2-H4folate) to 5-methyltetrahydrofolate (CH3-H4folate). The enzyme employs a noncovalently-bound flavin adenine dinucleotide (FAD), which accepts reducing equivalents from NAD(P)H and transfers them to CH2-H4folate. The reaction provides the sole source of CH3-H4folate, which is utilized by methionine synthase in the synthesis of methionine from homocysteine. MTHFR plays a key role in folate metabolism and in the homeostasis of homocysteine; mutations in the enzyme lead to hyperhomocyst(e)inemia. A common C677T polymorphism in MTHFR has been associated with an increased risk for the development of cardiovascular disease, Alzheimer's disease, and depression in adults, and of neural tube defects in the fetus. The mutation also confers protection for certain types of cancers. This review presents the current knowledge of the enzyme, its biochemical characterization, and medical significance.

  4. Distribution of common methylenetetrahydrofolate reductase gene mutations in patients with obstructive sleep apnoea.

    PubMed

    Bekci, T T; Kocak, N; Kesli, R

    2009-01-01

    Homocysteine levels have been investigated in patients with obstructive sleep apnoea syndrome (OSAS), a syndrome associated with a high level of comorbid cardiovascular disease (CVD). While significant increases in homocysteine levels have been observed in OSAS patients with CVD, no increases have been noted in OSAS patients without CVD. This study was designed to investigate the methylenetetrahydrofolate reductase (MTHFR) gene, which is essential for homocysteine metabolism and has been shown to have a causal role in the development of CVD. Eighty subjects, 30 diagnosed with OSAS by polysomnography and 50 controls (healthy volunteers with no symptoms of OSAS) were enrolled. Two mutations in the MTHFR gene were investigated using polymerase chain reactions and restriction fragment length polymorphisms. No significant differences were found in mean age, body mass index, homocysteine levels, or MTHFR allele or genotype distributions between patient and control groups.

  5. Thyroid vein thrombosis in a young woman with methylenetetrahydrofolate reductase gene mutation receiving cyproterone acetate/ethinylestradiol treatment for polycystic ovary syndrome: a case report.

    PubMed

    Nazli, Yunus; Colak, Necmettin; Aksoy, Omer N; Cakir, Omer

    2011-06-01

    Thyroid vein thrombosis is a rare variety of venous thrombosis. The use of oral contraceptives and heterozygous methylenetetrahydrofolate reductase (MTHFR) gene mutation could have synergistic effects on the onset of venous thromboembolism. We report a 28-year-old woman with thyroid vein thrombosis. The thrombosis was possibly provoked by a combination of heterozygous MTHFR gene mutation and the use of a combined oral contraceptive (COC) containing cyproterone acetate/ethinylestradiol (CPA/EE) for polycystic ovary syndrome (PCOS). The patient was treated successfully with low molecular weight heparin and oral anticoagulation. The thyroid vein thrombosis resolved and the patient was advised to maintain lifelong use of anticoagulation therapy. Our report emphasizes that the combination of heterozygous MTHFR gene mutation, PCOS, and the use of a COC-containing CPA/EE could increase risk of thyroid vein thrombosis in young adults.

  6. A Case of Diverticular Perforation in a Young Patient with Rheumatoid Arthritis on Methotrexate

    PubMed Central

    Chang, Ian; Guggenheim, Carla; Laird-Fick, Heather

    2015-01-01

    Background. Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX), are associated with gastrointestinal toxicity. MTX inhibits dihydrofolate reductase, but it is unclear if polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene predict toxicity. Case. We describe a 33-year-old male with polyarticular rheumatoid arthritis who developed sigmoid diverticular perforation while receiving methotrexate, folic acid, prednisone, and naproxen. He tested heterozygous for the C677T allele MTHFR gene. Discussion. Rheumatoid arthritis and its treatments are associated with increased risk of gastrointestinal disease. In one study, perforation was highest among individuals with concomitant exposure to NSAIDs, nonbiologic DMARDs, and glucocorticoids. Multiple mutations of the MTHFR gene have been identified, but their association with MTX toxicity is unclear. This case adds to a growing body of literature that could help inform the treatment of others in the future. PMID:26064129

  7. Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency.

    PubMed

    Urreizti, R; Moya-García, A A; Pino-Ángeles, A; Cozar, M; Langkilde, A; Fanhoe, U; Esteves, C; Arribas, J; Vilaseca, M A; Pérez-Dueñas, B; Pineda, M; González, V; Artuch, R; Baldellou, A; Vilarinho, L; Fowler, B; Ribes, A; Sánchez-Jiménez, F; Grinberg, D; Balcells, S

    2010-11-01

    Methylenetetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism. Disturbed function of the enzyme results in hyperhomocysteinemia and causes severe vascular and neurological disorders and developmental delay. Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene. All patients presented symptoms of severe central nervous system disease. Two patients died, at the ages of 15 months and 14 years. One patient is currently 32 years old, and is being treated with betaine and folinic acid. The other two patients, with an early diagnosis and a severe course of the disease, are currently improving under treatment. MTHFR enzyme activity in the fibroblasts of four of the patients was practically undetectable. We found four novel mutations, three of which were missense changes c.664G> T (p.V218L), c.1316T> C (p.F435S) and c.1733T> G (p.V574G), and the fourth was the 1-bp deletion c.1780delC (p.L590CfsX72). We also found the previously reported nonsense mutation c.1420G> T (p.E470X). All the patients were homozygous. Molecular modelling of the double mutant allele (p.V218L; p.A222V) revealed that affinity for FAD was not affected in this mutant. For the p.E470X mutation, the evidence pointed to nonsense-mediated mRNA decay. In general, genotype-phenotype analysis predicts milder outcomes for patients with missense changes than for those in which mutations led to severe alterations of the MTHFR protein.

  8. Effects of folic acid supplementation on serum homocysteine and lipoprotein (a) levels during pregnancy

    PubMed Central

    Hekmati Azar Mehrabani, Zohreh; Ghorbanihaghjo, Amir; Sayyah Melli, Manizheh; Hamzeh-Mivehroud, Maryam; Fathi Maroufi, Nazila; Bargahi, Nasrin; Bannazadeh Amirkhiz, Maryam; Rashtchizadeh, Nadereh

    2015-01-01

    Introduction:There are many ideas concerning the etiology and pathogenesis of preeclampsia including endothelial dysfunction, inflammation and angiogenesis. Elevated levels of total homocysteine (Hcy) and lipoprotein (a) [Lp(a)] are risk factors for endothelial dysfunction. This study aimed to evaluate the effect of high dose folic acid (FA) on serum Hcy and Lp(a) concentrations with respect to methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677C→T during pregnancy. Methods: In a prospective uncontrolled intervention, 90 pregnant women received 5 mg FA supplementation before pregnancy till 36th week of pregnancy. The MTHFR polymorphisms 677C→T, serum lactate dehydrogenase activity, urine protein and creatinine concentrations were measured before starting folic acid administration. Serum levels of Hcy and Lp(a) were determined before and after completion of folic acid supplementation period. Results: Supplementation of the patients with FA for 36 week decreased the median (minimum– maximum) levels of serum Hcy from 11.40 μmol/L (4.40-28.70) to 9.70 (1.60-20.80) μmol/L (p=0.001). There was no significant change in serum Lp(a) after FA supplementation (p=0.17). The overall prevalence of genotypes in pregnant women that were under study for MTHFR C677T polymorphism was 53.3% CC, 26.7% CT and 20.0% TT. There was no correlation between decreasing level of serum Hcy in the patients receiving FA and MTHFR polymorphisms. Conclusion:Although FA supplementation decreased serum levels of Hcy in different MTHFR genotypes, serum Lp(a) was not changed by FA supplements. Our data suggests that FA supplementation effects on serum Hcy is MTHFR genotype independent in pregnant women. PMID:26929921

  9. Effects of methionine synthase and methylenetetrahydrofolate reductase gene polymorphisms on markers of one-carbon metabolism.

    PubMed

    Ho, Vikki; Massey, Thomas E; King, Will D

    2013-11-01

    Genetic and nutritional factors play a role in determining the functionality of the one-carbon (1C) metabolism cycle, a network of biochemical reactions critical to intracellular processes. Genes encoding enzymes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) may determine biomarkers of the cycle including homocysteine (HCY), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). MTHFR C677T is an established genetic determinant of HCY but less is known of its effect on SAM and SAH. Conversely, the relationship between MTR A2756G and HCY remains inconclusive, and its effect on SAM and SAH has only been previously investigated in a female-specific population. Folate and vitamin B12 are essential substrate and cofactor of 1C metabolism; thus, consideration of gene-nutrient interactions may clarify the role of genetic determinants of HCY, SAM and SAH. This cross-sectional study included 570 healthy volunteers from Kingston, Ontario, Ottawa, Ontario and Halifax, Nova Scotia, Canada. Least squares regression was used to examine the effects of MTR and MTHFR polymorphisms on plasma HCY, SAM and SAH concentrations; gene-gene and gene-nutrient interactions were considered with the inclusion of cross-products in the model. Main effects of MTR and MTHFR polymorphisms on HCY concentrations were observed; however, no gene-gene or gene-nutrient interactions were found. No association was observed for SAM. For SAH, interactions between MTR and MTHFR polymorphisms, and MTHFR polymorphism and serum folate were found. The findings of this research provide evidence that HCY and SAH, biomarkers of 1C metabolism, are influenced by genetic and nutritional factors and their interactions.

  10. Chromosomal aberration leads to recurrent pregnancy loss and partial trisomy of 5p12-15.3 in the offspring: report of a Syrian couple and review of the literature .

    PubMed

    Al-Achkar, Walid; Moassass, Faten; Al-Ablog, Ayman; Liehr, Thomas; Fan, Xiaobo; Wafa, Abdulsamad

    2015-03-01

    Here we describe a Syrian couple having recurrent pregnancy loss in the first trimester, fetal malformations, and/or neonatal death. The father had a balanced chromosomal translocation t(5;15), an sY125 microdeletion of locus b in the azoospermia factor (AZF) gene, and an MTHFR C677T homozygous polymorphism with normal phenotype. Interestingly, his healthy wife had another MTHFR A1298C homozygous polymorphism. The couple experienced two pregnancy losses and had two stillborn children with severe malformations due to partial trisomy of the short arm of chromosome 5. The couple does not have any living offspring after 10 years of marriage.

  11. Methyltetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia as a novel risk factor for diabetic nephropathy.

    PubMed

    Ukinc, Kubilay; Ersoz, Halil Onder; Karahan, Caner; Erem, Cihangir; Eminagaoglu, Selcuk; Hacihasanoglu, Arif Bayram; Yilmaz, Mustafa; Kocak, Mustafa

    2009-10-01

    Hyperhomocysteinemia is a well-defined risk factor for endothelial dysfunction and atherosclerosis. A point mutation (677 C-T) of MTHFR gene results in a significant increase at plasma homocysteine levels. In this study we aimed to evaluate the effects of MTHFR gene mutation and consequent hyperhomocysteinemia on the development of diabetic microvascular complications in comparison with the other defined risk factors. Diabetic patients without a history of macrovascular complication or overt nephropathy enrolled into the study. The presence of MTHFR 677 C-T point mutation was evaluated by Real-Time PCR technique by using a LightCycler. MTHFR heterozygous mutation was present in 24 patients over 52. Patients with diabetes were divided into two groups according to the presence of MTHFR gene mutation. Both groups were well matched regarding age and diabetes duration. Metabolic parameters, plasma homocysteine, microalbuminuria, folic acid, and vitamin B12 levels were also studied. Presence of neuropathy and retinopathy were evaluated by specific tests. Duration of diabetes, BMI, systolic and diastolic blood pressure, plasma CRP, HbA1c, and lipid levels were not different between the two groups. Plasma homocysteine (12.89 +/- 1.74 and 8.98 +/- 1.91 micromol/l; P < 0.0001) and microalbuminuria levels (73.40 +/- 98.15 and 29.53 +/- 5.08 mg/day; P = 0.021) were significantly higher in the group with MTHFR gene mutation while creatinine clearance levels (101.1 +/- 42.6 and 136.21 +/- 51.50 ml/min; P = 0.008) were significantly lower. Sixteen over 22 (73%) of the patients with diabetic nephropathy had MTHFR gene mutation, while this was only 27% (8 over 30) in normoalbuminuric patients (P = 0.017). There was a significant correlation of plasma homocysteine level with microalbuminuria (r = 0.54; P = 0.031) in the patients with diabetic nephropathy who had C677T polymorphism. We did not find any specific association of MTHFR gene mutation and hyperhomocysteinemia with

  12. Methylenetetrahydrofolate Reductase C677T Polymorphism and Type 2 Diabetes Mellitus in Chinese Population: A Meta-Analysis of 29 Case-Control Studies

    PubMed Central

    Zhu, Bo; Wu, Xiaomei; Zhi, Xueyuan; Liu, Lei; Zheng, Quanmei; Sun, Guifan

    2014-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, had significant effects on the homocysteine levels. The common functional MTHFR C677T polymorphism had been extensively researched. Several studies had evaluated the relationship between MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM), but the results were still controversial in the Chinese Han population. This meta-analysis was conducted to evaluate the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. Methods We searched the relevant studies in multiple electronic databases, which published up to December 2013. We reviewed and extracted data from all the included studies on the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) were used to evaluate the relationship. Fixed-effects and random-effects meta-analysis were used to pool ORs by the heterogeneity. Publication bias and sensitivity analysis were also examined. Results 29 studies were finally included in our meta-analysis, which contained 4656 individuals with T2DM and 2127 healthy controls. There was a significant relationship between MTHFR C677T polymorphism and T2DM under dominant (OR: 1.70, 95% CI: 1.42–2.02), recessive (OR: 1.48, 95% CI: 1.21–1.80), homozygous (OR: 1.89, 95% CI: 1.47–2.42), heterozygous (OR: 1.58, 95% CI: 1.33–1.87), and additive (OR: 1.46, 95% CI: 1.28–1.68) genetic model in a random-effects model. Subgroup analysis also reached similar results. Sensitivity analysis indicated that the overall result were dependable. Conclusions There was a significant relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The results of our meta-analysis suggested that MTHFR 677T allele might be a risk genetic factor of T2DM in the Chinese Han population. PMID:25047451

  13. PubMed

    De Quintana Sancho, A; Piris García, X; Valle García, J N; Hierro Cámara, M

    2016-12-30

    La alopecia frontal fibrosante (AFF) es un tipo de alopecia cicatricial cuya incidencia está aumentando de forma significativa en nuestro país. Se caracteriza por un retroceso en la línea de implantación del pelo a nivel frontotemporal que afecta mayoritariamente a mujeres postmenopaúsicas, con un impacto negativo en su calidad de vida. Se asocia a menopausia precoz en un 14% de los casos y a hipotiroidismo en un 15%. Con respecto al tratamiento, son los inhibidores de la 5α-reductasa, los fármacos que han demostrado mejoría de la enfermedad en un mayor número de casos. Presentamos un caso de AFF en una mujer de 77 años tratada con éxito con finasteride a dosis de 2,5mg/día.

  14. Folate Pathway Gene Methylenetetrahydrofolate Reductase C677T Polymorphism and Alzheimer Disease Risk in Asian Population.

    PubMed

    Rai, Vandana

    2016-07-01

    The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to Alzheimers disease (AD) was controversial in previous studies. The present meta-analysis was designed to investigate the association of MTHFR C677T polymorphism with AD. Nine studies were identified by search of PubMed, Google Scholar, Elsevier, Springer Link databases, up to January 2013. Odds ratios (ORs) with corresponding 95 % confidence interval (CI) were calculated using fixed effects model or random effects model. All statistical analysis was done by Mix version 1.7. MTHFR C677T polymorphism had a significant association with susceptibility to AD in all genetic models (for T vs C: OR 1.29, 95 % CI 1.15-1.44, p < 0.0001; for TT + CT vs CC: OR 1.38, 95 % CI 1.16-1.364, p = 0.0002; for TT vs CC: OR 1.60, 95 % CI 1.25-2.04, p = 0.0001; for CT vs CC: OR 1.28, 95 % CI 1.1-1.53, p < 0.008; for TT vs CT + CC: OR 1.37, 95 % CI 1.12-1.67, p = 0.002). Results from present meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of AD in Asian population.

  15. Novel Approaches to Investigate One-Carbon Metabolism and Related B-Vitamins in Blood Pressure

    PubMed Central

    McMahon, Amy; McNulty, Helene; Hughes, Catherine F.; Strain, J. J.; Ward, Mary

    2016-01-01

    Hypertension, a major risk factor for heart disease and stroke, is the world’s leading cause of preventable, premature death. A common polymorphism (677C→T) in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) is associated with increased blood pressure, and there is accumulating evidence demonstrating that this phenotype can be modulated, specifically in individuals with the MTHFR 677TT genotype, by the B-vitamin riboflavin, an essential co-factor for MTHFR. The underlying mechanism that links this polymorphism, and the related gene-nutrient interaction, with hypertension is currently unknown. Previous research has shown that 5-methyltetrahydrofolate, the product of the reaction catalysed by MTHFR, appears to be a positive allosteric modulator of endothelial nitric oxide synthase (eNOS) and may thus increase the production of nitric oxide, a potent vasodilator. Blood pressure follows a circadian pattern, peaking shortly after wakening and falling during the night, a phenomenon known as ‘dipping’. Any deviation from this pattern, which can only be identified using ambulatory blood pressure monitoring (ABPM), has been associated with increased cardiovascular disease (CVD) risk. This review will consider the evidence linking this polymorphism and novel gene-nutrient interaction with hypertension and the potential mechanisms that might be involved. The role of ABPM in B-vitamin research and in nutrition research generally will also be reviewed. PMID:27845713

  16. Folate Metabolism and Human Reproduction

    PubMed Central

    Thaler, C. J.

    2014-01-01

    Folate metabolism affects ovarian function, implantation, embryogenesis and the entire process of pregnancy. In addition to its well-established effect on the incidence of neural tube defects, associations have been found between reduced folic acid levels and increased homocysteine concentrations on the one hand, and recurrent spontaneous abortions and other complications of pregnancy on the other. In infertility patients undergoing IVF/ICSI treatment, a clear correlation was found between plasma folate concentrations and the incidence of dichorionic twin pregnancies. In patients supplemented with 0.4 mg/d folic acid undergoing ovarian hyperstimulation and oocyte pick-up, carriers of the MTHFR 677T mutation were found to have lower serum estradiol concentrations at ovulation and fewer oocytes could be retrieved from them. It appears that these negative effects can be compensated for in full by increasing the daily dose of folic acid to at least 0.8 mg. In carriers of the MTHFR 677TT genotype who receive appropriate supplementation, AMH concentrations were found to be significantly increased, which could indicate a compensatory mechanism. AMH concentrations in homozygous carriers of the MTHFR 677TT genotype could even be overestimated, as almost 20 % fewer oocytes are retrieved from these patients per AMH unit compared to MTHFR 677CC wild-type individuals. PMID:25278626

  17. Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan.

    PubMed

    Ma, Enbo; Iwasaki, Motoki; Kobayashi, Minatsu; Kasuga, Yoshio; Yokoyama, Shiro; Onuma, Hiroshi; Nishimura, Hideki; Kusama, Ritsu; Tsugane, Shoichiro

    2009-01-01

    We investigated associations among intake of folate, vitamin B2, vitamin B6, vitamin B12, and polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes and breast cancer risk in a Japanese population. A hospital based, case-control study was conducted in Nagano Prefecture, Japan, in 388 pairs of patients with histologically confirmed invasive breast cancer and age- and area-matched controls selected from medical checkup examinees. Energy-adjusted intakes of folate and other B vitamins were derived from a validated food frequency questionnaire. Genotyping was completed for MTHFR (C677T and A1298T) and MTR (A2756G). Odds ratios and 95% confidence intervals were calculated by the conditional logistical regression model. Median dietary folate intake (microg/day) in the control group was 438.2 (interquartile range: 354.9-542.9). Neither dietary intake of folate, vitamin B2, vitamin B6, or vitamin B12 nor polymorphisms of MTHFR or MTR genes were significantly associated with breast cancer risk. Further, no significant interaction was found among nutrients, polymorphisms, and breast cancer risk. Associations of nutrients with breast cancer risk did not differ by hormone receptors status. We conclude that dietary intake of folate and related B vitamins and genotypes of MTHFR or MTR have no overall association with breast cancer risk in Japanese women.

  18. [Clinical course of acute coronary syndrome in dependence on containing of homozystein and С677Т methylenetetrahydrofolate reductase gene polymorphism].

    PubMed

    Pristupa, L N; Grek, A V; Ataman, Iu A; Orlovskiy, A V; Opolonska, N A

    2015-01-01

    Nowadays to a numerous factors of IHD development risks hyperhomocysteinemia (HHc), C-reactive protein, fibrogen, as well as genetic disorders are relating. With development of IHD and its complications associated methylentetrahudrofolate reductase gene mutation of С677Т polymorphism. The purpose of the investigation was studying the connection between acute coronary syndrome severity (ACS) in dependence on plasma homocysteine containing and genotype by С677Т polymorphism MTHFR gene. Examined: 161 patients with ACS and 87 almost healthy people. Identification of 4th exon allelic polymorphism MTHFR С677Т gene (rs1801133) was conducted with method of polymerase chain reaction, the investigation of homocysteine containing with immunoenzymated method. The statistic analyze was performed with using of SPSS - 17 programme. According to results of study patients with ACS of homozygote by minor allele T С677Т MTHFR gene polymorphism by main allele C and heterozygote were associated with high homocysteine containing in plasma. While frequencies of T/T genotype was reliably higher in patients with ACS with segment ST elevation and complicated course compare with patients with ACS with segment ST elevation and non-complicated course and ACS without climbs of segment ST. Also, statistically reliable difference in genotypes distribution by C677T MTHFR gene polymorphism in dependence on homocysteine plasma level and clinical course of ACS severity were established.

  19. Methylenetetrahydrofolate reductase gene germ-line C677T and A1298C SNPs are associated with colorectal cancer risk in the Turkish population.

    PubMed

    Ozen, Filiz; Sen, Metin; Ozdemir, Ozturk

    2014-01-01

    Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and the incidence is also increasing in Turkey. Our present aim was to investigate any association between germ-line methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey. A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study. Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reverse- hybridization principle and real-time PCR methods. Results were compared in Pearson Chi-square and multiple logistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allele frequency 4.2-fold increased in CRC when compared with the control group.The second SNP MTHFR 1298CC (homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group. The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>C genotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a larger sample size.

  20. Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.

    PubMed

    Froese, D Sean; Huemer, Martina; Suormala, Terttu; Burda, Patricie; Coelho, David; Guéant, Jean-Louis; Landolt, Markus A; Kožich, Viktor; Fowler, Brian; Baumgartner, Matthias R

    2016-05-01

    Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.

  1. [Posterior-predominant leukoencephalopathy which was caused by methylenetetrahydrofolate reductase deficiency and successfully treated with folic acid].

    PubMed

    Tamura, Asako; Sasaki, Ryogen; Kagawa, Ken; Nakatani, Kaname; Osaka, Hitoshi; Tomimoto, Hidekazu

    2014-01-01

    A 35-year-old woman was admitted with subacute intellectual deterioration. Laboratory studies showed elevated total homocysteine and decreased folic acid. MRI revealed leukoencephalopathy with a posterior predominance, and hyperintensity in the pyramidal tracts on T2-weighted and FLAIR images. The enzyme assay showed a deficiency of methylenetetrahydrofolate reductase (MTHFR) activity with low residual activity of 4.2% of the mean control value in cultured fibroblasts. Sequence analysis of the MTHFR gene demonstrated two homozygous missense mutations, c.677C>T (p.Ala222Val) and c.685A>C (p.Ile225Leu). c.677C>T (p.Ala222Val) is known as a common polymorphism and c.685A>C (p.Ile225Leu) is considered to be a novel polymorphism. A diagnosis of MTHFR deficiency was made. Treatment with folic acid, vitamin B12 and B6 made significant improvement of intellectual deterioration and reduction in the total homocysteine level. They also made marked resolution of leukoencephalopathy. Posterior-predominant leukoencephalopathy was found to be an excellent marker of MTHFR deficiency, and may help to establish the diagnosis.

  2. Alteration of the alkaloid profile in genetically modified tobacco reveals a role of methylenetetrahydrofolate reductase in nicotine N-demethylation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of the tetrahydrofolate (THF)-mediated one-carbon (C1) metabolic network. This enzyme catalyzes reduction of 5,10-methylene-THF to 5-methyl-THF. The latter donates its methyl group to homocysteine forming Met, which is then used for the syn...

  3. Genetic variations observed in arterial and venous thromboembolism--relevance for therapy, risk prevention and prognosis.

    PubMed

    Harrington, Dominic J; Malefora, Agata; Schmeleva, Veronika; Kapustin, Sergey; Papayan, Ludmila; Blinov, Mikhail; Harrington, Pip; Mitchell, Mike; Savidge, Geoffrey F

    2003-04-01

    We undertook genetic and biochemical assays in patients with arterial (n = 146) and venous (n = 199) thromboembolism and survivors of pulmonary embolism (n = 58) to study causation and gene-life style interactions. In the clinical material from North Western Russia, factor V Leiden was found to be a risk factor in venous thrombosis (OR = 3.6), while the methylenetetrahydrofolate reductase (MTHFR) C677T mutation was a significant variable in both venous (p = 0.03) and arterial thrombosis (p = 0.004). Homocysteine levels were determined (n = 84) and hyperhomocysteinemia correlated with the T allele of the MTHFR gene, and with smoking and coffee consumption. Vitamin supplementation reduced homocysteine levels dependent on MTHFR genotype (36% TT, 25% CT, 22% CC). In pulmonary embolism patients, frequency of the -455G/A beta-fibrinogen dimorphism was studied. Carriers of this allele were significantly underrepresented (p < 0.02) among pulmonary embolism survivors (34.5%) compared to controls (56.7%). Additionally, -455AA homozygotes were found in 11.7% controls but only 1.7% of pulmonary embolism patients (p = 0.006). In venous and arterial thrombosis cases, MTHFR and homocysteine data led to effective dietary supplementation with a reduced risk of disease progression. Results from the pulmonary embolism study may indicate that screening tests for the -455G/A beta-fibrinogen genetic variation could be of prognostic value, and may point the way for novel anticoagulation strategies.

  4. Association of methylenetetrahydrofolate reductase (A1298C and C677T) polymorphisms with retinal vein occlusion in Tunisian patients.

    PubMed

    Mrad, Meriem; Wathek, Cheima; Saleh, Mekki Ben; Baatour, Makrem; Rannen, Riadh; Lamine, Khaled; Gabsi, Salem; Gritli, Nasreddine; Fekih-Mrissa, Najiba

    2014-04-01

    The role of two polymorphisms C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) gene in the etiology of retinal vein occlusion (RVO) has not been adequately clarified. The aim of this study was to examine the prevalence of these polymorphisms among RVO Tunisian patients with and without systemic risk factors. Seventy-two patients with retinal vein occlusion (RVO) were studied. The control group included140 people matched for age, sex, and risk factors. Participants in the study were genotyped for the MTHFR C677T and A1298C polymorphisms. The genotyping was performed by PCR-RFLP. No significant differences were found in the frequencies of the three genotypes (AA, AC, CC) of the MTHFR A1298C polymorphism between RVO patients and healthy controls. However, the prevalence of the group of mutated genotypes (AC+CC) of the missense variant MTHFR A1298C was significantly different between patients and controls (16.67% vs. 6.42%, p=.01). Additionally, the frequency of the CT genotype as well as the group of combined mutated genotypes (CT+TT) for the C677T variant was significantly higher among RVO patients compared with controls (p<10(-3), p<10(-3)). This suggests an association between this polymorphism and RVO. Large study populations would be required to understand more completely the contribution of these markers in the risk of RVO.

  5. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R.

    1995-05-01

    5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

  6. Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

    PubMed Central

    Lopomo, Angela; Ricciardi, Roberta; Maestri, Michelangelo; De Rosa, Anna; Melfi, Franca; Lucchi, Marco; Mussi, Alfredo; Coppedè, Fabio; Migliore, Lucia

    2016-01-01

    Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood. PMID:27999265

  7. The relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and diabetic nephropathy in Croatian type 2 diabetic patients.

    PubMed

    Tomić, Nives Gojo; Marusić, Srećko; Bozikov, Velimir; Kusec, Rajko; Bacić-Vrca, Vesna; Tadić, Mario

    2013-09-01

    Methylenetetrahydrofolate reductase (MTHFR) polymorphism has been shown to be associated with the development of diabetic nephropathy in many ethnic groups. In this study, we examined the correlation between MTHFR C677T polymorphism and microalbuminuria in patients with diabetes mellitus type 2 in Croatian patients. 85 patients with diabetes mellitus type 2 were recruited. Patients were classified into two groups--with and without diabetic nephropathy according to urinary albumin excretion rate in urine collected during 24 hours. The C677T genotype was determined by real-time PCR analysis. The genotype frequencies were CC 36.5%, CT 42.3% and TT 21.2% in diabetic patients without nephropathy versus CC 39.4%, CT 45.4% and TT 15.2% in those with nephropathy. There was no statistically significant difference in allele distribution between patients with nephropathy and those without (p = 0.788). Our study did not show a correlation between mutations in the MTHFR gene and diabetic nephropathy in Croatian patients. Diabetic nephropathy is influenced by multiple risk factors which can modify the importance of MTHFR polymorphism in its development.

  8. Methylenetetrahydrofolate reductase C677T polymorphism is associated with increased risk of coronary artery disease in young South African Indians.

    PubMed

    Ramkaran, Prithiksha; Phulukdaree, Alisa; Khan, Sajidah; Moodley, Devapregasan; Chuturgoon, Anil A

    2015-10-15

    Methylenetetrahydrofolate reductase (MTHFR) reduces 5',10'-methylenetetrahydrofolate to 5'-methyltetrahydrofolate, and is involved in remethylation of homocysteine to methionine, two important reactions involved in folate metabolism and methylation pathways. The common MTHFR C677T single nucleotide polymorphism (SNP) (rs1801133) has been associated with raised levels of homocysteine, a well known risk factor for coronary artery disease (CAD). CAD is a major cause of mortality worldwide. The age of onset of this chronic disorder is on the decline, particularly in the Indian population. Indians in South Africa (SA) have a higher prevalence of premature CAD compared to Black South Africans. The MTHFR C677T SNP has not been investigated in the SA Indian population. The present study therefore investigated the MTHFR C677T SNP in young SA Indian males with CAD compared to young Indian and Black male controls. A total of 290 subjects were recruited into this study which included 106 CAD patients (diagnosed on angiography, mean age 37.5, range 24-45 years), 100 Indian male controls (mean age 37.5, range 28-45 years), and 84 Black male controls (mean age 36.4, range 25-45). Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) was used to genotype CAD patients and healthy controls. Data for clinical markers were obtained from pathology reports. There was a significant association between the 677 MTHFR variant (T) allele and CAD patients compared to the healthy Indian controls (p=0.0353, OR=2.105 95% CI 1.077-4.114). Indian controls presented with a higher frequency of the variant allele compared to Black controls (7% vs. 2% respectively, p=0.0515 OR=3.086 95% CI 0.9958-9.564). The MTHFR C677T SNP did not influence levels of total cholesterol, LDL, HDL, triglycerides, fasting glucose, fasting insulin, HbA1c or hsCRP. The higher frequency of the MTHFR 677 variant allele in South African Indians may be a contributing factor to the higher

  9. Impact of Genetic Polymorphism of methylenetetrahydrofolate reductase C677T on Development of Hyperhomocysteinemia and Related Oxidative Changes in Egyptian β-Thalassemia Major Patients

    PubMed Central

    Abd-Elmawla, Mai A.; Rizk, Sherine M.; Youssry, Ilham; Shaheen, Amira A.

    2016-01-01

    Background β-thalasemia major (β-TM) patients often suffer from various vascular complications together with increased oxidative stress. Hyperhomocysteinemia (Hhcy) has been defined as a risk factor for these complications. Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to cause Hhcy particularly in individuals with low B-vitamins. However, the status of homocysteine (hcy) in β-TM has not yet been adequately defined. Aim To evaluate the genetic polymorphism of MTHFR C677T among β-TM patients and its prospective contribution to Hhcy and related oxidative changes. Subjects and Methods Genotyping for MTHFR C677T was done by PCR-RFLP technique. Plasma hcy, vitamin B12, folate, malondialdehyde (MDA), total antioxidant capacity (TAC), oxidized low density lipoprotein (oxLDL), total nitric oxide (NOx) and lipid profile were determined in 66 β-TM patients and 66 control subjects of matched age and sex. Results The prevalence of MTHFR 677TT genotype was significant among β-TM patients (12%) compared to (3%) controls (OR = 4.9, 95%CI:1.2–24.2,P = 0.03). A strong association between Hhcy and MTHFR TT genotype was observed (OR = 7.7, 95%CI:2.8–20.9) where all β-TM patients with TT genotype were hyperhomocystienemic (≥ 15 μmol/l) and having sub-optimal folate level than those with CT or CC genotypes. Hyperhomocystienemic patients have suffered from increased oxidative stress characterized by significant increase in plasma MDA and oxLDL, and a significant reduction of plasma TAC and total NOx. Lipid profile of those patients was severely affected indicated by reduction in HDL and HDL/LDL and elevation in atherogenic index as compared with CC genotype. Other measured parameters were not significantly different among β-TM patients with different MTHFR genotypes. Conclusion This study suggests that Egyptian β-TM patients with MTHFR 677TT genotype could be at increasing risk of developing Hhcy particularly with folate

  10. Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women

    PubMed Central

    2009-01-01

    Background Several studies have determined that dietary intake of B vitamins may be associated with breast cancer risk as a result of interactions between 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) in the one-carbon metabolism pathway. However, the association between B vitamin intake and breast cancer risk in Brazilian women in particular has not yet been investigated. Methods A case-control study was conducted in São Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B6, and vitamin B12 were derived from a validated Food Frequency Questionnaire (FFQ). Genotyping was completed for MTHFR A1298C and C677T, and MTR A2756G polymorphisms. A logistical regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Results Neither dietary intake of folate, vitamin B6, or vitamin B12 nor MTHFR polymorphisms were independently associated with breast cancer risk. Analysis stratified by menopausal status showed a significant association between placement in the highest tertile of folate intake and risk of breast cancer in premenopausal women (OR = 2.17, 95% CI: 1.23–3.83; Ptrend = 0.010). The MTR 2756GG genotype was associated with a higher risk of breast cancer than the 2756AA genotype (OR = 1.99, 95% CI = 1.01–3.92; Ptrend = 0.801), and statistically significant interactions with regard to risk were observed between the MTHFR A1298C polymorphism and folate (P = 0.024) or vitamin B6 (P = 0.043), and between the MTHFR C677T polymorphism and folate (P = 0.043) or vitamin B12 (P = 0.022). Conclusion MTHFR polymorphisms and dietary intake of folate, vitamin B6, and vitamin B12 had no overall association with breast cancer risk. However, increased risk was observed in total women with the MTR 2756GG genotype and in premenopausal women with high folate intake. These findings, as well as significant interactions between MTHFR polymorphisms and B vitamins

  11. C677T methylenetetrahydrofolate reductase and plasma homocysteine levels among Thai vegans and omnivores.

    PubMed

    Kajanachumpol, Saowanee; Atamasirikul, Kalayanee; Tantibhedhyangkul, Phieuvit

    2013-01-01

    Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia.

  12. Analysis of genetic polymorphisms of brain-derived neurotrophic factor and methylenetetrahydrofolate reductase in depressed patients in a Slovak (Caucasian) population.

    PubMed

    Evinova, Andrea; Babusikova, Eva; Straka, Stanislav; Ondrejka, Igor; Lehotsky, Jan

    2012-12-01

    Major depressive disorder (MDD) is a complex neuropsychiatric disorder where both gene-gene and gene-environment interactions play an important role, but the clues are still not fully understood. One carbon metabolism in the CNS plays a critical role in the synthesis and release of neurotransmitters which are relevant to depressive disorder. We studied genetic polymorphisms of the brain derived neurotrophic factor (BDNF) and the methylenetetrahydrofolate reductase (MTHFR) in association with major depressive disorder. We genotyped the BDNF G196A, the MTHFR C677T, and A1298C polymorphisms in 134 patients diagnosed with major depression and 143 control subjects in Slovak (Caucasian) cohort of patients and probands. We found no significant association of either the BDNF G196A or MTHFR C677T polymorphisms with major depressive disorder neither in female nor male group of patients. However, the MTHFR A1298C genotype distribution was 36.6% (for AA genotype), 48.5% (AC) and 14.9% (CC) for the depressed patients, and 48.9% (AA), 42.7% (AC) and 8.4% (CC), respectively, for the control subjects. Patients with MDD had a higher prevalence of the CC genotype (OR = 2.38; 95% CI = 1.07-5.32; p = 0.032) and the AC + CC genotype (OR = 1.67; 95% CI = 1.03-2.69; p = 0.037) in comparison with the control subjects. This study shows that CC genotype of the MTHFR A1298C is associated with higher risk of MDD in Slovak population.

  13. The model homologue of the partially defective human 5,10-methylenetetrahydrofolate reductase, considered as a risk factor for stroke due to increased homocysteine level, can be protected and reactivated by heat shock proteins.

    PubMed

    Grabowski, Michał; Banecki, Bogdan; Kadziński, Leszek; Jakóbkiewicz-Banecka, Joanna; Gabig-Cimińska, Magdalena; Węgrzyn, Alicja; Węgrzyn, Grzegorz; Banecka-Majkutewicz, Zyta

    2016-10-01

    The A222 V substitution in the human MTHFR gene product (5,10-methylenetetrahydrofolate reductase) is responsible for a decreased activity of this enzyme. This may cause an increased homocysteine level, considered as a risk factor for arteriosclerosis and stroke. The bacterial homologue of the human enzyme, MetF, has been found to be a useful model in genetic and biochemical studies. The similarity of Escherichia coli MetF and human MTHFR proteins is so high that particular mutations in the corresponding human gene can be reflected by the bacterial mutants. For example, the A222 V substitution in MTHFR (caused by the C667T substitution in the MTHFR gene) can be ascribed to the A117 V substitution in MetF. Here, it is reported that a temperature-sensitive MetF117 (A117 V) protein can be partially protected from a thermal inactivation by the heat shock proteins from the Hsp70/100 systems. Moreover, activity of the thermally denatured enzyme can be partially restored by the same heat shock proteins. High temperature protein G (HtpG) had no effect on MetF117 activity in both experimental systems. The presented results indicate that functions of heat shock proteins may be required for maintenance of the MetF117 function. This may have implications for the mechanisms of arteriosclerosis and stroke, especially in the light of previous findings that the A222 V MTHFR polymorphism may be a risk factor for stroke, as well as recently published results which demonstrated the increased levels of antibodies against heat shock proteins in stroke patients.

  14. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease

    SciTech Connect

    Kluijtmans, L.A.J.; Heuvel, L.P.W.J. van den; Stevens, E.M.B.

    1996-01-01

    Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine P-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T{yields}C (1278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C{yields}T; A{yields}V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHFR activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T{yields}C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-{yields}T mutation in the MTHFR gene was found in 9 (15%) of 60 cardiovascular patients and in only 6 ({approximately}5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.21]). Because of both the high prevalence of the 833T-{yields}C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease. 35 refs., 3 figs., 1 tab.

  15. Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature

    PubMed Central

    Zhang, Ti; Lou, Jiao; Zhong, Rong; Wu, Jing; Zou, Li; Sun, Yu; Lu, Xuzai; Liu, Li; Miao, Xiaoping; Xiong, Guanglian

    2013-01-01

    Background Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996–2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association. Methods and Findings We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons MTHFR C677T (42 studies; 4374 cases, 7232 controls), MTHFR A1298C (22 studies; 2602 cases, 4070 controls), MTR A2756G (9 studies; 843 cases, 1006 controls), MTRR A66G (8 studies; 703 cases, 1572 controls), and RFC-1 A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of MTHFR C677T (OR 1.23; 95%CI 1.07–1.42) and suggestive evidence of RFC-1 A80G (OR 1.55; 95%CI 1.24–1.92). However, we found no significant effects of MTHFR A1298C, MTR A2756G, MTRR A66G in risk of NTDs in dominant, recessive or in allelic models. Conclusions Our meta-analysis strongly suggested a significant association of the variant MTHFR C677T and a suggestive association of RFC-1 A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs. PMID:23593147

  16. Choline Intake, Plasma Riboflavin, and the Phosphatidylethanolamine N-Methyltransferase G5465A Genotype Predict Plasma Homocysteine in Folate-Deplete Mexican-American Men with the Methylenetetrahydrofolate Reductase 677TT Genotype12

    PubMed Central

    Caudill, Marie A.; Dellschaft, Neele; Solis, Claudia; Hinkis, Sabrina; Ivanov, Alexandre A.; Nash-Barboza, Susan; Randall, Katharine E.; Jackson, Brandi; Solomita, Gina N.; Vermeylen, Francoise

    2009-01-01

    We previously showed that provision of the folate recommended dietary allowance and either 300, 550, 1100, or 2200 mg/d choline for 12 wk resulted in diminished folate status and a tripling of plasma total homocysteine (tHcy) in men with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype. However, the substantial variation in tHcy within the 677TT genotype at wk 12 implied that several factors were interacting with this genotype to affect homocysteine. As an extension of this work, the present study sought to identify the main predictors of wk-12 plasma tHcy, alone and together with the MTHFR C677T genotype (29 TT, 31 CC), using linear regression analysis. A basic model explaining 82.5% of the variation (i.e. adjusted R2 = 0.825) was constructed. However, the effects of the variables within this model were dependent upon the MTHFR C677T genotype (P for interaction ≤ 0.021). Within the 677TT genotype, serum folate (P = 0.005) and plasma riboflavin (P = 0.002) were strong negative predictors (inversely related) explaining 12 and 15%, respectively, of the variation in tHcy, whereas choline intake (P = 0.003) and serum creatinine (P < 0.001) were strong positive predictors, explaining 19 and 25% of the variation. None of these variables, except creatinine (P = 0.021), correlated with tHcy within the 677CC genotype. Of the 8 additional polymorphisms tested, none appeared to influence tHcy. However, when creatinine was not in the model, the phosphatidylethanolamine N-methyltransferase 5465G→A variant predicted lower tHcy (P < 0.001); an effect confined to the MTHFR 677TT genotype. Thus, in folate-deplete men, several factors with roles in 1-carbon metabolism interact with the MTHFR C677T genotype to affect plasma tHcy. PMID:19211833

  17. Methylenetetrahydrofolate Reductase A1298C Polymorphism and Breast Cancer Risk: A Meta-analysis of 33 Studies

    PubMed Central

    Rai, V

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) enzyme is essential for DNA synthesis and DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and different types of cancers. Several studies have investigated the association between the MTHFR A1298C polymorphism and breast cancer (BC) risk, but the results were inconclusive. To assess the risk associated with MTHFR A1298C polymorphism, a comprehensive meta-analysis was performed. PubMed, Google Scholar, Elsevier and Springer Link databases were searched for case-control studies relating the association between MTHFR A1298C polymorphism and BC risk and estimated summary odds ratios (ORs) with confidence intervals (CIs) for assessment. Up to January 2014, 33 case-control studies involving 15,919 BC patients and 19,700 controls were included in the present meta-analysis. The results showed that the A1298C polymorphism was not associated with BC risk in all the five genetic models (C vs. A allele (allele contrast): OR = 0.99, 95% confidence interval (CI): 0.93–1.05; AC versus AA (heterozygote/codominant): OR = 0.97, 95% CI: 0.89–1.04; CC versus AA (homozygote): OR = 0.99, 95% CI: 0.91–1.06; CC + AC versus AA (dominant model): OR = 0.97, 95% CI: 0.90–1.05; and CC versus AC + AA (recessive model): OR = 0.99, 95% CI: 0.91–1.07). The present meta-analysis did not support any association between the MTHFR A1298C polymorphism and BC risk. PMID:25506474

  18. [C677T polymorphism of the methylentetrahydrofolate reductase gene in mothers of children affected with neural tube defects].

    PubMed

    Morales de Machín, Alisandra; Méndez, Karile; Solís, Ernesto; Borjas de Borjas, Lisbeth; Bracho, Ana; Hernández, María Luisa; Negrón, Aimara; Delgado, Wilmer; Sánchez, Yanira

    2015-09-01

    Neural tube defects (NTD) are the most common congenital anomalies of the central nervous system, with a multifactorial pattern of inheritance, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene 677C>T polymorphism has been implicated as a risk factor for NTD. The main objective of this research was to investigate the association of the 677C>T polymorphism of the MTHFR gene as a genetic risk factor for NTD. Molecular analysis was performed in DNA samples from 52 mothers with antecedent of NTD offspring and from 119 healthy control mothers. Using the Polymerase Chain Reaction, a 198 bases pairs fragment was digested with the restriction enzyme Hinfi. 677T MTHFR allele frequencies for the problem and the control groups were 51.92% and 34.45%, respectively, and 677C MTHFR allele frequencies were 48.08% and 65.55%, respectively. There were significant differences in allele (p: 0.002) and genotype (p: 0.007) frequencies between these two groups. The odds ratio (OR) to the TT genotype vs. the CC genotype was estimated as OR: 4.9 [95% CI: 1,347-6.416] p: 0.002; CT+TT vs. CC: OR: 2.9 [95% CI: 1.347-6.416] p: 0.005; TT vs. CT+CC: OR: 2.675 [95% CI: 1,111-6.441] p: 0.024. The data presented in this study support the relationship between MTHFR 677C>T polymorphism and risk in mothers with antecedent of NTD offspring.

  19. "Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis".

    PubMed

    Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakash; Rai, Vandana

    2015-02-01

    Epidemiological studies have evaluated the association between maternal methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms and risk of neural tube defects (NTDs) in offspring. However, the results from the published studies on the association between these three polymorphisms and NTD risk are conflicting. To derive a clearer picture of association between these three maternal polymorphisms and risk of NTD, we performed meta-analysis. A comprehensive search was conducted to identify all case-control studies of maternal MTHFR and MTRR polymorphisms and NTD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, we found that maternal MTHFR C677T polymorphism (OR(TvsC) =1.20; 95% CI = 1.13-1.28) and MTRR A66G polymorphism (OR(GvsA) = 1.21; 95% CI = 0.98-1.49) were risk factors for producing offspring with NTD but maternal MTHFR A1298C polymorphism (OR(CvsA) = 0.91; 95% CI = 0.78-1.07) was not associated with NTD risk. However, in stratified analysis by geographical regions, we found that the maternal C677T polymorphism was significantly associated with the risk of NTD in Asian (OR(TvsC) = 1.43; 95% CI: 1.05-1.94), European (OR(TvsC) = 1.13; 95% CI: 1.04-1.24) and American (OR(TvsC) = 1.26; 95% CI: 1.13-1.41) populations. In conclusion, present meta-analysis supports that the maternal MTHFR C677T and MTRR A66G are polymorphisms contributory to risk for NTD.

  20. Genetic association analyses of nitric oxide synthase genes and neural tube defects vary by phenotype.

    PubMed

    Soldano, Karen L; Garrett, Melanie E; Cope, Heidi L; Rusnak, J Michael; Ellis, Nathen J; Dunlap, Kaitlyn L; Speer, Marcy C; Gregory, Simon G; Ashley-Koch, Allison E

    2013-10-01

    Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes.

  1. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

    PubMed Central

    van der Put, N M; Gabreëls, F; Stevens, E M; Smeitink, J A; Trijbels, F J; Eskes, T K; van den Heuvel, L P; Blom, H J

    1998-01-01

    Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs. PMID:9545395

  2. Association between the methylenetetrahydrofolate reductase c.677C>T polymorphism and bone mineral density: an updated meta-analysis.

    PubMed

    Li, Hong-Zhuo; Wang, Wei; Liu, Yi-Ling; He, Xiao-Feng

    2016-02-01

    Many studies have reported an association between the methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism and reduced bone mineral density (BMD), but results have been inconsistent. We, therefore, performed a meta-analysis to further explore this association. Twenty-one studies, comprising 33,045 subjects, analyzed the association of MTHFR c.677C>T with femoral neck BMD. Significant association with reduced BMD was observed in Caucasians (recessive model: WMD = -0.004 g/cm(2), 95 % CI -0.008 to -0.006), post-menopausal women (recessive model: WMD = -0.005 g/cm(2), 95 % CI -0.007 to -0.003), men (dominant model: WMD = -0.004 g/cm(2), 95 % CI -0.005 to -0.004; recessive model: WMD = -0.004 g/cm(2), 95 % CI -0.005 to -0.004; TT vs. CC: WMD = -0.006 g/cm(2), 95 % CI -0.006 to -0.006; CT vs. CC: WMD = -0.003 g/cm(2), 95 % CI -0.003 to -0.003), and cohort studies (recessive model: WMD = -0.003 g/cm(2), 95 % CI -0.006 to -0.001). Twenty-two studies, which included 32,271 subjects, analyzed the MTHFR c.677C>T association with lumbar spine BMD. Significant association with reduced BMD was observed in Caucasians, women, post-menopausal women, men, and cohort studies. Seven studies, comprising 6806 subjects, analyzed the MTHFR c.677C>T association with total hip BMD, but no significant association was observed in any population. Nine studies involving 5591 subjects analyzed the association with total body BMD. Significant association with reduced BMD was observed in overall and women subgroup analyses. In summary, this meta-analysis indicates that the MTHFR c.677C>T polymorphism is associated with reduced BMD in lumbar spine and femoral neck in Caucasians, post-menopausal women, and men, and with total body BMD in women. In addition, our results suggest that new studies examining the association between MTHFR c.677C>T polymorphism and BMD of lumbar spine and femoral neck in Asians is warranted, because I (2) > 75.0 % was observed.

  3. Association between 11 genetic polymorphisms in folate-metabolising genes and head and neck cancer risk.

    PubMed

    Galbiatti, Ana Lívia Silva; da Silva, Lidia Maria Rebolho Batista; Ruiz-Cintra, Mariangela Torreglosa; Raposo, Luis Sérgio; Maníglia, José Victor; Pavarino, Erika Cristina; Goloni-Bertollo, Eny Maria

    2012-07-01

    Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G, MTHFD1 G1958A, CBS 844ins68, TC2 C776G and A67G, SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ≥ 49 years (P<0.001), male gender (P=0.03), tobacco habit (P<0.001), MTHFR 1298AC/CC (P=0.028), MTR 2756AG/GG (P=0.010) and RFC1 80AG/GG (P=0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 (P=0.005); age ≥ 49 years and MTR 2756 AG/GG (P=0.004) and RFC1 80AG/GG (P=0.006) genotypes; male gender and MTHFR 1298 AC/CC (P=0.030), MTR 2756 AG/GG (P=0.006) and RFC1 80 AG/GG (P=0.009); tobacco non-habit and MTHFD1 1958GA/AA (P=0.040); tobacco and MTHFR 1298 AC/CC (P=0.054) and MTR 2756 AG/GG (P=0.010); alcohol non-consume and RFC1 80 AG/GG (P=0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours (P=0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

  4. B-vitamin and choline supplementation increases neuroplasticity and recovery after stroke.

    PubMed

    Jadavji, Nafisa M; Emmerson, Joshua T; MacFarlane, Amanda J; Willmore, William G; Smith, Patrice D

    2017-04-07

    Folates are B-vitamins that play an important role in brain function. Dietary and genetic deficiencies in folate metabolism result in elevated levels of homocysteine which have been linked to increased risk of developing a stroke. Reducing levels of homocysteine before or after a stroke through B-vitamin supplementation has been a focus of many clinical studies, however, the results remain inconsistent. Animal model systems provide a powerful mechanism to study and understand functional impact and mechanisms through which supplementation affects stroke recovery. The aim of this study was to understand the role of B-vitamins in stroke pathology using in vivo and in vitro mouse models. The first objective assessed the impact of folate deficiency prior to ischemic damage followed by B-vitamins and choline supplementation. Ischemic damage targeted the sensorimotor cortex. C57Bl/6 wild-type mice were maintained on a folic acid deficient diet for 4weeks prior to ischemic damage to increased levels of plasma homocysteine, a risk factor for stroke. Post-operatively mice were placed on a B-vitamin and choline supplemented diet for a period of four weeks, after which motor function was assessed in mice using the rotarod, ladder beam and forepaw asymmetry tasks. The second objective was to determine how a genetic deficiency in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism, increases vulnerability to stroke. Primary cortical neurons were isolated from Mthfr(+/+), Mthfr(+/-) and Mthfr(-/-) embryos and were exposed to in vitro models of stroke which include hypoxia or oxygen glucose deprivation. Cell viability was measured 24-h after exposure stroke like conditions in vitro. In supplemented diet mice, we report improved motor function after ischemic damage compared to mice fed a control diet after ischemic damage. Within the perilesional cortex, we show enhanced proliferation, neuroplasticity and anti-oxidant activity in mice fed the

  5. A magnetic nanoparticles-based method for DNA extraction from the saliva of stroke patients

    PubMed Central

    Yi, Li; Huang, Ying; Wu, Ting; Wu, Jun

    2013-01-01

    C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for stroke, suggesting that widespread detection could help to prevent stroke. DNA from 70 stroke patients and 70 healthy controls was extracted from saliva using a magnetic nanoparticles-based method and from blood using conventional methods. Real-time PCR results revealed that the C677T polymorphism was genotyped by PCR using DNA extracted from both saliva and blood samples. The genotype results were confirmed by gene sequencing, and results for saliva and blood samples were consistent. The mutation TT genotype frequency was significantly higher in the stroke group than in controls. Homocysteine levels were significantly higher than controls in both TT genotype groups. Therefore, this noninvasive magnetic nanoparticles-based method using saliva samples could be used to screen for the MTHFR C677T polymorphism in target populations. PMID:25206624

  6. Acute renal infarction associated with homozygous methylenetetrahydrofolate reductase mutation C677T and IgA beta-2-glycoprotein antibodies.

    PubMed

    Vlachostergios, Panagiotis J; Dufresne, François

    2015-07-01

    Arterial thrombosis of the kidney(s) is a rare clinical entity usually presenting as a result of cardioembolic disease, though rare inherited hypercoagulable states have also been implicated. Within this context, both hyperhomocysteinemia triggered by a mutated methylenetetrahydrofolate reductase (MTHFR) gene product and the presence of antiphospholipid antibodies have been separately associated with arterial thrombotic events, including renal artery embolism. We present a case of combined homozygous MTHFR C677T mutation and IgA beta-2-glycoprotein antibody positivity resulting in acute renal infarction and previous silent myocardial infarction. An acute and otherwise unexplained thrombotic event of unusual location always warrants further investigation, which should include testing for hereditary thrombophilic disorders.

  7. The Prevalence of Factor V Leiden (G1691A) and Methylenetetrahydrofolate Reductase C677T Mutations in Sickle Cell Disease in Western India.

    PubMed

    Kangne, Harshada K; Jijina, Farah F; Italia, Yazdi M; Jain, Dipti L; Nadkarni, Anita H; Ghosh, Kanjaksha K; Colah, Roshan B

    2015-03-01

    The prevalence of the Factor V Leiden (FVL; G1691A) mutation and the methylenetetrahydrofolate reductase (MTHFR; C677T) mutation was determined in 180 patients with sickle cell (SS) disease (126 sickle homozygous and 54 sickle β-thalassaemia--age 1-47 years) and in 130 healthy controls. The FVL mutation in the heterozygous state was present in only 3 patients with SS disease and was absent in the controls. Genotyping of MTHFR 677C > T revealed increased frequency of the C allele than the T allele in patients as well as in controls. This suggests that these genetic markers may not be major risk factors for a hypercoagulable state in Indian patients with SS disease.

  8. Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans.

    PubMed

    Jakubowski, Hieronim; Boers, Godfried H J; Strauss, Kevin A

    2008-12-01

    Severely elevated plasma homocysteine (Hcy) levels observed in genetic disorders of Hcy metabolism are associated with pathologies in multiple organs and lead to premature death due to vascular complications. In addition to elevating plasma Hcy, mutations in cystathionine beta-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR) gene lead to markedly elevated levels of circulating Hcy-thiolactone. The thiooester chemistry of Hcy-thiolactone underlies its ability to form isopeptide bonds with protein lysine residues (N-Hcy-protein), which may impair or alter the protein's function. However, it was not known whether genetic deficiencies in Hcy metabolism affect N-Hcy-protein levels in humans. Here we show that plasma N-Hcy-protein levels are significantly elevated in CBS- and MTHFR-deficient patients. We also show that CBS-deficient patients have significantly elevated plasma levels of prothrombotic N-Hcy-fibrinogen. These results provide a possible explanation for increased atherothrombosis observed in CBS-deficient patients.

  9. Genetic variants of homocysteine/folate metabolism pathway and risk of inflammatory bowel disease: a synopsis and meta-analysis of genetic association studies.

    PubMed

    Zintzaras, Elias

    2010-02-01

    A synopsis and meta-analysis of studies that investigated the association between genetic variants involved in the homocysteine/folate metabolism pathway and risk of inflammatory bowel disease (IBD) were conducted. Four variants (MTHFR C6TTT, MTHFR A1298C, MTR A2756G and MTRR A66G) showed significant associations in individual studies. In meta-analyses, only the variant MTR A2756G indicated an association with the risk of IBD for the allele contrast and the dominant model (odds ratio (OR) 1.48 (1.12-1.97) and OR 1.55 (1.12-2.15), respectively). The effect sizes for Crohn's disease and ulcerative colitis were similar to IBD. Cumulative meta-analysis for C677T indicated a downward trend of association as information accumulates.

  10. A variety of gene polymorphisms associated with idiopathic granulomatous mastitis

    PubMed Central

    Destek, Sebahattin; Gul, Vahit Onur; Ahioglu, Serkan

    2016-01-01

    Idiopathic granulomatous mastitis (IGM) is a rare and chronic inflammatory disorder. IGM mimics breast cancer regarding its clinical and radiological features. Etiology of IGM remains unclarified. Our patient was 37-year-old and 14 weeks pregnant. There was pain, redness and swelling in the right breast. The mass suggestive of malignancy was detected in sonography. Serum CA 125 and CA 15-3 levels were high. Genetic analysis was performed for the etiology. methylenetetrahydrofolate reductase (MTHFR) C 677 TT, β-fibrinogen-455 G>A, plasminogen activator inhibitor (PAI)-1 5 G/5 G, angiotensin-converting enzyme (ACE) I/D mutation was found. IGM was diagnosed by cor biopsy. An association was also reported between breast cancer and mutations in MTHFR-C 677 T, PAI-1, ACE genes. Genetic polymorphisms may involve in the development of IGM as it was seen in our case. Further studies should be conducted to better clarify this plausible association. PMID:27619324

  11. Combined choroidal neovascularization and hypopituitarism in a patient with homozygous mutation in methylenetetrahydrofolate reductase gene

    PubMed Central

    Aydogdu, Aydogan; Haymana, Cem; Baskoy, Kamil; Durukan, Ali H.; Ozgur, Gokhan; Azal, Omer

    2014-01-01

    We report a case of choroidal neovascularization (CNV) secondary to methylenetetrahydrofolate reductase (MTHFR) gene mutation in a 20-year-old male patient with hypopituitarism. Treatment with three consecutive injections of intravitreal ranibizumab (anti-vascular endothelial growth factor) resulted in significant improvement of the patient's vision and the appearance of the macula. A search of the literature produced no previously reported case of MTHFR gene mutation associated both CNV and possibly hypopituitarism. With hormone replacement therapy of hypopituitarism, acetyl salicylic acid 100 mg/day also was started. The patient was clinically stable both for CNV and other thromboembolic disorders over a 6-month follow-up and also 1-year follow-up period. PMID:24672570

  12. Summary of Synoptic Meteorological Observations. Siberian Coastal Marine Areas. Volume 4. Area 22 - Onekotan Island, Area 23 - Onekotan Island SE, Area 24 - Soya Strait W, Area 25 - Soya Strait E, Area 26 - Urup Island, Area 27 - Vladivostok, Area 28 - Sea of Japan N

    DTIC Science & Technology

    1975-10-01

    8217’"■■ "~-^ ■ "/-■,--■■■.!■’.•:" ’ :-,’’^- »imro: H70.l»Tl TttLE 1 «RE> 002i Sf« OF J1F1N N 42.IN 139,*( ’(•CENT FKEfiUENCV OF » MTHfR OCCUKIKNCe IV

  13. Methylenetetrahydrofolate Reductase C677T Polymorphism and Recurrent Pregnancy Loss Risk in Asian Population: A Meta-analysis.

    PubMed

    Rai, Vandana

    2016-10-01

    The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was implicated to be associated with thrombophilia due to its role in catalyzing the formation of 5-methylenetetrahydrofolate, a co-substrate for the conversion of homocysteine to methionine. Several case-control studies were investigated MTHFR C677T polymorphism as risk for recurrent pregnancy loss (RPL). These studies rendered contradictory results, some indicating that the polymorphism is associated with the risk of RPL whereas others concluded there is no association. To shed light on these inconclusive findings, a meta-analysis of all available studies published from Asian population relating the C677T polymorphism to the risk of RPL was conducted. The following electronic databases were searched without language restrictions: PubMed, Google Scholars, Elsevier and Springer Link up to December, 2015. Meta-analysis was performed using MetaAnalyst and Mix version 1.7. Meta-analysis results suggested that MTHFR C677T polymorphism contributed to the increased RPL risk in Asian population using all five genetic models (for T vs. C: OR 1.35, 95 % CI 1.09-1.68, p = 0.009; for TT + CT vs. CC: OR 1.44, 95 % CI 1.14-1.82, p = 0.006; for CT vs. CC: OR 1.39, 95 % CI 1.07-1.8, p = 0.01; for TT vs. CC: OR 1.79, 95 % CI 1.23.2.6, p = 0.007; for TT vs. CT + CC: OR 1.61, 95 % CI 1.02-2.56, p = 0.04). In conclusion, this meta-analysis demonstrates a strong association between the MTHFR C677T variant and RPL in Asian population and raising the importance of the use of folate in its treatment and prevention.

  14. The Drop That Spilled the Cup: Acute Myocardial Infarction in a Young Woman with Underlying Thrombophilic Polymorphisms and Oral Contraceptive Use

    PubMed Central

    Capilli, Gianfranco; Patané, Anella Antonietta

    2014-01-01

    We present the case of a 28-year-old woman who was admitted to our cardiology unit for acute coronary syndrome. Her history was notable for cardiovascular disease familiarity, active smoking, and oral contraceptive use. On further analysis, she was noted to have thrombophilic polymorphisms involving the plasminogen activator inhibitor (PAI), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR) genes. We discuss the implications that these cofactors may have had in the genesis of the disease. PMID:25587456

  15. Potential Risk Factors Associated With Vascular Diseases in Patients Receiving Treatment for Hypertension

    PubMed Central

    Kim, Hyunjung; Park, Joonhong; Chae, Hyojin; Lee, Gun Dong; Lee, Sang Yoon; Lee, Jong Min; Oh, Yong-Seog

    2016-01-01

    Background Currently, the hypertension (HTN) patients undergo appropriate medical treatment, and traditional risk factors are highly controlled. Therefore, potential risk factors of atherosclerotic vascular diseases (AVD) and venous thromboembolisms (VTE) in HTN should be reconsidered. We investigated thrombophilic genetic mutations and existing biomarkers for AVD or VTE in HTN patients receiving treatment. Methods A total of 183 patients were enrolled: AVD with HTN (group A, n=45), VTE with HTN (group B, n=62), and HTN patients without any vascular diseases (group C, n=76). The lipid profile, homocysteine (Hcy) levels, D-dimers, fibrinogen, antithrombin, lupus anticoagulant, and anti-cardiolipin antibody (aCL) were evaluated. Prothrombin G20210A, Factor V G1691A, and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were analyzed. Results All patients revealed wild type prothrombin G20210A and Factor V G1691A polymorphisms. The frequency of MTHFR polymorphisms was 677CT (n=84, 45.9%); 677TT (n=46, 25.1%); 1298AC (n=46, 25.1%); and 1298CC (n=2, 1.1%). The MTHFR 677TT genotype tended to increase the odds ratio (OR) to AVD events in HTN patients (OR 2.648, confidence interval 0.982-7.143, P=0.05). The group A demonstrated significantly higher Hcy levels (P=0.009), fibrinogen (P=0.004), and platelet counts (P=0.04) than group C. Group B had significantly higher levels of D-dimers (P=0.0001), platelet count (P=0.0002), and aCL (P=0.02) frequency than group C. Conclusions The MTHFR 677TT genotype and Hcy level could be potential risk factors associated with development of AVD in HTN patients receiving treatment. D-dimer and aCL might be useful to estimate the occurrence of VTE in them. PMID:26915609

  16. High circulating folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring.

    PubMed

    Kiefte-de Jong, Jessica C; Timmermans, Sarah; Jaddoe, Vincent W V; Hofman, Albert; Tiemeier, Henning; Steegers, Eric A; de Jongste, Johan C; Moll, Henriette A

    2012-04-01

    Recent studies suggest that in utero exposure of methyl donors influences programming of the fetal immune system in favor of development of allergic disease. The aim of this study was to assess whether the MTHFR C677T polymorphism, folic acid supplementation, and circulating folate and vitamin B-12 concentrations during pregnancy were associated with wheezing, shortness of breath, and atopic dermatitis in offspring. The study was a population-based birth cohort from fetal life until 48 mo (n = 8742). The use of folic acid supplementation during pregnancy was assessed by questionnaire. Plasma folate and serum vitamin B-12 concentrations and the MTHFR C677T polymorphism were available from blood collected in early pregnancy. Atopic dermatitis, wheezing, and shortness of breath in the offspring were assessed by parental-derived questionnaires at 12, 24, 36, and 48 mo. Maternal folate >16.2 nmol/L and vitamin B-12 >178 pmol/L were positively associated with the development of atopic dermatitis [adjusted OR: 1.18 (95% CI: 1.05-1.33) and adjusted OR: 1.30 (95% CI: 1.06-1.60) for the highest quartiles of folate and vitamin B-12 concentrations, respectively] but not with wheezing and shortness of breath. Maternal MTHFR C677T polymorphism and folic acid supplementation were not associated with wheezing, shortness of breath, and atopic dermatitis. No interactions were found by age, family history of atopy, folic acid supplementation, MTHFR C677T polymorphism, or maternal smoking (P-interaction > 0.10). High folate and vitamin B-12 levels during pregnancy are associated with increased prevalence of atopic dermatitis in the offspring. Potential risks of high folate and vitamin B-12 concentrations on allergic outcomes should be evaluated when discussing mandatory fortification programs.

  17. Genetic thromobophilia in pregnancy: a case-control study among North Indian women.

    PubMed

    Kaur, Lovejeet; Puri, Manju; Kaushik, Shweta; Sachdeva, Mohinder Pal; Trivedi, Shubha Sagar; Saraswathy, Kallur Nava

    2013-02-01

    In the present study, an attempt is made to understand the role of genetic thrombophilias i.e. MTHFR C677T and FVL in the causation of various pregnancy complications like pregnancy induced hypertension (PIH), recurrent abortions, intra-uterine growth retardation (IUGR) and intra-uterine death on the whole and also individually along with the comparative assessment of pathophysiological basis of various pregnancy complications via the genetic proximities. One thousand and eleven (1,011) women of reproductive age group were recruited in the present study comprising various complications and controls. Recruitment criteria for all the pregnancy complications and controls was made and followed strictly. MTHFR C677T and FVL mutation detection was done in all the subjects. Vegetarianism was found to be significant risk factors for all the pregnancy complications and also when assessed individually. With respect to MTHFR C677T polymorphism, higher frequency of 677T allele was found among controls as compared to cases. 677T allele was found to pose decreased risk for various pregnancy complications on the whole and also individually. On adjusting the diet, regression analysis revealed no risk of mutant allele (T) for various pregnancy complications. FVL homozygous mutants were found to be absent among controls. In conclusion, the present study depicts dietary pattern as one of the most important factors in demonstrating the role of MTHFR C677T in various pregnancy complications and is indicative of a relatively deleterious effect of double dose of FVL in the presently studied population. Additionally, these polymorphisms play an important role in the orchestration of PIH to IUGR and vice versa.

  18. Thermolabile Methylenetetrahydrofolate Reductase C677T Polymorphism and Homocysteine Are Risk Factors for Coronary Artery Disease in Moroccan Population

    PubMed Central

    Bennouar, Nawal; Allami, Abdellatif; Azeddoug, Houssine; Bendris, Abdenbi; Laraqui, Abdelilah; El Jaffali, Amal; El Kadiri, Nizar; Benzidia, Rachid; Benomar, Anwar; Fellat, Seddik; Benomar, Mohamed

    2007-01-01

    Increased plasma total homocysteine (tHcy) levels have been shown to be a risk factor for coronary artery disease (CAD). The common methylenetetrahydrofolate reductase C677T (MTHFR C677T) polymorphism has been reported to be a strong predictor of mild hyperhomocysteinaemia (HHcy). We assessed whether this mutation was associated with increased risk of CAD and plasma levels of tHcy. We also evaluated interactions between this polymorphism, mild elevated tHcy levels and conventional risk factors of CAD. Method. Using PCR-RFLP analysis, we studied the frequency of the C677T genotypes and its effect on CAD and on tHcy concentrations in 400 subjects without and with CAD angiographically confirmed. There were 210 subjects with CAD and 190 subjects without CAD. Results. The frequencies of the C677T genotypes were 53% (59.5% in controls versus 48.1% in cases), 34.8% (32.1 in controls versus 37.1 in cases), and 11.8% (8.4% in controls versus 14.8% in cases), respectively, for 677CC, 677CT, and 677TT. The genotype frequencies were significantly different between case and control groups (P < .05). The 677T allele enhances the risk of CAD associated to HHcy (P < .01). In multivariate analysis models, MTHFR C677T polymorphism effect on CAD was masked by other risk factors. HHcy was only and independently influenced by MTHFR polymorphism and smoking habits, and it is a strong predictor of CAD independently of conventional risk factors. Conclusion. Our data suggest that HHcy is strongly and independently associated to CAD risk increase; and MTHFR C677T polymorphism and smoking habits were the main predictors of tHcy levels. The CAD risk increase is mainly associated with mild HHcy in 677TT, whereas in 677CT and 677CC it is mainly associated with the conventional risk factors. PMID:17497026

  19. Seven novel mutations at the 5,10-methylenetetrahydrofolate reductase locus

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen, R.

    1994-09-01

    5,10-methylenetetrahydrofolate reductase (MTHFR), a flavoprotein, catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cofactor for methionine synthase in the methylation of homocysteine to methionine. Severe MTHFR deficiency, which causes homocysteinemia, is an autosomal recessive disorder with variable clinical features; developmental delay, perinatal death, mental retardation and asymptomatic individuals have been observed. A milder deficiency has been reported in patients with cardiovascular disease. We have recently described the isolation of a cDNA for MTHFR and the identification of 2 mutations in patients with severe MTHFR deficiency. We report here the characterization of 7 additional mutations at this locus: 5 missense mutations and 2 splicing mutations. Mutation analysis was performed by SSCP on PCR products generated either from reverse transcription-PCR of patients` total fibroblast RNA or from PCR of patients` genomic DNA. The 5 missense mutations are as follows: 1 Arg to Cys substitution in a hydrophilic segment proposed to be the hinge region that connects the catalytic and regulatory domains, 2 different Arg to Cys substitutions in 2 patients whose enzymatic thermolability is responsive to FAD, 1 Thr to Met substitution affecting an evolutionarily-conserved residue and a Pro to Leu substitution. The 2 splicing mutations affect the 5{prime} splice site and the 3{prime} splice site of 2 introns, respectively. The 5{prime} splice site mutation generates a 57 bp in-frame deletion of the RNA through the utilization of a cryptic 5{prime} splice site within the coding sequence. The identification of 9 mutations at this locus has allowed us to make preliminary correlations between genotype and phenotype and to contribute to a structure:function analysis of the enzyme.

  20. Individual and Joint Associations of Methylenetetrahydrofolate Reductase C677T Genotype and Plasma Homocysteine With Dyslipidemia in a Chinese Population With Hypertension.

    PubMed

    Liu, Yanhong; Li, Kang; Venners, Scott A; Hsu, Yi-Hsiang; Jiang, Shanqun; Weinstock, Justin; Wang, Binyan; Tang, Genfu; Xu, Xiping

    2017-04-01

    We aimed to examine the cross-sectional associations of plasma total homocysteine (tHcy) concentrations and methylenetetrahydrofolate reductase ( MTHFR) C677T genotype with dyslipidemia. A total of 231 patients with mild-to-moderate essential hypertension were enrolled from the Huoqiu and Yuexi communities in Anhui Province, China. Plasma tHcy levels were measured by high-performance liquid chromatography. Genotyping was performed by TaqMan allelic discrimination technique. Compared with MTHFR 677 CC + CT genotype carriers, TT genotype carriers had higher odds of hypercholesterolemia (adjusted odds ratio [OR] [95% confidence interval (CI)]: 2.7 [1.4-5.2]; P = .004) and higher odds of abnormal low-density lipoprotein cholesterol (adjusted OR [95% CI]: 2.3 [1.1-4.8]; P = .030). The individuals with the TT genotype had higher concentrations of log(tHcy) than those with the 677 CC + CT genotype (adjusted β [standard error]: .2 [0.03]; P < .001). Patients with tHcy ≥ 10 μmol/L had significantly higher odds of hypercholesterolemia (adjusted OR [95% CI]: 2.4 [1.2-4.7]; P = .010). Furthermore, patients with both the TT genotype and the tHcy ≥ 10 μmol/L had the highest odds of hypercholesterolemia (adjusted OR [95% CI]: 4.1 [1.8-9.4]; P = .001) and low-density lipoprotein cholesterol (adjusted OR [95% CI]: 2.4 [1.0-6.0]; P = .064). This study suggests that both tHcy and the MTHFR C677T gene polymorphism may be important determinants of the incidence of dyslipidemia in Chinese patients with essential hypertension. Further studies are needed to confirm the role of tHcy and the MTHFR C677T mutation in the development of dyslipidemia in a larger sample.

  1. Detection of thrombophilic mutations related to spontaneous abortions by a multiplex SNaPshot method.

    PubMed

    Madjunkova, Svetlana; Volk, Marija; Peterlin, Borut; Plaseska-Karanfilska, Dijana

    2012-04-01

    Spontaneous abortion is a significant clinical problem of different etiologies. Certain thrombophilia gene mutations have been associated with an increased risk of spontaneous abortion. Also, mutations in folate-related genes can lead to abnormal chromosomal segregation during meiosis which is the most common cause of spontaneous abortion. We have developed a multiplex single-base extension reaction assay that allows simultaneous analysis of 10 different mutations in thrombophilia- and folate-related genes (Factor V Leiden G1691A, Factor V H1299R, Factor II G20210A, Factor XIII V34L, PAI-I -675 4G/5G, FGB -455G/A, MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G). Using this method we have studied 232 women who had a spontaneous abortion and 209 of their male partners. Prevalence of Factor II G20210A and Factor V H1299R mutations was significantly higher in the women than in their male partners (2.4% and 0.7%, respectively [p=0.0499] for the Factor II mutation and 9.3% and 5.7%, respectively [p=0.0485] for the Factor V mutation). The prevalence of MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G mutations did not differ between the studied groups. In conclusion, we have developed a rapid, simple, reliable, and inexpensive multiplex SNaPshot method for determination of 10 thrombophilic mutations that may result in spontaneous abortions.

  2. Detection of Thrombophilic Mutations Related to Spontaneous Abortions by a Multiplex SNaPshot Method

    PubMed Central

    Madjunkova, Svetlana; Volk, Marija; Peterlin, Borut

    2012-01-01

    Spontaneous abortion is a significant clinical problem of different etiologies. Certain thrombophilia gene mutations have been associated with an increased risk of spontaneous abortion. Also, mutations in folate-related genes can lead to abnormal chromosomal segregation during meiosis which is the most common cause of spontaneous abortion. We have developed a multiplex single-base extension reaction assay that allows simultaneous analysis of 10 different mutations in thrombophilia- and folate-related genes (Factor V Leiden G1691A, Factor V H1299R, Factor II G20210A, Factor XIII V34L, PAI-I -675 4G/5G, FGB -455G/A, MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G). Using this method we have studied 232 women who had a spontaneous abortion and 209 of their male partners. Prevalence of Factor II G20210A and Factor V H1299R mutations was significantly higher in the women than in their male partners (2.4% and 0.7%, respectively [p=0.0499] for the Factor II mutation and 9.3% and 5.7%, respectively [p=0.0485] for the Factor V mutation). The prevalence of MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G mutations did not differ between the studied groups. In conclusion, we have developed a rapid, simple, reliable, and inexpensive multiplex SNaPshot method for determination of 10 thrombophilic mutations that may result in spontaneous abortions. PMID:22023244

  3. Genetic and Environmental Determinants of Plasma Total Homocysteine Levels: Impact of Population-wide Folate Fortification

    PubMed Central

    Nagele, Peter; Meissner, Konrad; Francis, Amber; Födinger, Manuela; Saccone, Nancy L.

    2011-01-01

    Objectives Folate metabolism is an important target for drug therapy. Drug-induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several non-genetic (e.g., folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nation-wide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy. Methods Two cohorts were compared in this study, one from the U.S. (with folate fortification, n=281), and one from Austria (without folate fortification, n=139). Several environmental factors as well as previously identified gene variants important for tHcy levels (MTHFR C677T, MTHFR A1298C, MTRR A66G) were examined for their ability to predict plasma tHcy in a multiple linear regression model. Results Non-genetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R2 ~ 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate fortified cohort (R2= 0.021) compared to the non-folate fortified cohort (R2= 0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male gender, smoking and folate levels were important predictors for non-folate fortified patients; age for folate fortified. Conclusions Population-wide folate fortification had a significant effect on the variability of plasma tHcy and reduced the influence of genetic factors, most importantly the MTHFR 677TT genotype, and may be an important confounder for a personalized drug therapy. PMID:21597397

  4. Association of methylenetetrahydrofolate reductase and methionine synthase polymorphisms with breast cancer risk and interaction with folate, vitamin B6, and vitamin B 12 intakes.

    PubMed

    Jiang-Hua, Qiao; De-Chuang, Jiao; Zhen-Duo, Lu; Shu-de, Cui; Zhenzhen, Liu

    2014-12-01

    We assessed the association between dietary intake of folate and the MTHFR genotype with breast cancer in a Chinese population, with additional analysis of the interactions of gene polymorphisms and dietary intake of folate, vitamin B6, and vitamin B12. A case-control study was performed, and 535 patients with newly diagnosed breast cancer and 673 controls were enrolled into this study. The MTHFR 667TT genotype (odds ratio (OR) = 1.82, 95 % confidence interval (CI) = 1.24-2.97) and T allele (OR 0= 1.48, 95 % CI = 1.15-1.78) were correlated with a moderately significant increased risk of breast cancer when compared with the CC genotype. Individuals carrying the MTR 2756GG genotype (OR = 1.66, 95 % CI = 1.16-2.56) and G allele (OR = 1.42, 95 % CI = 1.26-1.81) had a higher risk of breast cancer when compared with subjects with the AA genotype. The MTHFR 667 T allele and MTR 2756 G allele were associated with a higher risk of breast cancer in individuals with low folate intake, vitamin B6, and vitamin B12, but the association disappeared among subjects with moderate and high intake of folate, vitamin B6, and vitamin B12. This case-control study found that the MTHFR C677T and MTR A2756G polymorphisms are associated with risk of breast cancer, and folate, vitamin B6, and vitamin B12 intakes influence these associations.

  5. Impact of methionine synthase gene and methylenetetrahydrofolate reductase gene polymorphisms on the risk of sudden sensorineural hearing loss.

    PubMed

    Gross, Menachem; Friedman, Gideon; Eliashar, Ron; Koren-Morag, Nira; Goldschmidt, Neta; Atta, Iman Abou; Ben-Yehuda, Arie

    2006-01-01

    Idiopathic sudden sensorineural hearing loss (SSNHL) represents a frequently encountered otological disease of unknown etiology. In recent years, several inherited risk factors have been found in the pathogenesis of vascular diseases. In the present study, we determined whether specific polymorphism or the combination of polymorphisms in folate-dependent homocysteine metabolism genes can act as predisposing inherited vascular risk factors in the development of SSNHL. We conducted a prospective case-control study using DNA samples extracted from 81 patients diagnosed as suffering from SSNHL and 264 healthy control subjects. Three functional polymorphisms were analyzed by polymerase chain reaction amplification, restriction enzyme digestion, and DNA fragment separation by electrophoresis: methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, and methionine synthase (MTR) A2756G polymorphisms. The prevalence of the homozygous genotype of MTR 2756GG in the SSNHL patients (9%) was significantly higher than in the control group (4%) (p = 0.011). The allelic frequency of the G allele of the MTR A2756G polymorphism among SSNHL patients (12.5%) was also significantly higher than in the control group (5%) (p = 0.033). The prevalence of patients possessing two polymorphisms (31%) and three polymorphisms (17%) in the SSNHL group was significantly higher than in the control group (23 and 9%, respectively; p = 0.019). The frequency of patients with a very high rank risk (double homozygous) was significantly higher in the SSNHL group, MTHFR 677TT/MTR 2675GG--7%, than the frequency of patients in the control group, MTHFR 677TT/MTR 2675GG--3% (p = 0.030). Certain polymorphisms in genes encoding enzymes in the folate-dependent homocysteine metabolism are associated with SSNHL. In our case-control study, a significant association between MTR 2756GG genotype and SSNHL was found which may represent an inherited vascular risk factor in the pathogenesis of SSNHL.

  6. Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

    PubMed

    Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J; Bergeson, Susan E; Henderson, George I; Kruman, Inna I

    2012-12-21

    The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

  7. Genetic variants and increased risk of meningioma: an updated meta-analysis

    PubMed Central

    Han, Xiao-Yong; Wang, Wei; Wang, Lei-Lei; Wang, Xi-Rui; Li, Gang

    2017-01-01

    Purpose Various genetic variants have been reported to be linked to an increased risk of meningioma. However, no confirmed conclusion has been obtained. The purpose of the study was to investigate potential meningioma-associated gene polymorphisms, based on published evidence. Materials and methods An updated meta-analysis was performed in September 2016. After electronic database searching and study screening, we selected eligible case-control studies and extracted data for meta-analysis, using Mantel–Haenszel statistics. P-values, pooled odds ratios (ORs), and 95% confidence intervals were calculated. Results We finally selected eight genes with ten polymorphisms: MLLT10 rs12770228, CASP8 rs1045485, XRCC1 rs1799782, rs25487, MTHFR rs1801133, rs1801131, MTRR rs1801394, MTR rs1805087, GSTM1 null/present, and GSTT1 null/present. Results of meta-analyses showed that there was increased meningioma risk in case groups under all models of MLLT10 rs12770228 (all OR >1, P<0.001), compared with control groups. Similar results were observed under the allele, homozygote, dominant, and recessive models of MTRR rs1801394 (all OR >1, P<0.05), and the heterozygote and dominant models of MTHFR rs1801131 in the Caucasian population (all OR >1, P<0.05). However, no significantly increased meningioma risks were observed for CASP8 rs1045485, XRCC1 rs25487, rs1799782, MTHFR rs1801133, MTR rs1805087, or GSTM1/GSTT1 null mutations. Conclusion Our updated meta-analysis provided statistical evidence for the role of MLLT10 rs12770228, MTRR rs1801394, and MTHFR rs1801131 in increased susceptibility to meningioma.

  8. Methylenetetrahydrofolate Reductase 677TT Genotype may be Associated with an Increased Lung Cancer Risk in North China: An Updated Meta

    PubMed Central

    Liu, Nan-Bo; Li, Jun; Qi, Jia-Feng; Zhang, Zhen-Zhong; Wu, Xu; Zhang, Jun-Hua

    2014-01-01

    Background Although many epidemiology studies have investigated the methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and their associations with lung cancer (LC), definite conclusions cannot be drawn. To clarify the effects of MTHFR polymorphisms on the risk of LC, we performed a meta-analysis in Chinese populations. Material/Methods Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) until 16 February 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. Results A total of 11 studies with 2487 LC cases and 3228 controls were included in this meta-analysis. Overall, no significant association was found between MTHFR C677T polymorphism and LC risk when all studies in Chinese populations were pooled into this meta-analysis. In subgroup analyses stratified by geographical location and source of controls, significantly increased risk was found in North China (T vs. C: OR=1.28, 95% CI: 1.14–1.44; TT vs. CC: OR=1.67, 95% CI: 1.33–2.10; TT + CT vs. CC, OR=1.39, 95% CI=1.15–1.69; TT vs. CC + CT: OR=1.46, 95% CI: 1.03–2.06) and in population-based studies (TT vs. CC: OR=1.37, 95% CI: 1.14–1.65; TT vs. CC + CT: OR=1.25, 95% CI: 1.07–1.45). Conclusions This meta-analysis provides evidence that MTHFR C677T polymorphism may contribute to LC development in North China. Studies with larger sample sizes and wider spectrum of populations are warranted to verify this finding. PMID:25544260

  9. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.

    PubMed Central

    Kluijtmans, L. A.; van den Heuvel, L. P.; Boers, G. H.; Frosst, P.; Stevens, E. M.; van Oost, B. A.; den Heijer, M.; Trijbels, F. J.; Rozen, R.; Blom, H. J.

    1996-01-01

    Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T-->C (I278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C-->T; A-->V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHRF activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T-->C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-->T mutation in the MTHFR gene was found in (15%) of 60 cardiovascular patients and in only 6 (approximately 5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.2]). Because of both the high prevalence of the 833T-->C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease. PMID:8554066

  10. [Association between methylene-tetrahydrofolate reductase gene polymorphisms and chronic myeloid leukemia].

    PubMed

    Dorgham, Samia; Aberkane, Meriem; Boughrara, Wefa; Antar Soltan, Badra; Mehalhal, Nemra; Touhami, Hadj; Sidimansour, Noureddine; Merad Boudia, Nadia; Louhibi, Lotfi; Boudjema, Abdallah

    2014-09-01

    Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolism. Few studies were reported about its relationship with chronic myeloid leukemia (CML). We conducted a case-control study analyzing the prevalence of the polymorphisms MTHFR C677T and MTHFR A1298C in Algerians CML patients. Using TaqMan(®) allelic discrimination assay, we investigate MTHFR C677T and A1298C polymorphism distribution in 90 cases of CML and 100 healthy subjects. The frequencies of 677T alleles and genotypes 677TT and 677CT were significantly higher in cases than in control (P = 1E-6; OR = 6.77 [4.22-10.86]) and (P = 1E-6; OR = 10.38 [4.56-23.6]) respectively. Also, the frequencies of 1298C alleles and genotypes 1298CC and 1298AC were higher in cases (P = 9 E-6; OR = 2.65 [1.71-4.10]) and (P = 0.008; OR = 2.22 [1.21-4.06]) respectively. We report also the higher significance of the haplotype 677T/1298A and 677T/1298C in cases (P = 0.007; OR = 2.57 [1.26-5.24]) and (P = 5 E-6, OR = 6.91 [2.7646-17.2899]) respectively. Our results demonstrate that 677T and 1298C alleles are both associated with an increased risk of CML in Algeria.

  11. Association between C677T Polymorphism of Methylene Tetrahydrofolate Reductase and Congenital Heart Disease: Meta-Analysis of 7,697 Cases and 13,125 Controls

    PubMed Central

    Mamasoula, Chrysovalanto; Prentice, R. Reid; Pierscionek, Tomasz; Pangilinan, Faith; Mills, James L.; Druschel, Charlotte; Pass, Kenneth; Russell, Mark W.; Hall, Darroch; Töpf, Ana; Brown, Danielle L.; Zelenika, Diana; Bentham, Jamie; Cosgrove, Catherine; Bhattacharya, Shoumo; Riveron, Javier Granados; Setchfield, Kerry; Brook, J. David; Bu'Lock, Frances A.; Thornborough, Chris; Rahman, Thahira J.; Doza, Julian Palomino; Tan, Huay L.; O'Sullivan, John; Stuart, A. Graham; Blue, Gillian; Winlaw, David; Postma, Alex V.; Mulder, Barbara J.M.; Zwinderman, Aelko H.; van Engelen, Klaartje; Moorman, Antoon F.M.; Rauch, Anita; Gewillig, Marc; Breckpot, Jeroen; Devriendt, Koen; Lathrop, G. Mark; Farrall, Martin; Goodship, Judith A.; Cordell, Heather J.; Brody, Lawrence C.; Keavney, Bernard D.

    2013-01-01

    Background Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. Methods and Results We compared genotypes between CHD cases and controls, and between mothers of CHD cases and controls. We placed our results in context by conducting metaanalyses of previously published studies. Among 5,814 cases with primary genotype data and 10,056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (OR 0.96 [95% CI 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7,697 cases and 13,125 controls) suggested the presence of association (OR 1.25 [95% CI 1.03-1.51]; p=0.022), but with substantial heterogeneity among contributing studies (I2=64.4%), and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR less than 0.05), which together contributed 83% of all cases, yielded no evidence of association (OR 0.97 [95% CI 0.91-1.03]), without significant heterogeneity (I2=0). Moreover, meta-analysis of 1,781 mothers of CHD cases (829 of whom were genotyped in this study) and 19,861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR 1.13 [95% CI 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. Conclusions The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association. PMID:23876493

  12. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status

    PubMed Central

    Friso, Simonetta; Choi, Sang-Woon; Girelli, Domenico; Mason, Joel B.; Dolnikowski, Gregory G.; Bagley, Pamela J.; Olivieri, Oliviero; Jacques, Paul F.; Rosenberg, Irwin H.; Corrocher, Roberto; Selhub, Jacob

    2002-01-01

    DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/μg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status. PMID:11929966

  13. Alcohol-induced One-carbon Metabolism Impairment Promotes Dysfunction of DNA Base Excision Repair in Adult Brain*

    PubMed Central

    Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G.; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J.; Bergeson, Susan E.; Henderson, George I.; Kruman, Inna I.

    2012-01-01

    The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr+/− mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain. PMID:23118224

  14. Primary thrombophilia in Mexico: a single tertiary referral hospital experience.

    PubMed

    Lacayo-Leñero, Dennis; Hernández-Hernández, Darinel; Valencia-Martínez, Andrés; Barrales-Benítez, Olga; Vargas-Ruiz, Angel G

    2016-12-01

    Thrombophilia is a complex hypercoagulable state that increases the risk of thrombosis. Most reports in medical literature of the Mexican population with this disease lack statistical validity. Therefore, the aim of this study is to describe the prevalence of primary thrombophilia in a tertiary referral hospital in Mexico. This is a study of patients referred to our hospital because of a hypercoagulable state and who later on were diagnosed with primary thrombophilia. The thrombophilia workup included methylenetetrahydrofolate reductase (MTHFR) C677T, antiphospholipid antibodies, protein C, protein S, antithrombin, factor VIII, factor V Leiden, prothrombin mutation G20210A, activated protein C resistance, JAK2 V617F and homocysteine. Ninety-five individuals were tested. The MTHFR C677T polymorphism was the most frequent anomaly in 84.1% of the tested individuals. There was a relatively low prevalence of factor V Leiden (5.2%) and anticoagulant protein deficiency (8.3%). The MTHFR C677T polymorphism has a very high prevalence compared with the low prevalence of anticoagulant protein deficiency and factor V Leiden mutation in Mexicans.

  15. Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals

    PubMed Central

    Wu, Wei; Guo, Ye; Cui, Wei

    2015-01-01

    Background Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy), folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism on risk of cancer overall. Method Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs) and mean differences and presented with 95% confidence intervals (95% CIs) and 2-sided probability values. Results We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC) polymorphism was positively associated with overall risk of cancer. Conclusion Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer. PMID:25985325

  16. Hyperhomocysteinemia and the compound heterozygous state for methylene tetrahydrofolate reductase are independent risk factors for deep vein thrombosis among South Indians.

    PubMed

    Naushad, Sm; Jamal, Nurul Jain; Angalena, R; Prasad, C Krishna; Devi, A Radha Rama

    2007-03-01

    To investigate the role of methylene tetrahydrofolate reductase (MTHFR) (677 C-->T and 1298 A-->C), factor V (1691 G-->A), factor II (20210 G-->A) genetic polymorphisms and hyperhomocysteinemia in the aetiology of deep vein thrombosis (DVT) in 163 cases and 163 controls. Polymerase chain reaction-restriction fragment length polymorphism was used for genotyping, reverse-phase high-performance liquid chromatography for plasma homocysteine, and Student's t-test and Fisher exact tests were used for statistical analysis. Elevated mean plasma homocysteine levels were observed in DVT cases irrespective of gender differences. Homocysteine elevation above the 95th percentile of the control group associated with 9.4-fold and 7.6-fold increased risk for DVT in men and women, respectively. Genotyping showed the MTHFR 677CT/1298AC genotype (i.e. compound heterozygosity) is associated with 3.5-fold risk for thrombosis. The factor V Leiden mutation frequency was higher in DVT cases, but not statistically significant; however, genetic predisposition to this mutation was associated with early age of DVT onset. Factor II mutation was absent in cases and controls. Co-segregation of two or more risk factors was associated with 11.7-fold increased risk for thrombosis. This study projects that hyperhomocysteinemia and compound heterozygous state for MTHFR are independent risk factors for DVT among South Indians.

  17. Alcohol consumption, genetic variants in the alcohol- and folate metabolic pathways and colorectal cancer risk: the JPHC Study

    PubMed Central

    Svensson, Thomas; Yamaji, Taiki; Budhathoki, Sanjeev; Hidaka, Akihisa; Iwasaki, Motoki; Sawada, Norie; Inoue, Manami; Sasazuki, Shizuka; Shimazu, Taichi; Tsugane, Shoichiro

    2016-01-01

    The association between alcohol intake and colorectal cancer (CRC) may vary secondary to single nucleotide polymorphisms (SNPs) in two pathways related to alcohol intake. 375 cases of CRC were identified among 38 373 Japan Public Health Center-based prospective Study (JPHC Study) participants who had returned a baseline questionnaire, reported no diagnosis of any cancer and provided blood samples. For each case, two controls were selected on matching variables. Logistic regression models were used to determine matched Odds Ratios (OR) and 95% Confidence Intervals (CI) for the association between alcohol consumption, genetic polymorphisms of enzymes in the alcohol- and folate metabolic pathways (e.g. methylenetetrahydrofolate reductase (MTHFR) rs1801133) and CRC risk. Compared to never/occasional alcohol intake, moderate to heavy alcohol intake was associated with CRC (OR = 2.12, 95% CI, 1.34–3.36). When compared to the CC genotype, the MTHFR rs1801133 CT/TT genotype was inversely associated with CRC (OR = 0.72, 95% CI, 0.54–0.97). Never/occasional consumers of alcohol with the MTHFR rs1801133 CT/TT genotype were also at a reduced risk of CRC compared to never/occasional drinkers with the CC genotype (OR = 0.68, 95% CI, 0.47–0.98) (P for interaction = 0.27). The results indicate that the folate pathway is likely to be involved in alcohol-related CRC development. PMID:27827401

  18. 5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects

    SciTech Connect

    Ou, C.Y.; Brown, V.K.; Khoury, M.J.

    1996-06-28

    Persons with a thermolabile form of the enzyme 5,10 methylenetetrahydrofolate reductase (MTHFR) have reduced enzyme activity and increased plasma homocysteine which can be lowered by supplemental folic acid. Thermolability of the enzyme has recently been shown to be caused by a common mutation (677C{sup {r_arrow}}T) in the MTHFR gene. We studied 41 fibroblast cultures from NTD-affected fetuses and compared their genotypes with those of 109 blood specimens from individuals in the general population. 677C{sup {r_arrow}}T homozygosity was associated with a 7.2 fold increased risk for NTDs (95% confidence interval: 1.8-30.3; p value: 0.001). These preliminary data suggest that the 677C{sup {r_arrow}}T polymorphism of the MTHFR gene is a risk factor for spina bifida and anencephaly that may provide a partial biologic explanation for why folic acid prevents these types of NTD. 13 refs., 1 fig., 1 tab.

  19. Elevated total plasma homocysteine and 667C{r_arrow}T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease

    SciTech Connect

    De Franchis, R.; Sebastio, G.; Andria, G.

    1996-07-01

    Moderate elevation of total plasma homocysteine (tHcy) has been reported as an independent risk factor for thrombotic vascular disease, a well-known multifactorial disorder. Possible genetic causes of elevated tHcy include defects of the sulfur-containing amino acids metabolism due to deficiencies of cystathionine {Beta}-synthase, of 5,10-methylenetetrahydrofolate reductase (MTHFR), and of the enzymes of cobalamin metabolism. An impaired activity of MTHFR due to a thermolabile form of the enzyme has been observed in {le}28% of hyperhomocysteinemic patients with premature vascular disease. More recently, the molecular basis of such enzymatic thermolability has been related to a common mutation of the MTHFR gene, causing a C-to-T substitution at nt 677 (677C{r_arrow}T). This mutation was found in 38% of unselected chromosomes from 57 French Canadian individuals. The homozygous state for the mutation was present in 12% of these subjects and correlated with significantly elevated tHcy. Preliminary evidence indicates that the frequency of homozygotes for the 677C{r_arrow}T mutation may vary significantly in populations from different geographic areas. 5 refs., 2 tabs.

  20. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression.

    PubMed

    Bhatia, Pankaj; Singh, Nirmal

    2015-12-01

    Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression.

  1. Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients.

    PubMed

    Burda, Patricie; Schäfer, Alexandra; Suormala, Terttu; Rummel, Till; Bürer, Céline; Heuberger, Dorothea; Frapolli, Michele; Giunta, Cecilia; Sokolová, Jitka; Vlášková, Hana; Kožich, Viktor; Koch, Hans Georg; Fowler, Brian; Froese, D Sean; Baumgartner, Matthias R

    2015-06-01

    5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations.

  2. Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state.

    PubMed

    Dell'edera, Domenico; Tinelli, Andrea; Milazzo, Giusi Natalia; Malvasi, Antonio; Domenico, Carone; Pacella, Elena; Pierluigi, Compagnoni; Giuseppe, Tarantino; Marcello, Guido; Francesco, Lomurno; Epifania, Annunziata Anna

    2013-08-01

    The role of hyperhomocysteinemia (HHcy) as a cardiovascular risk factor remains a matter of debate, while it correlates with folates, it demonstrates inverse correlation with plasma homocysteine (Hcy) levels and vitamin B12 levels and reduces plasma Hcy levels following supplementation with multivitamins. The purpose of this study was to demonstrate that administering multivitamins at specific doses for 90 days restores normal plasma Hcy levels in women who are homozygous for the thermolabile variant of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T). We enrolled 106 healthy females aged between 30 and 42 years, who were non-smokers, non-vegetarian, normotensive and who had no history of food abuse in the previous months. Only females were enrolled in order to rule out any bias due to the variation in Hcy plasma concentrations between males and females. Patient blood sampling was performed in order to determine plasma Hcy, serum folic acid and vitamin B12 levels. Furthermore, molecular characterization of the C677T polymorphism present in the MTHFR gene, was also performed. The results of this study demonstrated that supplementation with specific multivitamins restores normal plasma Hcy levels, regardless of the MTHFR genotype. Furthermore, it is unnecessary to adminster high doses of folate to reduce plasma Hcy levels, and administering high doses of folate may cause pro-inflammatory and pro-proliferative effects.

  3. Recurrent cerebral venous thrombosis associated with heterozygote methylenetetrahydrofolate reductase C677T mutation and sickle cell trait without homocysteinemia: an autopsy case report and review of literature.

    PubMed

    Ali, Z; Troncoso, J C; Fowler, D R

    2014-09-01

    Elevated blood homocysteine concentration and certain genetic mutations have been associated with increased risk for developing arterial and venous thrombosis. A common mutation of methylenetetrahydrofolate reductase, MTHFR C677T, has been associated with elevated homocysteine concentration and increased risk for developing thrombosis in homozygote carriers. Heterozygote carriers for this gene mutation, if associated with other major or minor risk factors for thrombophilia, appear to be prone to develop thrombosis. A postmortem genetic testing for common mutations resulting in thrombophilia should be performed in all individuals who die as a result of thrombosis, regardless of predisposing risk factors, to determine the true prevalence of mutations in these individuals, and to assess the true role of a certain mutation, such as heterozygote MTHFR C677T, in the pathogenesis of thrombosis. Postmortem genetic testing for common mutations associated with thrombophilia in selected cases has potentially life-saving importance to surviving family members. We report a case of recurrent cerebral venous thrombosis in a 19 year old male with history of sickle cell trait, obesity, and high normal blood homocysteine, who was heterozygote for MTHFR C677T mutation.

  4. The MET13 methylenetetrahydrofolate reductase gene is essential for infection-related morphogenesis in the rice blast fungus Magnaporthe oryzae.

    PubMed

    Yan, Xia; Que, Yawei; Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J; Wang, Zhengyi

    2013-01-01

    Methylenetetrahydrofolate reductases (MTHFRs) play a key role in the biosynthesis of methionine in both prokaryotic and eukaryotic organisms. In this study, we report the identification of a novel T-DNA-tagged mutant WH672 in the rice blast fungus Magnaporthe oryzae, which was defective in vegetative growth, conidiation and pathogenicity. Analysis of the mutation confirmed a single T-DNA insertion upstream of MET13, which encodes a 626-amino-acid protein encoding a MTHFR. Targeted gene deletion of MET13 resulted in mutants that were non-pathogenic and significantly impaired in aerial growth and melanin pigmentation. All phenotypes associated with Δmet13 mutants could be overcome by addition of exogenous methionine. The M. oryzae genome contains a second predicted MTHFR-encoding gene, MET12. The deduced amino acid sequences of Met13 and Met12 share 32% identity. Interestingly, Δmet12 mutants produced significantly less conidia compared with the isogenic wild-type strain and grew very poorly in the absence of methionine, but were fully pathogenic. Deletion of both genes resulted in Δmet13Δmet12 mutants that showed similar phenotypes to single Δmet13 mutants. Taken together, we conclude that the MTHFR gene, MET13, is essential for infection-related morphogenesis by the rice blast fungus M. oryzae.

  5. Levels of Key Enzymes of Methionine-Homocysteine Metabolism in Preeclampsia

    PubMed Central

    Pérez-Sepúlveda, Alejandra; España-Perrot, Pedro P.; Fernández B, Ximena; Ahumada, Verónica; Bustos, Vicente; Arraztoa, José Antonio; Dobierzewska, Aneta; Figueroa-Diesel, Horacio; Rice, Gregory E.; Illanes, Sebastián E.

    2013-01-01

    Objective. To evaluate the role of key enzymes in the methionine-homocysteine metabolism (MHM) in the physiopathology of preeclampsia (PE). Methods. Plasma and placenta from pregnant women (32 controls and 16 PE patients) were analyzed after informed consent. Protein was quantified by western blot. RNA was obtained with RNA purification kit and was quantified by reverse transcritase followed by real-time PCR (RT-qPCR). Identification of the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and A2756G methionine synthase (MTR) SNP was performed using PCR followed by a high-resolution melting (HRM) analysis. S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH) were measured in plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). The SNP association analysis was carried out using Fisher's exact test. Statistical analysis was performed using a Mann-Whitney test. Results. RNA expression of MTHFR and MTR was significantly higher in patients with PE as compared with controls. Protein, SAM, and SAH levels showed no significant difference between preeclamptic patients and controls. No statistical differences between controls and PE patients were observed with the different SNPs studied. Conclusion. The RNA expression of MTHFR and MTR is elevated in placentas of PE patients, highlighting a potential compensation mechanism of the methionine-homocysteine metabolism in the physiopathology of this disease. PMID:24024209

  6. Association between Thrombophilia and Repeated Assisted Reproductive Technology Failures

    PubMed Central

    Hamdi, Kobra; Vaezi, Maryam; Dagigazar, Behrooz; Mehrzad Sadagiani, Mahzad; Farzadi, Laya; Pashaei-Asl, Maryam

    2012-01-01

    Purpose: This study was performed to investigate the incidence of thrombophilic gene mutations in repeated assisted reproductive technology (ART) failures. Methods: The prevalence of mutated genes in the patients with a history of three or more previous ART failures was compared with the patients with a history of successful pregnancy following ARTs. The study group included 70 patients, 34 with three or more previously failed ARTs (A) and control group consisted of 36 patients with successful pregnancy following ARTs (B). All patients were tested for the presence of mutated thrombophilic genes including factor V Leiden (FVL), Methylenetetrahydrofolate reductase (MTHFR) and Prothrombin (G20210A) using real-time polymerase chain reaction (RT- PCR). Results: Mutation of FVL gene was detected in 5.9% women of group A (2 of 34) compared with 2.8% women (1 of 36) of control group (P = 0.6). Mutation of MTHFR gene was found in 35.3% (12 cases) as compared with 50% (18 cases) of control (35.3% versus 50%; P = 0.23). Regarding Prothrombin, only control group had 5.6% mutation (P = 0.49). No significant differences were detected in the incidences of FVL, Prothrombin and MTHFR in the study group A compared with the control group B. Conclusion: The obtained results suggest that thrombophilia does not have a significant effect in ART failures. PMID:24312798

  7. Gene-gene interactions in the folate metabolic pathway influence the risk for acute lymphoblastic leukemia in children.

    PubMed

    Petra, Bohanec Grabar; Janez, Jazbec; Vita, Dolzan

    2007-04-01

    Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Genetic polymorphisms in the folate metabolic pathway may contribute to the susceptibility to childhood ALL because they affect the DNA synthesis, methylation and repair. We analysed common genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MS) and methionine synthase reductase (MTRR) in 68 children with ALL and 258 healthy controls to investigate their influence on the risk for ALL. No significant differences in frequencies of separate polymorphisms were observed between both groups. Combined MTHFR 677CT/TT and MS 2756AG/GG genotypes showed a nonsignificant tendency to reduce the risk for ALL 2.24-fold (CI: 0.191 - 1.037, P: 0.061). The risk was significantly reduced in carriers of combined MTHFR 677CT/TT, MS 2756AG/GG and MTRR 66AG/GG genotypes (OR: 0.312; CI: 0.107 - 0.907; P: 0.032). Our results suggest that gene - gene interactions that may decrease the methylation capacity might have a protective effect on the risk for childhood ALL.

  8. [Vascular diseases, spina bifida and schizophrenia in a single family associated with the heterozygote mutation of the heat-sensitive variant of methylenetetrahydrofolate reductase].

    PubMed

    Horváth, A; Morava, E; Tóth, G; Czakó, M; Melegh, B; Kosztolányi, G

    2001-07-08

    Homozygous mutation of the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) may result in hyperhomocystinemia, leading to an increased risk for early cardiovascular disease, neural tube defects, and possibly major depression, schizophrenia. According to recent studies heterozygosity for the thermolabile variant of the MTHFR gene mutation is also more frequent in patients with thrombotic disease compared to that in the average population. We report on a family with different types of early vascular disease. In four consecutive generations MTHFR heterozygosity was detected: in the proband and in her mother, grandfather and daughter. Further conditions of the family members, possibly due to carrying the mutation, came to light by the pedigree analysis and examinations. The patient had pulmonary emboli at young age, her aunt died of spina bifida shortly after birth. The patient's mother suffers from schizophrenia and depression. The grandfather had pulmonary emboli, her sister with spina bifida occulta also carries the same mutation, as does her daughter who is sofar asymptomatic. In other asymptomatic members of the family no mutations were found. Unexpectedly, hyperhomocystinemia was detected in all heterozygote individuals. Our study demonstrates the necessity for folic acid therapy in mutation carriers to prevent early vascular events, depression and schizophrenia, and also to reduce the risk for neural tube defects in a preconception setting.

  9. Methylenetetrahydrofolate reductase C677T polymorphism and Factor V Leiden variant in Mexican women with preeclampsia/eclampsia.

    PubMed

    Dávalos, I P; Moran, M C; Martínez-Abundis, E; González-Ortiz, M; Flores-Martínez, S E; Machorro, V; Sandoval, L; Figuera, L E; Mena, J P; Oliva, J M; Tlacuilo-Parra, J A; Sánchez-Corona, J; Salazar-Páramo, M

    2005-01-01

    The etiology of preeclampsia is still a matter of controversy. An association between hyperhomocysteinemia and preeclamptic patients has been described. A common missense mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased plasma homocysteine concentrations. In addition, the polymorphism of gene encoding for Factor V Leiden G1691A is associated with a prothrombotic state in heterozygous subjects. Both mutations in these thrombophilic proteins appear to have different prevalence in the general population and in patients with preeclampsia/eclampsia (PE/E). We studied single nucleotide polymorphisms for MTHFR C677T and coagulation Factor V Leiden in 33 Mexican patients with PE/E as a genetic risk factor for these diseases, comparing with a normotensive pregnant control group. The genotype and allele frequencies of MTHFR C677T and Factor V Leiden mutations between Mexican women with PE/E and healthy controls were not different. We conclude that these polymorphisms do not contribute in the etiology of PE/E as it has been reported in other populations.

  10. Recent insights into the molecular genetics of the homocysteine metabolism.

    PubMed

    Födinger, M; Wagner, O F; Hörl, W H; Sunder-Plassmann, G

    2001-02-01

    The homocysteine plasma level is determined by non-genetic and genetic factors. In recent years evidence has accumulated that the total homocysteine plasma level of patients under different forms of renal replacement therapy is influenced by a common mutation at nucleotide position 677 of the gene coding for 5,10-methylenetetrahydrofolate reductase (MTHFR 677C-->T). Furthermore, compound heterozygosity for the 677T allele and a novel A-->C polymorphism at nucleotide position 1298 of MTHFR is suggested to correlate with a decrease of folate plasma concentrations. Because polymorphisms of genes coding for proteins involved in the metabolism of homocysteine may contribute to elevated total homocysteine plasma concentrations, molecular genetic analyses of the homocysteine pathways experienced a drift towards screening for candidate genes with a putative relationship to total homocysteine plasma levels. One example is the cloning of the FOLR1 gene coding for the folate-binding protein (Folbp1), which has recently been inactivated in mice, thus representing an elegant model to investigate the consequence on the homocysteine metabolism. Furthermore, the recent characterization of the CUBN gene encoding the intrinsic factor-vitamin B12 receptor (cubilin) provides a basis to identify the causative mutations in patients suffering from a hereditary syndrome of hyperhomocysteinemia that presents with megaloblastic anemia and proteinuria. This review focuses on recent insights into the molecular genetics of MTHFR, FOLR1, and CUBN, and their relationships to the metabolism of the amino acid homocysteine.

  11. Methylation analysis of multiple genes in blood DNA of Alzheimer's disease and healthy individuals.

    PubMed

    Tannorella, Pierpaola; Stoccoro, Andrea; Tognoni, Gloria; Petrozzi, Lucia; Salluzzo, Maria Grazia; Ragalmuto, Alda; Siciliano, Gabriele; Haslberger, Alexander; Bosco, Paolo; Bonuccelli, Ubaldo; Migliore, Lucia; Coppedè, Fabio

    2015-07-23

    We collected blood DNA from 120 late-onset Alzheimer's disease (AD) patients and 115 healthy matched controls and analysed the methylation levels of genes involved in amyloid-beta peptide production (PSEN1 and BACE1), in DNA methylation (DNMT1, DNMT3A and DNMT3B), and in one-carbon metabolism (MTHFR), searching for correlation with age and gender, with biomarkers of one-carbon metabolism (plasma homocysteine, and serum folate and vitamin B12 levels), and with disease status (being healthy or having AD). We also evaluated the contribution of the APOE ϵ4 allele, the major late-onset AD genetic risk factor, to the studied gene methylation levels. All the genes showed low mean methylation levels (<5%) in both AD and control DNA, no difference between groups, and no correlation with the studied biomarkers, except for MTHFR that showed methylation levels ranging from 5% to 75%, and correlation with circulating biomarkers of one-carbon metabolism. However, mean MTHFR methylation levels were similar between groups (31.1% in AD and 30.7% in controls, P=0.58). Overall, present data suggest that none of the studied regions is differently methylated in blood DNA between AD and control subjects.

  12. The MET13 Methylenetetrahydrofolate Reductase Gene Is Essential for Infection-Related Morphogenesis in the Rice Blast Fungus Magnaporthe oryzae

    PubMed Central

    Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J.; Wang, Zhengyi

    2013-01-01

    Methylenetetrahydrofolate reductases (MTHFRs) play a key role in the biosynthesis of methionine in both prokaryotic and eukaryotic organisms. In this study, we report the identification of a novel T-DNA-tagged mutant WH672 in the rice blast fungus Magnaporthe oryzae, which was defective in vegetative growth, conidiation and pathogenicity. Analysis of the mutation confirmed a single T-DNA insertion upstream of MET13, which encodes a 626-amino-acid protein encoding a MTHFR. Targeted gene deletion of MET13 resulted in mutants that were non-pathogenic and significantly impaired in aerial growth and melanin pigmentation. All phenotypes associated with Δmet13 mutants could be overcome by addition of exogenous methionine. The M. oryzae genome contains a second predicted MTHFR-encoding gene, MET12. The deduced amino acid sequences of Met13 and Met12 share 32% identity. Interestingly, Δmet12 mutants produced significantly less conidia compared with the isogenic wild-type strain and grew very poorly in the absence of methionine, but were fully pathogenic. Deletion of both genes resulted in Δmet13Δmet12 mutants that showed similar phenotypes to single Δmet13 mutants. Taken together, we conclude that the MTHFR gene, MET13, is essential for infection-related morphogenesis by the rice blast fungus M. oryzae. PMID:24116181

  13. Investigation of CBS, MTR, RFC-1 and TC polymorphisms as maternal risk factors for Down syndrome.

    PubMed

    Fintelman-Rodrigues, N; Corrêa, J C; Santos, J M; Pimentel, M M G; Santos-Rebouças, C B

    2009-01-01

    Recent evidence shows that almost 92% of the DS children are born from young mothers, suggesting that other risk factors than advanced maternal age must be involved. In this context, some studies demonstrated a possible link between DS and maternal polymorphisms in genes involved in folate metabolism. These polymorphisms, as well as low intake of folate could generate genomic instability, DNA hypomethylation and abnormal segregation, leading to trisomy 21. We compared the frequency of CBS 844ins68, MTR 2756A>G, RFC-1 80G> A and TC 776C>G polymorphisms among 114 case mothers and 110 matched controls, in order to observe whether these variants act as risk factors for DS. The genotype distributions revealed that there were not significant differences between both samples. However, when we proceed the multiplicative interaction analyses between the four polymorphisms described above together with the previously studied MTHFR 677C>T, MTHFR 1298A>C and MTRR 66A>G polymorphisms, our results show that the combined genotype TC 776CC / MTHFR 677TT and TC 776CC / MTR 2756AG were significantly higher in the control sample. Nevertheless, there was no significant association after Bonferroni correction. Our results suggest that maternal folate-related polymorphisms studied here have no influence on trisomy 21 susceptibility in subjects of Brazilian population.

  14. Etiopathogenesis of Sheehan's Syndrome: Roles of Coagulation Factors and TNF-Alpha

    PubMed Central

    Bayram, Fahri; Tascioglu, Nazife; Simsek, Yasin; Dundar, Munis

    2014-01-01

    Sheehan's Syndrome (SS) is defined as pituitary hormone deficiency due to ischemic infarction of the pituitary gland as a result of massive postpartum uterine hemorrhage. Herein, we aimed to investigate the roles of Factor II (G20210A), Factor V (G1691A), MTHFR (C677T and A1298C), PAI-1 4G/5G, and TNF-α (−308  G > A) gene polymorphisms in the etiopathogenesis of SS. Venous blood samples were obtained from 53 cases with SS and 43 healthy women. Standard methods were used to extract the genomic DNAs. Factor II (G20210A), Factor V (G1691A), and MTHFR (C677T and A1298C) polymorphisms were identified by real-time PCR. PAI-1 4G/5G and TNF-α (−308  G > A) gene polymorphisms were detected with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. According to statistical analysis, none of the polymorphisms were found to be significantly higher in the SS group compared to the control group. Hence, we suggest that genetic factors other than Factor II, Factor V, MTHFR, PAI-1, and TNF-α gene polymorphisms should be researched in the etiopathogenesis of SS. PMID:24891849

  15. Etiopathogenesis of Sheehan's Syndrome: Roles of Coagulation Factors and TNF-Alpha.

    PubMed

    Diri, Halit; Sener, Elif Funda; Bayram, Fahri; Tascioglu, Nazife; Simsek, Yasin; Dundar, Munis

    2014-01-01

    Sheehan's Syndrome (SS) is defined as pituitary hormone deficiency due to ischemic infarction of the pituitary gland as a result of massive postpartum uterine hemorrhage. Herein, we aimed to investigate the roles of Factor II (G20210A), Factor V (G1691A), MTHFR (C677T and A1298C), PAI-1 4G/5G, and TNF- α (-308  G > A) gene polymorphisms in the etiopathogenesis of SS. Venous blood samples were obtained from 53 cases with SS and 43 healthy women. Standard methods were used to extract the genomic DNAs. Factor II (G20210A), Factor V (G1691A), and MTHFR (C677T and A1298C) polymorphisms were identified by real-time PCR. PAI-1 4G/5G and TNF- α (-308  G > A) gene polymorphisms were detected with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. According to statistical analysis, none of the polymorphisms were found to be significantly higher in the SS group compared to the control group. Hence, we suggest that genetic factors other than Factor II, Factor V, MTHFR, PAI-1, and TNF- α gene polymorphisms should be researched in the etiopathogenesis of SS.

  16. Population-level diversity in the association of genetic polymorphisms of one-carbon metabolism with breast cancer risk.

    PubMed

    Naushad, Shaik Mohammad; Divya, Chandrasekhar; Janaki Ramaiah, M; Hussain, Tajamul; Alrokayan, Salman A; Kutala, Vijay Kumar

    2016-10-01

    Aberrations in one-carbon metabolism were reported to increase breast cancer risk by influencing the DNA synthesis and methylation of DNA and catecholamines. However, the results of these association studies remain inconclusive. We have explored the contribution of eight genetic polymorphisms in modulating the susceptibility to breast cancer by performing a meta-analysis of worldwide studies. In total, 62 case-control studies representing 17 different populations involving 18,117 breast cancer cases and 23,573 healthy controls were included in this meta-analysis. Out of the eight polymorphisms analyzed, methylenetetrahydrofolate reductase (MTHFR) C677T exhibited positive association with the breast cancer risk in both fixed effects (OR 1.14, 95 % CI 1.10-1.17) and random effects (OR 1.10, 95 % CI 1.02-1.18) models. Solute carrier family 19 (folate transporter), member 1 (SLC19A1) G80A exhibited positive association (OR 1.16, 95 % CI 1.03-1.31) while MTR A2756G exhibited an inverse association (OR 0.78, 95 % CI 0.75-0.82) with the breast in fixed effect model alone. Significant heterogeneity was observed in the association of MTHFR C677T with breast cancer even between studies from the same geographical area, specifically among Chinese, Indians, and Turks. Subgroup analysis revealed MTHFR C677T-mediated breast cancer risk in post-menopausal women and women with low dietary intake of folate. Geographical area wise segregation of data revealed MTHFR-mediated increased breast cancer risk in populations who consume methionine-rich diet. Altitude-level variations were observed in the association of SHMT1 C1420T with breast cancer. India and Brazil of same altitude showed an inverse association with this polymorphism, while USA and China that share similar altitude showed a null association. MTHFR C677T and SLC19A1 G80A are the two polymorphisms of one-carbon metabolic pathway that increase breast cancer in the worldwide population. Dietary patterns and altitudinal

  17. Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children.

    PubMed

    Chan, Jason Yong-Sheng; Ugrasena, Dewa G; Lum, Danny Wai-Kiong; Lu, Yi; Yeoh, Allen Eng-Juh

    2011-09-01

    Xenobiotic and folate metabolic pathways are important for the maintenance of genetic stability and may influence susceptibility to the development of childhood acute lymphoblastic leukaemia (ALL). In this study, we investigated 10 polymorphisms in 6 genes (GSTM1-present/null, GSTT1-present/null, GSTP1 1578A > G, NQO1 609C > T, MTHFR 677C > T, MTHFR 1298A > C, MTHFD1 1958G > A, 3'-TYMS 1494 6bp-deletion/insertion, 5'-TYMS 28bp-tandem repeats, and SLC19A1 80G > A) in a cohort of 185 Javanese children with ALL and 177 healthy controls. In ALL patients, none of the polymorphisms demonstrated a statistically significant association with ALL after correcting for multiple comparisons. Gender-stratified analysis showed that in girls, GSTT1-null genotype was associated with increased ALL risk (OR = 2.20; p = 0.027), while GSTP1 1578AG genotype was associated with reduced risk (OR = 0.43; p = 0.031). Strong linkage disequilibrium between the MTHFR 677C > T and 1298A > C polymorphisms was observed (D' = 1.0; r(2) = 0.072). The haplotypes 677C-1298C and 677T-1298A were associated with a reduced risk of ALL (OR = 0.68 and 0.64, respectively; gender-adjusted global p = 0.028). Classification and regression tree (CART) analysis was employed to identify potential high-order gene-gene interactions and cluster subjects into susceptibility groups. SLC19A1 80G > A emerged as the predominant polymorphism associated with risk of ALL. Individuals simultaneously carrying MTHFR 1298AA, 3'-TYMS 6bp deletion(s) and SLC19A1 80A-allele(s) were at higher disease risk (OR = 2.21; p < 0.001). On the contrary, simultaneous possession of MTHFR 1298CC, 3'-TYMS 6bp homozygosity and SLC19A1 80A-allele(s) conferred lower risk (OR = 0.25; p = 0.004). Carriage of NQO1 609C-allele amongst SLC19A1 80GG genotype was associated with lower risk (OR = 0.47; p = 0.003). In conclusion, our study has demonstrated the importance of gender and gene-gene interaction within the xenobiotic and folate pathways in

  18. Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

    PubMed Central

    2010-01-01

    Background The association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and serum lipid profiles is still controversial in diverse ethnics. Bai Ku Yao is an isolated subgroup of the Yao minority in China. The aim of the present study was to eveluate the association of MTHFR C677T polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 780 subjects of Bai Ku Yao and 686 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the MTHFR C677T was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05-0.001). The frequency of C and T alleles was 77.4% and 22.6% in Bai Ku Yao, and 60.9% and 39.1% in Han (P < 0.001); respectively. The frequency of CC, CT and TT genotypes was 58.7%, 37.3% and 4.0% in Bai Ku Yao, and 32.6%, 56.4% and 11.0% in Han (P < 0.001); respectively. The levels of TC and LDL-C in both ethnic groups were significant differences among the three genotypes (P < 0.05-0.01). The T allele carriers had higher serum TC and LDL-C levels than the T allele noncarriers. The levels of ApoB in Han were significant differences among the three genotypes (P < 0.05). The T allele carriers had higher serum ApoB levels as compared with the T allele noncarriers. The levels of TC, TG and LDL-C in Bai Ku Yao were correlated with genotypes (P < 0.05-0.001), whereas the levels of LDL-C in Han were associated with genotypes (P < 0.001). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, cigarette smoking, and blood pressure in the both ethnic

  19. Hearing impairment risk and interaction of folate metabolism related gene polymorphisms in an aging study

    PubMed Central

    2011-01-01

    Background Recent investigations demonstrated many genetic contributions to the development of human age-related hearing impairment (ARHI), however, reports of factors associated with a reduction in the ARHI risk are rare. Folate metabolism is essential for cellular functioning. Despite the extensive investigations regarding the roles of folate metabolism related gene polymorphisms in the pathophysiology of complex diseases, such as cancer, cardio-cerebrovascular disease, and atherosclerosis, little is known about the association with ARHI. The aim of this study is to investigate the effects of the methionine synthase (MTR) A2756G and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms on the risk of hearing impairment in middle-aged and elderly Japanese. Methods Data were collected from community-dwelling Japanese adults aged 40-84 years who participated in the Longitudinal Study of Aging biennially between 1997 and 2008. We analyzed cumulative data (5,167 samples in accumulated total) using generalized estimating equations. Results The MTHFR 677T allele was significantly associated with a reduced risk of hearing impairment only when the subjects were wild-type homozygotes for MTR A2756G. The per-T allele odds ratio of MTHFR for the risk of developing hearing impairment was 0.7609 (95% CI: 0.6178-0.9372) in the MTR AA genotype. In addition, a subgroup analysis demonstrated that the favorable effect of the MTHFR 677T allele on the risk of developing hearing impairment was independent of folate and homocysteine level, whereas plasma total homocysteine level was independently associated with an increased risk of developing hearing impairment. The interactive effect of gene polymorphisms associated with folate metabolism may modify the risk of developing hearing impairment after middle age. These results contribute to the elucidation of the causes of ARHI. Conclusions The present study has found that the MTHFR 677T allele has a favorable effect on a

  20. The polymorphisms in methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and the risk of colorectal cancer.

    PubMed

    Zhou, Daijun; Mei, Qiang; Luo, Han; Tang, Bo; Yu, Peiwu

    2012-01-01

    Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.

  1. The Polymorphisms in Methylenetetrahydrofolate Reductase, Methionine Synthase, Methionine Synthase Reductase, and the Risk of Colorectal Cancer

    PubMed Central

    Zhou, Daijun; Mei, Qiang; Luo, Han; Tang, Bo; Yu, Peiwu

    2012-01-01

    Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results. PMID:22719222

  2. Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies

    PubMed Central

    Rai, Vandana; Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakesh

    2014-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis. Aim A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome. Methods PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment. Results Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR = 1.26, 95% CI = 1.09–1.46, p = 0.001; for TT vs. CC, OR = 1.49, 95% CI = 1.13–1.97, p = 0.008; for CT vs. CC, OR = 1.29, 95% CI = 1.10–1.51, p = 0.001; for TT+CT vs. CC, OR = 1.35, 95% CI = 1.13–1.60, p = 0.0008; for TT vs. CT+CC, OR = 0.76, 95% CI = 0.60–0.94, p = 0.01). Conclusion The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy. PMID:25265565

  3. Fundamental Role of Methylenetetrahydrofolate Reductase 677 C → T Genotype and Flavin Compounds in Biochemical Phenotypes for Schizophrenia and Schizoaffective Psychosis

    PubMed Central

    Fryar-Williams, Stephanie

    2016-01-01

    The Mental Health Biomarker Project (2010–2016) explored variables for psychosis in schizophrenia and schizoaffective disorder. Blood samples from 67, highly characterized symptomatic cases and 67 gender and age matched control participants were analyzed for methyl tetrahydrofolate reductase (MTHFR) 677C → T gene variants and for vitamin B6, B12 and D, folate, unbound copper, zinc cofactors for enzymes in the methylation cycle, and related catecholamine pathways. Urine samples were analyzed for indole-catecholamines, their metabolites, and oxidative-stress marker, hydroxylpyrolline-2-one (HPL). Rating scales were Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale, Global Assessment of Function scale, Clinical Global Impression (CGI) score, and Social and Occupational Functioning Assessment Scale (SOFAS). Analysis used Spearman’s correlates, receiver operating characteristics and structural equation modeling (SEM). The correlative pattern of variables in the overall participant sample strongly implicated monoamine oxidase (MAO) enzyme inactivity so the significant role of MAO’s cofactor flavin adenine nucleotide and its precursor flavin adenine mononucleotide (FMN) within the biochemical pathways was investigated and confirmed as 71% on SEM of the total sample. Splitting the data sets for MTHFR 677C → T polymorphism variants coding for the MTHFR enzyme, discovered that biochemistry variables relating to the wild-type enzyme differed markedly in pattern from those coded by the homozygous variant and that the hereozygous-variant pattern resembled the wild-type-coded pattern. The MTHFR 677C → T-wild and -heterozygous gene variants have a pattern of depleted vitamin cofactors characteristic of flavin insufficiency with under-methylation and severe oxidative stress. The second homozygous MTHFR 677TT pattern related to elevated copper:zinc ratio and a vitamin pattern related to flavin sufficiency and risk of over-methylation. The

  4. Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci.

    PubMed

    Martínez-González, J J; Guevara-Flores, A; Rendón, J L; del Arenal, I P

    2015-05-01

    Previously, we have studied the effect of the gold-compound auranofin (AF) on both thioredoxin-glutathione reductasa (TGR) activity and viability of Taenia crassiceps cysticerci. It was demonstrated that micromolar concentrations of AF were high enough to fully inhibit TGR and kill the parasites. In this work, the dynamics of changes in the glutathione pool of T. crassiceps cysticerci following the addition of AF, was analyzed. A dose-dependent decrease in the internal glutathione concentration, concomitant with an increase in ROS production was observed. These changes were simultaneous with the formation of glutathione-protein complexes and the export of glutathione disulfide (GSSG) to the culture medium. Incubation of cysticerci in the presence of both AF and N-acetyl cysteine (NAC) prevents all the above changes, maintaining cysticerci viability. By contrast, the presence of both AF and buthionine sulfoximine (BSO) resulted in a potentiation of the effects of the gold compound, jeopardizing cysticerci viability. These results suggest the lethal effect of AF on T. crassiceps cysticerci, observed at micromolar concentrations, can be explained as a consequence of major changes in the glutathione status, which results in a significant increase in the oxidative stress of the parasites.

  5. Comprehensive Evaluation of One-Carbon Metabolism Pathway Gene Variants and Renal Cell Cancer Risk

    PubMed Central

    Gibson, Todd M.; Brennan, Paul; Han, Summer; Karami, Sara; Zaridze, David; Janout, Vladimir; Kollarova, Helen; Bencko, Vladimir; Navratilova, Marie; Szeszenia-Dabrowska, Neonila; Mates, Dana; Slamova, Alena; Pfeiffer, Ruth M.; Stolzenberg-Solomon, Rachael Z.; Mayne, Susan T.; Yeager, Meredith; Chanock, Stephen; Rothman, Nat; Chow, Wong-Ho; Rosenberg, Philip S.; Boffetta, Paolo; Moore, Lee E.

    2011-01-01

    Introduction Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer. Methods Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes. Results The strongest associations with RCC risk were observed for SLC19A1 (Pmin-P = 0.03) and MTHFR (Pmin-P = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake. Conclusions To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings. PMID:22039442

  6. The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma

    PubMed Central

    Sarbia, M; Stahl, M; von Weyhern, C; Weirich, G; Pühringer-Oppermann, F

    2006-01-01

    The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy±surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value. PMID:16333305

  7. Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer.

    PubMed

    Naushad, Shaik Mohammad; Pavani, Addepalli; Digumarti, Raghunadha Rao; Gottumukkala, Suryanarayana Raju; Kutala, Vijay Kumar

    2011-11-01

    In view of growing body of evidence substantiating the role of aberrations in one-carbon metabolism in the pathophysiology of breast cancer and lack of studies on gene-gene interactions, we investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating the breast cancer risk in 244 case-control pairs of Indian women and explored possible gene-gene interactions using Multifactor dimensionality reduction analysis (MDR). Dietary micronutrient status was assessed using the validated Food Frequency Questionnaire. Genotyping was done for glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier (RFC)1 G80A, cytosolic serine hydroxymethyltransferase (cSHMT) C1420T, thymidylate synthase (TYMS) 5'-UTR tandem repeat, TYMS 3'-UTR ins6/del6, methylenetetrahydrofolate reductase (MTHFR) C677T, methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G, methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) A66G polymorphisms by using the PCR-RFLP/AFLP methods. Low dietary folate intake (P < 0.001), RFC1 G80A (OR: 1.38, 95% CI 1.06-1.81) and MTHFR C677T (OR: 1.74 (1.11-2.73) were independently associated with the breast cancer risk whereas cSHMT C1420T conferred protection (OR: 0.72, 95% CI 0.55-0.94). MDR analysis demonstrated a significant tri-variate interaction among RFC1 80, MTHFR 677 and TYMS 5'-UTR loci (P (trend) < 0.02) with high-risk genotype combination showing inflated risk for breast cancer (OR 4.65, 95% CI 1.77-12.24). To conclude, dietary as well as genetic factors were found to influence susceptibility to breast cancer. Further, the current study highlighted the importance of multi-loci analyses over the single-locus analysis towards establishing the epistatic interactions between loci of one-carbon metabolism modulate susceptibility to the breast cancer.

  8. X-Ray Cross-Complementing Group 1 and Thymidylate Synthase Polymorphisms Might Predict Response to Chemoradiotherapy in Rectal Cancer Patients

    SciTech Connect

    Lamas, Maria J.

    2012-01-01

    Purpose: 5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. Methods and Materials: A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m{sup 2}/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). Results: The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR{sub C}677 and MTHFR{sub A}1298 expression. Conclusions: XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.

  9. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism.

    PubMed

    Reed, Michael C; Nijhout, H Frederik; Neuhouser, Marian L; Gregory, Jesse F; Shane, Barry; James, S Jill; Boynton, Alanna; Ulrich, Cornelia M

    2006-10-01

    Impaired folate-mediated 1-carbon metabolism has been linked to multiple disease outcomes. A better understanding of the nutritional and genetic influences on this complex biochemical pathway is needed to comprehend their impact on human health. To this end, we created a mathematical model of folate-mediated 1-carbon metabolism. The model uses published data on folate enzyme kinetics and regulatory mechanisms to simulate the impact of genetic and nutritional variation on critical aspects of the pathway. We found that the model predictions match experimental data, while providing novel insights into pathway kinetics. Our primary observations were as follows: 1) the inverse association between folate and homocysteine is strongest at very low folate concentrations, but there is no association at high folate concentrations; 2) the DNA methylation reaction rate is relatively insensitive to changes in folate pool size; and 3) as folate concentrations become very high, enzyme velocities decrease. With regard to polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), the modeling predicts that decrease MTHFR activity reduces concentrations of S-adenosylmethionine and 5-methyltetrahydrofolate, as well as DNA methylation, while modestly increasing S-adenosylhomocysteine and homocysteine concentrations and thymidine or purine synthesis. Decreased folate together with a simulated vitamin B-12 deficiency results in decreases in DNA methylation and purine and thymidine synthesis. Decreased MTHFR activity superimposed on the B-12 deficiency appears to reverse the declines in purine and thymidine synthesis. These mathematical simulations of folate-mediated 1-carbon metabolism provide a cost-efficient approach to in silico experimentation that can complement and help guide laboratory studies.

  10. Influence of pre-hydration and pharmacogenetics on plasma methotrexate concentration and renal dysfunction following high-dose methotrexate therapy.

    PubMed

    Yanagimachi, Masakatsu; Goto, Hiroaki; Kaneko, Tetsuji; Naruto, Takuya; Sasaki, Koji; Takeuchi, Masanobu; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Shoko; Takahashi, Hiroyuki; Mori, Masaaki; Kai, Sumio; Yokota, Shumpei

    2013-12-01

    High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p < 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.

  11. Correlation of Homocysteine Metabolic Enzymes Gene Polymorphism and Mild Cognitive Impairment in the Xinjiang Uygur Population

    PubMed Central

    Luo, Mei; Ji, Huihui; Zhou, Xiaohui; Liang, Jie; Zou, Ting

    2015-01-01

    Background The aim of this study was to investigate the genetic polymorphisms in the homocysteine (HCY) metabolic enzymes in the Xinjiang Uygur population who have mild cognitive impairment (MCI). Material/Methods Based on the epidemiological investigation, 129 cases of diagnosed Uygur MCI patients and a matched control group with 131 cases were enrolled for analyzing the association between the polymorphisms in the HCY metabolism related genes (C677T, A1298C, and G1968A polymorphisms in MTHFR, as well as the A2756G polymorphism in MS) and MCI by using the SNaPshot method. We then determined the homocysteine level in patients. Results In Xinjiang Uygur subjects, the A1298C polymorphisms in MTHFR and the A2756G polymorphisms in the MS gene in the MCI group were different from those in the control group. However, the C677T and G1968A polymorphisms in the MTHFR gene in MCI patients were not different from those in the control group. Multivariate logistic regression showed that, in addition to the well-known risk factors, such as low education level, high cholesterol level, high level of low-density lipoprotein, and high homocysteine levels, the A>G mutation in the MS gene at the rs1805087 locus was another independent risk factor for MCI in the Uyghur MCI population. The risk of MCI in G allele carriers was 2.265 times higher than that in matched control individuals (95% CI: 1.205~4.256, P<0.05). Conclusions The genetic polymorphism of HCY metabolizing enzymes is correlated to the occurrence of MCI in the Xinjiang Uygur population. The A2756G polymorphism in the MS gene could be an independent risk factor for MCI in the Xinjiang Uygur population. PMID:25625218

  12. Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: a multicenter case-control study.

    PubMed

    Candito, Mirande; Rivet, Romain; Herbeth, Bernard; Boisson, Catherine; Rudigoz, René-Charles; Luton, Dominique; Journel, Hubert; Oury, Jean-François; Roux, François; Saura, Robert; Vernhet, Isabelle; Gaucherand, Pascal; Muller, Françoise; Guidicelli, Béatrice; Heckenroth, Hélène; Poulain, Patrice; Blayau, Martine; Francannet, Christine; Roszyk, Laurence; Brustié, Cécile; Staccini, Pascal; Gérard, Philippe; Fillion-Emery, Nathalie; Guéant-Rodriguez, Rosa-Maria; Van Obberghen, Emmanuel; Guéant, Jean-Louis

    2008-05-01

    Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6.

  13. The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother.

    PubMed Central

    Shields, D C; Kirke, P N; Mills, J L; Ramsbottom, D; Molloy, A M; Burke, H; Weir, D G; Scott, J M; Whitehead, A S

    1999-01-01

    Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype. PMID:10090889

  14. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

    PubMed Central

    Ongaro, Alessia; De Mattei, Monica; Della Porta, Matteo Giovanni; Rigolin, GianMatteo; Ambrosio, Cristina; Di Raimondo, Francesco; Pellati, Agnese; Masieri, Federica Francesca; Caruso, Angelo; Catozzi, Linda; Gemmati, Donato

    2009-01-01

    Background The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and Methods The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. Results Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45). Conclusions Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. PMID:19648163

  15. Association between the methylenetetrahydrofolate reductase gene C677T polymorphism and sudden sensorineural hearing loss: a meta-analysis.

    PubMed

    Shu, Jingcheng; Yin, Shihua; Tan, An-Zhou; He, Meirong

    2015-09-01

    A variety of epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and sudden sensorineural hearing loss (SSNHL), but the results were inconsistent. The aim of this meta-analysis was to clarify more accurately the association of this polymorphism with SSNHL. A systematic literature search of the associated studies up to May 1, 2014, was conducted using the following electronic databases: PubMed, Embase, Medline, and the China National Knowledge Infrastructure. Statistical analyses were performed by STATA12.0 software, with odds ratios (ORs) and their 95 % confidence intervals (CIs). Six eligible studies including covering 1,271 objects were identified. A pooled analysis of these studies showed no significant association between C677T polymorphism and risk of SSNHL: T vs. C (OR = 1.334, POR = 0.105); TT vs. CC (OR = 1.580, POR = 0.231); CT vs. CC (OR = 1.500, POR = 0.123); TT vs. CC + CT (OR = 1.326, POR = 0.293); and TT + CT vs. CC (OR = 1.540, POR = 0.102). But in subgroup analysis, a significant association was found in European populations (T vs. C, OR = 1.542, 95 % CI 1.008-2.359, P = 0.046; TT vs. CT + CC, OR = 1.856, 95 % CI 1.245-2.767, P = 0.002). There was no significant association in any model in the Asian populations. The present meta-analysis suggests that MTHFR gene C677T polymorphism is significantly associated with increased risk of SSNHL disease in European populations, but no statistically significant association was found between the MTHFR C677T gene mutation and SSNHL in Asian. Further large and well-designed studies are needed to confirm this association.

  16. Primary Angle Closure and Sequence Variants within MicroRNA Binding Sites of Genes Involved in Eye Development

    PubMed Central

    Shi, Haihong; Zhang, Junfang; Zhu, Rongrong; Hu, Nan; Lu, Hong; Yang, Mei; Qin, Bai; Shi, Jian; Guan, Huaijin

    2016-01-01

    Purpose The formation of primary angle closure (PAC) and primary angle closure glaucoma (PACG) is regulated by a tissue remodeling pathway that plays a critical role in eye development. MicroRNAs (miRNAs) are powerful gene expression regulators and may exert their effects on tissue remodeling genes. This study investigated the associations between gene variants (single-nucleotide polymorphism, SNP) in miRNA binding sites in the 3’-UTR region of genes involved in eye development and PAC. Methods The sample consisted of 232 PAC subjects and 306 controls obtained from a population-based cohort in the Funing District of Jiangsu, China. The markers include 9 SNPs in the COL11A1, PCMTD1, ZNRF3, MTHFR, and ALPPL2 genes respectively. SNP genotyping was performed with a TaqMan-MGB probe using an RT-PCR system. Results Of the 9 SNPs studied, the frequency of the minor A allele of COL11A1 rs1031820 was higher in the PAC group than in the control group in allele analysis (p = 0.047). The genotype analysis indicated that MTHFR rs1537514 is marginally associated with PAC (p = 0.014). The CC genotype of rs1537514 was present solely in the PAC group. However, the differences lost significance after Bonferroni correction. Conclusion Our study reveals a possible association of COL11A1 and MTHFR with PAC in the Han Chinese population. These results will contribute to an improved understanding of the genetic basis of PACG. PMID:27824919

  17. Maternal gene polymorphisms involved in folate metabolism and the risk of having a Down syndrome offspring: a meta-analysis.

    PubMed

    Yang, Mei; Gong, Tian; Lin, Xiaofang; Qi, Ling; Guo, Yiyang; Cao, Zhongqiang; Shen, Min; Du, Yukai

    2013-11-01

    Down syndrome (DS) is the most common chromosomal abnormality. Many studies have assessed the association between maternal gene polymorphisms involved in folate metabolism and the risk of having a DS offspring, but data are conflicting. Our study aimed to arrive at a more accurate estimation. Therefore, we carried out a meta-analysis of 26, 17, 9, 15, 9 and 6 case-control studies on the relationship between maternal methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, methionine synthase reductase (MTRR) A66G, reduced folate carrier 1 A80G and cystathionine β-synthase 844ins68 polymorphisms and the risk of having a DS offspring. The allele contrast and model-free approach were used. Results showed marginal significant associations for MTHFR C677T, overall [odds ratio (OR) = 1.28 (1.22, 1.46) and generalised odds ratio (ORG) = 1.35 (1.16, 1.57)] and in Caucasian [OR = 1.15 (1.03, 1.29) and ORG = 1.20 (1.04, 1.38)], Asian [OR = 1.68 (1.08, 2.63) and ORG = 1.74 (1.08, 2.80)] and Brazilian [OR = 1.22 (1.04, 1.43) and ORG = 1.28 (1.06, 1.55)] populations; for MTRR A66G, overall [OR = 1.22 (1.02, 1.46) and ORG = 1.31 (1.06, 1.62)]; and for RFC1 A80G, overall [OR = 1.16 (1.02, 1.31) and ORG = 1.18 (1.01, 1.37)]. MTHFR A1298C, MTR 12756G and CBS 844ins68 polymorphisms produced non-significant results. Since potential confounders could not be ruled out completely in this meta-analysis, further studies are needed to confirm these results.

  18. The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma.

    PubMed

    Sarbia, M; Stahl, M; von Weyhern, C; Weirich, G; Pühringer-Oppermann, F

    2006-01-30

    The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy+/-surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value.

  19. Reduced folate carrier-1 G80a gene polymorphism is associated with neuroblastoma's development.

    PubMed

    de Miranda, Dyego O; Barros, Jemima E X S; Vieira, Maria Madalena S; Lima, Elker L S; Moraes, Vera L L; da Silva, Helker A; Garcia, Helder L B O; Lima, Cássia A; Gomes, Adriana V; Santos, Neide; Muniz, Maria T C

    2014-08-01

    Neuroblastoma is a malignant embryonal tumor of neural crest cells that give rise to the sympathetic nervous system, responsible for 10-70% of all cases of childhood cancer. Because of its early appearance, it has been suggested that risk factors active in the prenatal can be associated with the pathogenesis of neuroblastoma. The aim of this study was to investigate whether the genetic polymorphisms MTHFR C677T and A1298C, MTR A2756G, TYMS 2R/3R and SLC19A1 G80A, involved in folate metabolism, increase the risk of neuroblastoma in Brazilian children. This study comprised 31 Brazilian children (0-14 years old) diagnosed with neuroblastoma compared with 92 controls. Investigation of polymorphisms MTHFR C677T, MTR A2756G and SLC19A1 A80G was performed using PCR-RFLP, the TYMS 2R/3R using PCR and MTHFR A1298C using AS-PCR. The SLC19A1 A80A genotype was significantly associated with the development of neuroblastoma, compared with the control group (Williams G-Test = 0.0286; OR = 5.1667; 95% CI = 1.4481-18.4338; p = 0.0175). When analyzed together, the 80AG+AA genotypes showed a trend toward association (OR = 3.3033; 95% CI = 1.0586-10.3080; p = 0.0563). Our results suggest that individuals carriers of genotype AA for the SLC19A1 gene present risk for the development of neuroblastoma and possibly have difficulty in absorption of folic acid by the cells, and this may adversely affect the metabolism of folate causing genomic instability and promoting the development of cancer. This is the first retrospective/prospective study to examine the relationship between polymorphisms of folate pathway genes and risk of neuroblastoma.

  20. C677T mutation in methylenetetrahydrofolate reductase gene and neural tube defects: should Japanese women undergo gene screening before pregnancy?

    PubMed

    Kondo, Atsuo; Fukuda, Hiromi; Matsuo, Takuya; Shinozaki, Keiko; Okai, Ikuyo

    2014-02-01

    We analyzed the role of maternal C677T mutation in methylenetetrahydrofolate reductase (MTHFR) gene on spina bifida development in newborns. A total of 115 mothers who had given birth to a spina bifida child (SB mothers) gave 10 mL of blood together with written informed consent. The genotype distribution of C677T mutation was assessed and compared with that of the 4517 control individuals. The prevalence of the homozygous genotype (TT) among SB mothers was not significantly different from that among the controls (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.31-1.25; P = 0.182), suggesting that MTHFR 677TT genotype in Japan is not associated with spina bifida development in newborns. The T allele frequency was not increased in SB mothers (34.8%) as compared to that of the control individuals (38.2%). Further, the internationally reported association between the two groups was found to be similar in all 15 countries studied except the Netherlands, where the TT genotype was found to be a genetic risk factor for spina bifida. For the prevention of affected pregnancy every woman planning to conceive has to take folic acid supplements 400 μg a day and the government is asked to take action in implementing food fortification with folic acid in the near future. In conclusion, it is not necessary for Japanese women to undergo genetic screening C677T mutation of the MTHFR gene as a predictive marker for spina bifida prior to pregnancy, because the TT genotype is not a risk factor for having an affected infant.

  1. The C677T polymorphism of the methylenetetrahydrofolate reductase gene in Mexican mestizo neural-tube defect parents, control mestizo and native populations.

    PubMed

    Dávalos, I P; Olivares, N; Castillo, M T; Cantú, J M; Ibarra, B; Sandoval, L; Morán, M C; Gallegos, M P; Chakraborty, R; Rivas, F

    2000-01-01

    The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene, associated with the thermolabile form of the enzyme, has reportedly been found to be increased in neural-tube defects (NTD), though this association is still unclear. A group of 107 mestizo parents of NTD children and five control populations: 101 mestizo (M), 50 Huichol (H), 38 Tarahumara (T), 21 Purepecha (P) and 20 Caucasian (C) individuals were typed for the MTHFR C677T variant by the PCR/RFLP (HinfI) method. Genotype frequencies were in agreement with the Hardy-Weinberg expectations in all six populations. Allele frequency (%) of the C677T variant was 45 in NTD, 44 in M, 56 in H, 36 in T, 57 in P, 35 in C. Pairwise inter-population comparisons of allele frequency disclosed a very similar distribution between NTD and M groups (exact test, P=0.92). Among controls, differences between M and individual native groups were NS (0.06MTHFR C677T genotypes. Thus, the C677T variant cannot be regarded as a major genetic risk factor for NTD in Mexican mestizo parents. Otherwise, C677T in Mexico is very frequent, especially in Huichol and Purepecha natives, as compared with other groups world wide.

  2. Prediction of ischemic stroke in young Indians: is thrombophilia profiling a way out?

    PubMed

    Chatterjee, Tathagata; Gupta, Neha; Choudhry, Ved Prakash; Behari, Madhuri; Saxena, Renu; Ashraf, Mohammad Z

    2013-06-01

    Stroke in the young is attributed to the prevalence of thrombophilia, however, reports explaining the cause mechanisms from Indian populations are largely not known. The information about the association of inherited thrombophilia and occurrence of stroke is still missing. Therefore, we describe here 52 cases of young ischemic stroke of which 22 cases were of recurrent stroke and 30 cases of first episode stroke along with an equal number of healthy controls. Imaging techniques (CT/MRI/Doppler studies) were used to identify the type and location of infarcts among various regions of the brain. All the patients and controls were screened for hypercoagulable state by employing Pro C global test. Those tested positive for the latter were evaluated for conventional thrombophilic factors, activity levels of protein C and protein S, antithrombin III levels, plasma homocysteine levels and presence of activated protein C resistance, lupus anticoagulant, methylenetetrahydrofolate reductase (MTHFR C677T) and prothrombin G20210A polymorphisms. Out of 52 cases there were 22 cases of recurrent stroke and 30 cases of first ischemic stroke. Infarcts were single in 39 out of 52 cases and multiple in 13 cases. Among the different regions of brain internal capsule infarcts were seen in 13 of 52 (25%) cases, and cerebellum, basal ganglion and midbrain infarcts were seen in five cases (9.6%) each and remaining infarcts were in other anatomical regions of the brain. Left middle cerebral artery territory was involved in 17 of 52 (32.7%) cases. The prevalence of individual thrombophilia among cases ranged from 28.8% (15/52) for protein S and 11.5% (6/52) for protein C deficiencies respectively. All cases of protein C were protein S deficient. Five cases of protein C deficiency patients were of 25 years and younger as compared with one case in the at least 25 years age group. Plasma homocysteine levels were elevated in three cases (5.7%) as compared with normal levels in controls

  3. Plasmatic higher levels of homocysteine in Non-alcoholic fatty liver disease (NAFLD)

    PubMed Central

    2013-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The increased serum levels of homocysteine (Hcy) may be associated with hepatic fat accumulation. Genetic mutations in the folate route may only mildly impair Hcy metabolism. The aim of this study was to investigate the relation between liver steatosis with plasma homocysteine level and MTHFR C677T and A1298C polymorphisms in Brazilian patients with NAFLD. Methods Thirty-five patients diagnosed with NAFLD by liver biopsy and forty-five healthy controls neither age nor sex matched were genotyped for C677T and A1298C MTHFR polymorphisms using PCR-RFLP and PCR-ASA, respectively, and Hcy was determined by HPLC. All patients were negative for markers of Wilson’s, hemochromatosis and autoimmune diseases. Their daily alcohol intake was less than 100 g/week. A set of metabolic and serum lipid markers were also measured at the time of liver biopsies. Results The plasma Hcy level was higher in NAFLD patients compared to the control group (p = 0.0341). No statistical difference for genotypes 677C/T (p = 0.110) and 1298A/C (p = 0.343) in patients with NAFLD and control subjects was observed. The genotypes distribution was in Hardy-Weinberg equilibrium (677C/T p = 0.694 and 1298 A/C p = 0.188). The group of patients and controls showed a statistically significant difference (p < 0.001) for BMI and HOMA_IR, similarly to HDL cholesterol levels (p < 0,006), AST, ALT, γGT, AP and triglycerides levels (p < 0.001). A negative correlation was observed between levels of vitamin B12 and Hcy concentration (p = 0.005). Conclusion Our results indicate that plasma Hcy was higher in NAFLD than controls. The MTHFR C677T and A1298C polymorphisms did not differ significantly between groups, despite the 677TT homozygous frequency was higher in patients (17

  4. Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients

    PubMed Central

    Pruvost, Alain; Torres, Ferran; Salazar, Juliana; Gutierrez, Maria del Mar; Domingo, Joan Carles; Fernandez, Irene; Villarroya, Francesc; Vidal, Francesc; Baiget, Montserrat; de la Calle-Martín, Oscar

    2013-01-01

    Purpose To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). Methods Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method. Results HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53–3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): ‘A+A’; OR for ‘A+B’ vs. ref.: 1.39 [0.69–2.80]; OR for ‘B+A’ vs. ref.: 2.16 [1.22–3.83]; OR for ‘B+B’ vs. ref.: 3.13, 95%CI: 1.54–6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56–4.14, P = 0.001), (c) use of EFV (1.10 [1.00–1.21], P = 0.008, per year of use). Conclusion HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine. PMID:23840581

  5. Association of Thymidylate Synthase Polymorphisms with Acute Pancreatitis and/or Peripheral Neuropathy in HIV-Infected Patients on Stavudine-Based Therapy

    PubMed Central

    Torres, Ferran; Salazar, Juliana; Gutierrez, Maria del Mar; Mateo, Maria Gracia; Martínez, Esteban; Domingo, Joan Carles; Fernandez, Irene; Villarroya, Francesc; Ribera, Esteban; Vidal, Francesc; Baiget, Montserrat

    2013-01-01

    Background Low expression thymidylate synthase (TS) polymorphism has been associated with increased stavudine triphosphate intracellular (d4T-TP) levels and the lipodystrophy syndrome. The use of d4T has been associated with acute pancreatitis and peripheral neuropathy. However, no relationship has ever been proved between TS polymorphisms and pancreatitis and/or peripheral neuropathy. Methods We performed a case-control study to assess the relationship of TS and methylene-tetrahydrofolate reductase (MTHFR) gene polymorphisms with acute pancreatitis and/or peripheral neuropathy in patients exposed to d4T. Student’s t test, Pearson’s correlations, one-way ANOVA with Bonferroni correction and stepwise logistic regression analyses were done. Results Forty-three cases and 129 controls were studied. Eight patients (18.6%) had acute pancreatitis, and 35 (81.4%) had peripheral neuropathy. Prior AIDS was more frequent in cases than in controls (OR = 2.36; 95%CI 1.10–5.07, P = 0.0247). L7ow expression TS and MTHFR genotype associated with increased activity were more frequent in patients with acute pancreatitis and/or peripheral neuropathy than in controls (72.1% vs. 46.5%, OR = 2.97; 95%CI: 1.33–6.90, P = 0.0062, and 79.1% vs. 56.6%, OR = 2.90, 95%CI: 1.23–7.41, P = 0.0142, respectively). Independent positive or negative predictors for the development of d4T-associated pancreatitis and/or peripheral neuropathy were: combined TS and MTHFR genotypes (reference: A+A; P = 0.002; ORA+B = 0.34 [95%CI: 0.08 to 1.44], ORB+A = 3.38 [95%CI: 1.33 to 8.57], ORB+B = 1.13 [95%CI: 0.34 to 3.71]), nadir CD4 cell count >200 cells/mm3 (OR = 0.38; 95%CI: 0.17–0.86, P = 0.021), and HALS (OR = 0.39 95%CI: 0.18–0.85, P = 0.018). Conclusions Low expression TS plus a MTHFR genotype associated with increased activity is associated with the development of peripheral neuropathy in d4T-exposed patients. PMID:23468971

  6. Epigenetic profiles in children with a neural tube defect; a case-control study in two populations.

    PubMed

    Stolk, Lisette; Bouwland-Both, Marieke I; van Mil, Nina H; van Mill, Nina H; Verbiest, Michael M P J; Eilers, Paul H C; Zhu, Huiping; Suarez, Lucina; Uitterlinden, André G; Steegers-Theunissen, Régine P M

    2013-01-01

    Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of -0.33% in cases, P-value = 0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value = 0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value = 0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively.

  7. Unexplained fetal loss: the fetal side of thrombophilia.

    PubMed

    Tranquilli, Andrea Luigi; Saccucci, Franca; Giannubilo, Stefano Raffaele; Cecati, Monia; Nocchi, Linda; Lorenzi, Sara; Emanuelli, Monica

    2010-06-01

    Carrier status of the fetus for factor V polymorphism or double homozygosity for mutant alleles of the PAI-1 4 G/4 G and MTHFR T677 T polymorphisms must be considered risk factors for intrauterine fetal death. The clinical implications of these data need to be addressed in a prospective study to confirm our preliminary data and to answer the question of whether or not double homozygous individuals should be treated with low molecular-weight heparin and/or low-dose aspirin.

  8. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls

    PubMed Central

    Simone, B; De Stefano, V; Leoncini, E; Zacho, J; Martinelli, I; Emmerich, J; Rossi, E; Folsom, AR; Almawi, WY; Scarabin, PY; den Heijer, M; Cushman, M; Penco, S; Vaya, A; Angchaisuksiri, P; Okumus, G; Gemmati, D; Cima, S; Akar, N; Oguzulgen, KI; Ducros, V; Lichy, C; Fernandez-Miranda, C; Szczeklik, A; Nieto, JA; Torres, JD; Le Cam-Duchez, V; Ivanov, P; Cantu, C; Shmeleva, VM; Stegnar, M; Ogunyemi, D; Eid, SS; Nicolotti, N; De Feo, E; Ricciardi, W; Boccia, S

    2014-01-01

    BACKGROUND Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden,FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. METHODS We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). RESULTS We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95% confidence intervals [CI]: 0.98–1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR=4.22; 95% CI: 3.35–5.32; and OR=2.79;95% CI: 2.25–3.46, respectively), in double hterozygotes (OR=3.42; 95%CI 1.64-7.13), and in homozygous FVL or PT20210A (OR=11.45; 95%CI: 6.79-19.29; and OR: 2.79; 95%CI: 2.25 – 3.46, respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤45 years (p-value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). CONCLUSIONS In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought. PMID:23900608

  9. Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: Large and comprehensive study

    PubMed Central

    Huo, Xinying; Shen, Lili; Wang, Chun; Tang, Yongfei; Wu, Peng; He, Jason; Gong, Weida; He, Ming-Liang; Chen, Jinfei

    2015-01-01

    Although it has been shown that polymorphisms in one-carbon metabolism (OCM) pathway are associated with gastric cancer (GC), their interactions and contributions for patients’ survival are elusive. In this study, we investigated the effects of polymorphisms and their interactions on the survival of GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR 677C > T, 1298A > C), Methionine synthase reductase (MTRR 66A > G), Methionine synthase (MTR 2756A > G), and Thymidylate synthase (TS 3′-UTR ins6 > del6, 5′-UTR 2R > 3R). We recruited 919 GC patients from 1998 to 2006. The Kaplan–Meier plots, Cox regression analyses and the log-rank tests were carried out in this study. MTHFR 1298CC genotype showed protective effect (HR = 0.444, 95% CI = 0.210–0.940). MTRR 66 GA + GG genotypes decreased the risk of death (HR = 0.793, 95% CI = 0.651–0.967) in general, and in subgroups with more pronounced diffuse type, greater depth of invasion (T2/T3/T4), higher level lymph node metastasis (N1/N2/N3), advanced TNM stages (II/III level) and 5-Fu treatment. However, the improved survival disappeared when GC patients simultaneously had MTR 2756 GA + GG genotypes (HR = 1.063, 95% CI = 0.750–1.507). Although MTRR 66GA genotype was not associated with the survival of GC patients, patients with simultaneous MTRR 66GA and MTR 2756AA genotypes exhibited significant risk reduction of death (HR = 0.773, 95% CI = 0.609–0.981). MTHFR 1298 CA + CC combined with TS 5-UTR 2R3R + 3R3R genotypes (HR = 0.536, 95% CI = 0.315–0.913) also increased patient survival rates. Our results suggest that the MTRR 66A > G and MTHFR 1298A > C polymorphisms may be useful prognostic biomarkers for GC patients. PMID:25840420

  10. Relationship between genetic polymorphisms of methylenetetrahydrofolate reductase and breast cancer chemotherapy response.

    PubMed

    Yang, L; Wang, X W; Zhu, L P; Wang, H L; Wang, B; Wu, T; Zhao, Q; JinSiHan, D L X T; Wang, X Y

    2016-09-23

    Activity of methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism, is influenced by mutations in the corresponding gene, contributing to a decrease in 5,10-MTHF. Due to such polymorphisms, individuals differ in MTHFR enzyme activity and plasma folate levels. We investigated the relationship between two common MTHFR polymorphisms (C677T and A1298C) and breast cancer (BC) chemotherapy response. From February 2013 to January 2016, 148 advanced BC patients at the Center Hospital of Cangzhou were enrolled and treated with six different chemotherapy regimens. Subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Forty-one (27.7%), 70 (47.3%), and 37 (25.0%) patients carried the C/C, C/T, and T/T C677T genotypes, respectively; 101 (68.2%), 42 (28.4%), and 5 (3.4%) had the A/A, A/C, and C/C genotypes of A1298C, respectively. Total chemotherapy efficacy was 66.9% (99/148), with 7 (4.7%), 92 (62.2%), 36 (24.3%), and 13 (8.8%) cases showing complete response, partial response, no change, and progressive disease, respectively. Chemotherapy regimens did not differ in effectiveness (P > 0.05). Efficacy rates associated with C677T C/C, C/T, and T/T genotypes were 58.5, 58.6, and 91.9%, respectively, with T/T carriers exhibiting significantly better responses than the C/C (P < 0.05) and C/T groups (P < 0.05). Effectiveness among A1298C A/A, A/C, and C/C carriers was 70.6, 64.3, and 0.0%, respectively, but no difference was established between these genotypes in this regard (P > 0.05). The MTHFR C677T genotype may be associated with BC chemotherapy response, and could be of great value in guiding individualized treatment for this disease.

  11. Risk of Breast Cancer Associated with Reproductive and Fertility Factors According to a Family History of Breast Cancer

    DTIC Science & Technology

    1999-10-01

    mutation (C677T) in the MTHFR gene is associated with reduced enzyme ac- tions in one of five DNA-mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1,VyA... mutations than in noncarriers. 2 1 Since a family history of breast cancer may not only reflect shared genes but also shared exposures, a family study...unchanged. To study families most likely to be carrying a mutation in BRCA1 or BRCA2, analyses were conducted in high-risk families defined by the number

  12. Association between SNPs in genes involved in folate metabolism and preterm birth risk.

    PubMed

    Wang, B J; Liu, M J; Wang, Y; Dai, J R; Tao, J Y; Wang, S N; Zhong, N; Chen, Y

    2015-02-02

    We investigated the association between 12 single nucleotide polymorphisms (SNPs) in 11 genes involved in folate metabolic and preterm birth. A subset of SNPs selected from 11 genes/loci involved in the folic acid metabolism pathway were subjected to SNaPshot analysis in a case-control study. Twelve SNPs (CBS-C699T, DHFR-c594+59del19, GST01-C428T, MTHFD-G1958A, MTHFR-C677T, MTHFR-A1298C, MTR-A2756G, MTRR-A66G, NFE2L2-ins1+C11108T, RFC1-G80A, TCN2-C776G, and TYMS-1494del6) in 503 DNA samples were simultaneously tested, and included 315 preterm births and 188 controls. None of the 12 SNP genotype distributions related to the folic acid metabolism pathway showed a significant difference between preterm and term babies. The frequency of the compound mutation genotype of MTHFD-G1958A, MTR-A2756G and RFC1-G80A in preterm babies was 7.3%, which was significantly higher than the 2.7% in term babies. Seven babies carried the compound mutation genotype of MTHFD-G1958A, MTR-A2756G, and CBS-C699T, but this was not observed in term babies. The frequency of the combined wild-type genotype of MTHFD-G1958A, MTR-A2756G, MTRR-A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1- G80A in preterm babies was 3.17%, which was significantly lower than the 7.4% in term babies. The 12 SNPs screened in this study were not independent risk factors of preterm birth. Compound mutation genotypes, including MTHFD-G1958A, MTR-A2756G, and RFC1- G80A and MTHFD-G1958A, MTR-A2756G, and CBS-C699T, may increase the risk of preterm birth. The combined wild-type genotype MTHFD-G1958A, MTR-A2756G, MTRR-A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1-G80A may decrease the risk of preterm birth.

  13. Polymorphisms of folate metabolism genes in patients with cirrhosis and hepatocellular carcinoma

    PubMed Central

    Peres, Nathália Perpétua; Galbiatti-Dias, Ana Lívia Silva; Castanhole-Nunes, Márcia Maria Urbanin; da Silva, Renato Ferreira; Pavarino, Érika Cristina; Goloni-Bertollo, Eny Maria; Ruiz-Cintra, Mariangela Torreglosa

    2016-01-01

    AIM To evaluated the association of the risk factors and polymorphisms in MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genes. METHODS Patients with cirrhosis (n = 116), hepatocellular carcinoma (HCC) (n = 71) and controls (n = 356) were included. Polymerase chain reaction followed by enzymatic digestion and allelic discrimination technique real-time PCR techniques were used for analysis. MINITAB-14.0 and SNPstats were utilized for statistical analysis. RESULTS Showed that age ≥ 46 years (OR = 10.31; 95%CI: 5.66-18.76; P < 0.001) and smoking (OR = 0.47; 95%CI: 0.28-0.78; P = 0.003) were associated with cirrhosis. Age ≥ 46 years (OR = 16.36; 95%CI: 6.68-40.05; P < 0.001) and alcohol habit (OR = 2.01; 95%CI: 1.03-3.89; P = 0.039) were associated with HCC. MTHFR A1298C in codominant model (OR = 3.37; 95%CI: 1.52-7.50; P = 0.014), recessive model (OR = 3.04; 95%CI: 1.43-6.47; P = 0.0051) and additive model (OR = 1.71; 95%CI: 1.16-2.52; P = 0.0072) was associated with HCC, as well as MTR A2756G in the additive model (OR = 1.68; 95%CI: 1.01-2.77; P = 0.047), and MTRR A66G in the codominant model (OR = 3.26; 95%CI: 1.54-6.87; P < 0.001), dominant model (OR = 2.55; 95%CI: 1.24-5.25; P = 0.007) and overdominant model (OR = 3.05; 95%CI: 1.66-5.62; P < 0.001). MTR A2756G in the additive model (OR = 1.54; 95%CI: 1.02-2.33; P = 0.042) and smokers who presented at least one polymorphic allele for MTRR A66G (OR = 1.71; 95%CI: 0.77-3.82; P = 0.0051) showed increased risk for cirrhosis. There was no association between clinical parameters and polymorphisms. CONCLUSION Age ≥ 46 years, alcohol habit and MTR A2756G, MTHFR A1298C and MTRR A66G polymorphisms are associated with an increased risk of HCC development; age ≥ 46 years, tobacco habit and the MTR A2756G polymorphism are associated with cirrhosis. PMID:27803768

  14. Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives.

    PubMed

    Ozbek, Zeynep; Kucukali, Cem Ismail; Ozkok, Elif; Orhan, Nurcan; Aydin, Makbule; Kilic, Gamze; Sazci, Ali; Kara, Ihsan

    2008-07-01

    We investigated the effect of polymorphic variants of c.1298A>C (Glu429Ala) and c.677C>T (Ala222Val) in methylenetetrahydrofolate (MTHFR) gene on the total homocysteine (tHcy), folate and B12 levels in patients with bipolar disorder, first-degree relatives of patients, and controls. The c.677C>T and c.1298A>C polymorphisms in MTHFR were determined by polymerase chain reaction-restriction fragment length polymorphism in 197 bipolar patients, 278 relatives and 238 controls. tHcy and folate and vitamin B12 levels were measured by Fluorescence Polarization Immunoassay and Electrochemiluminescence, respectively. The tHcy was significantly increased in patients and relatives. In contrast, folate and B12 were significantly lower in patients and relatives. Gender was not considered as a significant determinant in the multivariate analysis. Genotypes of c.1298A>C and c.677C>T were correlated with tHcy, folate and B12. Patients and relatives carrying TT and/or AA and AC genotypes had elevated tHcy and reduced folate and B12 levels. High tHcy but low folate and vitamin B12 levels may be a risk factor for development of bipolar disorder.

  15. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes.

    PubMed

    Lucock, M

    2000-01-01

    This paper reviews the chemistry, metabolism, and molecular biology of folic acid, with a particular emphasis on how it is, or may be, involved in many disease processes. Folic acid prevents neural tube defects like spina bifida, while its ability to lower homocysteine suggests it might have a positive influence on cardiovascular disease. A role for this B vitamin in maintaining good health may, in fact, extend beyond these clinical conditions to encompass other birth defects, several types of cancer, dementia, affective disorders, Down's syndrome, and serious conditions affecting pregnancy outcome. The effect of folate in these conditions can be explained largely within the context of folate-dependent pathways leading to methionine and nucleotide biosynthesis, and genetic variability resulting from a number of common polymorphisms of folate-dependent enzymes involved in the homocysteine remethylation cycle. Allelic variants of folate genes that have a high frequency in the population, and that may play a role in disease formation include 677C --> T-MTHFR, 1298A --> C-MTHFR, 2756A --> G-MetSyn, and 66A --> G-MSR. Future work will probably uncover further polymorphisms of folate metabolism, and lead to a wider understanding of the interaction between this essential nutrient and the many genes which underpin its enzymatic utilization in a plethora of critical biosynthetic reactions, and which, under adverse nutritional conditions, may promote disease.

  16. Inherited genetic markers for thrombophilia in northeastern Iran (a clinical-based report)

    PubMed Central

    Keify, Fatemeh; Azimi-Nezhad, Mohsen; Zhiyan-abed, Narges; Nasseri, Mojila; Abbaszadegan, Mohammad Reza

    2014-01-01

    Background: Thrombophilia is a main predisposition to thrombosis due to a procoagulant state. Several point mutations play key roles in blood-clotting disorders, which are grouped under the term thrombophilia. These thrombophilic mutations are methylenetetrahydrofolate reductase (MTHFR, C677T, and A1298C), factor V Leiden (G1691A), prothrombin gene mutation (factor II, G20210A), and plasminogen activator inhibitor (PAI). In the present study, we assessed the prevalence of the above thrombophilia markers in patients with recurrent pregnancy loss or first and second trimester abortions, infertility, and failed in vitro fertilization (IVF). Methods: This study was conducted among 457 cases those were referred to detect the inherited genetic markers for thrombophilia. Markers for MTHFR, Factor II, and Factor V were assessed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and PAI was assessed by Amplification Refractory Mutation System (ARMS-PCR). Results: Two hundred sixty cases (56.89%) were diagnosed as having at least one thrombophilia marker, whereas 197 cases (43.11%) had no thrombophilia markers and were normal. Conclusion: According to the current study, the pattern of abnormal genetic markers for thrombophilia in northeastern Iran demonstrates the importance of genetic evaluations in patients who show clinical abnormalities with recurrent spontaneous abortion (RSA) or other serious obstetric complications. PMID:26989725

  17. Expression of genes encoding enzymes involved in the one carbon cycle in rat placenta is determined by maternal micronutrients (folic acid, vitamin B12) and omega-3 fatty acids.

    PubMed

    Khot, Vinita; Kale, Anvita; Joshi, Asmita; Chavan-Gautam, Preeti; Joshi, Sadhana

    2014-01-01

    We have reported that folic acid, vitamin B12, and omega-3 fatty acids are interlinked in the one carbon cycle and have implications for fetal programming. Our earlier studies demonstrate that an imbalance in maternal micronutrients influence long chain polyunsaturated fatty acid metabolism and global methylation in rat placenta. We hypothesize that these changes are mediated through micronutrient dependent regulation of enzymes in one carbon cycle. Pregnant dams were assigned to six dietary groups with varying folic acid and vitamin B12 levels. Vitamin B12 deficient groups were supplemented with omega-3 fatty acid. Placental mRNA levels of enzymes, levels of phospholipids, and glutathione were determined. Results suggest that maternal micronutrient imbalance (excess folic acid with vitamin B12 deficiency) leads to lower mRNA levels of methylene tetrahydrofolate reductase (MTHFR) and methionine synthase , but higher cystathionine b-synthase (CBS) and Phosphatidylethanolamine-N-methyltransferase (PEMT) as compared to control. Omega-3 supplementation normalized CBS and MTHFR mRNA levels. Increased placental phosphatidylethanolamine (PE), phosphatidylcholine (PC), in the same group was also observed. Our data suggests that adverse effects of a maternal micronutrient imbalanced diet may be due to differential regulation of key genes encoding enzymes in one carbon cycle and omega-3 supplementation may ameliorate most of these changes.

  18. Risk of prostate cancer and thrombosis-related factor polymorphisms

    PubMed Central

    GHASEMI, SOMAYEHSADAT; TAVAKOLI, AYDIN; MOGHADAM, MOHAMAD; ZARGAR, MOHAMAD ALI; ABBASPOUR, MARYAM; HATAMNEJADIAN, NASIM; EBRAHIMI, AHMAD

    2014-01-01

    Venous thromboembolism (VTE) is a complication commonly encountered in cancer patients and is considered to be a major cause of morbidity and mortality. The genetic polymorphisms of thrombophilic factors in cancer patients have been focused on during the last few years. However, the number of available studies on the association between prostate cancer and thromboembolic diseases is limited. Prostate cancer is one of the four major types of cancer and its development is affected by a variety of environmental and genetic factors. In the present study we aimed to focus on the effects of thromboembolic factor gene variations on the risk of prostate cancer. In order to conduct our prospective study, we used amplification-refractory mutation system-polymerase chain reaction to investigate three polymorphisms [factor V Leiden (FVL) G1691A, factor II (prothrombin, PTH) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T] in prostate cancer patients, via comparison with normal individuals. The results demonstrated no significant differences in FVL and PTH gene variations between cases and controls (P>0.05). Although some cases with the T allele of MTHFR 677 were identified, no significant solidarity was established by statistical analysis (P>0.05). Therefore, non-genetic factors that may disturb homeostatic balance should also be considered in future studies, in order to determine the exact association between VTE and prostate cancer. PMID:24649068

  19. Global DNA methylation and one-carbon metabolism gene polymorphisms and the risk of breast cancer in the Sister Study.

    PubMed

    Deroo, Lisa A; Bolick, Sophia C E; Xu, Zongli; Umbach, David M; Shore, David; Weinberg, Clarice R; Sandler, Dale P; Taylor, Jack A

    2014-02-01

    Global decrease in DNA methylation is a common feature of cancer and is associated with genomic and chromosomal instability. Retrospective case-control studies have reported that cancer patients have lower global methylation levels in blood DNA than do controls. We used prospectively collected samples and a case-cohort study design to examine global DNA methylation and incident breast cancer in 294 cases and a sample of 646 non-cases in the Sister Study, a study of 50 884 women aged 35-74 years who had not been diagnosed with breast cancer at the time of blood draw. Global methylation in DNA from peripheral blood was assessed by pyrosequencing of the LINE-1 repetitive element. Quartiles of LINE-1 methylation levels were associated with the risk of breast cancer in a dose-dependent fashion (P, trend = 0.002), with an increased risk observed among women in the lowest quartile compared with those in the highest quartile (hazard ratio = 1.75; 95% confidence interval 1.19, 2.59). We also examined 22 polymorphisms in 10 one-carbon metabolism genes in relation to both LINE-1 methylation levels and breast cancer. We found three single-nucleotide polymorphisms in those genes associated with LINE-1 methylation: SLC19A1 (rs1051266); MTRR (rs10380) and MTHFR (rs1537514), one of which was also associated with breast cancer risk: MTHFR (rs1537514). PON1 (rs757158) was associated with breast cancer but not methylation.

  20. The C677T mutation in the methylenetetrahydrofolate reductase gene among the Indonesian Javanese population.

    PubMed

    Sadewa, Ahmad Hamim; Sunarti; Sutomo, Retno; Hayashi, Chiyo; Lee, Myeong Jin; Ayaki, Hitoshi; Sofro, Abdul Salam M; Matsuo, Masafumi; Nishio, Hisahide

    2002-12-01

    The presence of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene has been regarded as a genetic risk factor for coronary artery diseases and neural tube defects. Although the prevalence of this mutation has been reported from various ethnic populations, few data concerning Indonesian populations are available. We have investigated the frequency of the mutation in 68 Indonesian Javanese (residents of Java Island) and compared it with the data from 244 Japanese (residents of Honshu Island). The frequencies of the three genotypes in Javanese were C/C 0.84, C/T 0.16 and T/T 0.00, whereas those in Japanese were C/C 0.39, C/T 0.48 and T/T 0.13. The rarity of the T/T genotype in the Indonesian Javanese population may be due to malnutrition in pregnant women, because insufficient intake of folate is considered to be a survival disadvantage for fetuses with the T/T genotype. In conclusion, homozygosity for the C677T mutation in the MTHFR gene does not constitute a genetic risk factor for coronary artery diseases and neural tube defects in the Indonesian Javanese population.

  1. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy.

    PubMed

    Tamura, T; Aiso, K; Johnston, K E; Black, L; Faught, E

    2000-06-01

    We hypothesized that elevated plasma homocysteine concentrations (hyperhomocysteinemia) exist in patients receiving antiepileptic drugs (AED), and a long-term administration of AED may result in an increased risk of occlusive vascular disease in these patients. A total of 62 patients who received AED monotherapy (phenytoin, lamotrigine, carbamazepine or valproate) participated in this study. Blood concentrations of homocysteine, folate, vitamin B-12 and pyridoxal-5'-phosphate (PLP, a coenzyme form of vitamin B-6) were measured, and thermolabile genotypes of 5, 10-methylenetetrahydrofolate reductase (MTHFR) were also determined. Of 62 patients, only seven (11.4%) had hyperhomocysteinemia. Of 20 patients who received phenytoin, three (15.0%) had hyperhomocysteinemia, whereas 85% of these had plasma folate concentrations below the normal range. However, erythrocyte folate concentrations were abnormally low in only 25% of the patients who received phenytoin. Valproate administration increased serum vitamin B-12 concentrations. Over 55% of the entire patients had PLP concentrations below the normal range, although the reason is unknown. Only three patients had the homozygous thermolabile genotype of MTHFR; therefore, meaningful statistical analysis was not possible in this study. However, one patient with homozygous genotype who received phenytoin therapy had hyperhomocysteinemia with poor folate nutritional status, and the other two had normal homocysteine concentrations with normal folate status. Our data suggest that hyperhomocysteinemia is not a serious clinical concern in epileptic patients when folate nutriture is adequate.

  2. Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms

    PubMed Central

    Davydov, Dmitry M.; Zhdanov, Renad I.; Dvoenosov, Vladimir G.; Kravtsova, Olga A.; Voronina, Elena N.; Filipenko, Maxim L.

    2015-01-01

    A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF-HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits. PMID:26024428

  3. Altered LINE-1 Methylation in Mothers of Children with Down Syndrome

    PubMed Central

    Babić Božović, Ivana; Stanković, Aleksandra; Živković, Maja; Vraneković, Jadranka; Kapović, Miljenko; Brajenović-Milić, Bojana

    2015-01-01

    Down syndrome (DS, also known as trisomy 21) most often results from chromosomal nondisjunction during oogenesis. Numerous studies sustain a causal link between global DNA hypomethylation and genetic instability. It has been suggested that DNA hypomethylation might affect the structure and dynamics of chromatin regions that are critical for chromosome stability and segregation, thus favouring chromosomal nondisjunction during meiosis. Maternal global DNA hypomethylation has not yet been analyzed as a potential risk factor for chromosome 21 nondisjunction. This study aimed to asses the risk for DS in association with maternal global DNA methylation and the impact of endogenous and exogenous factors that reportedly influence DNA methylation status. Global DNA methylation was analyzed in peripheral blood lymphocytes by quantifying LINE-1 methylation using the MethyLight method. Levels of global DNA methylation were significantly lower among mothers of children with maternally derived trisomy 21 than among control mothers (P = 0.000). The combination of MTHFR C677T genotype and diet significantly influenced global DNA methylation (R2 = 4.5%, P = 0.046). The lowest values of global DNA methylation were observed in mothers with MTHFR 677 CT+TT genotype and low dietary folate. Although our findings revealed an association between maternal global DNA hypomethylation and trisomy 21 of maternal origin, further progress and final conclusions regarding the role of global DNA methylation and the occurrence of trisomy 21 are facing major challenges. PMID:26017139

  4. The effects of genomic polymorphisms in one-carbon metabolism pathways on survival of gastric cancer patients received fluorouracil-based adjuvant therapy

    PubMed Central

    Zhao, Tingting; Xu, Zhi; Gu, Dongying; Wu, Peng; Huo, Xinying; Wei, Xiaowei; Tang, Yongfei; Gong, Weida; He, Ming-Liang; Chen, Jinfei

    2016-01-01

    5-fluorouracil (5-FU) is widely used to treat patients with gastric cancer (GC). However, the response rate is quite heterogeneous. The single nucleotide polymorphisms (SNPs) and their interactions of genes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR), and Thymidylate synthase (TS), significantly affect 5-FU metabolism. In this study, 650 stage II-III patients were recruited from 1998 to 2006. Among them, 251 received 5-FU treatment and other 399 patients were untreated. The Cox regression analysis, log-rank tests and Kaplan–Meier plots were adopted. In the chemotherapy cohort, MTRR 66 GA + GG genotypes decreased death risk, however, the protect effect of MTRR 66 GA + GG disappeared when GC patients simultaneously had MTHFR 677TT + TC or MTR 2756GG + GA genotypes. TS 5′-UTR 2R3R + 3R3R genotypes also prolonged overall survival of patients treated with 5-FU. And this favorable prognosis obviously enhanced when GC patients simultaneously had TS 3′-UTR DD + DI and TS 5′-UTR 2R3R + 3R3R genotypes. Our findings showed that the polymorphisms of MTRR 66 A > G and TS 5′-UTR 3R > 2R may be potential prognostic factors for GC patients receiving 5-FU. PMID:27456431

  5. The Effect of Multiple Single Nucleotide Polymorphisms in the Folic Acid Pathway Genes on Homocysteine Metabolism

    PubMed Central

    Liang, Shuang; Zhou, Yuanpeng; Wang, Huijun; Qian, Yanyan; Ma, Duan; Tian, Weidong; Persaud-Sharma, Vishwani; Yu, Chen; Ren, Yunyun; Zhou, Shufeng; Li, Xiaotian

    2014-01-01

    Objective. To investigate the joint effects of the single nucleotide polymorphisms (SNPs) of genes in the folic acid pathway on homocysteine (Hcy) metabolism. Methods. Four hundred women with normal pregnancies were enrolled in this study. SNPs were identified by MassARRAY. Serum folic acid and Hcy concentration were measured. Analysis of variance (ANOVA) and support vector machine (SVM) regressions were used to analyze the joint effects of SNPs on the Hcy level. Results. SNPs of MTHFR (rs1801133 and rs3733965) were significantly associated with maternal serum Hcy level. In the different genotypes of MTHFR (rs1801133), SNPs of RFC1 (rs1051266), TCN2 (rs9606756), BHMT (rs3733890), and CBS (rs234713 and rs2851391) were linked with the Hcy level adjusted for folic acid concentration. The integrated SNPs scores were significantly associated with the residual Hcy concentration (RHC) (r = 0.247). The Hcy level was significantly higher in the group with high SNP scores than that in other groups with SNP scores of less than 0.2 (P = 0.000). Moreover, this difference was even more significant in moderate and high levels of folic acid. Conclusion. SNPs of genes in the folic acid pathway possibly affect the Hcy metabolism in the presence of moderate and high levels of folic acid. PMID:24524080

  6. The association between end-stage diabetic nephropathy and methylenetetrahydrofolate reductase genotype with macroangiopathy in type 2 diabetes mellitus.

    PubMed

    Hasegawa, G; Obayashi, H; Kamiuchi, K; Nakai, M; Kanatsuna, T; Yamaguchi, M; Tanaka, T; Shigeta, H; Fujii, M; Yoshikawa, T; Nakamura, N

    2003-05-01

    The T/T genotype of the methylenetetrahydrofolate reductase C677 T gene polymorphism is associated with elevated homocysteine levels and presumably with increased atherosclerotic risk. We evaluated the interaction between this gene polymorphism and end-stage diabetic nephropathy on the observed prevalence of macroangiopathy in type 2 diabetes mellitus. The methylenetetrahydrofolate reductase 677 C/T genotypes were determined in 174 type 2 diabetic patients: 80 with and 94 without renal failure due to diabetic nephropathy. In the patients with renal failure, the T/T genotype and T allele were significantly associated with macroangiopathy (T/T; 31 % vs. 2 %, P = 0.0001 T allele; 59 % vs. 29 %, P = 0.00014), whereas the associations were not significant in the patients without renal failure. In the multiple logistic regression analysis, age (10 years OR 4.05 [1.79 - 9.31], P < 0.0005) and 677 T allele (6.84 [2.12 - 22.05], P = 0.0013) were significantly associated with macroangiopathy in the patients with renal failure. In conclusion, this study demonstrated that the 677 T/T genotype and T allele of MTHFR were significantly associated with macroangiopathy in type 2 diabetic patients with renal failure. The MTHFR 677 T allele, together with renal dysfunction due to diabetic nephropathy, could be a strong risk factor for atherosclerotic disease.

  7. Vascular behcet and mutations in thrombogenic genes: methylene tetrahydrofolate reductase, factor V, and prothrombin.

    PubMed

    Dagan, Efrat; Baruch, Yoav; Fiorilli, Massimo; Rozenbaum, Michael; Rosner, Itzhak; Gershoni-Baruch, Ruth

    2012-01-01

    Vasculitis, thrombophlebitis, arterial aneurysms, and occlusions occur in about 25% of patients with Behçet's disease (BD). The common inherited gene defects, factor V (FV) 1691A (Leiden), methylene tetrahydrofolate reductase (MTHFR) 677T, and prothrombin 20210A, are known risk factors for thrombosis. The aim of the study was to evaluate the contribution of these mutations to thrombosis in Israeli patients with BD. Fifty-four patients with BD (n=54; 27 men and 27 women) underwent clinical and genetic evaluation. Most patients (n=43; 79.6%) were of Arab descent (31 sporadic and 12 familial cases from 4 families), and 11 patients (20.4%) were of Jewish descent (all sporadic cases). The FV Leiden mutation was identified in five patients (9.2%), and eight patients were MTHFR 677TT homozygotes (14.8%). None had the 20210A mutant prothrombin allele. No statistical differences between carriers and noncarriers with regards to demographic and disease manifestations were calculated. Arabs were diagnosed earlier than Jewish patients (25.8±11.6 compared with 37.2±10.7, p=0.01, respectively), but Jewish patients had, respectively, more events of deep vein thrombosis (DVT) compared with Arabs (3 of 11, 27.3% and 3 of 43, 7%, p=0.09). Thrombotic events in our patients with BD were not associated with variations in thrombophilic genes.

  8. Mutations in methylenetetrahydrofolate reductase and in cysthationine beta synthase: is there a link to homocysteine levels in peripheral arterial disease?

    PubMed

    Santos, Maria E R C; das C L E Silva, Francisco; Gomes, Karina B; Fernandes, Ana Paula M; Freitas, Fernanda R; Faria, Mayara C; Mota, Ana Paula L; Carvalho, Maria G

    2011-06-01

    Peripheral arterial disease (PAD) is an atherosclerotic disturbance characterized by a progressive obstruction of lower limb arteries. Many risk factors associated with PAD development have being reported in the literature. The present study aimed to investigate whether mutations in the methylenetetrahydrofolate reductase (MTHFR) or in the cystathionine beta synthase (CBS) genes are associated with higher levels of homocysteine and the risk of PAD in patients from Brazil. This study analyzed 39 patients with PAD and 32 without PAD in whom risk factors and C677T mutations in the MTHFR gene and both 844ins68 and T833C mutations in the CBS gene were investigated. Although higher levels of homocysteine could be observed in patients with PAD compared to controls, no association between the increase of homocysteine and the frequency of C677T, 844ins68, and T833C mutations could be observed. The results suggest that these mutations do not appear to be related to either homocysteine levels or the development of the disease. However, hyperhomocysteinemia and smoking are important factors in PAD development.

  9. One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study.

    PubMed

    Suzuki, Takeshi; Matsuo, Keitaro; Hasegawa, Yasuhisa; Hiraki, Akio; Wakai, Kenji; Hirose, Kaoru; Saito, Toshiko; Sato, Shigeki; Ueda, Ryuzo; Tajima, Kazuo

    2007-09-01

    Low consumption of vegetables and fruits, which leads to insufficient folate intake, is associated with increased risk of several types of cancer, including head and neck squamous cell carcinoma (HNSCC). Functional polymorphisms in genes encoding one-carbon metabolism enzymes, such as methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism and thus might impact on HNSCC risk. We conducted a case-control study with 237 HNSCC cases newly and histologically diagnosed and 711 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms. Gene-environment interactions between polymorphisms and smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. Dietary folate intake was inversely associated with HNSCC risk. None of the polymorphisms showed any significant impact on HNSCC risk by genotype alone, but we found interactions between drinking habit and MTHFR C667T (P = 0.04), MTR A2756G (P = 0.04) and MTRR A66G (P = 0.03) polymorphisms. The results suggest that there may be interactions between one-carbon metabolism-related polymorphisms and alcohol drinking for HNSCC risk.

  10. Hyperhomocysteinemia and related genetic polymorphisms correlate with ulcerative colitis in Chinese Han population in Central China [corrected].

    PubMed

    Jiang, Yi; Xia, Xuanping; Wang, Wenxing; Lin, Limiao; Xu, Changlong; Cai, Zhenzai; Zheng, Bo; Pei, Jihua; Shen, Sujian; Xia, Bing

    2012-01-01

    Increased levels of homocysteine are found systemically and in intestinal mucosa of patients with inflammatory bowel disease, and, specifically, in ulcerative colitis (UC). However, there are controversial reports regarding the factors contributing to increased levels of homocysteine in UC. Furthermore, little information is available regarding the relationship between hyperhomocysteinemia (HHcy), vitamin status, and genetic polymorphisms of homocysteine-related enzymes in these patients. This study examined four functional polymorphisms linked to homocysteine metabolism (MTHFR C677T and A1298C, MTR A2756G and MTRR A66G), and evaluated plasma levels of homocysteine, folate, and vitamin B(12) in 310 consecutive patients with UC and 936 age- and sex-matched healthy controls from southeast China. The variant allele and genotypic frequencies in MTHFR A1298C, MTR A2756G and MTRR A66G genes were significantly higher in patients with UC compared to healthy controls. Further, HHcy and low levels of folate and vitamin B(12) were more frequent in patients with UC. The MTR 2756G allele, extent of the disease, and gender were the independent determinants of HHcy in these patients. These findings suggest that genetic and nutritional factors have a synergetic effect on HHcy in patients with UC. In conclusion, our data highlight a prevention strategy for moderation of HHcy and supplementation with folate and vitamine B(12) in patients with UC from Southeast China.

  11. Polymorphisms in Methionine Synthase, Methionine Synthase Reductase and Serine Hydroxymethyltransferase, Folate and Alcohol Intake, and Colon Cancer Risk

    PubMed Central

    Steck, Susan E.; Keku, Temitope; Butler, Lesley M.; Galanko, Joseph; Massa, Beri; Millikan, Robert C.; Sandler, Robert S.

    2009-01-01

    Background/Aims We examined associations among folate and alcohol intake, SNPs in genes involved in one-carbon metabolism and colon cancer risk. Methods Colon cancer cases (294 African Americans and 349 whites) were frequency matched to population controls (437 African Americans and 611 whites) by age, race and sex from 33 North Carolina counties from 1996 to 2000. Folate and alcohol intakes were collected by dietary interview. Five SNPs were genotyped using DNA from whole blood: SHMT C1420T; MTRR A66G; MTR A2756G, and the previously-reported MTHFR C677T and MTHFR A1298C. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Results An inverse association was observed for SHMT TT genotype as compared to CC genotype in whites (OR=0.6, 95%CI=0.4, 1.0), but not in African Americans. Inverse associations were observed for high folate intake in individuals carrying 0 or 1 variant allele [OR 0.2 (95%CI 0.06 – 0.8) for African Americans; OR 0.2 (95%CI 0.1– 0.6) for whites] compared to low folate intake. Modest interactions between these SNPs and alcohol or folate intakes were observed. Conclusions Our results are consistent with other findings and provide needed data on these associations among African Americans. PMID:19776626

  12. Gene-Gene Interactions in the Folate Metabolic Pathway and the Risk of Conotruncal Heart Defects

    PubMed Central

    Lupo, Philip J.; Goldmuntz, Elizabeth; Mitchell, Laura E.

    2010-01-01

    Conotruncal and related heart defects (CTRD) are common, complex malformations. Although there are few established risk factors, there is evidence that genetic variation in the folate metabolic pathway influences CTRD risk. This study was undertaken to assess the association between inherited (i.e., case) and maternal gene-gene interactions in this pathway and the risk of CTRD. Case-parent triads (n = 727), ascertained from the Children's Hospital of Philadelphia, were genotyped for ten functional variants of nine folate metabolic genes. Analyses of inherited genotypes were consistent with the previously reported association between MTHFR A1298C and CTRD (adjusted P = .02), but provided no evidence that CTRD was associated with inherited gene-gene interactions. Analyses of the maternal genotypes provided evidence of a MTHFR C677T/CBS 844ins68 interaction and CTRD risk (unadjusted P = .02). This association is consistent with the effects of this genotype combination on folate-homocysteine biochemistry but remains to be confirmed in independent study populations. PMID:20111745

  13. Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates.

    PubMed

    Ment, Laura R; Adén, Ulrika; Lin, Aiping; Kwon, Soo Hyun; Choi, Murim; Hallman, Mikko; Lifton, Richard P; Zhang, Heping; Bauer, Charles R

    2014-01-01

    Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5-min Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1, a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role.

  14. Endothelial function markers in parkinsonian patients with hyperhomocysteinemia.

    PubMed

    Bostantjopoulou, Sevasti; Katsarou, Zoe; Frangia, Theodora; Hatzizisi, Olga; Papazisis, Kostas; Kyriazis, George; Kiosseoglou, Gregory; Kazis, Aristidis

    2005-08-01

    Hyperhomocysteinemia is considered a risk factor for vascular disease causing endothelial damage and consequently atherogenesis. The purpose of this study was to investigate the effect of elevated homocysteine on certain biochemical markers of endothelial function in patients with idiopathic Parkinson's disease (PD). Blood homocysteine levels were assessed in 57 PD patients and 40 matched normal controls. Investigation of the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) genotype was also performed in 43 PD patients. The following markers of endothelial function were assessed: superoxide dismutase (SOD), nitric oxide (NO), sICAM-1 and sE-selectin. Homocysteine levels were found mildly elevated in PD patients particularly in those treated with L-Dopa. MTHFR genotype did not influence significantly this finding. SOD activity was found reduced but it was not correlated to homocysteine levels. All other parameters measured were normal and were not related to hyperhomocysteinemia. Our findings indicate that mild hyperhomocysteinemia in PD patients was not associated with endothelial dysfunction.

  15. Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke

    PubMed Central

    Szolnoki, Z; Somogyvari, F; Kondacs, A; Szabo, M; Fodor, L; Bene, J; Melegh, B

    2003-01-01

    Objectives: Ischaemic stroke is a frequent heterogeneous multifactorial disease that is affected by a number of genetic mutations and environmental factors. We hypothesised the clinical importance of the interactions between common, unfavourable genetic mutations and clinical risk factors in the development of ischaemic stroke. Methods: The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations, the angiotensin converting enzyme I/D (ACE I/D), and apolipoprotein allele e4 (APO e4) genotypes were examined by the polymerase chain reaction (PCR) technique in 867 ischaemic stroke patients and 743 healthy controls. Logistic regression models were used to estimate the roles of the co-occurrences of the clinical risk factors and common genetic mutations in ischaemic stroke. Results: The Leiden V mutation in combination with hypertension or diabetes mellitus increased the risk of ischaemic stroke. We found synergistic effects between the ACE D/D and MTHFR 677TT genotypes and drinking or smoking. The presence of the APO e4 greatly facilitated the unfavourable effects of hypertension, diabetes mellitus, smoking, or drinking on the incidence of ischaemic stroke. Conclusion: In certain combinations, pairing of common unfavourable genetic factors, which alone confer only minor or non-significant risk, with clinical risk factors can greatly increase the susceptibility to ischaemic stroke. PMID:14638877

  16. Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates

    PubMed Central

    Ment, Laura R.; Ådén, Ulrika; Lin, Aiping; Kwon, Soo Hyun; Choi, Murim; Hallman, Mikko; Lifton, Richard P.; Zhang, Heping; Bauer, Charles R.

    2014-01-01

    Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd – 33rd week post-conception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory and vascular pathways, and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH suggesting an as yet unknown environmental trigger. The methylenetetra-hydrofolate reeducates (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5 minute Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1 (COL4A1), a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role. PMID:24192699

  17. Folate metabolism genes, vegetable intake and renal cancer risk in central Europe.

    PubMed

    Moore, Lee E; Hung, Rayjean; Karami, Sara; Boffetta, Paolo; Berndt, Sonya; Hsu, Charles C; Zaridze, David; Janout, Vladimir; Kollarova, Helen; Bencko, Vladmir; Navratilova, Marie; Szeszenia-Dabrowska, N; Mates, Dana; Mukeria, Anush; Holcatova, Ivana; Yeager, Meredith; Chanock, Stephen; Garcia-Closas, Montse; Rothman, Nat; Chow, Wong-Ho; Brennan, Paul

    2008-04-15

    In a multicenter case-control study of renal cell carcinoma (RCC) conducted in central and eastern Europe, we reported a strong inverse association with high vegetable intake and RCC risk. The odds ratio (OR) for high compared to the lowest tertile of vegetable intake was OR = 0.67; (95% confidence interval (CI): 0.53-0.83; p-trend < 0.001). We hypothesized that variation in key folate metabolism genes may modify this association. Common variation in 5 folate metabolism genes (CBS: Ex9+33C > T (rs234706), Ex13 +41C > T (rs1801181), Ex18 -391 G > A (rs12613); MTHFR: A222V Ex5+79C > T (rs1801133), Ex8-62A > C (rs1801131); MTR: Ex26 20A > G (rs1805087), MTRR: Ex5+136 T > C (rs161870), and TYMS:IVS2-405 C > T (rs502396), Ex8+157 C > T (rs699517), Ex8+227 A > G (rs2790)) were analyzed among 1,097 RCC cases and 1,555 controls genotyped in this study. Having at least 1 variant T allele of MTHFR A222V was associated with higher RCC risk compared to those with 2 common (CC) alleles (OR = 1.44; 95% CI: 1.17-1.77; p = 0.001). After stratification by tertile of vegetable intake, the higher risk associated with the variant genotype was only observed in the low and medium tertiles (p-trend = 0.001), but not among those in the highest tertile (p-interaction = 0.22). The association remained robust after calculation of the false discovery rate (FDR = 0.05). Of the 3 TYMS SNPs examined, only the TYMS IVS2 -405 C (rs502396) variant was associated with a significantly lower risk compared to the common genotype (OR = 0.73; 95% CI: 0.57-0.93). Vegetable intake modified the association between all 3 TYMS SNPs and RCC risk (p-interaction < 0.04 for all). In summary, these findings suggest that common variation in MTHFR and TYMS genes may be associated with RCC risk, particularly when vegetable intake is low.

  18. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer.

    PubMed

    de Vogel, Stefan; Wouters, Kim A D; Gottschalk, Ralph W H; van Schooten, Frederik J; de Goeij, Anton F P M; de Bruïne, Adriaan P; Goldbohm, Royle A; van den Brandt, Piet A; Weijenberg, Matty P; van Engeland, Manon

    2009-11-01

    Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of folate metabolizing enzymes (MTHFR, MTR, and MTRR), DNA methyltransferase DNMT3b, and histone methyltransferases (EHMT1, EHMT2, and PRDM2), with colorectal cancers, with or without the CpG island methylator phenotype (CIMP), MLH1 hypermethylation, or microsatellite instability. Incidence rate ratios were calculated in case-cohort analyses, with common homozygotes as reference, among 659 cases and 1,736 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852). Men with the MTHFR 677TT genotype were at decreased colorectal cancer risk (incidence rate ratio, 0.49; P = 0.01), but the T allele was associated with increased risk in women (incidence rate ratio, 1.39; P = 0.02). The MTR 2756GG genotype was associated with increased colorectal cancer risk (incidence rate ratio, 1.58; P = 0.04), and inverse associations were observed among women carrying DNMT3b C-->T (rs406193; incidence rate ratio, 0.72; P = 0.04) or EHMT2 G-->A (rs535586; incidence rate ratio, 0.76; P = 0.05) polymorphisms. Although significantly correlated (P < 0.001), only 41.5% and 33.3% of CIMP tumors harbored MLH1 hypermethylation or microsatellite instability, respectively. We observed inverse associations between MTR A2756G and CIMP among men (incidence rate ratio, 0.58; P = 0.04), and between MTRR A66G and MLH1 hypermethylation among women (incidence rate ratio, 0.55; P = 0.02). In conclusion, MTHFR, MTR, DNMT3b, and EHMT2 polymorphisms are associated with colorectal cancer, and rare variants of MTR and MTRR may reduce promoter hypermethylation. The incomplete overlap between CIMP, MLH1 hypermethylation, and microsatellite instability indicates that these related "methylation

  19. Detailed Analysis of Gene Polymorphisms Associated with Ischemic Stroke in South Asians

    PubMed Central

    Yadav, Sunaina; Hasan, Nazeeha; Marjot, Thomas; Khan, Muhammad S.; Prasad, Kameshwar; Bentley, Paul; Sharma, Pankaj

    2013-01-01

    The burden of stroke is disproportionately high in the South Asian subcontinent with South Asian ethnicity conferring a greater risk of ischemic stroke than European ancestry regardless of country inhabited. While genes associated with stroke in European populations have been investigated, they remain largely unknown in South Asians. We conducted a comprehensive meta-analysis of known genetic polymorphisms associated with South Asian ischemic stroke, and compared effect size of the MTHFR C677T-stroke association with effect sizes predicted from homocysteine-stroke association. Electronic databases were searched up to August 2012 for published case control studies investigating genetic polymorphisms associated with ischemic stroke in South Asians. Pooled odds ratios (OR) for each gene-disease association were calculated using a random-effects model. We identified 26 studies (approximately 2529 stroke cases and 2881 controls) interrogating 33 independent genetic polymorphisms in 22 genes. Ten studies described MTHFR C677T (108 with TT genotype and 2018 with CC genotype) -homocysteine relationship and six studies (735 stroke cases and 713 controls) described homocysteine-ischemic stroke relationship. Risk association ORs were calculated for ACE I/D (OR 5.00; 95% CI, 1.17–21.37; p = 0.03), PDE4D SNP 83 (OR 2.20; 95% CI 1.21–3.99; p = 0.01), PDE4D SNP 32 (OR 1.57; 95% CI 1.01–2.45, p = 0.045) and IL10 G1082A (OR 1.44; 95% CI, 1.09–1.91, p = 0.01). Significant association was observed between elevated plasma homocysteine levels and MTHFR/677 TT genotypes in healthy South Asians (Mean difference (ΔX) 5.18 µmol/L; 95% CI 2.03–8.34: p = 0.001). Our results demonstrate that the genetic etiology of ischemic stroke in South Asians is broadly similar to the risk conferred in Europeans, although the dataset is considerably smaller and warrants the same clinical considerations for risk profiling. PMID:23505425

  20. Three genetic polymorphisms of homocysteine-metabolizing enzymes and risk of coronary heart disease: a meta-analysis based on 23 case-control studies.

    PubMed

    Chen, Ling; Liu, Liu; Hong, Kui; Hu, Jianxin; Cheng, Xiaoshu

    2012-02-01

    Many epidemiological studies have explored the relationships between three genetic polymorphisms of genes encoding homocysteine-metabolizing enzymes (methionine synthase [MTR] A2756G, methionine synthase reductase [MTRR] A66G, and N(5),N(10)-methylenetetrahydrofolate reductase [MTHFR] A1298C) and risk of coronary heart disease (CHD), but no conclusive results were obtained. Therefore, we performed a meta-analysis of 23 case-control studies. Odds ratio (OR) and 95% confidence interval (95% CI) were used to examine the strength of the associations. Among those primary studies, 22 studies were for Europeans, and one study focused on the MTR A2756G polymorphism in Asians. The results of combined analyses of the MTR A2756G polymorphism suggested that the G allele was associated with increased risk of CHD and myocardial infarction (MI) especially for Europeans (GG vs. AA for CHD: OR [95% CI]=1.63 [1.18-2.25], p(z)(-test)=0.001, p(heterogeneity)=0.274; GG+AG vs. AA for MI: OR [95% CI]=1.44 [1.08-1.93], p(z)(-test)=0.014, p(heterogeneity)=0.611). In addition, the G allele was also associated with higher risk CHD based on population-based case-control studies (PCC) (GG vs. AA: OR [95% CI]=1.75 [1.24-2.49], p(z)(-test)=0.002, p(heterogeneity)=0.316). The results suggested that the MTRR A66G polymorphism was not associated with risk of CHD for Europeans (AA vs. GG: OR [95% CI]=1.07 [0.59-1.94], p(z)(-test)=0.831, p(heterogeneity)<0.01). The results suggested that the C allele of the MTHFR A1298C polymorphism might be associated with the increased risk of MI for Europeans (CC vs. CA+AA: OR [95% CI]=1.37 [1.03-1.84], p(z)(-test)=0.033, p(heterogeneity)=0.668). However, when subgroup analyses for sources of controls were performed, conflicting results were obtained. The results suggested that the C allele was associated with decreased risk of CHD based on hospital-based case-control studies, but associated with increased risk of CHD based on PCC. This meta-analysis suggests that

  1. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility

    PubMed Central

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-01-01

    There are several evidences supporting the role of 5–10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03–1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02–1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06–1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01–1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03–1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06–1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99–1.14; p = 0.05). PMID:26629412

  2. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility.

    PubMed

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-12-01

    There are several evidences supporting the role of 5-10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03-1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02-1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06-1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01-1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03-1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06-1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99-1.14; p = 0.05).

  3. Pharmacogenetic predictors of toxicity to platinum based chemotherapy in non-small cell lung cancer patients.

    PubMed

    Pérez-Ramírez, Cristina; Cañadas-Garre, Marisa; Alnatsha, Ahmed; Villar, Eduardo; Delgado, Juan Ramón; Faus-Dáder, María José; Calleja-Hernández, Miguel Ángel

    2016-09-01

    Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real-Time with Taqman(®) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy.

  4. Choline and methionine differentially alter methyl carbon metabolism in bovine neonatal hepatocytes

    PubMed Central

    Chandler, Tawny L.

    2017-01-01

    Intersections in hepatic methyl group metabolism pathways highlights potential competition or compensation of methyl donors. The objective of this experiment was to examine the expression of genes related to methyl group transfer and lipid metabolism in response to increasing concentrations of choline chloride (CC) and DL-methionine (DLM) in primary neonatal hepatocytes that were or were not exposed to fatty acids (FA). Primary hepatocytes isolated from 4 neonatal Holstein calves were maintained as monolayer cultures for 24 h before treatment with CC (61, 128, 2028, and 4528 μmol/L) and DLM (16, 30, 100, 300 μmol/L), with or without a 1 mmol/L FA cocktail in a factorial arrangement. After 24 h of treatment, media was collected for quantification of reactive oxygen species (ROS) and very low-density lipoprotein (VLDL), and cell lysates were collected for quantification of gene expression. No interactions were detected between CC, DLM, or FA. Both CC and DLM decreased the expression of methionine adenosyltransferase 1A (MAT1A). Increasing CC did not alter betaine-homocysteine S-methyltranferase (BHMT) but did increase 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) and methylenetetrahydrofolate reductase (MTHFR) expression. Increasing DLM decreased expression of BHMT and MTR, but did not affect MTHFR. Expression of both phosphatidylethanolamine N-methyltransferase (PEMT) and microsomal triglyceride transfer protein (MTTP) were decreased by increasing CC and DLM, while carnitine palmitoyltransferase 1A (CPT1A) was unaffected by either. Treatment with FA decreased the expression of MAT1A, MTR, MTHFR and tended to decrease PEMT but did not affect BHMT and MTTP. Treatment with FA increased CPT1A expression. Increasing CC increased secretion of VLDL and decreased the accumulation of ROS in media. Within neonatal bovine hepatocytes, choline and methionine differentially regulate methyl carbon pathways and suggest that choline may play a critical role in

  5. Implantation of left ventricular assist device complicated by undiagnosed thrombophilia.

    PubMed

    Szarszoi, Ondrej; Maly, Jiri; Turek, Daniel; Urban, Marian; Skalsky, Ivo; Riha, Hynek; Maluskova, Jana; Pirk, Jan; Netuka, Ivan

    2012-01-01

    A patient with dilated cardiomyopathy and no history of thromboembolic events received a surgically implanted axial-flow left ventricular assist device. After implantation, transesophageal echocardiography revealed a giant thrombus on the lateral and anterior aspects of the left ventricle. The inflow cannula inserted through the apex of the left ventricle was not obstructed, and the device generated satisfactory blood flow. Laboratory screening for thrombophilia showed protein S deficiency, heterozygous factor V Leiden mutation, and heterozygous MTHFR C667T mutation. During the entire duration of circulatory support, no significant suction events were detected, and the patient was listed for heart transplantation. Ventricular assist device implantation can unmask previously undiagnosed thrombophilia; therefore, it should be necessary to identify thrombophilic patients before cardiac support implantation.

  6. Laughing Gas in a Pediatric Emergency Department-Fun for All Participants: Vitamin B12 Status Among Medical Staff Working With Nitrous Oxide.

    PubMed

    Staubli, Georg; Baumgartner, Matthias; Sass, Jörn Oliver; Hersberger, Martin

    2016-12-01

    The efficiency of nitrous oxide in an equimolar mixture with oxygen or in concentrations up to 70% is approved for short painful procedures. Evaluation of the vitamin B12 levels in anesthetic staff applying nitrous oxide showed reduced vitamin B12 plasma levels. This study examines the vitamin B12 status of medical staff working with nitrous oxide in a pediatric emergency department (ED). Medical staff of the ED at the University Children's Hospital Zurich participated. The vitamin B12 status was evaluated by measuring homocysteine, methylmalonic acid, vitamin B12, blood count, and the MTHFR C677T genotype. As a control group, medical personnel working in the "nitrous oxide-free" pediatric intensive care unit were recruited.

  7. Molecular-based choice of cancer therapy: realities and expectations.

    PubMed

    Imyanitov, Evgeny N; Moiseyenko, Vladimir M

    2007-04-01

    Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success. Molecular research provides some opportunities to personalize antitumor treatment. For example, life-threatening toxic reactions can be avoided by the identification of subjects, who carry susceptible genotypes of drug-metabolizing genes (e.g. TPMT, UGT1A1, MTHFR, DPYD). Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response. Tailoring of antiestrogen and trastuzumab therapy based on hormone and HER2 receptor status has already become a classical example of customized medicine. Other predictive markers have been identified both for cytotoxic and for targeted therapies, and include, for example, expression of TS, TP, DPD, OPRT, ERCC1, MGMT, TOP2A, class III beta-tubulin molecules as well as genomic alterations of EGFR, KIT, ABL oncogenes.

  8. Prothrombin G20210A and methylenetetrahydrofolate reductase C677T polymorphisms in peripheral capillary nonperfusion: a case report.

    PubMed

    Wathek, Chaima; Mrad, Meriem; Abdessalem, Nadia Ben; Maalej, Afef; Gritli, Nasreddine; Gabsi, Salem; Rannen, Riadh; Fekih-Mrissa, Najiba

    2015-09-01

    The G20210A mutation in the prothrombin gene is an established risk factor for venous thrombosis. However, there is some controversy as to the role played by this mutation in arterial thrombotic disease. The association of peripheral capillary nonperfusion with prothrombin G20210A mutation has never been reported before. We present the case of 34-year-old man who presented with peripheral capillary nonperfusion. The fundus examination of his right eye revealed an epiretinal membrane, peripheral (mainly temporally) retinal haemorrhages, exudates and microaneurismal alterations of the vascular bed. Fluorescein angiography of his right eye demonstrated an extended area of capillary nonperfusion distal to the microaneurismal lesions. Evaluation revealed mutations of the G20210A prothrombin and MTHFR genes. Screening for hereditary thrombophilia should be considered, regardless of patient age, in patients with peripheral retinal ischemia. The prothrombin G20210A mutation, a genetic risk factor, may be associated with peripheral capillary nonperfusion.

  9. Free-floating thrombus of the carotid artery with a homozygous methylenetetrahydrofolate reductase gene mutation: a case report.

    PubMed

    Colak, Necmettin; Nazli, Yunus; Kosehan, Dilek; Alpay, Mehmet Fatih; Cakir, Omer

    2013-02-01

    Free-floating thrombus (FFT) of the carotid artery is a rare condition of currently unknown etiology. We describe a symptomatic patient with an FFT in the left common carotid artery. A duplex ultrasonography scan showed the presence of a mobile floating thrombus moving in cyclical motion with the cardiac cycles in the left common carotid artery. During emergency surgery, an FFT was seen at this location and removed. No underlying wall defect was seen at the time of surgery. In a genetic screening test, TT homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms was detected. The patient recovered uneventfully, with no neurogical events. Lifelong anticoagulant therapy was recommended. An aggressive surgical approach is recommended in the patient to prevent embolic episodes.

  10. Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study.

    PubMed

    Azık, Fatih; Gökçebay, Dilek Gürlek; Tavil, Betül; Işık, Pamir; Tunç, Bahattin; Uçkan, Duygu

    2015-09-01

    Amaç: Hematopoetik kök hücre nakli (HSCT) yapılan hastalarda venöz tromboembolizm (VTE) yüksek morbiditeye sahiptir. Bu çalışmanın amacı pediatrik allojenik HSCT alıcılarındaki VTE insidansını belirlemek ve pretransplant protrombotik risk faktörlerinin trombozdaki rolünü saptamaktır. Yöntem ve Gereçler: Nisan 2010-Kasım 2012 tarihleri arasında allojenik HSCT yapılan ve HSCT sonrası 100 gününü tamamlayan 92 hasta retrospektif olarak değerlendirildi. Kök hücre nakli öncesinde tüm hastalardan koagülasyon profili, kazanılmış ve konjenital protrombotik risk faktörlerinden faktör V Leiden, protrombin G20210A, metilentetrahidrofolat redüktaz (MTHFR) C677T, MTHFR A1298C mutasyonları ile serum homosistein ve lipoprotein(a), plazma antitrombin III, protein C ve protein S düzeyleri alındı. Bulgular: Trombofili taramasında; toplam sekiz hasta (%9) faktör V Leiden heterozigot, beş hasta (%6) MTHFR 677TT homozigot, 12 hasta (%14) MTHFR 1298CC homozigot ve iki (%2) hasta prothrombin G20210A heterozigot mutasyonuna sahipti. Venöz tromboembolizm beş hastada (%5.4) izlendi; herhangi bir protrombotik risk faktörü beş hastadan üçünde tespit edilirken, dört hastanın santral venöz kateteri vardı. Venöz tromboembolizm ile kalıtsal protrombotik risk faktörleri arasında anlamlı ilişki saptanmadı. Sonuç: Hematopoetik kök hücre nakli sonrasında VTE; muhtemelen düşük dozda düşük moleküler ağırlıklı heparin kullanımına bağlı olarak az sıklıkta görülebilen bir komplikasyon olup, prospektif bir çalışma yapılmaksızın kalıtsal protrombotik risk faktörlerinin trombozdaki rolünün tam olarak dışlanması mümkün değildir.

  11. B vitamin polymorphisms and behavior: evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline.

    PubMed

    Mitchell, E Siobhan; Conus, Nelly; Kaput, Jim

    2014-11-01

    The B vitamins folic acid, vitamin B12 and B6 are essential for neuronal function, and severe deficiencies have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia. Polymorphisms of genes involved in B vitamin absorption, metabolism and function, such as methylene tetrahydrofolate reductase (MTHFR), cystathionine β synthase (CβS), transcobalamin 2 receptor (TCN2) and methionine synthase reductase (MTRR), have also been linked to increased incidence of psychiatric and cognitive disorders. However, the eff