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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. A possible genetic link between MTHFR genotype and smoking behavior.

    PubMed

    Linnebank, Michael; Moskau, Susanna; Semmler, Alexander; Hoefgen, Barbara; Bopp, Gisela; Kallweit, Ulf; Maier, Wolfgang; Schütz, Christian G; Wüllner, Ullrich

    2012-01-01

    Hyperhomocysteinemia is an independent risk factor for stroke and other vascular events. The variant methylenetetrahydrofolate reductase (MTHFR) C677T is associated with elevated homocysteine levels, cardiovascular disease and stroke, which supports a causal relationship between hyperhomocysteinemia and vascular disease. However, MTHFR variants have also been reported to be associated with smoking behavior, which could be an important confounder. We analyzed the MTHFR variants C677T and A1298C in two independent samples of 525 and 535 individuals, respectively. 21% of the non-smokers, but only 12% of the smokers were homozygous carriers of both MTHFR wildtype alleles, i.e. 677CC and 1298AA (Chi² = 15.8; p<0.001; binary regression). Plasma homocysteine levels were higher in smokers (13.9±4.1 µmol/L) than in non-smokers (12.6±4.0 µmol/L; F = 11.4; p = 0.001; ANOVA). Smoking MTHFR 677TT individuals had the highest plasma homocysteine levels (16.2±5.2 µmol/L), non-smoking 677CC individuals had the lowest (12.2±13.6 µmol/L). In our study samples, MTHFR variants and smoking behaviour were associated with homocysteine plasma levels. In addition, the MTHFR variants were associated with smoking behaviour. Such an association may be a relevant confounder between MTHFR variants, homocysteine plasma levels and vascular diseases.

  5. 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.

  6. 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.

  7. MTRR and MTHFR polymorphism: link to Down syndrome?

    PubMed

    O'Leary, Valerie B; Parle-McDermott, Anne; Molloy, Anne M; Kirke, Peadar N; Johnson, Zachary; Conley, Mary; Scott, John M; Mills, James L

    2002-01-15

    Polymorphisms in genes encoding the folate metabolizing enzymes methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase reductase (MTRR A66G) have been linked to the etiology of Down syndrome. We examined the prevalence of these variant genotypes in mothers who had given birth to a child with Down syndrome (n = 48) and in control mothers (n = 192), and investigated the biochemical factors influenced by the presence of MTRR A66G and MTHFR C677T. The frequency of the MTRR variant genotypes (AG, GG) was significantly higher in mothers of children with Down syndrome compared to controls (P = 0.0028). MTHFR C677T genotype frequencies were not significantly altered in mothers of children with Down syndrome (P = 0.74). However, mothers who had a MTHFR CT or TT genotype and a MTRR GG genotype had a 2.98-fold increased risk of having a child with Down syndrome (P = 0.02). The MTRR polymorphism did not increase plasma homocysteine. Higher homocysteine was found with the presence of the MTHFR T allele. In conclusion, MTRR A66G is significantly more common in mothers of children with Down syndrome but does not appear to increase the risk for Down syndrome by changing homocysteine metabolism. Women who have both the MTRR and MTHFR variant genotypes are also at increased risk of producing offspring with Down syndrome.

  8. 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.

  9. Association of Methylenetetrahydrofolate Reductase (MTHFR-677 and MTHFR-1298) Genetic Polymorphisms with Occlusive Artery Disease and Deep Venous Thrombosis in Macedonians

    PubMed Central

    Spiroski, Igor; Kedev, Sashko; Antov, Slobodan; Arsov, Todor; Krstevska, Marija; Dzhekova-Stojkova, Sloboda; Kostovska, Stojanka; Trajkov, Dejan; Petlichkovski, Aleksandar; Strezova, Ana; Efinska-Mladenovska, Olivija; Spiroski, Mirko

    2008-01-01

    Aim To analyze the association of methylenetetrahydrofolate reductase polymorphisms (MTHFR-677 and MTHFR-1298) with occlusive artery disease and deep venous thrombosis in Macedonians. Methods We examined 83 healthy respondents, 76 patients with occlusive artery disease, and 67 patients with deep venous thrombosis. Blood samples were collected and DNA was isolated from peripheral blood leukocytes. Identification of MTHFR mutations was done with CVD StripAssay (ViennaLab, Labordiagnostika GmbH, Vienna, Austria) and the population genetics analysis package, PyPop, was used for the analysis. Pearson P values, crude odds ratio, and Wald’s 95% confidence intervals were calculated. Results The frequency of C alleles of MTHFR-677 was 0.575 in patients with deep venous thrombosis, 0.612 in patients with occlusive artery disease, and 0.645 in healthy participants. The frequency of T allele of MTHFR-677 was lower in healthy participants (0.355) than in patients with occlusive artery disease (0.388) and deep venous thrombosis (0.425). The frequency of A allele for MTHFR-1298 was 0.729 in healthy participants, 0.770 in patients with occlusive artery disease, and 0.746 in patients with deep venous thrombosis. The frequency of C allele of MTHFR-1298 was 0.271 in healthy participants, 0.230 in patients with occlusive artery disease, and 0.425 in patients with deep venous thrombosis. No association of MTHFR-677 and MTHFR-1289 polymorphisms with occlusive artery disease and deep venous thrombosis was found, except for the protective effect of MTHFR/CA:CC diplotype for occlusive artery disease. Conclusion We could not confirm a significant association of MTHFR-677 and MTHFR-1289 polymorphisms with occlusive artery disease or deep venous thrombosis in Macedonians, except for the protective effect of MTHFR/CA:CC diplotype against occlusive artery disease. PMID:18293456

  10. Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR.

    PubMed

    Dean, John; Robertson, Zoe; Reid, V; Wang, Q Diana; Hailey, Hazel; Moore, Sue; Rasalam, A Dee; Turnpenny, Peter; Lloyd, David; Cardy, Amanda; Shaw, Duncan; Little, Julian

    2007-10-01

    The malformations found in fetal anticonvulsant syndromes (FACS) are associated with folic acid deficiency and methylene-tetrahydrofolate reductase (MTHFR) polymorphisms in the general population. To investigate a possible association between FACS and MTHFR genotype, we recruited 200 mothers who had taken anti-epileptic drugs in pregnancy, and delivered at Aberdeen Maternity Hospital over a 26-year period. Clinical findings in the mothers and their 337 children were documented. A clinical algorithm was devised to diagnose FACS objectively. Case-parent triads were genotyped for polymorphisms in MTHFR, serine hydroxymethyl transferase (SHMT1), methionine synthase (MTR), and methionine synthase reductase (MTRR), and analyzed by log-linear regression. No effect of the child's genotype on congenital malformation, neurodevelopmental disorder or FACS was detected using this method. The risk of having a child with congenital malformation or FACS was three to four times higher for mothers who were MTHFR 677TT homozygotes compared with MTHFR 677CC homozygotes. MTR 2756A > G and MTRR 66A > G genotype frequencies in children with FACS and neurodevelopmental disorder were different from those in healthy blood donor controls. 2007 Wiley-Liss, Inc

  11. 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.

  12. 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

  13. [MTHFR polymorphisms, dietary folate intake and risks to breast cancer].

    PubMed

    Gao, Chang-Ming; Kazuo, Tajima; Tang, Jin-Hai; Cao, Hai-Xia; Ding, Jian-Hua; Wu, Jian-Zhong; Wang, Jie; Liu, Yan-Ting; Li, Su-Ping; Su, Ping; Keitaro, Matsuo; Toshiro, Takezaki

    2009-07-01

    To evaluate the relationship between dietary folate intake and genetic polymorphisms of 5, 10-methylenetetrahydrofolate reductase (MTHFR) with reference to breast cancer risk. A case-control study was conducted with 669 cases and 682 population-based controls in Jiangsu province of China. MTHFR C677T and A1298C genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Dietary folate intake was assessed by using an 83-item food frequency questionnaire. Odds ratios (OR) were estimated with an unconditional logistic model. The frequencies of MTHFR C677T C/C, C/T and T/T genotypes were 32.37% (202/624), 48.88% (305/624) and 18.75% (117/624) in cases and 37.66% (235/624), 48.24% (301/624) and 14. 10% (88/624) in controls, respectively. The difference in distribution was significant (chi2 = 6.616, P = 0.037), the T/T genotype being associated with an elevated OR for breast cancer (1.62, 95% CI: 1.14 -2.30). The frequencies of MTHFR A1298C A/A, A/C and C/C were 71.47% (446/624), 27.08% (169/624) and 1.44% (9/624) in cases and 68.11%(425/624), 30.13% (188/624) and 1.76% (11/624)in controls,with no significant differences found (chi2 = 1.716, P= 0.424). Folate intake of cases [(263.00 +/- 137.38) microg/d] was significantly lower than that of controls [(285.12 +/- 149.61) microg/d] (t = -2. 830, P =0.005). Compared with the lowest tertile (< or = 199.08 microg/d) of folate intake, the adjusted OR for breast cancer in the top tertile (> or = 315.11 microg/d) was 0.70 (95% CI: 0.53 -0.92). Among individuals with the MTHFR A1298C A/A genotype,adjusted OR for breast cancer were 0.89 (95% CI: 0.62 - 1.27) and 1.69 (95% CI: 1.20 - 2.36) for the second to the third tertile of folate intake compared with the highest folate intake group (X2trend = 11.372, P = 0.001). The findings of the present study suggest that MTHFR genetic polymorphisms,and dietary intake of folate may modify susceptibility to breast cancer.

  14. 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

  15. MTHFR 677C>T polymorphism and cluster headache.

    PubMed

    Schürks, Markus; Neumann, Franziska A; Kessler, Christof; Diener, Hans-Christoph; Kroemer, Heyo K; Kurth, Tobias; Völzke, Henry; Rosskopf, Dieter

    2011-02-01

    An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene (MTHFR) and cluster headache is plausible, but has not been investigated. To investigate this association among Caucasians. Case-control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni-corrected P value <.004 as significant. Mean age at study entry among patients was 44.9 years (SD 11.4), of whom 76.2% were men. The genotype distribution among controls and patients was in Hardy-Weinberg equilibrium. The genotype and allele distribution did not differ between patients with any cluster headache and controls. We also did not find an association when assuming additive, dominant or recessive genetic models. When we looked at subgroups, the effect estimates suggested an increased risk for chronic cluster headache (dominant model: odds ratio = 2.82; 99.6% confidence interval = 0.72-11.07; P = .03). Data from our case-control study do not indicate an association between genotypes of the MTHFR 677C>T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies. © 2010 American Headache Society.

  16. 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

  17. 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

  18. 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.

  19. 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. © 2014 WILEY PERIODICALS, INC.

  20. 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

  1. 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

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

    PubMed

    Choi, Youngsok; Kim, Jung Oh; 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.

  3. 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

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

    PubMed

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

    2015-04-01

    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. 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. 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. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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. © 2013.

  9. Decreased expression of methylene tetrahydrofolate reductase (MTHFR) gene in patients with rheumatoid arthritis.

    PubMed

    Remuzgo-Martínez, Sara; Genre, Fernanda; López-Mejías, Raquel; Ubilla, Begoña; Mijares, Veronica; Pina, Trinitario; Corrales, Alfonso; Blanco, Ricardo; Martín, Javier; Llorca, Javier; González-Gay, Miguel Á

    2016-01-01

    Impairment of methylene tetrahydrofolate reductase (MTHFR), a key enzyme in the folate metabolism, results in an elevated plasma level of homocysteine, considered an independent risk factor for cardiovascular (CV) disease. Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased risk of CV death. Polymorphisms in the MTHFR gene increase the frequency of CV disease in RA. The aim of this study was to determine the expression of MTHFR gene in patients with RA, with and without ischaemic heart disease (IHD). Relative expression of MTHFR gene and beta-actin and GAPDH as housekeeping genes was quantified by quantitative real-time polymerase chain reaction. It was analysed by the comparative Ct (threshold cycle) method in peripheral blood from 26 Spanish patients with RA (12 with IHD and 14 without IHD) and 10 healthy controls. MTHFR expression level in RA patients was also assessed according to disease activity, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies status. MTHFR expression was significantly reduced in patients with RA compared to controls (fold change = 0.85, p=0.029). It was especially true for RA patients with IHD (fold change= 0.79, p=0.021). However, no statistically significant relationship between MTHFR expression level in patients with RA and DAS28 CRP, DAS28 ESR, RF and anti-CCP status was observed. Patients with RA, in particular those with IHD, show a decreased expression of the MTHFR gene. This may support a potential implication of the transcriptional regulation of MTHFR in the pathogenesis of RA.

  10. 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.

  11. 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.

  12. The use of B vitamins for cutaneous ulcerations mimicking pyoderma gangrenosum in patients with MTHFR polymorphism.

    PubMed

    New, Douglas; Eaton, Philip; Knable, Al; Callen, Jeffrey P

    2011-04-01

    Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are associated with thrombophilia and vasculopathy that may result in cutaneous ulceration. Pyoderma gangrenosum (PG) is a clinical diagnosis that may be made following exclusion of alternate causes of ulceration, including vascular inflammatory or occlusive disease, infection, and malignant neoplasm. We describe 2 patients with MTHFR polymorphisms discovered during hypercoagulable evaluation for cutaneous ulcerations on the lower extremities. Both patients showed a rapid improvement following treatment with oral vitamin supplementation and local wound care. One patient developed several subsequent ulcers when he decided to discontinue his therapy, and following reinitiation of therapy, the new ulcerations healed. The treatment was tolerated well without any adverse effects. MTHFR polymorphisms should be part of a comprehensive laboratory evaluation during hypercoagulable workup. Vitamin supplementation with folic acid (B(9)), pyridoxine hydrochloride (B(6)), and cyanocobalamin (B(12)) may result in healing of cutaneous ulcerations in some patients with MTHFR mutations.

  13. 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

  14. [Association of MTHFR and MTRR genes polymorphisms with non-disjunctions of chromosomes 18 and 21].

    PubMed

    Guo, Qiannan; Wang, Hongdan; Yang, Ke; Zhang, Bo; Li, Tao; Liao, Shixiu

    2015-06-01

    To explore the effect of MTHFR and MTRR genes polymorphisms on chromosomes 18 and 21 non-disjunction through investigation of Henan Han Chinese young females with a gestational history of trisomy 21 (Down syndrome, DS) or trisomy 18 (Edwards syndrome, ES). Polymorphisms of MTHFR 677C/T, MTHFR 1298A/C and MTRR 66A/G were analyzed in 73 healthy females (controls group), 78 females with a gestational history of DS (DS group) and 54 females with a gestational history of ES (ES group) by direct sequencing of PCR products from amplification of peripheral blood lymphocyte DNA. The frequency of MTHFR 677T allele was significantly different among the DS group, ES group and the control group (P<0.05). The frequency of MTRR 66G allele was significantly different only between the DS group and the control group (P<0.05). MTHFR 1298A/C polymorphisms were not associated with either ES or DS. Compared with the wild genotype MTHFR 677CC or MTRR 66AA, carriers of the MTHFR 677CT, 677TT, or MTRR 66GG genotypes had respectively 2.694 times (95%CI: 1.204-6.025, P<0.05), 5.451 times (95%CI: 2.211-13.435, P<0.05) and 9.618 times (95%CI: 2.085-44.365, P<0.05) risk of bearing a DS baby. Compared with the wild genotype MTHFR 677CC, carriers of the MTHFR 677CT and 677TT genotype had respectively 2.701 times (95%CI: 1.133-6.438, P<0.05) and 3.804 times (95%CI: 1.406-10.293, P<0.05) risk of bearing a ES baby. Neither MTRR 66AG or 66GG genotype was associated with the occurrence of ES. The MTHFR 677T and MTRR 66G may represent a risk factor for DS gestation, while MTHFR 677T may represent a risk factor for ES gestation for Chinese Han females.

  15. Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease.

    PubMed

    Gromadzka, Grażyna; Rudnicka, Magdalena; Chabik, Grzegorz; Przybyłkowski, Adam; Członkowska, Anna

    2011-10-01

    Wilson's disease (WND) is an autosomal recessive disorder of copper (Cu) transport, resulting from pathogenic mutations in the ATP7B gene. The reason for the high variability in phenotypic expressions of WND is unknown. Hepatotoxic and neurotoxic effects of homocysteine (Hcy), as well as interrelationships between Hcy and Cu toxicity, were documented. We genotyped the two 5,10-methylenetetrahydrofolate reductase (one of the key folate/Hcy pathway enzymes) gene (MTHFR) polymorphisms: C677T and A1298C in 245 WND patients. Next, we tested the modulation of WND phenotypes by genotypes of MTHFR. MTHFR C677T genotype distribution deviated from that expected from a population in Hardy-Weinberg equilibrium (C677T, χ(2) = 12.14, p = 0.0005). Patients with the MTHFR 1298C allele were younger at symptoms' onset than those without this allele (median (IQR) age, 24.9 (14.0) years vs. 28.5 (12.0) years, p = 0.006). Carriers of MTHFR "high activity" diplotype (double wild-type homozygotes 677CC/1298AA) manifested WND at older age, than non-carriers (median (IQR) age, 33.5 (9.0) years vs. 25.0 (13.0) years, p = 0.0009). Patients with the MTHFR 677T allele less frequently exhibited the neurological WND phenotype (31 (29.5%) vs. 36 (48.0%)), and more frequently presented with hepatic WND (44 (41.9%) vs. 22 (29.3%)), compared with subjects MTHFR 677T(-). We postulate that MTHFR polymorphism contributes to the phenotypic variability of WND. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  16. 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.

  17. 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.

  18. Effects of single-nucleotide polymorphisms in MTHFR and MTRR on mortality and allograft loss in kidney transplant recipients.

    PubMed

    Winkelmayer, Wolfgang C; Kramar, Reinhard; Sunder-Plassmann, Gere; Födinger, Manuela

    2005-12-01

    Plasma total homocysteine (tHcy) is associated with cardiovascular outcomes in kidney transplant recipients (KTR). The methylenetetrahydrofolate-reductase (MTHFR) 677C>T polymorphism, an important determinant of plasma tHcy concentrations, could therefore constitute an important prognostic marker. We prospectively followed 710 KTR over >6 years. The MTHFR677C>T, MTHFR1298A>C, MTHFR1793G>A, and MTRR66A>G polymorphisms were analyzed. Demographic, clinical, and transplant-related information was obtained, and patients were followed-up using the Austrian Dialysis and Transplant Registry. Using Cox regression, we established the independent relations of each genotype to the risk of death from any cause, and/or kidney allograft loss. During a median follow-up of 6.1 years, 154 participants died and 260 kidney allografts were lost. Compared to patients with the MTHFR677CC genotype, patients with MTHFR677CT had an adjusted relative mortality risk of 1.02 (95%CI 0.70-1.47), and those with MTHFR677TT of 0.98 (95%CI 0.52-1.85). Compared to MTHFR677CC, the relative risks of kidney allograft loss were 0.93 (95%CI 0.70-1.23; MTHFR677CT) and 0.78 (95%CI 0.47-1.30; MTHFR677TT), respectively. None of the other genotypes were associated with the risks studied, either. These findings did not depend on whether we controlled for tHcy levels. This study does not support the routine use of MTHFR or MTRR genotyping for prognostic evaluation or risk-stratification in kidney transplant recipients.

  19. 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.

  20. MTHFR Gene Polymorphism-Mutations and Air Pollution as Risk Factors for Breast Cancer: A Metaprediction Study.

    PubMed

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

    The methylenetetrahydrofolate reductase gene (MTHFR) is one of the most investigated genes associated with breast cancer for its role in epigenetic pathways. 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. 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. 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. 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.

  1. Associations of variants in MTHFR and MTRR genes with male infertility in the Jordanian population.

    PubMed

    Mfady, Doaa S; Sadiq, May F; Khabour, Omar F; Fararjeh, Abdulfattah S; Abu-Awad, Aymen; Khader, Yousef

    2014-02-15

    Folate pathway is expected to play an important role in spermatogenesis since it is involved in DNA synthesis, repair and methylation. The purpose of this study was to examine the association between male infertility and the MTHFR (C677T and A1298C) and MTRR (A66G) polymorphisms. A group of 300 males was recruited in this study from different Jordanian infertility clinics. Of these, 150 cases of infertile men that included oligozoospermia cases (n=45), severe oligozoospermia (n=71) and azoospermia (n=34) were studied. The other 150 males were age matched fertile controls. Genotyping of MTHFR and MTRR polymorphisms was performed using PCR-RFLP technique. The results showed an association between MTHFR 677TT genotype and male infertility (P<0.05). However, the distribution of MTHFR A1298C and MTRR A66G genotypes were not different between the fertile and infertile groups (P>0.05). In addition, none of the examined polymorphisms was related to any of the semen parameters in the infertile group. In conclusion, this study showed that MTHFR C677T polymorphism is associated with male infertility in Jordanians. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Polymorphisms in MTHFR and MTRR genes associated with blood plasma homocysteine concentration and sperm counts.

    PubMed

    Montjean, Debbie; Benkhalifa, Moncef; Dessolle, Lionel; Cohen-Bacrie, Paul; Belloc, Stéphanie; Siffroi, Jean-Pierre; Ravel, Célia; Bashamboo, Anu; McElreavey, Kenneth

    2011-02-01

    To investigate the relationship between MTHFR and MTRR genetic variants with respect to both blood plasma homocysteine concentration and sperm counts. Polymerase chain reaction followed by specific enzymatic digestion to determine the genotype of the individuals and blood plasma homocysteine quantification by high-performance liquid chromatography. Research laboratory. Two hundred sixty-eight men seeking infertility counseling and 254 partners of infertile women. We studied three MTHFR (c.1286A → C, c.665C → T and c.203G → A) and two MTRR (c.66A → G and c.524C → T) single-nucleotide polymorphisms and characterized sperm parameters in both oligozoospermic and normospermic men. A cohort of 522 men was examined for this study. A subgroup of 103 men was constituted for quantification of Hcy levels. Semen samples were collected for determinations of sperm concentration, motility, and morphology according to World Health Organization guidelines as well as for DNA isolation. Blood samples of the corresponding individuals were obtained to quantify plasma homocysteine levels. We did not observe a relationship between homocysteinemia and sperm counts. The MTHFR c.665C → T variant is associated with mild hyperhomocysteinemia in blood plasma in the TT homozygous state. No association was found between MTHFR/MTRR genetic variants and sperm counts. Although no association was observed with reduced sperm counts, the MTHFR 665TT genotype is associated with a significant increase in blood plasma homocysteine levels. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  3. 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

  4. 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.

  5. 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.

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

    PubMed

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

    2015-01-01

    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. To establish the frequency of the C> T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. 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. 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). 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.

  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. Association of C677T transition of the human methylenetetrahydrofolate reductase (MTHFR) gene with male infertility.

    PubMed

    Karimian, Mohammad; Colagar, Abasalt Hosseinzadeh

    2016-04-01

    The human methylenetetrahydrofolate reductase (MTHFR) gene encodes one of the key enzymes in folate metabolism. This gene is located on chromosome 1 (1p36.3), which has 12 exons. The aim of the present study was to investigate the possible association of the two (C677T and A1298C) polymorphisms of this gene with male infertility. In a case-control study, 250 blood samples were collected from IVF centres in Sari and Babol (Iran): 118 samples were from oligospermic men and 132 were from controls. Two single nucleotide polymorphisms of the MTHFR genotype were detected using polymerase chain reaction-restriction fragment length polymorphism. There was no association found between the A1298C variant and male infertility. However, carriers of the 677T allele (CT and TT genotypes) were at a higher risk of infertility than individuals with other genotypes (odds ratio 1.84; 95% confidence interval 1.11-3.04; P=0.0174). Structural analysis of human MTHFR flavoprotein showed that C677T transition played an important role in the change in affinity of the MTHFR-Flavin adenine dinucleotide binding site. Based on our results, we suggest that C677T transition in MTHFR may increase the risk of male infertility, and detection of the C677T polymorphism biomarker may be helpful in the screening of idiopathic male infertility.

  9. Determination of Methylenetetrahydrofolate Reductase (MTHFR) gene polymorphism in Turkish patients with nonsyndromic cleft lip and palate.

    PubMed

    Aşlar, Deniz; Özdiler, Erhan; Altuğ, Ayşe Tuba; Taştan, Hakkı

    2013-07-01

    To investigate the association between MTHFR C677T polymorphism and Turkish patients with nonsyndromic cleft lip and/or palate (nsCL/P) and to determine the prevalence of the Turkish population. Molecular analysis of gene polymorphisms were carried out using polymerase chain reactions and restriction enzyme digestions. In our study, 80 patients with nsCL/P and 125 unrelated individuals from Turkey were studied. We found that MTHFR C677T polymorphism is a significant risk factor for nsCL/P in Turkey (p=0.0004). These results support the impact of MTHFR C677T polymorphism and importance of folic acid intake in the etiology of nsCL/P. MTHFR gene which is localized in the relevant region of chromosome 1p36.3 not been studied Turkish patients with nsCL/P and the prevalence of our country not to be determined. We revealed statistically association between the MTHFR C677T gene polymorphism and nonsyndromic cleft lip and/or palate in the Turkish population. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. 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. © 2014 Blackwell Verlag GmbH.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  12. 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

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

    PubMed

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

    2017-04-01

    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. 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. 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. 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.

  14. 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

  15. 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.

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

    PubMed

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

    2015-01-01

    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. 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. 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. 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.

  17. Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression

    PubMed Central

    Lok, A; Bockting, C L H; Koeter, M W J; Snieder, H; Assies, J; Mocking, R J T; Vinkers, C H; Kahn, R S; Boks, M P; Schene, A H

    2013-01-01

    Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T− and TCE+ patients; 773 days for T+ and TCE− patients and 866 days for T− and TCE− patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma. PMID:23900311

  18. 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

  19. 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.

  20. Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression.

    PubMed

    Lok, A; Bockting, C L H; Koeter, M W J; Snieder, H; Assies, J; Mocking, R J T; Vinkers, C H; Kahn, R S; Boks, M P; Schene, A H

    2013-07-30

    Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T- and TCE+ patients; 773 days for T+ and TCE- patients and 866 days for T- and TCE- patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma.

  1. 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

  2. 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.

  3. [Mutations of MTHFR, MTR, MTRR genes as high risk factors for neural tube defects].

    PubMed

    Sliwerska, Elzbieta; Szpecht-Potocka, Agnieszka

    2002-01-01

    Neural tube defects (NTDs) have a polygenic background. There are numerous genes known to be high-risk genetic factors for NTDs. Ones of them are mutations of foliate metabolisms pathways genes. This paper shows the results of analysis of common mutations of MTHFR, MTR and MTRR genes. Results of screening mutations 2756A-->G and 66A-->G in MTR and MTRR genes respectively show that are might have an effect on NTDs incidence among the examined population. Analysis of data for the studied population does not prove the influence of mutations 677C-->T and 1298A-->C of MTHFR gene on NTDs.

  4. 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

  5. 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

  6. Association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with primary glaucoma in Saudi population.

    PubMed

    Al-Shahrani, Hamoud; Al-Dabbagh, Najwa; Al-Dohayan, Nourah; Arfin, Misbahul; Al-Asmari, Mohammad; Rizvi, Sadaf; Al-Asmari, Abdulrahman

    2016-09-01

    Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism is involved in DNA synthesis, DNA repair and DNA methylation. The functional polymorphism of MTHFR gene, C677T has been shown to impact various diseases and implicated as a risk factor for the development of various neurodegenerative disorders including glaucoma. We investigated MTHFR C677T genotypes and alleles frequencies in primary glaucoma [primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG)] patients and matched healthy controls in a case-control study. Two hundred ten primary glaucoma cases were studied for MTHFR C677T polymorphism and compared with 280 controls taken from the healthy population, employing the polymerase chain reaction-restriction fragment length polymorphism technique (PCR-RFLP). The MTHFR gene was amplified using specific primers. The PCR products (294 bp) was subsequently digested with HinfI (New England Biolabs) at 37 °C for 12 h, separated by electrophoresis on 2 % agarose gels, and visualized with ethidium bromide staining. The restriction digestion yielded 168 and 126 bp fragments for TT, 294, 168 and 126 bp fragments for CT and undigested PCR product 294 bp indicating CC genotype. We found the frequency of the genotypes and alleles of MTHFR C677T differ significantly between cases and controls. The frequencies of allele T and genotype CT were significantly higher while the frequencies of allele C and genotype CC were lower in primary glaucoma patients as compared to controls (p <0.05). Upon stratification of our results into POAG and PACG, significantly higher frequencies of allele T (19.44 %) and genotype CT (38.89 %) were found in POAG patients compared to controls (12.5 % and 25 % respectively). The frequencies of alleles and genotypes were almost similar in PACG and controls (p = 0.8). This study indicates that the allele T and genotype CT of MTHFR C677T polymorphism are significantly associated with POAG

  7. 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. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. 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.

  9. 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

  10. 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.

  11. 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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26046315

  13. MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort.

    PubMed

    Nursal, Ayse Feyda; Kaya, Süheyla; Sezer, Ozlem; Karakus, Nevin; Yigit, Serbulent

    2017-05-22

    Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine (Hcy) metabolism. We aimed to evaluate a possible relationship between MTHFR gene C677T (rs 1801133), A1298C (rs 1801131) variants and susceptibility to FMF in a Turkish cohort. This case-control study included 198 Turkish FMF patients and 100 healthy subjects as controls. MTHFR C677T and A1298C were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. The genotype distribution and allele frequency of the MTHFR C677T were statistically different between the patients and the control group (P=.006, P=.001, respectively). The frequency of the TT genotype and T allele of MTHFR C677T was significantly higher in the patients than in the controls. The genotype distribution of MTHFR A1298C variant did not show any statistically significant difference between the patients and the controls (P›.05). The patients had statistically different frequencies in allele C of MTHFR A1298C variant compared with the control (P=.032). We also examined the risk associated with inheriting the combined genotypes for the two MTHFR variants. According to these results, individuals who were CC homozygous at C677T locus and AA homozygous at A1298C locus have a lower risk of developing FMF (P=.002). Individuals who were TT homozygous at C677T locus and AC heterozygous at A1298C locus have higher risk of developing FMF (P=.033). Our findings clearly showed there was an association the MTHFR C677T/A1298C variants and susceptibility to FMF in the Turkish sample. © 2017 Wiley Periodicals, Inc.

  14. 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.

  15. 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

  16. Two Mutations in the Caprine MTHFR 3'UTR Regulated by MicroRNAs Are Associated with Milk Production Traits

    PubMed Central

    Song, Yuxuan; Gao, Teyang; Lei, Yingnan; Cao, Binyun

    2015-01-01

    Background 5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism by irreversibly converting 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, a predominant circulating form of folate. Folate is reportedly important for milk protein synthesis, and MTHFR may be a key regulatory point of folate metabolism for milk protein synthesis in mammary epithelial cells. Prior to this study, polymorphisms of the MTHFR gene were not associated with milk production traits from a breeding perspective. Single nucleotide polymorphisms (SNPs) at microRNA (miRNA) binding sites (miR-SNPs) can affect gene expression. This study aimed to identify the effects of miR-SNPs (g.2244A>G and g.2264A>G) in the caprine MTHFR 3' UTR on the milk production traits of dairy goats. Results Guanzhong dairy (GD, n = 325) goats were used to detect SNPs in the caprine MTHFR 3' UTR by DNA sequencing. Two novel SNPs (g.2244A>G and g.2264A>G) were identified in the said region. The homozygous haplotype A-G of the SNPs g.2244A>G and g.2264A>G was significantly associated with milk yield and milk protein levels in GD goats (P < 0.05). Functional assays indicated that the MTHFR 2244 A → G substitution could increase the binding activity of hsa-miR-1266 with the MTHFR 3' UTR. The MTHFR 2264 A → G substitution could decrease the binding activity of hsa-miR-616 with the MTHFR 3' UTR. In addition, we observed a significant increase in the MTHFR mRNA levels of homozygous haplotype A-G carriers relative to those of homozygous haplotype G-A carriers. These results indicated that both SNPs altered the MTHFR mRNA levels. These altered levels of MTHFR mRNA may account for the association of SNPs with milk production traits. Conclusions This study is the first to report that the g.2244A>G and g.2264A>G polymorphisms were associated with milk production traits in GD goats. Further investigations should explore the underlying miRNA-mediated mechanisms that are modified by

  17. Association between premature ovarian failure, polymorphisms in MTHFR and MTRR genes and serum homocysteine concentration.

    PubMed

    Hou, Ningning; Chen, Songchang; Chen, Feng; Jiang, Minmin; Zhang, Junyu; Yang, Yanmei; Zhu, Bo; Bai, Xiaoxia; Hu, Yuting; Huang, Hefeng; Xu, Chenming

    2016-04-01

    This study investigated the association between premature ovarian failure (POF), MTHFR C677T/A1298C and MTRR A66G genotypes and serum homocysteine (Hcy) concentration. A prospective study was conducted in Chinese women, which included POF patients (n = 180) and controls (n = 195). Peripheral blood samples were used to determine MTHFR C677T/A1298C and MTRR A66G genotypes, and serum Hcy and sex hormone concentrations. Results showed that serum Hcy concentrations of POF patients were significantly higher than those of controls (P < 0.0001). In POF patients, serum Hcy concentrations were significantly correlated with oestradiol and FSH concentrations (r = -0.174, P = 0.037 and r = +0.238, P = 0.006, respectively). There were no significant differences in the distributions of MTHFR C677T/A1298C or MTRR A66G genotypes between the two groups. However, these genetic variants influenced serum Hcy concentrations in POF patients, especially for MTRR 66 AA/AG/GG genotypes, which were significantly correlated with the patients' Hcy concentrations (τ = 0.166, P = 0.033). These results suggest that serum Hcy concentrations in Chinese POF patients are increased and correlated with serum oestradiol/FSH concentrations. In conclusion, MTHFR C667T/A1298C and MTRR A66G genotypes are not associated with POF development, but they affect the patients' serum Hcy concentrations. Copyright © 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  18. [Geographical distribution of MTHFR and MTRR gene polymorphisms among the Han women in Zhengzhou city].

    PubMed

    Cui, Huiling; Lu, Yanqiang; Ma, Shaojie; Xue, Yan; Wang, Ting; Duan, Gehong; Yang, Qi

    2015-07-01

    To explore the genotype distribution of 5,10-methylenetetrahydrofolate reductase (MTHFR) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) among Chinese Han women in Zhengzhou. 
 A total of 1 253 women were recruited from Zhengzhou city. The genotype of MTHFR C677T, A1298C and MTRR A66G was detected to analyze the distribution of gene polymorphisms and to compare them with the published data from other Han women.
 The frequency of the MTHFR 1298CC genotypes (1.3%) in Zhengzhou was lower than that in Xiangtan (4.8%), Yanbian (3.8%), Zhenjiang (3.5%), Jingzhou (3.2%), Kunming (2.7%), Deyang (6.3%), Huizhou (7.2%) and Wulumuqi (3.4%) (all P<0.05). The difference in allele frequency was significant compared with that in Yantai, Yanbian, Wulumuqi, Zhenjiang, Jingzhou, Kunming, Dezhou, Xiangtan or Huizhou (all P<0.05). The frequency of the MTRR 66GG genotypes (5.4%) in Zhengzhou was lower than that in Deyang (8.2%) (P<0.01) and allele frequency between them was significant difference (P<0.05). 
 The gene polymorphism of MTHFR A1298C and MTRR A66G among the Han women in Zhengzhou is statistically different from that in some regions of China.

  19. 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…

  20. 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.

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

    PubMed

    Ferlazzo, Nadia; Currò, Monica; Zinellu, Angelo; Caccamo, Daniela; Isola, Gaetano; Ventura, Valeria; Carru, Ciriaco; Matarese, Giovanni; Ientile, Riccardo

    2017-03-29

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

  2. 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…

  3. 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

  4. Association of Methylenetetrahydrafolate Reductase Gene Polymorphism (MTHFR) in Patients with Gallbladder Cancer.

    PubMed

    Dixit, Ruhi; Singh, Gyanendra; Pandey, Manoj; Basu, Somprakas; Bhartiya, Satyanam Kumar; Singh, K K; Shukla, Vijay Kumar

    2016-03-01

    5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism and plays a major role in DNA methylation. There are two popular MTHFR polymorphisms known as C677T and A1298C which are found to be involved in folate metabolism and lowering the enzyme activity, thus may be linked with cancer development. This study aims to look at the association of these polymorphisms in gallbladder cancer. Thirty patients each with gallbladder cancer, cholelithiasis, and normal gallbladder were genotyped for the above-given polymorphisms by PCR-restriction fragment length polymorphism (RFLP) method. C677T MTHFR polymorphism was not associated (χ(2) = 2.44, p = 0.85) with an increased likelihood of having gallbladder cancer. A1298C was significantly associated (χ(2) = 28.87, p < 0.001) with risk of developing gallbladder cancer. A1298C was significantly correlated with grade (r = 0.337, p < 0.001) and histopathology (r = 0.446, p < 0.001). This study proposed that MTHFR A1298C polymorphism may be associated with risk of developing gallbladder cancer, and there is no association between C677T polymorphism and gallbladder cancer.

  5. 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

  6. 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. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  7. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and susceptibility for cervical lesions: a meta-analysis.

    PubMed

    Long, Shuyu; Yang, Xingliang; Liu, Xiaojiao; Yang, Pei

    2012-01-01

    The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis. The previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping. Neither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P = 0.006, OR = 0.83, 95% CI = 0.72-0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69-1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53-1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P = 0.06, OR = 1.21, 95% CI = 0.99-1.49) and AC vs. AA (P = 0.09, OR = 1.21, 95% CI = 0.97-1.51). The MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study.

  8. Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Susceptibility for Cervical Lesions: A Meta-Analysis

    PubMed Central

    Liu, Xiaojiao; Yang, Pei

    2012-01-01

    Background The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis. Methods The previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping. Results Neither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P = 0.006, OR = 0.83, 95% CI = 0.72–0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69–1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53–1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P = 0.06, OR = 1.21, 95% CI = 0.99–1.49) and AC vs. AA (P = 0.09, OR = 1.21, 95% CI = 0.97–1.51). Conclusions The MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C

  9. Association of MTHFR A1298C polymorphism with conotruncal heart disease.

    PubMed

    Sayin Kocakap, Beyza D; Sanli, Cihat; Cabuk, Feryal; Koc, Murat; Kutsal, Ali

    2015-10-01

    Congenital heart diseases are common congenital anomalies with 1% prevalence worldwide and are associated with significant childhood morbidity and mortality. Among a wide range of aetiologically heterogeneous conditions, conotruncal anomalies account for approximately one-third of all congenital heart defects. The aetiology of conotruncal heart diseases is complex, with both environmental and genetic causes. Hyperhomocysteinaemia, which is often accompanied by the defects of folic acid metabolism, is known to cause conotruncal heart anomalies. In this study, we have evaluated three polymorphisms in the following two hyperhomocysteinaemia-related genes: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and nicotinamide N-methyl transferase (NNMT rs694539) in 79 children with conotruncal heart disease and 99 children without conotruncal heart disease. Genotype distribution of the MTHFR A1298C polymorphism showed a statistically significant difference between the two groups. In the case group, AC and CC genotypes were higher than the control group (p<0.05). We have found that MTHFR A1298C polymorphism is associated with conotruncal heart disease; C allele (p=0.028), AC (OR[95% CI]=2.48[1.24-4.95], p=0.010), CC (OR[95% CI]=3.01[1.16-7.83], p=0.023), and AC+CC (OR[95% CI]=2.60[1.36-4.99], p=0.004) genotypes are more frequent in the patient group. Genotype distributions of the MTHFR C677T and NNMT rs694539 polymorphisms were similar in the two groups when evaluated separately and also according to the dominant genetic model (p>0.05). Our results suggest that MTHFR 1298C allele is a risk factor for conotruncal heart disease.

  10. 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.

  11. 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

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

    PubMed

    Zhang, Qiang; Yin, Guo-Ying; Liu, Juan; Liang, Yue; Li, Yao-Yan; Zhao, Jing-Yu; Zhang, Li-Wen; Wang, Bai-Qi; Tang, Nai-Jun

    2017-04-01

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

  13. 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.

  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. 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

  16. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345

    PubMed Central

    Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas DE

    2015-01-01

    Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/− mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/− mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/− livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/− mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2

  17. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice.

    PubMed

    Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas D E; Rozen, Rima

    2015-03-01

    Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot

  18. 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

  19. 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

  20. Associations between asymmetric dimethylarginine, homocysteine, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in rheumatoid arthritis.

    PubMed

    Dimitroulas, T; Sandoo, A; Hodson, J; Smith, J; Douglas, K M; Kitas, G D

    2016-07-01

    The aim of our study was to determine whether asymmetric dimethylarginine (ADMA) levels are associated with homocysteine (Hcy) and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) gene variants in patients with rheumatoid arthritis (RA). Serum ADMA and Hcy levels were measured in 201 RA individuals [155 (77.1%) females, median age 67 years (interquartile range 59-73)]. The MTHFR C677T polymorphism was assessed by using the LightCyclerTM System. Initially, ADMA was compared across the categories of MTHFR using a one-way analysis of variance (ANOVA), followed by a multivariate model, which accounted for Hcy, age, erythrocyte sedimentation rate (ESR), and homeostatic model assessment (HOMA). In univariable analysis, ADMA differed significantly across the categories of MTHFR (p = 0.037). Patients with the MTHFR 677TT genotype had the highest ADMA levels, with a mean of 0.62 (SE = 0.03), significantly higher than either those patients carrying the MTHFR 677CT (0.55, SE = 0.01) or the MTHFR 677CC (0.55, SE = 0.01) genotype (p = 0.042) in both cases. In the multivariable model, Hcy (p = 0.022) and ESR (p < 0.001) were found to have significant positive associations with ADMA but the relationship between MTHFR gene variants and ADMA was found to be non-significant (p = 0.102). Hcy and ADMA are significantly associated in RA. It is plausible that abnormal Hcy metabolism plays an important role in premature atherosclerosis in RA by promoting ADMA accumulation and leading to the derangement of vascular haemostasis.

  1. 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.

  2. 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

  3. Coexistence of Neurofibromatosis Type-1 and MTHFR C677T Gene Mutation in a Young Stroke Patient: A Case Report.

    PubMed

    Yilmaz, Halim; Erkin, Gulten; Gumus, Haluk; Nalbant, Lutfiye

    2013-01-01

    In neurofibromatosis type-1 (NF1), cerebrovascular disorders are rarely encountered although vasculopathy is a well-known complication. Several mutations seen in methylenetetrahydrofolate reductase (MTHFR) give rise to the formation of hyperhomocysteinemia and homocystinuria, a considerable risk factor for cardiovascular and cerebrovascular disorders, by leading to enzymatic inactivation. In the paper, a 31-year-old young stroke female patient with the coexistence of neurofibromatosis and MTHFR C677T gene mutation was presented.

  4. Severe 5,10-methylenetetrahydrofolate reductase deficiency and two MTHFR variants in an adolescent with progressive myoclonic epilepsy.

    PubMed

    D'Aco, Kristin E; Bearden, David; Watkins, David; Hyland, Keith; Rosenblatt, David S; Ficicioglu, Can

    2014-08-01

    5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of the folate-recycling pathway that affects the remethylation of homocysteine to methionine. The clinical presentation of MTHFR deficiency is highly variable ranging from early neurological deterioration and death in infancy to a mild thrombophilia in adults. We describe an adolescent girl with a history of mild learning disabilities who presented at age 14 years with an epilepsy syndrome initially thought to be juvenile myoclonic epilepsy. She later developed intractable epilepsy with myoclonus, leg weakness, cognitive decline, and ataxia consistent with the syndrome of progressive myoclonic epilepsy. This prompted further evaluation that revealed elevated plasma homocysteine and decreased plasma methionine. The diagnosis of MTHFR deficiency was confirmed based on extremely reduced fibroblast MTHFR activity (0.3 nmol CHO/mg prot/hr) as well as mutation analysis that revealed two variants in the MTHFR gene, a splice site mutation p (IVS5-1G>A), as well as a missense mutation (c.155 G>A; p. Arg52Gln). Therapy with folinic acid, betaine, and methionine has produced significant clinical improvement, including improved strength, less severe ataxia, and decreased seizure frequency, as well as improvements in her electroencephalography and electromyography. This patient demonstrates the importance of considering MTHFR deficiency in the differential diagnosis of progressive myoclonic epilepsy because it is one of the few causes for which specific treatment is available. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Associations of MTHFR and MTRR polymorphisms with serum lipid levels in Chinese hypertensive patients.

    PubMed

    Jiang, Shanqun; Zhao, Ruimeng; Pan, Mingluo; Venners, Scott A; Zhong, Guisheng; Hsu, Yi-Hsiang

    2014-05-01

    To examine the effects of the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms and their interactions with environmental factors on serum lipid levels. We investigated totally 340 patients with essential hypertension, from Dongzhi community, Anhui, China. High-throughput TaqMan allelic discrimination assay was used for the genotyping of MTHFR C677T (Ala222Val), MTHFR A1298C (Glu429Ala), MTRR A66G (Ile22Met), and MTRR His595Tyr. Compared with the MTRR 66AA genotype carriers, the GG genotype carriers had lower serum total cholesterol (TC) levels (adjusted β ± standard error [SE]: -0.5 ± 0.2 mmol/L; P = .003) and low-density lipoprotein cholesterol (LDL-C) levels (adjusted β ± SE: -0.4 ± 0.2 mmol/L; P = .005). Their false discovery rate (FDR)-adjusted P values were 0.056 and 0.056, respectively. We further found that there was a statistically significant interaction between 677TT genotype and sex in their associations with LDL levels (P interaction = .020), and significant interaction between 677TT genotype and smoking on LDL levels (P interaction = .036). A similar pattern of interaction was found between 66GG and drinking on levels of TC (P interaction = .034) and LDL (P interaction = .020). However, there were no significant interactions observed after FDR adjustment. Both MTHFR and MTRR gene polymorphisms could be important genetic determinants of serum lipid levels in Chinese patients with hypertension. These findings need to be replicated in a larger sample.

  6. 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.

  7. 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

  8. 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

  9. MTHFR Polymorphisms, Folate Intake, and Carcinogen DNA Adducts in the Lung

    PubMed Central

    Lee, Mi-Sun; Asomaning, Kofi; Su, Li; Wain, John C.; Mark, Eugene J.; Christiani, David C.

    2011-01-01

    The methylenetetrahydrofolate reductase (MTHFR) genes and folate in one-carbon metabolism are essential for DNA methylation and synthesis. However, their role in carcinogen DNA damage in target lung tissue, a dosimeter for cancer risk, is not known. Our study aimed to investigate the association between genetic and nutritional one-carbon metabolism factors and DNA adducts in target lung. Data on 135 lung cancer cases from the Massachusetts General Hospital were studied. Genotyping was completed for MTHFR C677T (rs1801133) and A1298C (rs1801131). Information on dietary intake for one-carbon related micronutrients, folate and other B vitamin, was derived from a validated food frequency questionnaire. DNA adducts in lung were measured by 32P-postlabeling. After adjusting for potential confounders, DNA adduct levels in lung significantly increased by 69.2% [95% confidence interval (CI), 5.5% to 171.5%] for the MTHFR 1298AC+CC genotype. The high risk group, combining the A1298C (AC+CC) plus C677T (CT+TT) genotypes, had significantly enhanced levels of lung adducts by 210.7% (95% CI, 21.4% to 695.2%) in contrast to the A1298C (AA) plus C677T (CC) genotypes. Elevation of DNA adduct was pronounced - 111.3% (95% CI, −3.0 to 360.5%) among 1298AC+CC patients who consumed the lowest level of folate intake as compared with 1298AA individuals with highest tertile of intake. These results indicate that DNA adducts levels are influenced by MTHFR polymorphisms and low folate consumption, suggesting an important role of genetic and nutritional factors in protecting DNA damage from lung carcinogen in at-risk populations. PMID:22052259

  10. MTHFR polymorphisms, folate intake and carcinogen DNA adducts in the lung.

    PubMed

    Lee, Mi-Sun; Asomaning, Kofi; Su, Li; Wain, John C; Mark, Eugene J; Christiani, David C

    2012-09-01

    The methylenetetrahydrofolate reductase (MTHFR) genes and folate in one-carbon metabolism are essential for DNA methylation and synthesis. However, their role in carcinogen DNA damage in target lung tissue, a dosimeter for cancer risk, is not known. Our study aimed to investigate the association between genetic and nutritional one-carbon metabolism factors and DNA adducts in target lung. Data on 135 lung cancer cases from the Massachusetts General Hospital were studied. Genotyping was completed for MTHFR C677T (rs1801133) and A1298C (rs1801131). Information on dietary intake for one-carbon related micronutrients, folate and other B vitamin was derived from a validated food frequency questionnaire. DNA adducts in lung were measured by (32) P-postlabeling. After adjusting for potential confounders, DNA adduct levels in lung significantly increased by 69.2% [95% confidence interval (CI), 5.5% to 171.5%] for the MTHFR 1298AC+CC genotype. The high risk group, combining the A1298C (AC+CC) plus C677T (CT+TT) genotypes, had significantly enhanced levels of lung adducts by 210.7% (95% CI, 21.4% to 695.2%) in contrast to the A1298C (AA) plus C677T (CC) genotypes. Elevation of DNA adduct was pronounced-111.3% (95% CI, -3.0 to 360.5%) among 1298AC+CC patients, who consumed the lowest level of folate intake as compared to 1298AA individuals with highest tertile of intake. These results indicate that DNA adducts levels are influenced by MTHFR polymorphisms and low folate consumption, suggesting an important role of genetic and nutritional factors in protecting DNA damage from lung carcinogen in at-risk populations. Copyright © 2011 UICC.

  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. 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

  13. Comparison of homocysteinemia and MTHFR 677CT polymorphism with Framingham Coronary Heart Risk Score.

    PubMed

    Gariglio, Luis; Riviere, Stephanie; Morales, Analía; Porcile, Rafael; Potenzoni, Miguel; Fridman, Osvaldo

    2014-01-01

    The Framingham Coronary Heart Disease Risk Score is an important clinical tool. The aim of this cross-sectional study was to compare plasma homocysteine levels and polymorphism 677CT MTHFR with this score to determine the utility of these new biomarkers in clinical practice. Plasma homocysteine levels determined by chemiluminescence and polymorphism 677CT MTHFR, detected by PCR-RFLP, were compared with Framingham coronary risk score in a cross-sectional survey on 68 men and 165 women. Coronary heart disease risk augmented with an increase in the quartile of plasma homocysteine. In the 2nd, 3rd and 4th quartile of plasma homocysteine, men showed significantly (P<0.001) higher risk than women. For the highest quartile of plasma homocysteine, OR of high-risk (10-year risk≥20%) compared with the lowest quartile was 17.45 (95% CI: 5.79-52.01). Frequencies of CT and TT genotype and T allele were not over-represented in the individuals with score≥10%. The higher plasma homocysteine concentrations in individuals with score≥10% with respect to those with low risk (P<0.005 and P<0.001) were not due to the presence of T allele. The T allele (CT+TT genotypes) of the MTHFR C677T polymorphism was not significantly associated with an increased risk of coronary disease (OR=1.09, 95% CI=0.50-2.39, P=0.844). The present study demonstrated an association between plasma homocysteine levels and the severity of coronary heart disease estimated with the Framingham coronary risk score, and this association appeared to be independent on the genotype of MTHFR. We postulate that plasma homocysteine is effective enough, considered even in isolation. Copyright © 2013 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  14. 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

  15. 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.

  16. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients

    PubMed Central

    Etienne-Grimaldi, Marie-Christine; Milano, Gérard; Maindrault-Gœbel, Frédérique; Chibaudel, Benoist; Formento, Jean-Louis; Francoual, Mireille; Lledo, Gérard; André, Thierry; Mabro, May; Mineur, Laurent; Flesch, Michel; Carola, Elisabeth; de Gramont, Aimery

    2010-01-01

    AIMS To test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy. METHODS Advanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G→C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C→T, 1298A→C), dihydropyrimidine deshydrogenase (IVS14+1G→A) and Oxa: glutathione S-transferase (GST) π (105Ile→Val, 114Ala→Val), excision repair cross-complementing group 1 (ERCC1) (118AAT→AAC), ERCC2 (XPD, 751Lys→Gln) and XRCC1 (399Arg→Gln)] were determined (blood mononuclear cells). RESULTS None of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C→T (P= 0.042) and 1298A→C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTπ 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054). CONCLUSIONS These results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms. PMID:20078613

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

    PubMed Central

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

    2013-01-01

    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. PMID:23444906

  18. Association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and susceptibility to Graves' ophthalmopathy.

    PubMed

    Lee, Jae Yeun; Kim, Nam Keun; Cho, Yong Wook; Lew, Helen

    2016-09-01

    The pathogenesis of Graves' ophthalmopathy (GO) remains to be entirely elucidated. The present study aimed to determine the association between phenotypic expression of the MTHFR gene and susceptibility to GO in patients with Graves' disease (GD). A prospective case‑controlled study was conducted with 122 patients with GD and GO (n=72) or without GO (n=50) and 100 healthy controls in South Korea. Patient history, including smoking, nutritional status, thyroid function and antithyroid antibodies were investigated and clinical activity score, VISA classification (which includes vision, inflammation, strabismus and appearance/exposure) and orbit computed tomography were evaluated. Fasting plasma total homocysteine (tHcy) concentration was measured, and genotype analysis of the MTHFR gene was conducted. The TT homozygous genotype was associated with a two‑fold increased risk of GO [adjusted odds ratio (AOR), 2.19; 95% confidence interval (CI), 0.78‑6.14]. However, this result was not significant. The TT genotype significantly increased the risk of GO compared with that in healthy controls (AOR, 2.92; 95% CI, 1.11‑7.65). The MTHFR 677CT/1298AA genotype decreased the risk of GO in patients with GD (AOR, 0.26; 95% CI, 0.08‑0.91). tHcy levels in patients with GD without GO were significantly higher than in patients with GO, however, they were within the normal limit. The current study identified an association between MTHFR polymorphisms and GO. These results will aid understanding of the pathogenesis of GO and facilitate development of genetic therapeutic strategies.

  19. 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. © 2013 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  20. Association of MTHFR, MTR, and MTRR polymorphisms with Parkinson's disease among ethnic Chinese in Taiwan.

    PubMed

    Fong, Chin-Shih; Shyu, Hann-Yeh; Shieh, Jia-Ching; Fu, Yi-Ping; Chin, Ting-Yu; Wang, Hsiao-Wei; Cheng, Chun-Wen

    2011-01-30

    Influence of folate/homocysteine conversion is considered to be important in the pathogenesis of Parkinson's disease (PD). However, association of the folate metabolic pathway gene polymorphisms with PD susceptibility remains unclear. To test this possibility in PD, we conducted a hospital-based case-control study constituting 211 patients and 218 age- and sex-matched controls of ethnic Chinese in Taiwan. Genotyping assay was performed to screen for polymorphisms of the methylenetetrahydrofolate reductase (MTHFR C677T), methyltetrahydrofolate-homocysteine methyltransferase (MTR A2756G), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR A1049G and C1783T) genes and assess the association between these genotype polymorphisms and PD risk using logistic regression analysis. Of these four non-synonymous polymorphisms, the MTRR 1049GG variant was significantly associated with PD susceptibility (OR=3.17, 95%CI=1.08-9.35). Furthermore, we stratified our patients based on the MTHFR 677TT genotype in different strata, a significant association between the joint effect of polymorphisms and PD risk was observed in those patients whose genotypes were MTRR A1049G/MTR A2756G or MTRR C1783T/MTR A2756G (P<0.05). Our findings provide support for the synergistic effects of polymorphisms in the folate metabolic pathway genes in PD susceptibility; the increased PD risk would be more significant in carriers with the polymorphisms of MTHFR, MTR, and MTRR genes. Copyright © 2010 Elsevier B.V. All rights reserved.

  1. Folate Deficiency and Gene Polymorphisms of MTHFR, MTR and MTRR Elevate the Hyperhomocysteinemia Risk.

    PubMed

    Li, Wen-Xing; Cheng, Fei; Zhang, A-Jie; Dai, Shao-Xing; Li, Gong-Hua; Lv, Wen-Wen; Zhou, Tao; Zhang, Qiang; Zhang, Hong; Zhang, Tao; Liu, Fang; Liu, Dahai; Huang, Jing-Fei

    2017-03-01

    Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). We aimed to investigate the joint effect of homocysteine metabolism gene polymorphisms, as well as the folate deficiency on the risk of HHcy in a Chinese hypertensive population. This study enrolled 480 hypertensive patients aged 28 - 75 from six hospitals in different Chinese regions from 9/2005 - 12/2005. Known genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G were detected by PCRRFLP methods. Serum Hcy was measured by high-performance liquid chromatography and serum folate was measured by chemiluminescent immunoassay. MTHFR C677T and MTR A2756G can independently elevate the risk of HHcy (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA, p = 0.026, respectively), whereas MTHFR A1298C decreased HHcy risk (AC + CC vs. AA, p < 0.001) and showed a protective effect against HHcy risk. Importantly, the joint effect of these risk genotypes showed significantly higher odds of HHcy than non-risk genotypes, especially the patients with four risk genotypes. It is noteworthy that this deleterious effect was aggravated by folate deficiency. These findings were verified by generalized multifactor dimensionality reduction model (p = 0.001) and a cumulative effects model (p < 0.001). We have first demonstrated that the joint effect of homocysteine metabolism gene polymorphisms and folate deficiency lead to dramatic elevations in the HHcy risk.

  2. The importance of MTHFR, MTR, MTRR and CSE expression levels in Caucasian women with preeclampsia.

    PubMed

    Seremak-Mrozikiewicz, Agnieszka; Bogacz, Anna; Bartkowiak-Wieczorek, Joanna; Wolski, Hubert; Czerny, Boguslaw; Gorska-Paukszta, Malgorzata; Drews, Krzysztof

    2015-05-01

    Preeclampsia (PE) is a major cause of maternal and perinatal mortality and morbidity. The studies suggest that both polymorphisms and changes of expression in genes encoding enzymes involved in the methionine and homocysteine metabolism (MHM), such as methylenetetrahydrofolate, reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR) and cystathionine gamma-lyase (CSE), could play a role in the development of hypertension during pregnancy. The aim of the study was to determine the expression level of MTHFR, MTR, MTRR and CSE genes in the development of PE in Caucasian women. The control group consisted of 74 healthy pregnant women and 90 patients with diagnosed pre-eclampsia. Total RNA was isolated from placenta and the mRNA level of examined genes was to determine using real-time PCR. The expression level of MTHFR gene showed no statistically significant difference in the study group as compared to the control group. An increase of mRNA levels for MTR and CTH was observed by 124.7% (p<0.0001) and 26.6% (p>0.05), respectively. However, a decrease of placental expression was noted for MTRR by 50% in preeclamptic women as compared to control group (p<0.0001). Our findings suggest that the elevated RNA expression of MTR in placenta of preeclamptic patients is probably results of a potential compensation mechanism of the MHM while elevated CSE expression indicates that homocysteine may be eliminated through the alternate transsulfuration pathway. Copyright © 2015. Published by Elsevier Ireland Ltd.

  3. 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

  4. GST M1/T1 and MTHFR polymorphisms as risk factors for hypertension.

    PubMed

    Marinho, Cláudia; Alho, Irina; Arduíno, Daniela; Falcão, Luiz Menezes; Brás-Nogueira, José; Bicho, Manuel

    2007-02-09

    The aim of this study is to investigate GSTM1, GSTT1 and MTHFR genetic polymorphisms and its relation with total plasma glutathione (tGSH) levels in hypertension. Genotype distributions of GSTM1 and GSTT1 deletion polymorphisms and C677T variant of MTHFR were examined in a sample of 94 hypertensive patients with congestive heart failure and 207 healthy unrelated Portuguese individuals using PCR techniques. Plasma GST activity was determined spectrophotometrically. The antioxidant status was evaluated by fluorometric assays of tGSH. Genotype distributions of GSTT1 (chi2 test; p < 0.01) and MTHFR (chi2 test; p < 0.01) differ significantly between control and hypertensive patients with a greater prevalence of "non-null GSTT1/M1" and CT (heterozygous) genotypes. Moreover, GST activity and tGSH were markedly decreased in hypertension but there is no correlation with the studied polymorphisms. GSH depletion confirmed the possible involvement of oxidative stress in this pathology. Deletion of GSTT1 gene might be considered as protective factor for hypertension.

  5. 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.

  6. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms as risk factors for hepatocellular carcinoma in a Korean population.

    PubMed

    Kwak, Sun Young; Kim, Un Kyung; Cho, Hyo Jin; Lee, Hee Keun; Kim, Hye Jin; Kim, Nam Keun; Hwang, Seong Gyu

    2008-01-01

    Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer death in South Korea, but genetic susceptibility factors of HCC have not been examined extensively. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) play an essential role in both DNA synthesis and methylation and polymorphisms in the MTHFR gene, 677C>T, 1298A>C and the MTRR gene, 66A>G, are associated with several types of malignancy. In this study, the allelic frequencies and genotype distribution of three polymorphisms in the MTHFR and MTRR genes from 96 hepatocellular carcinoma (HCC) patients and 201 controls were examined to assess the association between these polymorphisms and the development of HCC in this Korean population. The 66AG+GG (G allele-bearing) genotype of the MTRR gene was significantly associated with an increased risk of HCC (odds ratio, OR, 1.687; 95% confidence interval, CI=1.022-2.787). Moreover, the combination of MTHFR 1298AA/MTRR 66AG+GG (OR=1.854, 95% CI=1.005-3.420) and MTHFR 1298AC+CC/MTRR 66AG+GG (OR=2.733, 95% CI=1.195-6.249) showed a significant association with HCC risk. In the data classified by age and etiology, MTRR 66A>G over the age of 65 years, MTHFR 1298A>C under the age of 65 years and the MTRR 66AG+GG genotype in the hepatitis B virus (HBV) patients were increased risk factors for the disease. The MTHFR 1298A>C and the MTRR 66A>G genotypes were associated with an increased risk of HCC in this Korean population. Further studies involving larger and varied populations could provide a potential tool for cancer risk assessment in patients who are at risk of developing HCC.

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

    PubMed

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

    2015-12-15

    Factor V Leiden, Prothrombin and MTHFR gene mutation, could have an influence in pregnancy with adverse outcome Preeclamsia, IUGR and Placental abruption. 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. 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. 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.

  8. 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).

  9. 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

  10. Polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) are associated with susceptibility to adult acute myeloid leukemia in a Chinese population.

    PubMed

    Huang, Lulu; Deng, Donghong; Peng, Zhigang; Ye, Fanghui; Xiao, Qiang; Zhang, Bing; Ye, Bingbing; Mo, Zengnan; Yang, Xiaobo; Liu, Zhenfang

    2015-06-01

    Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the metabolism of folate. Since acute myeloid leukemia (AML) is characterized by rapidly proliferating tissues that have a high requirement for DNA synthesis, it is possible that the presence of MTHFR polymorphisms could be linked to the multifactorial process of AML development. We evaluated the role of MTHFR C677T and A1298C polymorphisms in a case-control study comprising 98 AML patients and 2016 healthy controls in a Southern Chinese population. We further conducted a sub-study restricted to individuals who neither smoked nor drank alcohol (70 AML patients and 160 healthy controls). MTHFR polymorphisms in the patient and control groups were evaluated by SNaP shot genotype techniques and Illumina BeadChip, respectively. Logistic regression was used to assess the adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). The MTHFR 1298AC genotype and the 677CC/1298AC haplotype were significantly associated with a decreased risk of AML compared with the AA genotype and 677CC/1298AA haplotype (OR=0.60, 95% CI: 0.38-0.95, P=0.03; OR=0.49, 95% CI: 0.27-0.90, P=0.02, respectively). In addition, the 677TT genotype was significantly associated with an increased risk of AML compared with the AA genotype only in non-smokers and non-drinkers (OR=4.78; 95% CI=1.38-16.61, P=0.01). The results might suggest that MTHFR polymorphisms are significantly associated with AML risk. In addition, the role of MTHFR genetic susceptibility could be greater among non-smokers and non-drinkers. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. 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.

  12. 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.

  13. Analysis of MTHFR and MTRR Gene Polymorphisms in Iranian Ventricular Septal Defect Subjects

    PubMed Central

    Pishva, Seyyed Reza; Vasudevan, Ramachandran; Etemad, Ali; Heidari, Farzad; Komara, Makanko; Ismail, Patimah; Othman, Fauziah; Karimi, Abdollah; Sabri, Mohammad Reza

    2013-01-01

    Ventricular septal defect (VSD) is one of the most common types of congenital heart defects (CHD). There are vivid multifactorial causes for VSD in which both genetic and environmental risk factors are consequential in the development of CHD. Methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) are two of the key regulatory enzymes involved in the metabolic pathway of homocysteine. Genes involved in homocysteine/folate metabolism may play an important role in CHDs. In this study; we determined the association of A66G and C524T polymorphisms of the MTRR gene and C677T polymorphism of the MTHFR gene in Iranian VSD subjects. A total of 123 children with VSDs and 125 healthy children were included in this study. Genomic DNA was extracted from the buccal cells of all the subjects. The restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method was carried out to amplify the A66G and C524T polymorphism of MTRR and C677T polymorphism of MTHFR genes digested with Hinf1, Xho1 and Nde1 enzymes, respectively. The genotype frequencies of CC, CT and TT of MTRR gene among the studied cases were 43.1%, 40.7% and 16.3%, respectively, compared to 52.8%, 43.2% and 4.0%, respectively among the controls. For the MTRR A66G gene polymorphism, the genotypes frequencies of AA, AG and GG among the cases were 33.3%, 43.9% and 22.8%, respectively, while the frequencies were 49.6%, 42.4% and 8.0%, respectively, among control subjects. The frequencies for CC and CT genotypes of the MTHFR gene were 51.2% and 48.8%, respectively, in VSD patients compared to 56.8% and 43.2% respectively, in control subjects. Apart from MTHFR C677T polymorphism, significant differences were noticed (p < 0.05) in C524T and A66G polymorphisms of the MTRR gene between cases and control subjects. PMID:23358257

  14. Analysis of MTHFR and MTRR Gene Polymorphisms in Iranian Ventricular Septal Defect Subjects.

    PubMed

    Pishva, Seyyed Reza; Vasudevan, Ramachandran; Etemad, Ali; Heidari, Farzad; Komara, Makanko; Ismail, Patimah; Othman, Fauziah; Karimi, Abdollah; Sabri, Mohammad Reza

    2013-01-28

    Ventricular septal defect (VSD) is one of the most common types of congenital heart defects (CHD). There are vivid multifactorial causes for VSD in which both genetic and environmental risk factors are consequential in the development of CHD. Methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) are two of the key regulatory enzymes involved in the metabolic pathway of homocysteine. Genes involved in homocysteine/folate metabolism may play an important role in CHDs. In this study; we determined the association of A66G and C524T polymorphisms of the MTRR gene and C677T polymorphism of the MTHFR gene in Iranian VSD subjects. A total of 123 children with VSDs and 125 healthy children were included in this study. Genomic DNA was extracted from the buccal cells of all the subjects. The restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method was carried out to amplify the A66G and C524T polymorphism of MTRR and C677T polymorphism of MTHFR genes digested with Hinf1, Xho1 and Nde1 enzymes, respectively. The genotype frequencies of CC, CT and TT of MTRR gene among the studied cases were 43.1%, 40.7% and 16.3%, respectively, compared to 52.8%, 43.2% and 4.0%, respectively among the controls. For the MTRR A66G gene polymorphism, the genotypes frequencies of AA, AG and GG among the cases were 33.3%, 43.9% and 22.8%, respectively, while the frequencies were 49.6%, 42.4% and 8.0%, respectively, among control subjects. The frequencies for CC and CT genotypes of the MTHFR gene were 51.2% and 48.8%, respectively, in VSD patients compared to 56.8% and 43.2% respectively, in control subjects. Apart from MTHFR C677T polymorphism, significant differences were noticed (p < 0.05) in C524T and A66G polymorphisms of the MTRR gene between cases and control subjects.

  15. No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort.

    PubMed

    Szvetko, A L; Fowdar, J; Nelson, J; Colson, N; Tajouri, L; Csurhes, P A; Pender, M P; Griffiths, L R

    2007-01-15

    Multiple sclerosis (MS) is a complex neurological disease that affects the central nervous system (CNS) resulting in debilitating neuropathology. Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. Methionine synthase reductase (MTRR) is an enzyme that catalyzes the remethylation of homocysteine (Hcy) to methionine via cobalamin and folate dependant reactions. Cobalamin acts as an intermediate methyl carrier between methylenetetrahydrofolate reductase (MTHFR) and Hcy. MTRR plays a critical role in maintaining cobalamin in an active form and is consequently an important determinant of total plasma Hcy (pHcy) concentrations. Elevated intracellular pHcy levels have been suggested to play a role in CNS dysfunction, neurodegenerative, and cerebrovascular diseases. Our investigation entailed the genotyping of a cohort of 140 cases and matched controls for MTRR and MTHFR, by restriction length polymorphism (RFLP) techniques. Two polymorphisms: MTRR A66G and MTHFR A1298C were investigated in an Australian age and gender matched case-control study. No significant allelic frequency difference was observed between cases and controls at the alpha = 0.05 level (MTRR chi2 = 0.005, P = 0.95, MTHFR chi2 = 1.15, P = 0.28). Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS.

  16. 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.

  17. 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.

  18. 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.

  19. Association of MTHFR C677T polymorphism with bone mineral density of osteoporosis in postmenopausal Thai women.

    PubMed

    Tongboonchoo, Chutaporn; Tungtrongchitr, Anchalee; Phonrat, Benjaluck; Preutthipan, Sangchai; Tungtrongchitr, Rungsunn

    2013-02-01

    Osteoporosis and osteopenia is rising with the increase in numbers of postmenopausal women. Methylenetetrahydrofolate reductase (MTHFR), a homocysteine catabolizing enzyme, is involved in the regulation of bone mineral density (BMD). The association between MTHFR C677T polymorphism with osteoporosis in postmenopausal Thai women is hitherto unclear. To investigate the association between MTHFR C677T and BMD in postmenopausal Thai women. The study subjects consisted of 346 postmenopausal Thai women volunteers. Standard dual-energy X-ray absorptiometry (DXA) was used for measurement of BMD T-score. Restriction fragment length polymorphism (RFLP) analysis was used for measurement of MTHFR C677T polymorphism. In the evaluation of 346 postmenopausal Thai women heterozygous (CT) genotype had a risk of osteopenia than normal control (odds ratio (OR) = 5.66, p < 0.001). BMD T-scores at each bone position revealed that heterozygous (CT) genotype had increased risk of osteopenic bones than normal controls at lumbar spines 1, 2, and 4 (OR = 2.48, p < 0.001, OR = 1.98, p = 0.008 and OR = 1.83, p = 0.016 respectively), ward's triangle (OR = 2.08, p = 0.008), and head of radius (OR = 2.95, p = 0.008). These results indicate the possibility of using MTHFR C677T polymorphism to identify postmenopausal Thai women at high risk of osteopenia.

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

    PubMed

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

    2016-08-10

    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. 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. 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). 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.

  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. The methylenetetrahydrofolate reductase polymorphism (MTHFR c.677C>T) and elevated plasma homocysteine levels in a U.S. pediatric population with incident thromboembolism.

    PubMed

    Joachim, Emily; Goldenberg, Neil A; Bernard, Timothy J; Armstrong-Wells, Jennifer; Stabler, Sally; Manco-Johnson, Marilyn J

    2013-08-01

    Elevated plasma homocysteine (tHcy) and the MTHFR c.677C>T variant have been postulated to increase the risk of venous thromboembolism (VTE), although mechanisms and implications to pediatrics remain incompletely understood. The objectives of this study were to determine the prevalences of elevated tHcy and MTHFR variant in a pediatric population with VTE or arterial ischemic stroke (AIS), and to determine associations with thrombus outcomes. Subjects were enrolled in an institution-based prospective cohort of children with VTE or AIS. Inclusion criteria consisted of objectively confirmed thrombus, ≤21years at diagnosis, tHcy measured and MTHFR c.677C>T mutation analysis. Clinical and laboratory data were collected. Frequencies for elevated tHcy and MTHFR variant were compared with NHANES values for healthy US children and also between study groups (VTE vs AIS, provoked vs idiopathic) and by age. The prevalences of hyperhomocysteinemia or MTHFR variant were not increased in comparison to NHANES. tHcy did not differ between those with wild-type MTHFR versus either c.677C>T heterozygotes or homozygotes. There was no association between tHcy or MTHFR variant and thrombus outcomes. In this cohort of US children with VTE or AIS, neither the prevalence of hyperhomocysteinemia nor that of MTHFR variant was increased relative to reference values, and adverse thrombus outcomes were not definitively associated with either. While it is important to consider that milder forms of pyridoxine-responsive classical homocystinuria will be detected only by tHcy, we suggest that routine testing of MTHFR c.677C>T genotype as part of a thrombophilia evaluation in children with incident thromboembolism is not warranted until larger studies have been performed in order to establish or refute a link between MTHFR and adverse outcomes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Genetic polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and risk of vitiligo in Han Chinese populations: a genotype-phenotype correlation study.

    PubMed

    Chen, J-X; Shi, Q; Wang, X-W; Guo, S; Dai, W; Li, K; Song, P; Wei, C; Wang, G; Li, C-Y; Gao, T-W

    2014-05-01

    Recent evidence has revealed an elevation of total homocysteine (tHcy) in patients with vitiligo. Methylenetetrahydrofolate reductase (MTHFR) is one of the main enzymes regulating homocysteine (Hcy) metabolism. Thus, polymorphisms of MTHFR could potentially contribute to the development of vitiligo by affecting MTHFR activity and tHcy levels. To evaluate the potential association between MTHFR polymorphisms and vitiligo susceptibility. In total, 1000 patients with vitiligo and 1000 age- and sex-matched controls were enrolled in this hospital-based case-control study. Two single-nucleotide polymorphisms of the MTHFR gene (rs1801133 C>T and rs1801131 A>C) were selected and genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR, respectively. The MTHFR activity concentration and tHcy level in serum were measured by enzyme-linked immunosorbent assay. We found that allele T of rs1801133 in the MTHFR gene was associated with a significantly reduced risk of vitiligo (adjusted odds ratio 0·58, 95% confidence interval 0·43-0·76, P < 0·001). In addition, the patients with vitiligo had a lower activity concentration of MTHFR and higher level of tHcy than the controls. Correlation between these markers and the risk of vitiligo was also observed. Furthermore, the individuals with a no-risk genotype (CT + TT) of rs1801133 and higher activity concentration of MTHFR or lower level of tHcy had a significantly decreased risk of vitiligo. Our data suggest that MTHFR gene polymorphisms may play a vital role in genetic susceptibility to vitiligo. © 2014 British Association of Dermatologists.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease: a meta-analysis.

    PubMed

    Wu, Yi-Le; Ding, Xiu-Xiu; Sun, Ye-Huan; Yang, Hui-Yun; Sun, Liang

    2013-12-15

    The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease (PD) was controversial in previous studies. The present study was therefore designed to investigate a more reliable estimate. 15 studies were identified by a search of PubMed, EBMBASE, PDGENE, Elsevier, Springer Link, CBM (Chinese Biomedical Database), CNKI (Chinese National Knowledge Infrastructure), VIP (Chinese), and Wanfang (Chinese) databases, up to April 2013. Odds ratios (ORs) with corresponding 95% confidence interval (CI) were calculated using fixed effects model or random effects model. The subgroup analyses were made on the ethnicity. MTHFR C677T polymorphism had a significant association with susceptibility to PD in all genetic models (for T vs. C: OR=1.24, 95% CI=1.11-1.38; for TT+CT vs. CC: OR=1.27, 95% CI=1.10-1.46; for TT vs. CC: OR=1.56, 95% CI=1.22-1.98; for TT vs. CT+CC: OR=1.43, 95% CI=1.14-1.79). Subgroup analyses by ethnicity revealed that the association between the MTHFR C677T polymorphism and PD existed in Caucasian population and Asian population. However, no association was detected between the MTHFR A1298C polymorphism and PD. Results from this meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of PD. The MTHFR A1298C polymorphism may not increase the susceptibility to PD. Further studies are required to confirm our findings. © 2013.

  9. 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.

  10. MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies

    PubMed Central

    Gong, Mancheng; Dong, Wenjing; He, Tingyu; Shi, Zhirong; Huang, Guiying; Ren, Rui; Huang, Sichong; Qiu, Shaopeng; Yuan, Runqiang

    2015-01-01

    Background and Objectives Methylenetetrahydrofolate reductase (MTHFR) polymorphism may be a risk factor for male infertility. However, the epidemiologic studies showed inconsistent results regarding MTHFR polymorphism and the risk of male infertility. Therefore, we performed a meta-analysis of published case-control studies to re-examine the controversy. Methods Electronic searches of PubMed, EMBASE, Google Scholar and China National Knowledge Infrastructure (CNKI) were conducted to select eligible literatures for this meta-analysis (updated to June 19, 2014). According to our inclusion criteria and the Newcastle-Ottawa Scale (NOS), only high quality studies that observed the association between MTHFR polymorphism and male infertility risk were included. Crude odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the MTHFR polymorphism and male infertility risk. Results Twenty-six studies involving 5,575 cases and 5,447 controls were recruited. Overall, MTHFR 677C>T polymorphism showed significant associations with male infertility risk in both fixed effects (CT+TT vs. CC: OR = 1.34, 95% CI: 1.23–1.46) and random effects models (CT+TT vs. CC: OR = 1.39, 95% CI: 1.19–1.62). Further, when stratified by ethnicity, sperm concentration and control sources, the similar results were observed in Asians, Caucasians, Azoo or OAT subgroup and both in population-based and hospital-based controls. Nevertheless, no significant association was only observed in oligo subgroup. Conclusions Our results indicated that the MTHFR polymorphism is associated with an increased risk of male infertility. Further well-designed analytical studies are necessary to confirm our conclusions and evaluate gene-environment interactions with male infertility risk. PMID:25793386

  11. MTR, MTRR, and MTHFR Gene Polymorphisms and Susceptibility to Nonsyndromic Cleft Lip With or Without Cleft Palate

    PubMed Central

    Wang, Wei; Wang, Xiao-Ping; Sun, Xiang-Yu; Dong, Chen

    2016-01-01

    Objective: To examine the associations of methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the susceptibility to nonsyndromic cleft lip with or without cleft palate (NSCL/P). Methods: Between May 2012 and August 2014, 147 NSCL/P patients (case group) and 129 healthy volunteers (control group) were recruited for the study. The MTR A2756G, MTRR A66G, MTHFR C677T and MTHFR A1298C polymorphisms were assessed by polymerase chain reaction–restriction fragment length polymorphism. Haplotype analyses were performed with SHEsis software. Logistic regression analysis was used to evaluate the possible risk factors for NSCL/P. Generalized multifactor dimensionality reduction (GMDR) was applied to detect gene–gene interactions. Results: MTR A2756G, MTRR A66G, and MTHFR C677T gene polymorphisms were associated with the risk of NSCL/P (all p < 0.05). Logistic regression analysis revealed that MTR A2756G, MTR RA66G, and MTHFR C667T might increase the risk of NSCL/P (odds ratio [OR] = 0.270, 95% confidence interval [95% CI] = 0.106–0.689; OR = 0.159, 95% CI = 0.069–0.368; OR = 0.343, 95% CI = 0.139–0.844). The CA haplotype in the MTHFR gene may serve as a protective factor for NSCL/P (OR = 0.658, 95% CI = 0.470–0.923), and the TA haplotype might be a risk factor (OR = 2.001, 95% CI = 1.301–3.077). GMDR revealed that the optimal models were two- and four-dimensional models with prediction accuracies of 75.73% (p = 0.001) and 77.21% (p = 0.001) and the best cross-validation consistencies of 10/10 and 10/10, respectively. Conclusion: MTR A2756G, MTRR A66G, and MTHFR C677T polymorphisms may be related to NSCL/P, and interactions were detected between the MTR A2756G, MTRR A66G, and MTHFR C677T and A1298C polymorphisms. PMID:27167580

  12. MTR, MTRR, and MTHFR Gene Polymorphisms and Susceptibility to Nonsyndromic Cleft Lip With or Without Cleft Palate.

    PubMed

    Wang, Wei; Jiao, Xiao-Hui; Wang, Xiao-Ping; Sun, Xiang-Yu; Dong, Chen

    2016-06-01

    To examine the associations of methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the susceptibility to nonsyndromic cleft lip with or without cleft palate (NSCL/P). Between May 2012 and August 2014, 147 NSCL/P patients (case group) and 129 healthy volunteers (control group) were recruited for the study. The MTR A2756G, MTRR A66G, MTHFR C677T and MTHFR A1298C polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism. Haplotype analyses were performed with SHEsis software. Logistic regression analysis was used to evaluate the possible risk factors for NSCL/P. Generalized multifactor dimensionality reduction (GMDR) was applied to detect gene-gene interactions. MTR A2756G, MTRR A66G, and MTHFR C677T gene polymorphisms were associated with the risk of NSCL/P (all p < 0.05). Logistic regression analysis revealed that MTR A2756G, MTR RA66G, and MTHFR C667T might increase the risk of NSCL/P (odds ratio [OR] = 0.270, 95% confidence interval [95% CI] = 0.106-0.689; OR = 0.159, 95% CI = 0.069-0.368; OR = 0.343, 95% CI = 0.139-0.844). The CA haplotype in the MTHFR gene may serve as a protective factor for NSCL/P (OR = 0.658, 95% CI = 0.470-0.923), and the TA haplotype might be a risk factor (OR = 2.001, 95% CI = 1.301-3.077). GMDR revealed that the optimal models were two- and four-dimensional models with prediction accuracies of 75.73% (p = 0.001) and 77.21% (p = 0.001) and the best cross-validation consistencies of 10/10 and 10/10, respectively. MTR A2756G, MTRR A66G, and MTHFR C677T polymorphisms may be related to NSCL/P, and interactions were detected between the MTR A2756G, MTRR A66G, and MTHFR C677T and A1298C polymorphisms.

  13. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A.

    PubMed

    Rady, Peter L; Szucs, Sylvia; Grady, James; Hudnall, S David; Kellner, Leonard H; Nitowsky, Harold; Tyring, Stephen K; Matalon, Reuben K

    2002-01-15

    The importance of hyperhomocysteinemia, birth defects, and vascular diseases has been the subject of intense investigations. The polymorphic MTHFR mutations (C677T and A1298C) cause mild hyperhomocysteinemia, especially in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The subject of this report is the frequency of the polymorphic mutations in the MTHFR gene C677T, C1298A, and newly discovered mutation G1793A, as well as the association with MTRR polymorphic site A66G in different ethnic groups. Four ethnic groups were studied: African-Americans, Caucasians, Hispanics, and Ashkenazi Jews. There are statistically significant differences in the frequency of these alleles in the different populations studied, which impacts compound heterozygosity for such alleles in these populations. DNA samples obtained from the blood of healthy individuals of African-Americans, Hispanics, and Caucasians from south Texas were analyzed and compared to those obtained from Ashkenazi Jewish individuals. The polymorphic site, the G1793A allele, is least frequent among Ashkenazi individuals, 1.3%, compared to 6.9% among Caucasians (P = 0.001), 5.8% among Hispanics (P = 0.012), and 3.1% among African-Americans. The MTRR polymorphic site shows the lowest allele frequency among Hispanics, 28.6%, compared to 34% among African-Americans, 43.1% among Ashkenazi Jews (P = 0.002), and 54.4% among Caucasians (P < 0.0001). Statistically significant differences in allele frequencies of C677T and C1298A polymorphisms were also observed in these populations. Compound heterozygosity for multiple polymorphic alleles may play a role in birth defects and vascular diseases. Copyright 2001 Wiley-Liss, Inc.

  14. MAOA, MTHFR, and TNF-β genes polymorphisms and personality traits in the pathogenesis of migraine.

    PubMed

    Ishii, Masakazu; Shimizu, Shunichi; Sakairi, Yuki; Nagamine, Ayumu; Naito, Yuika; Hosaka, Yukiko; Naito, Yuko; Kurihara, Tatsuya; Onaya, Tomomi; Oyamada, Hideto; Imagawa, Atsuko; Shida, Kenji; Takahashi, Johji; Oguchi, Katsuji; Masuda, Yutaka; Hara, Hajime; Usami, Shino; Kiuchi, Yuji

    2012-04-01

    Migraine is a multifactorial disease with various factors, such as genetic polymorphisms and personality traits, but the contribution of those factors is not clear. To clarify the pathogenesis of migraine, the contributions of genetic polymorphisms and personality traits were simultaneously investigated using multivariate analysis. Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms analysis and NEO-FFI personality test were performed. At first, the univariate analysis was performed to extract the contributing factors to pathogenesis of migraine. We then extracted the factors that independently contributed to the pathogenesis of migraine using multivariate stepwise logistic regression analysis. Using the multivariate analysis, three gene polymorphisms including monoamine oxidase A (MAOA) T941G, methylenetetrahydrofolate reductase (MTHFR) C677T, and tumor necrosis factor beta (TNF-β) G252Α, and the neuroticism and conscientiousness scores in NEO-FFI were selected as significant factors that independently contributed to the pathogenesis of migraine. Their odds ratios were 1.099 (per point of neuroticism score), 1.080 (per point of conscientiousness score), 2.272 (T and T/T or T/G vs G and G/G genotype of MAOA), 1.939 (C/T or T/T vs C/C genotype of MTHFR), and 2.748 (G/A or A/A vs G/G genotype of TNF-β), respectively. We suggested that multiple factors, such as gene polymorphisms and personality traits, contribute to the pathogenesis of migraine. The contribution of polymorphisms, such as MAOA T941G, MTHFR C677T, and TNF-β G252A, were more important than personality traits in the pathogenesis of migraine, a multifactorial disorder.

  15. 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.

  16. 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

  17. 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

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

    PubMed

    He, Wei; Lu, Minzhi; Li, Guoqing; Sun, Zhigang; Liu, Dinghua; Gu, Lujun

    2017-01-01

    Genetic polymorphisms of methylene tetrahydrofolate reductase (MTHFR) were associated with ischemic stroke risk. This study analyzed MTHFR polymorphisms at the 3'-untranslated region for association with risk and outcome of ischemic stroke in a Chinese Han population. 500 patients and 600 healthy volunteers were enrolled for MTHFR rs868014 genotyping identified bioinformatically. The binding of miR-1203 to MTHFR rs868014 was determined by luciferase assay, MTHFR expression was assessed using qRT-PCR, and plasma homocysteine levels were assayed by ELISA. Cigarette smoking, alcohol consumption, diabetes, hypertension (all P <0.001), low levels of serum high-density lipoprotein-C (P = 0.01), and high levels of serum low-density lipoprotein-C (P = 0.005) were associated with an increased risk of developing ischemic stroke. BMI and total serum cholesterol concentration was not associated with ischemic stroke. MTHFR rs868014 TC and CC genotypes were significantly associated with increased risk of ischemic stroke compared with the TT genotype (OR: 1.52; 95% CI: 1.01-3.39 for TC genotype, while OR: 1.99; 95% CI: 1.29-3.88 for CC genotype). Furthermore, the MTHFR rs868014 SNP was associated with a poor short-term ischemic stroke outcome. qRT-PCR confirmed that MTHFR rs868014 TC or CC genotypes could facilitate miR-1203 binding leading to low MTHFR levels in cells. In addition, patients carrying the MTHFR rs868014 TC or CC genotypes were associated with accumulation of serum tHcy and a poor ischemic stroke outcome. Linkage disequilibrium analysis indicated that the newly identified SNP rs868014 was strongly linked with the MTHFR A1298C polymorphism. This study demonstrates that the MTHFR rs868014 SNP is associated with increased risk in developing ischemic stroke, miR-1203 binding, low MTHFR levels in cells, and poor shot term outcome of patients. © 2017 The Author(s)Published by S. Karger AG, Basel.

  19. Associations among objectively measured physical activity, fasting plasma homocysteine concentration, and MTHFR C677T genotype.

    PubMed

    Murakami, Haruka; Iemitsu, Motoyuki; Sanada, Kiyoshi; Gando, Yuko; Ohmori, Yumi; Kawakami, Ryoko; Sasaki, Satoshi; Tabata, Izumi; Miyachi, Motohiko

    2011-12-01

    Elevated fasting plasma homocysteine (Hcy) level is a vascular disease risk factor. Plasma Hcy is affected by 5,10-methylenetetrahydofolate reductase (MTHFR) genotype and dietary folate intake. This cross-sectional study in 434 Japanese adults examined the associations among objectively measured physical activity (PA), plasma Hcy adjusting for dietary folate intake, and MTHFR C677T genotype. Daily PA was measured by triaxial accelerometry and all subjects completed a questionnaire about their dietary habits. Plasma Hcy and MTHFR C677T genotype were determined. Plasma Hcy in subjects with the TT genotype was significantly higher than in those with CC or CT genotype (p < 0.001). Plasma Hcy was significantly different between ≥ 200 (7.6 ± 0.2 nmol/mL) and <200 µg/day (8.3 ± 0.3 nmol/mL) folate intake groups (p = 0.003). There were no differences in plasma Hcy adjusting for age, sex, and folate intake between groups according to PA category in all subjects. However, there were significant interactions between time spent in light PA (p = 0.003), vigorous PA (p = 0.001), or inactivity (p = 0.004), and MTHFR genotype. In only the TT genotype, shorter time spent in light PA was associated with higher plasma Hcy than a longer time spent in light PA (11.5 ± 3.3 nmol/mL vs. 8.5 ± 3.3 nmol/mL, p < 0.001), and longer time spent in vigorous PA and inactivity were associated with higher plasma Hcy (11.8 ± 3.3 nmol/mL vs. 8.4 ± 3.2 nmol/mL, 11.6 ± 3.3 nmol/mL vs. 8.4 ± 3.3 nmol/mL, respectively, p < 0.001). In conclusion, light and vigorous PA were associated with plasma Hcy only in the TT genotype, but there were no such associations in all genotypes.

  20. 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

  1. 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).

  2. Polymorphisms in the MTHFR and MTR genes and the risk of varicose veins in ethnical Russians.

    PubMed

    Shadrina, Alexandra Sergeevna; Sevost'ianova, Kseniya Sergeevna; Shevela, Andrey Ivanovich; Soldatsky, Evgenii Yurievich; Seliverstov, Evgenii Igorevich; Demekhova, Marina Yurievna; Shonov, Oleg Aleksandrovich; Ilyukhin, Evgenii Arkadievich; Smetanina, Mariya Aleksandrovna; Voronina, Elena Nikolaevna; Pikalov, Ilya Victorovich; Zolotukhin, Igor Anatolyevich; Filipenko, Maxim Leonidovich

    2016-11-01

    The objective of this study was to study the association of polymorphisms MTHFR C677T (rs1801133) and MTR A2756G (rs1805087) with the risk of varicose veins in ethnical Russians. We genotyped 475 patients with varicose veins, 168 individual without chronic venous disease, and the population-based group of 896 subjects. Association was studied using logistic regression analysis adopting co-dominant, additive, recessive, and dominant models of inheritance. None of the polymorphisms showed a statistically significant association with the risk of varicose veins. Our results provide evidence that the studied polymorphisms do not contribute to genetic susceptibility to varicose veins in ethnical Russians.

  3. Associations of MTHFR C677T and MTRR A66G gene polymorphisms with metabolic syndrome: a case-control study in Northern China.

    PubMed

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

    2014-11-25

    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.

  4. 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

  5. Association of factor V Leiden, Janus kinase 2, prothrombin, and MTHFR mutations with primary Budd-Chiari syndrome in Egyptian patients.

    PubMed

    El Sebay, Hatem M; Safan, Manal A; Daoud, Ashraf A; Tayel, Safaa I; Nouh, Mohamed A; El Shafie, Shymaa

    2016-01-01

    Budd-Chiari syndrome (BCS) is defined as obstruction of hepatic venous outflow anywhere from the small hepatic veins to the suprahepatic inferior vena cava. The pathogenesis of BCS is still not fully understood. This study aimed to evaluate the association of factor V Leiden (FVL), Janus kinase 2 (JAK2), prothrombin, and methylene tetrahydrofolate reductase (MTHFR) mutations with primary BCS. The study was carried out on 35 patients with primary BCS and 15 age and gender matched healthy individuals as a control group. Genotyping of FVL, prothrombin, and MTHFR mutations was determined by GENEQUALITY AB-THROMBO TYPE kit based on the reverse hybridization principle. JAK2 mutation was determined by polymerase chain reaction-restriction fragment length polymorphism. There was a statistically significant difference between patients and controls regarding FVL, MTHFR C677T, and MTHFR A1298C mutations with odds ratio of 1.83, 2.0, and 1.79, respectively. Hetero MTHFR C677T, hetero FVL, and hetero MTHFR A1298C were the most common etiological factors being responsible for 57.1, 42.9, and 42.9% of primary BCS cases, respectively. It could be concluded that BCS is a multifactorial disease; in the current study, MTHFR C677T mutation was the most common cause of disease. Identification of one cause of BCS should not eliminate investigations for detection of other etiological factors. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  6. 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.

  7. Polymorphisms of MTHFR C677T and A1298C associated with survival in patients with colorectal cancer treated with 5-fluorouracil-based chemotherapy.

    PubMed

    Yeh, Chih-Ching; Lai, Ching-Yu; Chang, Shih-Ni; Hsieh, Ling-Ling; Tang, Reiping; Sung, Fung-Chang; Lin, Yi-Kuei

    2017-06-01

    This study examined the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and survival of patients with colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)-based chemotherapy in Taiwan. We genotyped MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) for 498 CRC patients treated with 5-FU-based chemotherapy after receiving surgery. Survival analyses on MTHFR polymorphisms were performed using log-rank test and Kaplan-Meier curve. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MTHFR genotypes and survival. Overall survival (OS) was significantly longer in CRC patients with MTHFR 677 CT+TT genotypes compared with those with 677 CC genotype (HR 0.77; 95% CI 0.60-0.98). Although the MTHFR A1298C polymorphism was not associated with OS in CRC, this polymorphism was associated with significantly shorter OS in rectal cancer. Among rectal cancer patients, OS was shorter for patients with AC+CC genotypes than for those with the AA genotype (HR 1.95; 95% CI 1.35-2.83). In haplotype analysis, better OS was found for colon cancer patients carrying the MTHFR 677T-1298A haplotype (HR 0.73; 95% CI 0.55-0.97), but worse survival was linked to rectal cancer patients carrying the MTHFR 677C-1298C haplotype (HR 1.53; 95% CI 1.08-2.18). Our findings suggest that MTHFR genotypes provide prognostic information for CRC patients treated with 5-FU-based chemotherapy.

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

    PubMed

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

    2013-05-01

    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 . 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 SNP and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing. 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. These results suggest that MTRR variants may protect against migraine with aura in an older population.

  9. 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

  10. 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.

  11. 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.

  12. Evaluation of electronic microarrays for genotyping factor V, factor II, and MTHFR.

    PubMed

    Erali, Maria; Schmidt, Ben; Lyon, Elaine; Wittwer, Carl

    2003-05-01

    Genetic risk factors associated with venous thrombosis include mutations in the factor V (Leiden), factor II (prothrombin), and methylenetetrahydrofolate reductase (MTHFR) genes. We evaluated a method using electronically addressable microarrays for the detection of mutations in these genes that have been associated with vascular disease. The NanoChip Molecular Biology Workstation (Nanogen) uses electronic microarrays for mutation detection. Factor V, factor II, and MTHFR genotypes identified in the NanoChip system on 225 samples were compared with genotypes from LightCycler assays (Roche). We determined within- and between-cartridge signal and ratio variation and analyzed the effect of additional mutations at or near the detection area used for the NanoChip assays. Genotypes determined for all three mutations on the NanoChip platform were in complete concordance with LightCycler results. Within-cartridge signal variation as measured by the CV of fluorescence signals was <10% for each allele when present. The within-cartridge CV for heterozygous mutant/wild-type ratios was <8.5%, and between-cartridge CV was <18%. A dilution study showed that results could be obtained in this assay with 6 ng of nucleic acid per PCR, the lowest input tested. The presence of additional sequence variations near the expected mutations can produce equivocal or discrepant results. Mutation detection using the NanoChip Molecular Biology Workstation was accurate and reproducible for the three assays evaluated.

  13. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism among Gaddi tribe of Indian state of Himachal Pradesh.

    PubMed

    Khan, Simi; Thakur, Sunil; Kallur, Saraswathy Nava; Ghosh, Pradeep Kumar; Sachdeva, Mohinder Pal; Vadlamudi, Raghavendra Rao

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been suggested to be positively associated with several disorders. Distribution of the mutant T-allele varies in ethnic and geographical populations of the world. The aim of the present study was to investigate the distribution of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in a transhumant (Gaddi) tribal population of Himachal Pradesh dwelling at high and middle altitude and exposed to strong ultraviolet radiation. A total of 486 samples (141 males and 345 females) were randomly enrolled from the individuals aged 25-75 years who were unrelated up to first cousin. Among Gaddis, genotype frequencies of CC, CT and TT were 67.90%, 27.78% and 4.32%, respectively. Among males and females distribution of genotype frequencies also followed a similar trend. The studied population was in Hardy-Weinberg equilibrium (χ(2 )= 2.213, df = 1, p = 0.136). Frequency of mutant T-allele in the Gaddi population was found to be 0.183, which might be due to European ancestry, endogamous nature and selection.

  14. 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.

  15. Individualized supplementation of folic acid according to polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) reduced pregnant complications.

    PubMed

    Li, Xiujuan; Jiang, Jing; Xu, Min; Xu, Mei; Yang, Yan; Lu, Wei; Yu, Xuemei; Ma, Jianlin; Pan, Jiakui

    2015-01-01

    This study aimed to detect the genotype distributions and allele frequencies of methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms of pregnant women in Jiaodong region in China, and to investigate whether folic acid supplementation affect the pregnancy complications. A total of 7,812 pregnant women from the Jiaodong region in Shandong province in China. By using Taqman-MGB, 2,928 pregnant women (case group) were tested for the genotype distributions and allele frequencies of MTHFR C677T, A1298C and MTRR A66G polymorphisms. Folic acid metabolism ability was ranked at four levels and then pregnant women in different rank group were supplemented with different doses of folic acid. Their pregnancy complications were followed up and compared with 4,884 pregnant women without folic acid supplementation (control group) in the same hospital. The allele frequencies of MTHFR C677T were 49.1 and 50.9%; those of MTHFR A1298C were 80.2 and 19.8%, and those of MTRR A66G were 74.1 and 25.9%. After supplemented with folic acid, the complication rates in different age groups were significantly reduced, especially for gestational diabetes mellitus and hypertension. Periconceptional folic acid supplementation and healthcare following gene polymorphism testing may be a powerful measure to decrease congenital malformations. © 2015 S. Karger AG, Basel.

  16. 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.

  17. 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.

  18. Effects of Italian Mediterranean organic diet vs. low-protein diet in nephropathic patients according to MTHFR genotypes.

    PubMed

    Di Daniele, Nicola; Di Renzo, Laura; Noce, Annalisa; Iacopino, Leonardo; Ferraro, Pietro Manuel; Rizzo, Mariagiovanna; Sarlo, Francesca; Domino, Emidio; De Lorenzo, Antonino

    2014-10-01

    Several reports associate an Italian-style Mediterranean diet (IMD) with lower risk of cardiovascular disease and morbidity. The present study aimed to explore the effects of an Italian Mediterranean organic diet (IMOD) versus low-protein diet (LPD) in chronic kidney disease (CKD) patients, according to patients' carrier status for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. A total of 40 male patients with CKD and stable renal function (Kidney Disease Outcomes Quality Initiative stages 2 and 3) were classified according to MTHFR polymorphism as carrier T(+) or non carrier T(-). At the time of enrolment (T0) patients' diet consisted of LPD; they were then administered IMD for 14 days (T1), thereupon IMOD for 14 days (T2). Patients underwent a complete medical history, body composition assessment and biochemical analysis. Baseline homocysteine levels were on average 8.24 mol/l higher (95 % confidence interval 6.47, 10.00) among T(+) than T(-) and the difference was statistically significant (p < 0.001). We found a significant interaction between MTHFR status and the effect of both the IMD and IMOD on homocysteine levels compared to LPD (p for interaction <0.001). Both the IMD and IMOD resulted in significant variations of anthropometric and laboratory measurements. IMD and IMOD diets could represent a viable alternative to LPD in CKD patients on conservative therapy. The effect of these diets seems to be influenced by MTHFR genotypes.

  19. 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…

  20. 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…

  1. 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…

  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. Polymorphisms in NOS3, MTHFR, APOB and TNF-α Genes and Risk of Coronary Atherosclerotic Lesions in Iranian Patients.

    PubMed

    Heidari, Mohammad Mehdi; Khatami, Mehri; Hadadzadeh, Mehdi; Kazemi, Mahbobeh; Mahamed, Sahar; Malekzadeh, Pegah; Mirjalili, Massomeh

    2016-02-01

    Atherosclerosis is a complex multifocal arterial disease involving interactions between multiple genetic and environmental factors. In the present study, we investigated the possible association between NOS3 (rs1799983), MTHFR (rs1801133), APOB (rs5742904) and TNF-α (rs361525) polymorphisms and the risk of coronary atherosclerotic lesions in Iranian patients. In the case-control study, 108 patients with coronary atherosclerosis disease and 95 control subjects with no family history of cardiovascular disease were enrolled. Genotypes for NOS3, MTHFR, APOB and TNF-α polymorphisms were identified using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). We specifically detected the NOS3 TT genotype in 12 patients (11.11%) and did not find the same genotype in any of the controls. The frequencies of T allele in patients and the controls were 24% and 17.8%, respectively. The prevalence of the MTHFR TT genotype was 16.7% in patients and 2.2% in control groups. The prevalence of the APOB-100 (R3500Q) mutation in this patient population was 0%. The frequency of the A allele in the TNF-α gene was 11.1% and 11% in patients and controls, respectively, and the AA genotype was undetected. Our results show a significant association of NOS3 and MTHFR gene polymorphisms with coronary atherosclerotic lesions. Therefore, these variants might influence the risk of coronary artery disease, specifically in the Iranian population.

  4. 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

  5. Folic acid supplementation and methylenetetrahydrofolate reductase (MTHFR) gene variations in relation to in vitro fertilization pregnancy outcome.

    PubMed

    Murto, Tiina; Kallak, Theodora K; Hoas, Annica; Altmäe, Signe; Salumets, Andres; Nilsson, Torbjörn K; Skoog Svanberg, Agneta; Wånggren, Kjell; Yngve, Agneta; Stavreus-Evers, Anneli

    2015-01-01

    To study folic acid intake, folate status and pregnancy outcome after infertility treatment in women with different infertility diagnoses in relation to methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C and 1793G>A polymorphisms. Also the use of folic acid supplements, folate status and the frequency of different gene variations were studied in women undergoing infertility treatment and fertile women. Observational study. University hospital. Women undergoing infertility treatment and healthy, fertile, non-pregnant women. A questionnaire was used to assess general background data and use of dietary supplements. Blood samples were taken to determine plasma folate and homocysteine levels, and for genomic DNA extraction. A comparison of four studies was performed to assess pregnancy outcome in relation to MTHFR 677 TT vs. CC, and 1298 CC vs. AA polymorphisms. Folic acid supplement intake, and plasma folate, homocysteine and genomic assays. Women in the infertility group used significantly more folic acid supplements and had better folate status than fertile women, but pregnancy outcome after fertility treatment was not dependent on folic acid intake, folate status or MTHFR gene variations. High folic acid intakes and MTHFR gene variations seem not to be associated with helping women to achieve pregnancy during or after fertility treatment. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

  6. Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE).

    PubMed

    Amigou, Alicia; Rudant, Jérémie; Orsi, Laurent; Goujon-Bellec, Stéphanie; Leverger, Guy; Baruchel, André; Bertrand, Yves; Nelken, Brigitte; Plat, Geneviève; Michel, Gérard; Haouy, Stéphanie; Chastagner, Pascal; Ducassou, Stéphane; Rialland, Xavier; Hémon, Denis; Clavel, Jacqueline

    2012-08-01

    Fetal folate deficiency may increase the risk of subsequent childhood acute leukemia (AL), since folates are required for DNA methylation, synthesis, and repair, but the literature remains scarce. This study tested the hypothesis that maternal folic acid supplementation before or during pregnancy reduces AL risk, accounting for the SNPs rs1801133 (C677T) and rs1801131 (A1298C) in MTHFR and rs1801394 (A66G) and rs1532268 (C524T) in MTRR, assumed to modify folate metabolism. The nationwide registry-based case-control study, ESCALE, carried out in 2003-2004, included 764 AL cases and 1,681 controls frequency matched with the cases on age and gender. Information on folic acid supplementation was obtained by standardized telephone interview. The genotypes were obtained using high-throughput platforms and imputation for untyped polymorphisms. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. AL was significantly inversely associated with maternal folic acid supplementation before and during pregnancy (OR = 0.4; 95 % confidence interval: [0.3-0.6]). MTHFR and MTRR genetic polymorphisms were not associated with AL. However, AL was positively associated with homozygosity for any of the MTHFR polymorphisms and carriership of both MTRR variant alleles (OR = 1.6 [0.9-3.1]). No interaction was observed between MTHFR, MTRR, and maternal folate supplementation. The study findings support the hypothesis that maternal folic acid supplementation may reduce the risk of childhood AL. The findings also suggest that the genotype homozygous for any of the MTHFR variants and carrying both MTRR variants could be a risk factor for AL.

  7. 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

  8. 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

  9. Functional Polymorphism rs13306560 of the MTHFR Gene Is Associated With Essential Hypertension in a Mexican-Mestizo Population.

    PubMed

    Pérez-Razo, Juan Carlos; Cano-Martínez, Luis Javier; Vargas Alarcón, Gilberto; Canizales-Quinteros, Samuel; Martínez-Rodríguez, Nancy; Canto, Patricia; Roque-Ramírez, Bladimir; Palma-Flores, Carlos; Esteban-Martínez, Rosa; López-Hernández, Luz Berenice; Rojano-Mejía, David; Coral-Vázquez, Ramón M

    2015-08-01

    Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been associated with diastolic blood pressure, hypertension, and other cardiovascular diseases; however, results of these studies are still controversial. In this study, we sought to determine whether 2 functional variants (rs1801133 and rs13306560) within the MTHFR are associated with hypertension in Mexican-Mestizos. We performed a case-control study with 1214 subjects including adults and children to test for the association of both single nucleotide polymorphisms with essential hypertension. The adult group included 764 participants (372 patients and 391 controls) and the group of children included 418 participants (209 patients and 209 controls). rs13306560 was associated with essential hypertension in adults (odds ratio, 4.281; 95% confidence interval, 1.841-9.955; P=0.0003) with a statistical power >0.8. In children, none of the polymorphisms was associated with essential hypertension. In addition, we assessed the effect of the rs13306560 polymorphism on the MTHFR promoter region by means of luciferase reporter gene assays using human umbilical vein endothelial cells. Cells transfected with the pMTHFRaLUC construct showed an ≈25% reduction in luciferase activity (P=0.003). Furthermore, the promoter activity was reduced considerably by in vitro methylation of CpG sequences. Our data suggest that the rs13306560 polymorphism of the MTHFR may be part of the observed hypertension process in Mexican-Mestizo populations, but further studies are warranted. In addition, the allele A of the rs13306560 polymorphism as well as the in vitro methylation of CpGs reduced the promoter activity of the MTHFR regulatory region. © 2015 American Heart Association, Inc.

  10. A1298C polymorphism of the MTHFR gene and neural tube defects in the state of Yucatan, Mexico.

    PubMed

    Gonzalez-Herrera, Lizbeth; Castillo-Zapata, Ileana; Garcia-Escalante, Guadalupe; Pinto-Escalante, Doris

    2007-08-01

    Methylenetetrahydrofolate reductase (MTHFR) of the folate metabolism pathway is a candidate gene for neural tube defects (NTDs). Frequency of the second common polymorphism, A1298C, in the MTHFR gene is not well known in Mexico. Conflicting results exist regarding the association of A1298C-MTHFR with NTDs. One explanation for this controversy might be that alleles are differently distributed among various populations. The aim of the study was to determine the frequency of the A1298C-MTHFR polymorphism and its association with NTDs in a population of Yucatan, Mexico. Genotyping was performed by use of polymerase chain reaction with restriction fragment length polymorphisms using MbOII endonuclease (PCR-RFLPs MbOII). Allele and genotype frequencies were compared between cases with NTDs, their mothers and fathers with matched controls based on an association analysis using EpiInfo software. A1298C genotypes were distributed according to Hardy-Weinberg expectations for all studied groups. Frequencies of allele C and heterozygous AC genotype were significantly higher in males (p = .006 and p = .011, respectively) in control group. Significant differences were not observed between cases and controls, except in mothers of NTD cases compared with mothers of healthy offspring for both allele C and heterozygous AC genotype (p = .009 and p = .01, respectively). The polymorphism A1298C-MTHFR is not associated with NTDs, except for mothers, suggesting only a maternal association with having NTD-affected offspring in the Yucatan population. The frequency of allele C in the control population was 10%, which is significantly lower than in other reported control populations worldwide (p < .01). 2007 Wiley-Liss, Inc.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR gene) with ischemic stroke: a meta-analysis.

    PubMed

    Kumar, Amit; Kumar, Pradeep; Prasad, Manya; Sagar, Ram; Yadav, Arun Kumar; Pandit, Awadh Kishor; Jali, Vidishaa Prasad; Pathak, Abhishek

    2015-07-01

    Studies on association between methylenetetrahydrofolate reductase gene (MTHFR) C677T gene polymorphism and ischemic stroke have shown conflicting results. We have conducted a meta-analysis to determine the precise association of the C677T polymorphism of MTHFR gene with risk of ischemic stroke. We searched electronic databases Medline, EMBASE, and Google Scholar (last search dated till August 2014). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random or fixed-effects models were calculated. The methodological quality of included studies was determined by the quality assessment scale. Thirty eight case-control studies fulfilled our inclusion criteria comprising 6310 patients and 8297 controls. The significant associations between MTHFR C677T genetic polymorphism and risk of ischemic stroke were observed in dominant (OR, 1·09; 95% CI, 1·06-1·12, P-value < 0·001) and recessive (OR, 1·31; 95% CI, 1·19-1·44, P-value < 0·001) inheritance models. In an Asian population, significant association between the MTHFR polymorphism and ischemic stroke was observed (dominant model: OR 1·36, 95% CI 1·23-1·49 and under recessive model OR, 1·29; 95% CI, 1·15-1·45). In the Caucasian population borderline, non-significant association was observed under dominant model of inheritance (OR, 1·05; 95% CI, 0·99-1·10) but significant association was observed under the recessive model of inheritance (OR, 1·33; 95% CI, 1·13-1·58). The present study results suggest that MTHFR C677T genetic polymorphism is a probable risk of ischemic stroke.

  16. 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. Copyright © 2012 Wiley Periodicals, Inc.

  17. Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Age at Onset of Schizophrenia: No Consistent Evidence for an Association in the Nordic Population

    PubMed Central

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

    2012-01-01

    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. © 2012 Wiley Periodicals, Inc. PMID:23076983

  18. Associations of Polymorphisms in MTHFR Gene with the Risk of Age-Related Cataract in Chinese Han Population: A Genotype-Phenotype Analysis

    PubMed Central

    Wei, Li; Han, Ya-di; Cui, Ning-hua; Huang, Zhu-liang; Li, Zu-hua; Zheng, Fang; Yan, Ming

    2015-01-01

    Homocysteine (Hcy) is a potential risk factor for age-related cataract (ARC). Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for Hcy metabolism, and variants of MTHFR may affect MTHFR enzyme activity. This study mainly evaluated the associations between variants in MTHFR gene, plasma MTHFR enzyme activity, total Hcy (tHcy) levels and ARC risk in Chinese population. Four single nucleotide polymorphisms (SNPs) in MTHFR gene were genotyped using the high-resolution melting (HRM) method in 502 ARC patients (mean age, 70.2 [SD, 9.0], 46.0% male) and 890 healthy controls (mean age, 67.1 [SD, 11.1], 47.6% male). The plasma MTHFR activity, folic acid (FA), vitamins B12 and B6 levels were detected by enzyme-linked immunosorbent assays (ELISA). The plasma tHcy levels were measured by an automated enzymatic assay. After the Bonferroni correction, the minor allele T of SNP rs1801133 showed a significant association with an increased risk of overall ARC (OR = 1.26, P = 0.003). Consistent association was also found between SNP rs1801133 and cortical ARC risk (OR = 1.44, P = 0.003). Haplotype analyses revealed an adverse effect of the haplotype "C-A-T-C" (alleles in order of SNPs rs3737967, rs1801131, rs1801133 and rs9651118) on ARC risk (OR = 1.55, P = 0.003). Moreover, in a joint analysis of SNPs rs9651118 and rs1801133, subjects with two unfavorable genotypes had a 1.76-fold increased risk of ARC compared with the reference group, and a statistically significant dose-response trend (Ptrend = 0.001) was also observed. Further, in healthy controls and patients with cortical ARC, the allele T of SNP rs1801133 and the increasing number of unfavorable genotypes were significantly correlated with decreased MTHFR activity as well as increased tHcy levels. However, there was no significant association between FA, vitamins B12, B6 levels and MTHFR variants. Our data indicated that variants in MTHFR gene might individually and jointly influence susceptibility to ARC by

  19. 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.

  20. 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.

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

    PubMed

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

    2016-10-24

    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. 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. 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. 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.

  2. Association of Vitamin B12 Deficiency with Homozygosity of the TT MTHFR C677T Genotype, Hyperhomocysteinemia, and Endothelial Cell Dysfunction.

    PubMed

    Shiran, Avinoam; Remer, Eric; Asmer, Ihab; Karkabi, Basheer; Zittan, Eran; Cassel, Aliza; Barak, Mira; Rozenberg, Orit; Karkabi, Khaled; Flugelman, Moshe Y

    2015-05-01

    Hyperhomocysteinemia is associated with increased cardiovascular risk, but treatment with folic acid has no effect on outcome in unselected patient populations. To confirm previous observations on the association of homozygosity for the TT MTHFR genotype with B12 deficiency and endothelial dysfunction, and to investigate whether patients with B12 deficiency should be tested for 677MTHFR genotype. We enrolled 100 individuals with B12 deficiency, tested them for the MTHFR C677T polymorphism and measured their homocysteine levels. Forearm endothelial function was checked in 23 B12-deficient individuals (13 with TT MTHFR genotype and 10 with CT or CC genotypes). Flow-mediated dilatation (FMD) was tested after short-term treatment with B12 and folic acid in 12 TT MTHFR homozygotes. Frequency of the TT MTHFR genotype was 28/100 (28%), compared with 47/313 (15%) in a previously published cohort of individuals with normal B12 levels (P = 0.005). Mean homocysteine level was 21.2 ± 16 μM among TT homozygotes as compared to 12.3 ± 5.6 μM in individuals with the CC or CT genotype (P = 0.008). FMD was abnormal ( 6%) in 9/13 TT individuals with B12 deficiency (69%), and was still abnormal in 7/12 of those tested 6 weeks after B12 and folic treatment (58%). Among individuals with B12 deficiency, the frequency of the TT MTHFR genotype was particularly high. The TT polymorphism was associated with endothelial dysfunction even after 6 weeks of treatment with B12 and folic acid. Based on our findings we suggest that B12 deficiency be tested for MTHFR polymorphism in order to identify potential vascular abnormalities and increased cardiovascular risk.

  3. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and high plasma homocysteine in chronic hepatitis C (CHC) infected patients from the Northeast of Brazil

    PubMed Central

    2011-01-01

    Background/Aim Hyperhomocysteinemia due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T (Ala222Val) polymorphism were recently associated to steatosis and fibrosis. We analyzed the frequency of MTHFR gene in a cross-sectional study of patients affected by Chronic Hepatitis C (CHC) from Northeast of Brazil. Method One hundred seven-four untreated patients with CHC were genotyped for the C677T MTHFR. Genomic DNA was extracted from peripheral blood cells and the C677T MTHFR polymorphism was identified by PCR-RFLP. The homocysteine (Hcy) levels were determined by chemiluminescence method. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and have current and past daily alcohol intake less than 100 g/week. Results Among subjects infected with CHC genotype non-1 the frequency of MTHFR genotypes TT was 9.8% versus 4.4% genotype 1 (p = 0.01). Nevertheless, association was found between the MTHFR genotype TT × CT/CC polymorphism and the degree of steatosis and fibrosis in both hepatitis C genotype (p < 0.05). A significant difference was found on plasma Hcy levels in patients with steatosis regardless of HCV genotype (p = 0.03). Conclusion Our results indicate that plasma Hcy levels is highly prevalent in subjects with chronic hepatits C with steatosis regardless of HCV genotype and vitamin deficiency. The presence of genotype TT of MTHFR C677T polymorphism was more common in CHC genotype non-1 infected patient regardless of histopathological classification and genotype TT+CT frequencies were significant in the presence of fibrosis grade 1+2 and of steatosis in CHC infected patients from the northeast of Brazil regardless of HCV genotype. The genetic susceptibility of MTHFR C677T polymorphism should be confirmed in a large population. PMID:21854603

  4. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and high plasma homocysteine in chronic hepatitis C (CHC) infected patients from the Northeast of Brazil.

    PubMed

    Siqueira, Erika R F; Oliveira, Cláudia P M S; Muniz, Maria T C; Silva, Filipe; Pereira, Leila M M B; Carrilho, Flair J

    2011-08-19

    Hyperhomocysteinemia due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T (Ala222Val) polymorphism were recently associated to steatosis and fibrosis. We analyzed the frequency of MTHFR gene in a cross-sectional study of patients affected by Chronic Hepatitis C (CHC) from Northeast of Brazil. One hundred seven-four untreated patients with CHC were genotyped for the C677T MTHFR. Genomic DNA was extracted from peripheral blood cells and the C677T MTHFR polymorphism was identified by PCR-RFLP. The homocysteine (Hcy) levels were determined by chemiluminescence method. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and have current and past daily alcohol intake less than 100 g/week. Among subjects infected with CHC genotype non-1 the frequency of MTHFR genotypes TT was 9.8% versus 4.4% genotype 1 (p = 0.01). Nevertheless, association was found between the MTHFR genotype TT × CT/CC polymorphism and the degree of steatosis and fibrosis in both hepatitis C genotype (p < 0.05). A significant difference was found on plasma Hcy levels in patients with steatosis regardless of HCV genotype (p = 0.03). Our results indicate that plasma Hcy levels is highly prevalent in subjects with chronic hepatits C with steatosis regardless of HCV genotype and vitamin deficiency. The presence of genotype TT of MTHFR C677T polymorphism was more common in CHC genotype non-1 infected patient regardless of histopathological classification and genotype TT+CT frequencies were significant in the presence of fibrosis grade 1+2 and of steatosis in CHC infected patients from the northeast of Brazil regardless of HCV genotype. The genetic susceptibility of MTHFR C677T polymorphism should be confirmed in a large population.

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

    PubMed

    Cen, Han; Huang, Hua; Zhang, Li-Na; Liu, Li-Ya; Zhou, Li; Xin, Xia-Fei; Zhuo, Ren-Jie

    2017-02-01

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

  6. Parental Genetic Variants, MTHFR 677C>T and MTRR 66A>G, Associated Differently with Fetal Congenital Heart Defect.

    PubMed

    Guo, Qian-Nan; Wang, Hong-Dan; Tie, Li-Zhen; Li, Tao; Xiao, Hai; Long, Jian-Gang; Liao, Shi-Xiu

    2017-01-01

    Congenital heart defect (CHD) is one of the most common birth defects in the world. The methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are two of the most important candidate genes for fetal CHD. However, the correlations between the two genes and fetal CHD were inconsistent in various reports. Therefore, this study is aimed to evaluate the parental effects of the two genes on fetal CHD via three genetic polymorphisms, MTHFR 677C>T (rs1801133), MTHFR 1298 A>C (rs1801131), and MTRR 66A>G (rs1801394). Parents with pregnancy history of fetal CHD were divided into two subgroups: ventricular septal defect (VSD) (21) and non-VSD groups (78). VSD, non-VSD, and 114 control parents (controls) were analyzed in this study. Genotyping of these genetic polymorphisms was done by sequencing. The MTHFR 677C>T polymorphism of either mothers or fathers was independently associated with fetal non-VSD (P < 0.05) but not VSD, while the MTRR 66A>G polymorphism was independently associated with fetal VSD (P < 0.05) but not non-VSD. No significance was found for MTHFR 1298A>C polymorphism. In either maternal or paternal group, the MTHFR 677C>T polymorphism was independently related to fetal non-VSD, while the MTRR 66A>G polymorphism was independently related to fetal VSD.

  7. Parental Genetic Variants, MTHFR 677C>T and MTRR 66A>G, Associated Differently with Fetal Congenital Heart Defect

    PubMed Central

    Li, Tao

    2017-01-01

    Background Congenital heart defect (CHD) is one of the most common birth defects in the world. The methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are two of the most important candidate genes for fetal CHD. However, the correlations between the two genes and fetal CHD were inconsistent in various reports. Therefore, this study is aimed to evaluate the parental effects of the two genes on fetal CHD via three genetic polymorphisms, MTHFR 677C>T (rs1801133), MTHFR 1298 A>C (rs1801131), and MTRR 66A>G (rs1801394). Methods Parents with pregnancy history of fetal CHD were divided into two subgroups: ventricular septal defect (VSD) (21) and non-VSD groups (78). VSD, non-VSD, and 114 control parents (controls) were analyzed in this study. Genotyping of these genetic polymorphisms was done by sequencing. Results The MTHFR 677C>T polymorphism of either mothers or fathers was independently associated with fetal non-VSD (P < 0.05) but not VSD, while the MTRR 66A>G polymorphism was independently associated with fetal VSD (P < 0.05) but not non-VSD. No significance was found for MTHFR 1298A>C polymorphism. Conclusion In either maternal or paternal group, the MTHFR 677C>T polymorphism was independently related to fetal non-VSD, while the MTRR 66A>G polymorphism was independently related to fetal VSD. PMID:28758112

  8. 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

  9. 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.

  10. Association of Methylentetraydrofolate Reductase (MTHFR) 677 C > T gene polymorphism and homocysteine levels in psoriasis vulgaris patients from Malaysia: a case-control study

    PubMed Central

    2012-01-01

    Background The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and methyl donors. The methyl donors are required for the conversion of homocysteine to methionine. Mutation of MTHFR 677 C > T disrupts its thermostability therefore leads to defective enzyme activities and dysregulation of homocysteine levels. Methods This case-control study (n = 367) was conducted to investigate the correlation of the MTHFR gene polymorphism [NM_005957] and psoriasis vulgaris amongst the Malaysian population. Overnight fasting blood samples were collected from a subgroup of consented psoriasis vulgaris patients and matched controls (n = 84) for the quantification of homocysteine, vitamin B12 and folic acid levels. Results There was no significant increase of the MTHFR 677 C > T mutation in patients with psoriasis vulgaris compared with controls (χ2 = 0.733, p = 0.392). No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were observed (F = 0.91, df = 3, 80, p = 0.44). However, homocysteine levels in cases were negatively correlated with vitamin B12 (r = -0.173) and folic acid (r = -0.345) levels. Vitamin B12 and folic acid levels in cases were also negatively correlated (r = -0.164). Conclusions Our results indicate that there was no significant association between the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population. There was no significant increase of the plasma homocysteine level in the psoriasis patients compared to the controls. PMID:22217364

  11. Frequency of the C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene in patients with migraine with or without aura - a preliminary report.

    PubMed

    Szczygioł, Dorota; Motta, Ewa; Gołba, Anna; Stęposz, Arkadiusz; Witecka, Joanna; Dębski, Marek; Błaszkiewicz, Daria; Sieroń, Aleksander

    2012-01-01

    The aim of our study was to evaluate the frequency of the C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with migraine with or without aura and to find an association between this variant and vascular lesions in magnetic resonance imaging of the head, presence of patent foramen ovale (PFO) and increased level of homocysteine. Ninety-one patients with migraine, aged 19-57, were investigated in this study. The MTHFR C677T variant was genotyped in this group and levels of homocysteine, folic acid and vitamin B12 were measured. Transcranial Doppler sonography with test for PFO detection by injection of air contrast during the Valsalva manoeuvre was performed in each patient. Frequency of the C677T variant in the MTHFR gene was similar in patients and controls. Hyperhomocysteinaemia was significantly more frequent in migraine patients with the C677T variant. The prevalence of PFO was significantly higher in migraine patients with aura and the homozygous variant of the MTHFR gene. Frequency of the C677T variant in the MTHFR gene was similar in patients and controls. Significantly more frequent prevalence of PFO in migraine patients with aura (with homozygous recessive genotype of MTHFR probably suggests their common genetic basis. Hyperhomocysteinaemia was significantly more frequent in migraine patients with the C677T variant, which could be an additional risk factor of this disease.

  12. 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.

  13. Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations.

    PubMed

    Rai, Vandana

    2015-01-01

    Genetic and environmental factors play important roles in pathogenesis of digestive tract cancers like those in the esophagus, stomach and colorectum. Folate deficiency and methylenetetrahydrofolate reductase (MTHFR) as an important enzyme of folate and methionine metabolism are considered crucial for DNA synthesis and methylation. MTHFR variants may cause genomic hypomethylation, which may lead to the development of cancer, and MTHFR gene polymorphisms (especially C677T and A1298C) are known to influence predispositions for cancer development. Several case control association studies of MTHFR C677T polymorphisms and colorectal cancer (CRC) have been reported in different populations with contrasting results, possibly reflecting inadequate statistical power. The present meta-analysis was conducted to investigate the association between the C677T polymorphism and the risk of colorectal cancer. A literature search of the PubMed, Google Scholar, Springer link and Elsevier databases was carried out for potential relevant articles. Pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated to assess the association of MTHFR C677T with the susceptibility to CRC. Cochran's Q statistic and the inconsistency index (I2) were used to check study heterogeneity. Egger's test and funnel plots were applied to assess publication bias. All statistical analyses were conducted by with MetaAnalyst and MIX version 1.7. Thirty four case-control studies involving a total of 9,143 cases and 11,357 controls were retrieved according to the inclusion criteria. Overall, no significant association was found between the MTHFR C677T polymorphism and colorectal cancer in Asian populations (for T vs. C: OR=1.03; 95% CI= 0.92-1.5; p= 0.64; for TT vs CC: OR=0.88; 95%CI= 0.74-1.04; p= 0.04; for CT vs. CC: OR = 1.02; 95%CI= 0.93-1.12; p=0.59; for TT+ CT vs. CC: OR=1.07; 95%CI= 0.94-1.22; p=0.87). Evidence from the current meta-analysis indicated that the C677T

  14. 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

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

    PubMed

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

    2016-01-01

    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. 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. 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. 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.

  16. 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.

  17. Folate status, regulatory T cells and MTHFR C677T polymorphism study in allergic children.

    PubMed

    Socha-Banasiak, Anna; Kamer, Barbara; Gach, Agnieszka; Wysocka, Urszula; Jakubowski, Lucjusz; Głowacka, Ewa; Czkwianianc, Elżbieta

    2016-09-01

    This study aimed to investigate early-life folate serum concentrations in children with food, inhalant or mixed type allergy. The influence of folate levels on the FoxP3 expression in Treg (regulatory T) cells in the studied children, taking into account the MTHFR (5,10-methylenetetrahydrofolate reductase) genotypes was also analyzed. The study was performed in 83 allergic children (study group) and 49 healthy children (control group), aged 2-72 months. Medical history of each child was obtained and laboratory tests (serum folic acid concentrations and MTHFR C677T polymorphism) were carried out. The percentage of Treg cells was evaluated in almost a half of the examined subjects (48.5%). Significantly higher serum folate levels in the group of children with food allergy than in those with inhalant allergy was confirmed (P=0.037). In the study group the TT homozygotes were characterized by significantly lower folate concentrations than CC homozygotes (P=0.045). A negative correlation was demonstrated between the FoxP3 expression in CD4(+)CD25(high)FoxP3(+) peripheral blood lymphocytes and serum folic acid concentrations. The correlation was more pronounced in the group of allergic children and it was statistically significant (r=-0.339, P<0.05). The results of the study indicate a possibility of some effects of folate status on Treg cells, thus suggesting their potential role in the development and course of allergy in children. Copyright © 2016 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  18. 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

  19. 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.

  20. Association of MTHFR, MTR, MTRR, RFC1, and DHFR gene polymorphisms with susceptibility to sporadic colon cancer.

    PubMed

    Jokić, Mladen; Brčić-Kostić, Krunoslav; Stefulj, Jasminka; Catela Ivković, Tina; Božo, Lončar; Gamulin, Marija; Kapitanović, Sanja

    2011-10-01

    Altered folate levels may play an important role in colon carcinogenesis. The aim of this study was to investigate the association of polymorphisms in key folate-metabolizing genes with susceptibility to sporadic colon cancer. Six common polymorphisms (two in MTHFR and one each in MTR, MTRR, RFC1, and DHFR genes) were genotyped in 300 healthy subjects and 300 colon cancer patients from Croatia. Obtained results indicate possible protective role of MTRR 66 AA in sporadic colon cancer (OR=0.655; 95% CI=0.441-0.973; p=0.04). Maximum-likelihood analysis of haplotypes revealed a linkage disequilibrium (LD) between the two investigated polymorphisms of the MTHFR gene (C677T and A1298C), both in the control and patient groups (p<0.01 for both). LD was also detected between MTRR A66G and MTHFR A1298C polymorphisms but only in a group of patients (p<0.01). A haplotype of A66G and A1298C polymorphisms, A/A, proved to be protective (OR=0.775; 95% CI=0.603-0.996; p=0.04), whereas haplotype A/G was a risk factor for colon cancer (OR=1.270; 95% CI=1.007-1.602; p=0.04). Contrary to some previous studies, single-locus analyses identified no polymorphisms associated with risk for colon cancer, but demonstrated a possible protective effect of MTRR 66 AA genotype. The detected significant LD between two loci (MTHFR A1298C and MTRR A66G) located on different chromosomes indicates a strong selective force as a mechanism for the maintenance of their linkage. Specific combinations of alleles of these two polymorphisms showed a protective but also a risk effect on colon cancer susceptibility.

  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. 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.

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

    PubMed

    Rutten-Jacobs, Loes C A; 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

    2016-03-01

    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. 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. 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). 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. © 2016 The Authors.

  4. Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication of MTHFR rs1801133 and ATIC rs4673993 Polymorphisms

    PubMed Central

    Lima, Aurea; Monteiro, Joaquim; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Seabra, Vitor; Medeiros, Rui

    2014-01-01

    Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment. PMID:24967362

  5. Methylenetetrahydrofolate Reductase (MTHFR) (C677T and A1298C) Polymorphisms and Vascular Complications in Patients with Type 2 Diabetes.

    PubMed

    Fekih-Mrissa, Najiba; Mrad, Meriem; Ibrahim, Hazard; Akremi, Imen; Sayeh, Aicha; Jaidane, Amel; Ouertani, Haroun; Zidi, Borni; Gritli, Nasreddine

    2017-08-01

    To assess whether 2 polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, are risk factors for vascular complications in Tunisian patients with type 2 diabetes mellitus. The MTHFR polymorphisms were genotyped, and plasma homocysteine levels were evaluated in 160 Tunisian patients with type 2 diabetes mellitus. Prevalence of the 2 heterozygous polymorphisms of the thermolabile MTHFR gene (CT and AC) was encountered more commonly in patients with diabetes mellitus than in the healthy controls (p<10(-3)). Subjects with diabetes had significantly higher homocysteine (Hcy) levels than the control subjects; however, there was no statistical difference in plasma Hcy values between carriers of mutant genotypes (CT/TT for C677T and AC/CC for A1298C) and wild types (CC and AA) in patients with diabetes. Retinopathy was found to be a vascular complication in patients with either the 677CT or the 1298(AC+CC) genotype more commonly than in those with the wild-type genotypes (p=0.003; OR=3.2, 95% CI, 1.4 to 7.4; p<10(-3); OR=5.9, 95% CI, 2.7 to 13). Only patients who carry the A1298C mutation (AC+CC) are at risk for at least 1 complication (p=0.002). Double heterozygous mutants were at the greatest risk for retinopathy and for suffering at least 1 complication (p<10(-3)). Studies involving a larger study population and various ethnic groups are required before ruling out the role of MTHFR gene in type 2 diabetes mellitus and in vascular complications. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

  6. 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

  7. [Allelic polymorphism of MTHFR, MTR and MTRR genes in patients with cleft lip and/or palate and their mothers].

    PubMed

    Chorna, L B; Akopian, H R; Makukh, H V; Fedoryk, I M

    2011-01-01

    The frequency of common MTHFR, MTR and MTRR genes polymorphisms was evaluated among patients with non-syndromic cleft lip and/or palate (CL/P), their mothers and healthy persons from West-Ukrainian region. MTHFR 677TT genotype was shown to increase more than three-fold risk of CL/P and for mothers the risk of having CL/P children may increase two-fold compared with homozygous carriers of MTHFR 677CC genotype (OR = 3.3, OR = 1.92, respectively). The heterozygous MTR 2756AG genotype was associated with 1.5-fold increased risk of CL/P compared with the AA genotype (OR = 1.48). The heterozygous genotype MTRR 66AG was associated with the 5.56-fold increased CL/P risk (OR = 5.56) and for mothers with 2.6-fold increased risk of delivering a CL/P offspring (OR = 2.6). The results showed that MTRR 66G allele is more prevalent than MTRR 66A (wild type) and the MTRR 66GG genotype frequency was significantly lower among CL/P patients and their mothers than in control group among Western Ukrainian inhabitants.

  8. Polymorphisms in genes MTHFR, MTR and MTRR are not risk factors for cleft lip/palate in South Brazil.

    PubMed

    Brandalize, A P C; Bandinelli, E; Borba, J B; Félix, T M; Roisenberg, I; Schüler-Faccini, L

    2007-06-01

    Non-syndromic cleft lip and palate (CL/P) occurs due to interaction between genetic and environmental factors. Abnormalities in homocysteine metabolism may play a role in its etiology due to polymorphisms in genes involved in this pathway. Because of the involvement of MTHFR, MTR and MTRR genes with folate metabolism and the evidence that maternal use of folic acid in early pregnancy reduces the risk for CL/P, we evaluated the influence of their polymorphisms on the etiology of CL/P through a case-control study. The analyses involved 114 non-syndromic phenotypically white children with clefts (case) and 110 mothers, and 100 non-affected (control) children and their mothers. The polymorphisms 677C>T of MTHFR, 2756A>G of MTR, and 66A>G of MTRR genes were analyzed by PCR-RFLP. Allelic frequencies did not differ from other studies conducted on white populations for MTHFR 677T allele (0.35) and for MTR 2756G allele (0.17), but MTRR 66G allele frequency (0.35) was lower than observed elsewhere. The genotypic distribution of the 677C>T polymorphisms under study did not show significant differences between CL/P patients, their mothers and controls. These results suggest that the alterations of folate metabolism related to these polymorphisms are not involved in clefting in the population under study.

  9. 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.

  10. [Association of folate metabolism genes MTRR and MTHFR with complex congenital abnormalities among Chinese population in Shanxi Province, China].

    PubMed

    Zhang, Qin; Bai, Bao-Ling; Liu, Xiao-Zhen; Miao, Chun-Yue; Li, Hui-Li

    2014-08-01

    To explore the association of polymorphisms in folate metabolism genes, methionine synthase reductase (MTRR) gene and 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, with complex congenital abnormalities and to further investigate its association with complex congenital abnormalities derived from three germ layers. A total of 250 cases of birth defects (with complex congenital abnormalities including congenital heart disease, neural tube defects, and craniofacial anomalies) in Shanxi Province, China were included in the study. MTRR single nucleotide polymorphism (SNP) (rs1801394) and MTHFR SNP (rs1801133) were genotyped by the SNaPshot method, and the genotyping results were compared with those of controls (n=420). SNPs rs1801394 and rs1801133 were associated with multiple birth defects. For the recessive model, individuals with GG genotype at rs1801394 and CC genotype at rs1801133 had a relatively low risk of developing birth defects, so the two genotypes were protective factors against birth defects. The homozygous recessive genotype at rs1801133, which served as a protective factor, was associated with ectoderm- or endoderm-derived complex congenital abnormalities, while the homozygous recessive genotype at rs1801394, which served as a protective factor, was associated with ectoderm-, mesoderm- or endoderm-derived complex congenital abnormalities. Among the Chinese population in Shanxi Province, the SNPs in folate metabolism genes (MTRR and MTHFR) are associated with complex congenital abnormalities and related to ectoderm, mesoderm or endoderm development.

  11. 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.

  12. Polymorphisms of MTHFR Associated with Higher Relapse/Death Ratio and Delayed Weekly MTX Administration in Pediatric Lymphoid Malignancies

    PubMed Central

    Fukushima, Takashi; Sakai, Aiko; Suzuki, Ryoko; Nakajima-Yamaguchi, Ryoko; Kobayashi, Chie; Iwabuchi, Atsushi; Saito, Makoto; Yoshimi, Ai; Nakao, Tomohei; Kato, Keisuke; Tsuchida, Masahiro; Takahashi, Hideto; Koike, Kazutoshi; Kiyokawa, Nobutaka; Noguchi, Emiko; Sumazaki, Ryo

    2013-01-01

    Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkin's lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (P = 0.004). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies. PMID:24386571

  13. 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.

  14. Does the MTHFR C677T gene polymorphism indicate cardiovascular disease risk in type 2 diabetes mellitus patients?

    PubMed

    Bahadır, Anzel; Eroz, Recep; Türker, Yasin

    2015-07-01

    Diabetes mellitus is a major risk factor for cardiovascular disease (CVD). We investigated the relationship among biochemical and cardiac risk parameters with the methylenetetrahydrofolate reductase (MTHFR) C677T genotype in type 2 diabetes mellitus (T2DM) patients. One hundred seven T2DM subjects with severe CVD diagnosed by angiography were included consecutively in this cross-sectional study. Biochemical and clinical parameters were obtained from patients who were not positive for nephropathy and retinopathy. MTHFR C677T genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Normally and abnormally distributed continuous variables were analyzed using student t- and Mann-Whitney U tests. Categorical variables were analyzed using chi-square test. In the study, 31 T2DM subjects had the CC (29.0%), 62 had the CT (57.9%), and 14 had the TT (13.1%) genotypes. There were no significant differences between subjects with wild-type (677CC) and with mutant (677CT+677TT) alleles in terms of diabetes duration, visceral fat area, total cholesterol, triglyceride, fasting plasma glucose, systolic blood pressure, diastolic blood pressure, high-sensitivity C-reactive protein, homocysteine (Hcy), and carotid intima-media thickness values. This study suggests that MTHFR gene polymorphisms can not be used as a marker for the assessment of cardiovascular risk in T2DM patients.

  15. Does the MTHFR C677T gene polymorphism indicate cardiovascular disease risk in type 2 diabetes mellitus patients?

    PubMed Central

    Bahadır, Anzel; Eroz, Recep; Türker, Yasin

    2015-01-01

    Objective: Diabetes mellitus is a major risk factor for cardiovascular disease (CVD). We investigated the relationship among biochemical and cardiac risk parameters with the methylenetetrahydrofolate reductase (MTHFR) C677T genotype in type 2 diabetes mellitus (T2DM) patients. Methods: One hundred seven T2DM subjects with severe CVD diagnosed by angiography were included consecutively in this cross-sectional study. Biochemical and clinical parameters were obtained from patients who were not positive for nephropathy and retinopathy. MTHFR C677T genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Normally and abnormally distributed continuous variables were analyzed using student t- and Mann-Whitney U tests. Categorical variables were analyzed using chi-square test. Results: In the study, 31 T2DM subjects had the CC (29.0%), 62 had the CT (57.9%), and 14 had the TT (13.1%) genotypes. There were no significant differences between subjects with wild-type (677CC) and with mutant (677CT+677TT) alleles in terms of diabetes duration, visceral fat area, total cholesterol, triglyceride, fasting plasma glucose, systolic blood pressure, diastolic blood pressure, high-sensitivity C-reactive protein, homocysteine (Hcy), and carotid intima-media thickness values. Conclusion: This study suggests that MTHFR gene polymorphisms can not be used as a marker for the assessment of cardiovascular risk in T2DM patients. PMID:25537992

  16. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women.

    PubMed

    Barbosa, P R; Stabler, S P; Machado, A L K; Braga, R C; Hirata, R D C; Hirata, M H; Sampaio-Neto, L F; Allen, R H; Guerra-Shinohara, E M

    2008-08-01

    To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status. Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP). Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l. Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.

  17. Clinical Relevance of MTHFR, eNOS, ACE, and ApoE Gene Polymorphisms and Serum Vitamin Profile among Malay Patients with Ischemic Stroke.

    PubMed

    Wei, Loo Keat; Au, Anthony; Menon, Saras; Gan, Siew Hua; Griffiths, Lyn R

    2015-09-01

    The purpose of this study was threefold. First, it was to determine the relationship between serum vitamin profiles and ischemic stroke. The second purpose was to investigate the association of methylenetetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and apolipoprotein-E (ApoE) gene polymorphisms with ischemic stroke and further correlate with serum vitamin profiles among ischemic stroke patients. The third purpose of the study was to highlight the interaction of MTHFR and eNOS haplotypes with serum vitamin profiles and ischemic stroke risks. Polymorphisms of these genes were analyzed in age-, sex-, and ethnicity-matched case-controls (n = 594); serum vitamin profiles were determined using immunoassays. The MTHFR 677C>T, 1298A>C, eNOS intron 4a/b, and ApoE polymorphisms were significantly associated with the increased risk of ischemic stroke. Elevated serum homocysteine and vitamin B12 levels were associated with MTHFR 677C>T and eNOS intron 4a/b polymorphisms. The ApoE and eNOS -786T>C polymorphisms were associated with increased serum vitamin B12 levels. However, none of the polymorphisms influenced serum folate levels except for the MTHFR 1298A>C. Different patterns of MTHFR and eNOS haplotypes tend to affect serum vitamin profiles to different degrees, which contribute to either different susceptibility risk or protective effect on ischemic stroke. Overall, increased levels of serum homocysteine and vitamin B12 levels were associated with higher risk of ischemic stroke in the investigated population. The present study suggests that the genotypes and haplotypes of MTHFR 677C>T and eNOS intron 4a/b polymorphisms are potential serum biomarkers in the pathophysiological processes of ischemic stroke, by modulating homocysteine and vitamin B12 levels. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  18. Carrier-state of two or three polymorphic variants of MTHFR, IL-6 and ICAM1 genes increases the risk of coronary artery disease.

    PubMed

    Sarecka-Hujar, Beata; Zak, Iwona; Krauze, Jolanta

    2008-12-01

    Progression of coronary artery disease (CAD) depends on multiple genetic and environmental factors. Polymorphic variants of genes encoding proteins involved in endothelium dysfunction or proinflammatory state may genetically differentiate the human population and determine a susceptibility to the disease. To find the relationship between single polymorphisms of MTHFR, IL-6 and ICAM1 genes, double or triple combinations among their polymorphic variants and CAD in a patient population from the Upper Silesia region. The study population consisted of 177 patients with angiographically documented CAD and 202 blood donors with no signs of CAD. All examined individuals were white Polish Caucasians aged 18-55 years. The analysis of genetic polymorphisms was performed using the PCR-RFLP method. We observed a weak association between single gene polymorphism and the disease only in the case of the MTHFR T allele. We also found that the frequency of some double or triple combinations among analysed genes, especially for MTHFR+ICAM1 and MTHFR+ICAM1+IL-6 patterns, differentiated the entire patient group from controls (p=0.047 OR=1.75 and p=0.016 OR=1.75, respectively). These two combinations were also significantly more frequent in patients who were age-matched with controls, especially in the female subgroups (for MTHFR+ICAM1 p=0.007, OR=10.32 and for MTHFR+ ICAM1+IL-6, p=0.005, OR=17.95 in females). The present study showed that simultaneous carrier-state of MTHFR, IL-6 and ICAM1 genes increased the risk of CAD.

  19. 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

  20. Association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and essential hypertension: a systematic review and meta-analysis.

    PubMed

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

    2014-12-01

    Many studies have investigated the role of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) C677T/A1298C polymorphisms in essential hypertension (EH), but results are inconclusive. The purpose of this meta-analysis was to clarify the effects of MTHFR C677T/A1298C polymorphisms on the risk of EH. Electronic databases were searched to identify relevant studies published until January 2014. Data were extracted by two independent authors. Odds ratios (ORs) with 95%confidence intervals (CIs) were used to assess the association between MTHFR C677T/A1298C polymorphisms and the risk of EH using random effect models or fixed effect models. Finally,30 studies with 5207 cases and 5383 controls were included for C677T polymorphism and 6 studies with 1009 cases and 994 controls were included for A1298C polymorphism. Meta-analysis results indicated that MTHFR C677T polymorphism contributed to an increased risk of EH (for T vs. C: OR=1.30, 95%CI=1.18–1.43; for TT+CT vs. CC: OR=1.34, 95%CI=1.24–1.46; for TT vs. CC: OR=1.62, 95%CI=1.32–1.99; for TT vs. CT+CC: OR=1.41, 95%CI=1.26–1.59). However, no significant association was detected between MTHFR A1298C polymorphism and the risk of EH. This meta-analysis supports that MTHFR C677T polymorphism plays a role in developing EH. MTHFR A1298C polymorphism may not be associated with an increased risk of EH. Further large and well-designed studies are warranted to confirm these findings.

  1. Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine.

    PubMed

    García-Minguillán, Carlos J; Fernandez-Ballart, Joan D; Ceruelo, Santiago; Ríos, Lídia; Bueno, Olalla; Berrocal-Zaragoza, Maria Isabel; Molloy, Anne M; Ueland, Per M; Meyer, Klaus; Murphy, Michelle M

    2014-11-01

    Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), riboflavin-dependent enzymes, participate in homocysteine metabolism. Reported effects of riboflavin status on the association between the MTHFR 677C>T polymorphism and homocysteine vary, and the effects of the MTRR 66A>G or MTRR 524C>T polymorphisms on homocysteine are unclear. We tested the hypothesis that the effects of the MTHFR 677C>T, MTRR 66A>G and MTRR 524C>T polymorphisms on fasting plasma total homocysteine (tHcy) depend on riboflavin status (erythrocyte glutathionine reductase activation coefficient, optimum: <1.2; marginally deficient: 1.2-1.4; deficient: ≥1.4) in 771 adults aged 18-75 years. MTHFR 677T allele carriers with middle or low tertile plasma folate (<14.7 nmol/L) had 8.2 % higher tHcy compared to the 677CC genotype (p < 0.01). This effect was eliminated when riboflavin status was optimal (p for interaction: 0.048). In the lowest cobalamin quartile (≤273 pmol/L), riboflavin status modifies the relationship between the MTRR 66 A>G polymorphism and tHcy (p for interaction: 0.034). tHcy was 6.6 % higher in MTRR 66G allele carriers compared to the 66AA genotype with marginally deficient or optimal riboflavin status, but there was no difference when riboflavin status was deficient (p for interaction: 0.059). tHcy was 13.7 % higher in MTRR 524T allele carriers compared to the 524CC genotype when cobalamin status was low (p < 0.01), but no difference was observed when we stratified by riboflavin status. The effect of the MTHFR 677C>T polymorphism on tHcy depends on riboflavin status, that of the MTRR 66A>G polymorphism on cobalamin and riboflavin status and that of the MTRR 524C>T polymorphism on cobalamin status.

  2. Association between ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133), FTO (rs9939609) Genes Polymorphism and Type 2 Diabetes with Dyslipidemia.

    PubMed

    Raza, Syed Tasleem; Abbas, Shania; Siddiqi, Zeba; Mahdi, Farzana

    2017-01-01

    Diabetic dyslipidemia is one of the leading causes of coronary artery disease (CAD) death. Genetic and environmental factors play an important role in the development of type 2 diabetes mellitus (T2DM) and dyslipidemia. The present study was aimed to investigate the association of ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133) and FTO (rs9939609) genes polymorphism in T2DM with dyslipidemia. Totally, 559 subjects including 221 T2DM cases with dyslipidemia, 158 T2DM without dyslipidemia and 180 controls were enrolled. ACE genes polymorphism was evaluated by polymerase chain reaction (PCR), while MTHFR, FABP2, FTO genes polymorphisms were evaluated by PCR and restriction fragment length polymorphism (RFLP). Significant association of ACE and MTHFR genes polymorphisms were found in both group of cases [T2DM with dyslipidemia (P<0.001, and P=0.008, respectively) and T2DM without dyslipidemia (P=0.003, and P=0.010, respectively)] while FABP2 and FTO genes polymorphisms were significantly associated with T2DM without dyslipidemia (P=0.038, and P= 0.019, respectively). This study concludes that ACE, FABP2, FTO and MTHFR genes are associated with T2DM. Additionally, it also seems that ACE and MTHFR genes might be further associated with the development of dyslipidemia in T2DM cases.

  3. Association between ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133), FTO (rs9939609) Genes Polymorphism and Type 2 Diabetes with Dyslipidemia

    PubMed Central

    Raza, Syed Tasleem; Abbas, Shania; Siddiqi, Zeba; Mahdi, Farzana

    2017-01-01

    Diabetic dyslipidemia is one of the leading causes of coronary artery disease (CAD) death. Genetic and environmental factors play an important role in the development of type 2 diabetes mellitus (T2DM) and dyslipidemia. The present study was aimed to investigate the association of ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133) and FTO (rs9939609) genes polymorphism in T2DM with dyslipidemia. Totally, 559 subjects including 221 T2DM cases with dyslipidemia, 158 T2DM without dyslipidemia and 180 controls were enrolled. ACE genes polymorphism was evaluated by polymerase chain reaction (PCR), while MTHFR, FABP2, FTO genes polymorphisms were evaluated by PCR and restriction fragment length polymorphism (RFLP). Significant association of ACE and MTHFR genes polymorphisms were found in both group of cases [T2DM with dyslipidemia (P<0.001, and P=0.008, respectively) and T2DM without dyslipidemia (P=0.003, and P=0.010, respectively)] while FABP2 and FTO genes polymorphisms were significantly associated with T2DM without dyslipidemia (P=0.038, and P= 0.019, respectively). This study concludes that ACE, FABP2, FTO and MTHFR genes are associated with T2DM. Additionally, it also seems that ACE and MTHFR genes might be further associated with the development of dyslipidemia in T2DM cases. PMID:28890888

  4. 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.

  5. 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.

  6. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in psoriasis in southern Turkey.

    PubMed

    Izmirli, Muzeyyen; Sen, Bilge Bulbul; Rifaioglu, Eminenur; Gogebakan, Bulent; Aldemir, Ozgur; Sen, Tuba; Ekiz, Ozlem; Alptekin, Davut

    2016-01-01

    Psoriasis is a multigenic and multifactorial dermatological disease linked to cardiovascular diseases. Increased levels of homocysteine in patients with psoriasis have been demonstrated in many studies. The most frequently investigated genetic defect that plays a role in homocysteine metabolism is single point substitution (C to T) located on the 677th nucleotide of the methylenetetrahydrofolate reductase gene (MTHFR). In this study, we aimed to investigate methylenetetrahydrofolate C677T polymorphism in psoriasis patients in Turkey. The study included 96 patients with psoriasis and 77 controls from southern Turkey. Methylenetetrahydrofolate C677T polymorphism was analysed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism methods. In the psoriasis group, 34 CC (35.4%), 46 CT (47.9%) and 16 TT (16.7%) genotypes were found, respectively; while in the control group, the figures were 39 (50.6%), 35 (45.5%), 3 (3.9%). Homozygote and heterozygote T alleles of methylenetetrahydrofolate C677T polymorphism were significantly higher in the psoriasis than in the control group (p=0.013). We firstly found a correlation between methylenetetrahydrofolate C677T polymorphism and psoriasis among the southern Turkish population.

  7. MTHFR, MTR and MTRR polymorphisms and risk of chronic kidney disease in Japanese: cross-sectional data from the J-MICC Study.

    PubMed

    Hishida, Asahi; Okada, Rieko; Guang, Yin; Naito, Mariko; Wakai, Kenji; Hosono, Satoyo; Nakamura, Kazuyo; Turin, Tanvir Chowdhury; Suzuki, Sadao; Niimura, Hideshi; Mikami, Haruo; Otonari, Jun; Kuriyama, Nagato; Katsuura, Sakurako; Kubo, Michiaki; Tanaka, Hideo; Hamajima, Nobuyuki

    2013-12-01

    Chronic kidney disease (CKD) is well known as a strong risk factor for both of end-stage renal disease and cardiovascular disease. To clarify the associations of MTHFR, MTR, and MTRR polymorphisms with the risk of CKD in Japanese, we examined this association among Japanese subjects using cross-sectional data. The subjects for this analysis were 3,318 participants consecutively selected from the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. The polymorphisms were genotyped by a multiplex polymerase chain reaction-based Invader assay. Age- and sex-adjusted odds ratio (aOR) of CKD with stage 3-5 was calculated for each genotype. When those with MTHFR C677T C/C were defined as references, those with MTHFR C677T C/T and T/T demonstrated the aORs for CKD of 1.14 (95 % CI 0.93-1.40) and 1.39 (1.06-1.82), respectively. Marginally significantly decreased risk of CKD with increasing number of MTR A2756G G allele (p = 0.058) was observed. Stratified analyses by plasma folate low (<7.4 ng/ml) or high (≥7.4 ng/ml) suggested significantly higher OR of CKD for those with MTHFR C677T T/T and low serum folate with the aOR of 2.07 (95 % CI 1.30-3.31) compared with that for those with MTHFR C677T T/T and high serum folate. The present study found a significant association between the subjects with the T/T genotype of MTHFR C677T polymorphism and the elevated risk of CKD, which may suggest the possibility of the risk evaluation and prevention of this potentially life-threatening disease based on genetic traits in the near future.

  8. 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. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  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 D E; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

    2017-03-01

    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 deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid. © The Author 2017. Published by Oxford University Press.

  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. Clinical impact of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations among sickle cell disease patients of Central India.

    PubMed

    Nishank, Sudhansu Sekhar; Singh, Mendi Prema Shyam Sunder; Yadav, Rajiv

    2013-11-01

    It is known that patients with sickle cell disease (SCD) present activation of the blood coagulation and fibrinolytic systems, especially during vaso-occlusive crises and also during the steady state of the disease. We determined whether the presence of the factor prothrombin gene G20210A variant, factor V gene G1691A mutation (factor V Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms may be risk factors for vascular complications in individuals with SCD. The study involved 150 patients with sickle cell anemia and 150 healthy controls of Central India. Genotyping of three thrombophilic mutations was carried out by PCR-RFLP methods using MnlI, Hind III, and Hinf I, respectively, for factor V Leiden, prothrombin, and MTHFR mutations. Patients with SCD had significantly higher prevalence of mutant variants of MTHFR gene (28.0% heterozygotes and 14.6% homozygotes) and FVL gene (14.6% heterozygotes) as compared to normal/control individuals, but complete absence of mutant variants of prothrombin gene. The patients with SCD having mutant variants of MTHFR and FVL genes showed higher incidence of pain in chest, abdomen, and bone joints along with early age of onset of clinical manifestations as well as frequent dependence on blood transfusion than those patients with SCD having wild variants of these thrombotic genes. As compared to control subjects, SCD individuals having mutant variants of FVL and MTHFR genes had significant association with higher levels of prothrombin fragment (F1+2), D-dimer, thrombin-antithrombin (TAT), and lower level of protein C. MTHFR C677T and FVL G1691A polymorphisms may be risk factors for increased vascular complications in patient with SCD. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. MTHFR gene A1298C polymorphisms are associated with breast cancer risk among Chinese population: evidence based on an updated cumulative meta-analysis.

    PubMed

    Wang, Yadong; Yang, Haiyan; Duan, Guangcai

    2015-01-01

    Published studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphisms and breast cancer risk among Chinese population have yielded conflicting results. The purpose of this study was to clarify the association between MTHFR gene A1298C polymorphisms and breast cancer risk among Chinese population. Systematic searches were performed through the database of Medline/PubMed, Science Direct, Elsevier, CNKI and Wanfang Medical Online. Overall, a significantly increased risk of breast cancer was observed among the subjects carrying MTHFR gene A1298C AC+CC genotype (odds ratio [OR]=1.05 with 95% confidence interval [CI]: 1.01-1.10) as compared to those carrying AA genotype among total Chinese population. We did not observe any significant association between MTHFR gene A1298C polymorphisms and the risk of breast cancer under the additional genetic models of AC vs. AA, CC vs. AA and C-allele vs. A-allele (OR=1.00 with 95% CI: 0.97-1.02, OR=1.01 with 95% CI: 1.00-1.02 and OR=1.00 with 95% CI: 0.99-1.02, respectively). The cumulative meta-analysis showed similar results. In subgroup analysis, we observed subjects carrying AC+CC genotype had an increased breast cancer risk compared with those carrying AA genotype among the studies of sample size less than 1000. We did not observe any significant association between MTHFR gene A1298C polymorphisms and breast cancer risk in additional subgroup analyses. Our results suggest that MTHFR gene A1298C AC+CC genotype may be a risk factor for the development of breast cancer among Chinese population. Well-designed studies with a large sample size are needed to further confirm our findings.

  13. The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer.

    PubMed

    Hagleitner, M M; Coenen, M J H; Aplenc, R; Patiño-Garcia, A; Chiusolo, P; Gemmati, D; De Mattei, M; Ongaro, A; Krajinovic, M; Hoogerbrugge, P M; Vermeulen, S H H M; te Loo, D M W M

    2014-04-01

    Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events-National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue.

  14. 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.

  15. 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

  16. Association of methylenetetrahydrofolate reductase (MTHFR 677C>T) and thymidylate synthase (TSER and TS 1494del6) polymorphisms with premature ovarian failure in Korean women.

    PubMed

    Rah, HyungChul; Jeon, Young Joo; Choi, Youngsok; Shim, Sung Han; Yoon, Tae Ki; Choi, Dong Hee; Cha, Sun Hee; Kim, Nam Keun

    2012-11-01

    The aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C>T) and thymidylate synthase (TS) gene variants (TS enhancer region [TSER] and TS 1494del6) confer a risk for premature ovarian failure (POF). We genotyped 136 POF patients and 236 controls among Korean women for the three single nucleotide polymorphism sites using polymerase chain reaction restriction fragment length polymorphism analysis. Differences in the MTHFR 677C>T, TSER, and TS 1494del6 genotype frequencies between POF patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as a measure of the strength of the association between genotypes and POF. The MTHFR 677CT and CT + TT variant genotypes were more frequent in POF patients than in controls (OR, 2.249; 95% CI, 1.317-3.843; and OR, 2.132; 95% CI, 1.268-3.585, respectively). The combined genotype frequencies of MTHFR 677CT + TT/TSER 3R3R and 677CT + TT/TS 1494del6 del6/del6 were higher in patients than in controls (OR, 2.300; 95% CI, 1.219-4.337; and OR, 3.314; 95% CI, 1.623-6.767, respectively). The T-3R-del6 and T-2R-del6 (MTHFR 677C>T/TSER/TS 1494del6) haplotypes were more frequent in patients (OR, 1.450; 95% CI, 1.050-2.002; and OR, 2.911; 95% CI, 1.191-7.117, respectively), whereas the C-2R-del6 haplotype was less frequent in patients (OR, 0.372; 95% CI, 0.152-0.912). The T-del6 (MTHFR 677/TS 1494del6) haplotype frequency was higher among patients (OR, 1.653; 95% CI, 1.206-2.266), whereas the C-del6 haplotype frequency was lower among patients (OR, 0.700; 95% CI, 0.516-0.950). We did not find an association between TSER or TS 1494del6 polymorphisms and POF. Our data suggest that the MTHFR 677T allele may increase the risk for POF, which could lead to the development of novel genetic markers for predicting the risk of POF in patients.

  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. Dietary intake of folate and alcohol, MTHFR C677T polymorphism, and colorectal cancer risk in Korea.

    PubMed

    Kim, Jeongseon; Cho, Young Ae; Kim, Dong-Hyun; Lee, Bong-Hwa; Hwang, Dae-Yong; Jeong, Jinyoung; Lee, Hun-Jae; Matsuo, Keitaro; Tajima, Kazuo; Ahn, Yoon-Ok

    2012-02-01

    The incidence of colorectal cancer (CRC) is increasing sharply in Korea, and evidence has suggested the role of dietary methyl supply and related polymorphisms on colorectal carcinogenesis. We investigated the association between folate and alcohol intake, methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, and CRC risk in Koreans. A total of 787 cases and 656 controls were recruited from 2 university hospitals. Multiple logistic regression models were used to estimate ORs and corresponding 95% CIs. MTHFR 677T homozygotes were at a lower risk of CRC (OR: 0.60; 95% CI: 0.46, 0.78 for TT compared with CC/CT). High folate intake was associated with reduced CRC risk (OR: 0.64; 95% CI: 0.49, 0.84 for high compared with low intake), and high alcohol consumption was associated with increased risk of CRC (OR: 1.76; 95% CI: 1.26, 2.46 for high compared with low intake). When data were stratified by the amount of dietary methyl (combined intake of folate and alcohol), those with low-methyl diets had higher risk of CRC (OR: 2.32; 95% CI: 1.18, 4.56) than did those with high-methyl diets among CC/CT carriers, whereas the amount of dietary methyl did not affect the CRC risk among carriers with the TT homozygous variant. This association was stronger in patients with colon cancer than in patients with rectal cancer. We found that the effect of dietary methyl supply on colorectal carcinogenesis may differ according to MTHFR C677T genotype and the subsite of origin in a Korean population.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency.

    PubMed

    Huemer, Martina; Mulder-Bleile, Regina; Burda, Patricie; Froese, D Sean; Suormala, Terttu; Zeev, Bruria Ben; Chinnery, Patrick F; Dionisi-Vici, Carlo; Dobbelaere, Dries; Gökcay, Gülden; Demirkol, Mübeccel; Häberle, Johannes; Lossos, Alexander; Mengel, Eugen; Morris, Andrew A; Niezen-Koning, Klary E; Plecko, Barbara; Parini, Rossella; Rokicki, Dariusz; Schiff, Manuel; Schimmel, Mareike; Sewell, Adrian C; Sperl, Wolfgang; Spiekerkoetter, Ute; Steinmann, Beat; Taddeucci, Grazia; Trejo-Gabriel-Galán, Jose M; Trefz, Friedrich; Tsuji, Megumi; Vilaseca, María Antònia; von Kleist-Retzow, Jürgen-Christoph; Walker, Valerie; Zeman, Jiri; Baumgartner, Matthias R; Fowler, Brian

    2016-01-01

    Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

  5. The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women.

    PubMed

    Różycka, Agata; Słopień, Radosław; Słopień, Agnieszka; Dorszewska, Jolanta; Seremak-Mrozikiewicz, Agnieszka; Lianeri, Margarita; Maciukiewicz, Małgorzata; Warenik-Szymankiewicz, Alina; Grzelak, Teresa; Kurzawińska, Grażyna; Drews, Krzysztof; Klejewski, Andrzej; Jagodziński, Paweł P

    2016-02-01

    The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). Our study substantiates the involvement of the MAOA

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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

  13. MTHFR C677T polymorphism, homocysteine and B-vitamins status in a sample of Chinese and Malay subjects in Universiti Putra Malaysia.

    PubMed

    Choo, S C; Loh, S P; Khor, G L; Sabariah, M N; Rozita, R

    2011-08-01

    Methylenetetrahydrofolate reductase (MTHFR) C677T is involved in folate and homocysteine metabolism. Disruption in the activity of this enzyme will alter their levels in the body. This study assessed MTHFR C677T polymorphism and its relationship with serum homocysteine and B-vitamins levels in a sample of Chinese and Malays subjects in UPM, Serdang. One hundred subjects were randomly selected from among the university population. Folate, vitamin B12, B6, and homocysteine levels were determined using MBA, ECLIA, and HPLC, respectively. PCR coupled with HinfI digestion was used for detection of MTHFR C677T polymorphism. The frequency of T allele was higher in the Chinese subjects (0.40) compared to the Malay (0.14). Folate, vitamin B12 and B6 levels were highest in the wild genotype in both ethnic groups. Subjects with heterozygous and homozygous genotype showed the highest homocysteine levels. The serum folate and homocysteine were mainly affected by homozygous genotype. MTHFR C677T polymorphism plays an important role in influencing the folate and homocysteine metabolism.

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. Is the coexistence of mutations in the genes of factor V and MTHFR a predisposing factor for massive skin necrosis due to loxoscelism?

    PubMed

    Mandel, Y; Grotto, I; Gdalevich, M; Mimouni, D; Ashkenazi, I; Haviv, J; Shpilberg, O

    1998-01-01

    A 28-year-old previously healthy man was diagnosed as having an extensive necrotic lesion of his calf due to loxoscelism. One year later he was diagnosed as having co-inheritance of mutations in factor V and methyl tetrahydrofolate reductase (MTHFR). This is the first report of a possible etiologic connection between loxoscelism necrotic lesions and thrombogenic diseases.

  19. Association of the C677T polymorphism in the human methylenetetrahydrofolate reductase (MTHFR) gene with the genetic predisposition for type 2 diabetes mellitus in a Moroccan population.

    PubMed

    Benrahma, Houda; Abidi, Omar; Melouk, Leila; Ajjemami, Maria; Rouba, Hassan; Chadli, Asmaa; Oudghiri, Mounia; Farouqui, Ahmed; Barakat, Abdelhamid

    2012-05-01

    Type 2 diabetes mellitus (T2DM) is a major public health problem around the world. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be associated with T2DM and its complications. This study aimed to investigate this association in the Moroccan population. A case-control study was performed among 282 Moroccan diabetic patients and 232 healthy controls. The MTHFR C677T and A1298C polymorphisms were genotyped by polymerase chain reaction, followed by enzymatic digestion with HinfI and MboII enzymes, respectively. There was a significant association between C677T polymorphism and T2DM in both additive and dominant models. In addition, the 677T allele frequency differed significantly between the diabetic and control groups (26.06% vs. 33.20%, respectively). However, no significant association was found between A1298C polymorphism and T2DM. The frequencies of combined genotypes 677CC/1298AA and 677CT/1298AC differed significantly between the diabetic and control groups (32.62% vs. 20.61% and 9.57% vs. 17.55%, respectively). These results show an evident association between the MTHFR C677T polymorphism and T2DM in Moroccan patients but no significant association with the MTHFR A1298C polymorphism.

  20. Association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with preterm delivery and placental abruption: a systematic review and meta-analysis.

    PubMed

    Chen, Jian; Chen, Liang; Zhu, Li-Hua; Zhang, Si-Tong; Wu, Yi-Le

    2016-02-01

    The aim of this study was to summarize evidence on the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and odds of preterm delivery and placental abruption. PubMed, EMBASE, CBM (Chinese Biomedical Database) and CNKI (Chinese National Knowledge Infrastructure) were searched to identify eligible studies published in English or Chinese before 12 August 2014. The pooled odds ratios (ORs) with 95% confidence intervals were estimated for the association of MTHFR C677T polymorphism with preterm delivery and placental abruption using random effects models. A total of 22 studies that met inclusion and exclusion criteria were included in this meta-analysis. Regardless of the genetic model tested we found no statistically significant association of MTHFR C677T polymorphism with preterm delivery or placental abruption. Funnel plots inspections, Begg's test and Egger's test did not show evidence of publication bias. This meta-analysis demonstrated that overall there was no association of MTHFR C677T polymorphism with preterm delivery or placental abruption. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  2. 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

  3. Divergent effects of the 677C>T mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene on ovarian responsiveness and anti-Müllerian hormone concentrations.

    PubMed

    Pavlik, Roman; Hecht, Stephanie; Ochsenkühn, Robert; Noss, Ulrich; Lohse, Peter; Thaler, Christian J

    2011-06-01

    To investigate the influence of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation on serum anti-Müllerian hormone (AMH) concentrations and on the numbers of oocytes retrieved (NOR) following controlled ovarian hyperstimulation (COH). Prospective cohort study. University-based infertility clinic. Two hundred and seventy women undergoing COH for IVF with or without intracytoplasmic sperm injection. None. AMH levels were determined from blood samples collected after 10 days of GnRH superagonist treatment and before COH. The MTHFR 677C>T genotype was characterized by a TaqMan 5' nuclease assay. AMH serum concentrations correlated significantly with the NOR in all individuals studied. Average (±SD) AMH levels of TT carriers (2.85±2.23 ng/mL) were significantly higher than those of homozygous CC (1.91±1.59 ng/mL) or heterozygous CT individuals (2.23±1.74 ng/mL). When evaluated by multiple regression analysis, AMH had a significant positive effect on NOR, whereas age and MTHFR 677TT genotype had significant negative effects. The MTHFR 677TT genotype is associated with higher serum AMH concentrations and has a negative effect on NOR. This apparent paradox might be resolved in light of recent findings describing a negative feedback function of AMH in the coordination of follicle development. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  4. 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

  5. PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis.

    PubMed

    Pasta, Linda; Pasta, Francesca

    2015-12-18

    To evaluate the different roles of thrombophilia in patients with and without viral etiology. The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and prothrombin 20210A, were studied as risk factors in 1079 patients with liver cirrhosis (LC), enrolled from January 2000 to January 2014. All Caucasian LC patients consecutively observed in a fourteen-year period were included; the presence of portal vein thrombosis (PVT) and Budd Chiari syndrome (BCS) was registered. The differences between the proportions of each THRGF with regard to the presence or absence of viral etiology and the frequencies of the THRGF genotypes with those predicted in a population by the Hardy-Weinberg equilibrium were registered. Four hundred and seventeen/one thousand and seventy-six patients (38.6%) showed thrombophilia: 217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leiden factor and 41 prothrombin G20210 A, 84 with more than 1 THRGF; 350 presented with no viral liver cirrhosis (NVLC) and 729 with, called viral liver cirrhosis (VLC), of whom 56 patients were hepatitis C virus + hepatitis B virus. PAI-1 4G-4G, MTHFR C677TT, the presence of at least one TRHGF and the presence of > 1 THRGF, were statistically more frequent in patients with NVLC vs patients with VLC: All χ (2) > 3.85 and P < 0.05. Patients with PVT and/or BCS with at least one TRHGF were 189/352 (53.7%). The Hardy-Weinberg of PAI-1 and MTHFR 677 genotypes deviated from that expected from a population in equilibrium in patients with NVLC (respectively χ (2) = 39.3; P < 0.000 and χ (2) = 27.94; P < 0.05), whereas the equilibrium was respected in VLC. MTHFR 677TT was nearly twofold and PAI-1 4G-4G more than threefold more frequently found in NVLC vs patients with VLC; the Hardy-Weinberg equilibrium of these two polymorphisms confirms this data in NVLC. We suggest that PAI-1 4G-4G and MTHFR 677TT could be considered as factors of fibrosis and thrombosis mechanisms, increasing the inflammation response

  6. PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis

    PubMed Central

    Pasta, Linda; Pasta, Francesca

    2015-01-01

    AIM: To evaluate the different roles of thrombophilia in patients with and without viral etiology. The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and prothrombin 20210A, were studied as risk factors in 1079 patients with liver cirrhosis (LC), enrolled from January 2000 to January 2014. METHODS: All Caucasian LC patients consecutively observed in a fourteen-year period were included; the presence of portal vein thrombosis (PVT) and Budd Chiari syndrome (BCS) was registered. The differences between the proportions of each THRGF with regard to the presence or absence of viral etiology and the frequencies of the THRGF genotypes with those predicted in a population by the Hardy-Weinberg equilibrium were registered. RESULTS: Four hundred and seventeen/one thousand and seventy-six patients (38.6%) showed thrombophilia: 217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leiden factor and 41 prothrombin G20210 A, 84 with more than 1 THRGF; 350 presented with no viral liver cirrhosis (NVLC) and 729 with, called viral liver cirrhosis (VLC), of whom 56 patients were hepatitis C virus + hepatitis B virus. PAI-1 4G-4G, MTHFR C677TT, the presence of at least one TRHGF and the presence of > 1 THRGF, were statistically more frequent in patients with NVLC vs patients with VLC: All χ2 > 3.85 and P < 0.05. Patients with PVT and/or BCS with at least one TRHGF were 189/352 (53.7%). The Hardy-Weinberg of PAI-1 and MTHFR 677 genotypes deviated from that expected from a population in equilibrium in patients with NVLC (respectively χ2 = 39.3; P < 0.000 and χ2 = 27.94; P < 0.05), whereas the equilibrium was respected in VLC. CONCLUSION: MTHFR 677TT was nearly twofold and PAI-1 4G-4G more than threefold more frequently found in NVLC vs patients with VLC; the Hardy-Weinberg equilibrium of these two polymorphisms confirms this data in NVLC. We suggest that PAI-1 4G-4G and MTHFR 677TT could be considered as factors of fibrosis and thrombosis mechanisms, increasing

  7. Germline variation in the MTHFR and MTRR genes determines the nadir of bone density in pediatric acute lymphoblastic leukemia: a prospective study.

    PubMed

    te Winkel, M L; de Muinck Keizer-Schrama, S M P F; de Jonge, R; van Beek, R D; van der Sluis, I M; Hop, W C J; Pieters, R; van den Heuvel-Eibrink, M M

    2011-03-01

    This study aims to identify folate-metabolism-related genetic risk factors for low bone mineral density (BMD) during/after pediatric acute lymphoblastic leukemia (ALL) treatment. We investigated the influence of methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C) and methionine synthase reductase (MTRR 66A > G) single nucleotide polymorphisms (SNPs) on total body BMD (BMD(TB)) and lumbar spine BMD (BMD(LS)) in 83 patients. Homocysteine, folate and vitamin B12 were determined. BMD was measured repeatedly using dual-energy X-ray absorptiometry in patients ≥ 4 years (n = 68). Carriers of the MTHFR 677 T-allele showed a lower baseline BMD(TB) than non-carriers (-0.38 SDS vs. +0.55 SDS, p = 0.01) and BMD(TB) remained lower during/after treatment. MTHFR 677C>T did not influence treatment-related loss of BMD(TB) (p = 0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMD(TB) compared with non-carriers. Combining these two SNPs, patients carrying ≥ 2 risk alleles had a significantly lower BMD(TB) (-1.40 SDS) than patients with one (-0.80 SDS) or no risk alleles (-0.31 SDS). Although carriers of the MTHFR 1298A > C had higher homocysteine levels, this SNP was not related to BMD(TB). BMD(LS) of carriers was similar to non-carriers of the investigated SNPs. The MTHFR 677C>T SNP and the MTRR 66A >G SNP were identified as determinants of impaired BMD(TB) in childhood ALL patients. Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.

  8. Association between MTHFR C677T and A1298C, and MTRR A66G polymorphisms and susceptibility to schizophrenia in a Syrian study cohort.

    PubMed

    Lajin, Bassam; Alhaj Sakur, Amir; Michati, Roula; Alachkar, Amal

    2012-06-01

    The folate-homocystiene metabolic pathway has been shown to be involved in the susceptibility for developing schizophrenia by several studies. In the present study we investigated the role of three common polymorphisms of the folate-homocysteine metabolic pathway in an Arab population from Syria consisting of 85 schizophrenic patients and 126 healthy controls. The studied polymorphisms included the MTHFR C677T and A1298C, and MTRR A66G, all of which result into amino acid changes, and were previously shown to yield decreased enzymatic activity and alter plasma homocysteine concentration. While MTHFR C677T and A1298C polymorphisms were not previously studied in an Arab population with respect to the susceptibility for developing schizophrenia, the MTRR A66G was not previously investigated in any population around the world. Our results indicated a strong association between MTHFR A1298C and schizophrenia. The variant C allele frequency was significantly higher in the patients group (40% vs 29.4%, OR=1.6, 95% CI (1.06-2.41), p=0.023). A statistically significant association was found for MTHFR 677TT genotype under the recessive model in the male patients subgroup (OR=2.6, 95% CI (1.04-6.5), p=0.036), and MTHFR 677CT genotype under the overdominant model in the total patients group (OR=0.52 95% CI (0.29-0.92), p=0.024). No statistically significant association was found for MTRR A66G polymorphism on an individual basis. However, a borderline association was found for the CC/GG (C677T/A66G) compound genotype (OR=2.24, 95% CI (0.97-5.15), p=0.053). Our results support the hypothesis of association between schizophrenia and folate-homocystiene metabolic pathway genes. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. 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.

  10. MTHFR C677T polymorphisms are associated with aberrant methylation of the IGF-2 gene in transitional cell carcinoma of the bladder

    PubMed Central

    Cheng, Huan; Deng, Zhonglei; Wang, Zengjun; Zhang, Wei; Su, Jiantang

    2012-01-01

    The purpose of this study was to determine the relationship between methylation status of the insulin-like growth factor 2 (IGF-2) gene and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms in bladder transitional cell carcinoma tissues in a Chinese population. The polymorphisms of the folate metabolism enzyme gene MTHFR were studied by restrictive fragment length polymorphism (RFLP). PCR-based methods of DNA methylation analysis were used to detect the CpG island methylation status of the IGF-2 gene. The association between the methylation status of the IGF-2 gene and clinical characteristics, as well as MTHFR C677T polymorphisms, was analyzed. Aberrant hypomethylation of the IGF-2 gene was found in 68.3% bladder cancer tissues and 12.4% normal bladder tissues, respectively, while hypomethylation was not detected in almost all normal bladder tissues. The hypomethylation rate of the IGF-2 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables the variant allele of MTHFR C677T was found to be associated with hypomethylation of the IGF-2 gene. Compared with wildtype CC, the odds ratio was 4.33 (95% CI=1.06-10.59) for CT and 4.95 (95% CI=1.18-12.74) for TT. MTHFR 677 CC and CT genotypes might be one of the reasons that cause abnormal hypomethylation of the IGF-2 gene, and the aberrant CpG island hypomethylation of the IGF-2 gene may contribute to the genesis and progression of bladder transitional cell carcinoma. PMID:23554734

  11. 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

  12. MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case-control study

    PubMed Central

    2009-01-01

    Introduction The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been hypothesized to increase breast cancer risk. However, results have been inconsistent, and few studies have reported the association by menopausal status or by intakes of nutrients participating in one-carbon metabolism. Our aims were to investigate whether MTHFR C677T was associated with postmenopausal breast cancer risk and whether this relation was modified by intakes of folate, methionine, vitamins B2, B6, and B12, and alcohol. Methods We studied 318 incident breast cancer cases and 647 age- and race-matched controls participating in a nested case-control study of postmenopausal women within the VITamins And Lifestyle (VITAL) cohort. Genotyping was conducted for MTHFR C677T and dietary and supplemental intakes were ascertained from a validated questionnaire. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. Results We observed a 62% increased risk of breast cancer among postmenopausal women with the TT genotype (OR = 1.62; 95% CI: 1.05 to 2.48). Women with a higher number of variant T alleles had higher risk of breast cancer (P for trend = 0.04). Evidence of effect-modification by intakes of some B vitamins was observed. The most pronounced MTHFR-breast cancer risks were observed among women with the lowest intakes of dietary folate (P for interaction = 0.02) and total (diet plus supplemental) vitamin B6 (P for interaction = 0.01), with no significant increased risks among women with higher intakes. Conclusions This study provides support that the MTHFR 677TT genotype is associated with a moderate increase in risk of postmenopausal breast cancer and that this risk may be attenuated with high intakes of some one-carbon associated nutrients. PMID:20030812

  13. Plasma Homocysteine, Serum Folic Acid, Serum Vitamin B12, Serum Vitamin B6, MTHFR, and Risk of Normal-Tension Glaucoma.

    PubMed

    Li, Jinmiao; Xu, Fan; Zeng, Rui; Gong, Haijun; Lan, Yuqing

    2016-02-01

    This meta-analysis aims to comprehensively evaluate the association between total homocysteine (tHcy) levels, serum folic acid, vitamin B12, vitamin B6 levels, methylenetetrahydrofolate reductase (MTHFR) C677T genotype, and risk of normal-tension glaucoma (NTG). A systematic search of the EMBASE and PubMed databases was performed to evaluate plasma tHcy levels, serum folic acid, B vitamins' mean difference, and odds ratios of MTHFR C677T genotype between cases and controls. A total of 7 studies including 458 cases and 555 controls meeting the inclusion criteria were involved in this meta-analysis. There were 4 studies for tHcy (149 cases and 148 controls), 2 studies for vitamin B6, vitamin B12, and folate (90 cases and 82 controls), and 4 studies for MTHFR (343 cases and 449 controls). Overall, the mean plasma tHcy levels, serum folic acids, vitamin B12, and vitamin B6 levels were 1.16 μmol/L [95% confidence interval (CI), -0.13, 2.45], -0.62 μmol/L (95% CI, -1.98, 0.74), 5.81 μmol/L (95% CI, -3.53, 15.14), and -16.79 μmol/L (95% CI, -86.09, 52.51). MTHFR TT genotype was found to be unrelated to NTG risk (odds ratio=1.08; 95% CI, 0.69, 1.69). NTG is not associated with elevated plasma tHcy, serum folic acid, serum vitamin B12, serum vitamin B6, and MTHFR C677T genotype.

  14. Association between MTHFR gene polymorphisms (C677T, A1298C) and genetic susceptibility to prostate cancer: a meta-analysis.

    PubMed

    Chen, P L; Li, W T; Wang, J; Jiang, Y D; Wu, P; Chen, T; Zheng, S B

    2015-12-29

    Genetic polymorphisms (C677T and A1298C) in methylenetetrahydrofolate reductase (MTHFR) were shown to be related to prostate cancer risk in previous studies; however, the results are controversial. We performed a meta-analysis of previous studies and quantitatively estimated these associations. Pubmed, Embase, and Cochrane Library Database were searched for published case-control studies evaluating the association between C677T (or A1298C) and prostate cancer risk. Pooled associations were presented as odds ratios (ORs) along with their 95% confidence intervals. Twenty-one case control studies were identified for meta-analysis that included 21,581 participants. No significant associations were found between the MTHFR polymorphisms C677T or A1298C and prostate cancer risk in our meta-analysis. However, in subgroup analyses, the C677T CT polymorphism was associated with increased prostate cancer risk in East Asians (CT vs CC+TT: OR = 1.324, P = 0.03). The A1298C CC polymorphism in MTHFR was also linked to slightly reduced prostate cancer risk in European residents (CC vs AC+AA: OR = 0.751, P = 0.004; CC vs AA: OR = 0.768, P = 0.011), whereas it was associated with a significantly increased prostate cancer risk in Asian residents (CC vs AA: OR = 1.862, P = 0.006). The C677T CT polymorphism of MTHFR may be a risk factor for prostate cancer in East Asians. The association between the MTHFR A1298C CC genotype and prostate cancer risk may vary within different populations. Large-scale well-designed studies are required to confirm these associations.

  15. 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.

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

    PubMed

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

    2011-02-01

    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. 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. 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. 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). 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.

  17. Elderly women: homocysteine reduction by short-term folic acid supplementation resulting in increased glucose concentrations and affecting lipid metabolism (C677T MTHFR polymorphism).

    PubMed

    Chmurzynska, Agata; Malinowska, Anna M; Twardowska-Rajewska, Jolanta; Gawecki, Jan

    2013-06-01

    Serum homocysteine levels show interindividual variation and are determined by nutritional factors, such as B-vitamin intake, and by age and genetic influences, such as the genotype of the methylenetetrahydrofolate reductase (MTHFR) gene. Recently, the relation between one-carbon and lipid metabolism has been shown. Therefore, we hypothesized that folic acid supplementation would not only decrease homocysteine concentrations but also affect lipid metabolism. The aim of the present study was to evaluate the impact of short-term folic acid supplementation on homocysteine and lipid metabolism in Polish women older than 60 y with different C677T MTHFR genotypes. One hundred twenty-two volunteers were supplemented with folic acid 400 μg/d for 8 wk. Folate intake was assessed using a food-frequency questionnaire. The serum homocysteine level was analyzed using high-performance liquid chromatography. Serum biomarkers were measured with a Vitalab Flexor biochemical analyzer. MTHFR genotyping was performed using the polymerase chain reaction restriction fragment length polymorphism method. In the studied group, the MTHFR genotype frequencies were 0.14 for TT, 0.43 for CT, 0.43 for CC carriers. At baseline, the average folic acid and homocysteine concentrations were 12.16 ± 0.23 ng/mL and 7.94 ± 0.3 μmol/L, respectively. Folic acid supplementation lowered the serum homocysteine concentration. However, the dietary intervention also led to an increase in glucose concentrations (P < 0.01). The T-allele carriers had a larger waist circumference (P < 0.05) and a higher waist-to-hip ratio (P < 0.01). In elderly women, a short-term, low-dose folic acid supplementation lowered the serum homocysteine level but also increased glucose concentrations. The C677T MTHFR polymorphism affects the waist-to-hip ratio and lipid metabolism. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia

    PubMed Central

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

    2014-01-01

    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. PMID:24535549

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: results of a meta-analysis.

    PubMed

    Kelly, P J; Rosand, J; Kistler, J P; Shih, V E; Silveira, S; Plomaritoglou, A; Furie, K L

    2002-08-27

    Data are conflicting concerning risk for ischemic stroke associated with hyperhomocyst(e)inemia (hyper-Hcy) and a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR 677C-->T), which predisposes to hyper-Hcy in vivo. Search of MEDLINE, Science Citation Index, and abstracts of conference proceedings revealed relevant articles. Exposure was defined as follows: 1) prevalence of hyper-Hcy; 2) absolute difference in the mean Hcy concentration between subjects with and without ischemic stroke; and 3) the MTHFR TT genotype frequency. Outcome was defined as ischemic stroke with or without neuroimaging. Inclusion criteria were retrospective and prospective studies with reported odds ratios (OR) or hazard ratios (HR) or arithmetic mean Hcy levels. Exclusion criteria were absence of OR or HR, outcome defined as carotid atherosclerosis or intima-media thickening, stroke in patients younger than 18 years old, and studies in languages other than English. Statistical analyses for between-study heterogeneity and pooled risk estimates were performed using Stata software (Stata Corporation, College Station, TX). Among 16 studies (1,487 stroke and 2,554 nonstroke cases), the pooled mean Hcy level in patients with ischemic stoke was 2.32 micromol/L (95% CI, 1.6 to 3.04; p < 0.001) greater than that in those without ischemic stroke. Among 14 included studies (1,769 stroke and 7,400 nonstroke cases), the pooled OR estimate of ischemic stroke associated with hyper-Hcy was 1.79 (95% CI, 1.61 to 2.0; p < 0.001). Among 19 included studies (2,788 stroke and 3,962 nonstroke cases), the OR associated with the TT genotype was 1.23 (95% CI, 0.96 to 1.58; p = 0.1). These data support an association between mild-to-moderate hyper-Hcy and ischemic stoke. The MTHFR TT genotype may have a small influence in determining susceptibility to ischemic stoke.

  5. Presence of the methylenetetrahydrofolate reductase gene polymorphism MTHFR C677T in molar tissue but not maternal blood predicts failure of methotrexate treatment for low-risk gestational trophoblastic neoplasia.

    PubMed

    Qu, Jia; Usui, Hirokazu; Kaku, Hiroshi; Shozu, Makio

    2017-01-05

    Gestational trophoblastic neoplasia (GTN) is a rare tumor, and its genomic constitution is different from the maternal genome because of its gestational origin. Methotrexate (MTX) is a standard chemotherapeutic agent for low-risk GTN. An association between polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and MTX treatment outcome has been reported in various diseases. Thus, we examined the association between clinical outcome and MTHFR polymorphisms in both tumor and blood DNA of low-risk GTN patients. MTHFR C677T (rs1801133) and A1298C (rs1801131) were genotyped using high-resolution melting assays in 62 Japanese low-risk GTN patients and in 52 antecedent molar tissues. We compared the genotypes of MTHFR polymorphisms with the clinical outcome of 5-day MTX treatment. Twenty-five patients entered remission and 37 patients developed drug resistance or adverse effects that necessitated a drug change. The MTHFR 677T allele in molar tissue was significantly related to the need for drug change (P=0.006; odds ratio [OR], 3.13; 95% confidence interval [CI], 1.31-7.49), in contrast to MTHFR 1298C (P=0.18; OR, 0.63; 95% CI, 0.32-1.25). The MTHFR 677T and 1298C alleles obtained from patients' blood DNA were not related to MTX treatment outcome (P=0.49; OR 1.31; 95% CI, 0.61-2.91 and P=0.10; OR 0.52; 95% CI, 0.22-1.15, respectively). These data demonstrate for the first time that the genotype of MTHFR 677TT in molar tissue is associated with ineffective MTX treatment in Japanese low-risk GTN patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Gender-specific interactions of MTHFR C677T and MTRR A66G polymorphisms with overweight/obesity on serum lipid levels in a Chinese Han population.

    PubMed

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

    2016-10-28

    Little is known regarding the interactions of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with overweight/obesity on serum lipid profiles. The aim of the current study was to explore interactions between the two polymorphisms and overweight/obesity on four common lipid levels in a Chinese Han population and further to evaluate whether these interactions exhibit gender-specificity. A total of 2239 participants (750 females and 1489 males) were enrolled into this study. The genotypes of the MTHFR C677T and MTRR A66G were determined by a TaqMan assay. Overweight and obesity were defined as a body mass index between 24 and 27.99 and ≥ 28 kg/m(2), respectively. The interactions were examined by factorial design covariance analysis, and further multiple comparisons were conducted by Bonferroni correction. There was no significant difference in the genotypic and allelic frequencies between females and males (MTHFR 677 T allele: 54.47 % for females and 54.40 % for males; MTRR 66G allele: 24.73 % for females and 24.71 % for males). Interaction between the MTHFR C677T polymorphism and overweight/obesity on serum triglyceride levels, and interaction between the MTRR A66G polymorphism and overweight/obesity on serum high-density lipoprotein cholesterol levels were detected in women (P = 0.015 and P = 0.056, respectively). For female subjects with overweight/obesity, the serum triglyceride levels in MTHFR 677TT genotype [1.09 (0.78-1.50) mmol/L] were significantly higher as compared with MTHFR 677CC genotype [0.90 (0.60-1.15) mmol/L, P = 0.007], and the MTRR 66GG genotype carriers had higher serum high-density lipoprotein cholesterol levels than those with MTRR 66AG genotype (1.46 ± 0.50 vs. 1.19 ± 0.31 mmol/L, P = 0.058). Furthermore, in male subjects with overweight/obesity, the MTHFR 677CT genotype carriers had higher low-density lipoprotein cholesterol levels than those

  7. 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.

  8. MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin.

    PubMed

    Cecchin, E; Perrone, G; Nobili, S; Polesel, J; De Mattia, E; Zanusso, C; Petreni, P; Lonardi, S; Pella, N; D'Andrea, M; Errante, D; Rizzolio, F; Mazzei, T; Landini, I; Mini, E; Toffoli, G

    2015-06-01

    Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131-1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P-value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients.

  9. Joint associations of folate, homocysteine and MTHFR, MTR and MTRR gene polymorphisms with dyslipidemia in a Chinese hypertensive population: a cross-sectional study.

    PubMed

    Li, Wen-Xing; Lv, Wen-Wen; Dai, Shao-Xing; Pan, Ming-Luo; Huang, Jing-Fei

    2015-09-04

    Dyslipidemia is a well-established risk factor for cardiovascular disease. Serum lipids were affected by several gene polymorphisms, folate, homocysteine and other metabolite levels. We aim to investigate the effects of homocysteine metabolism enzyme polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) and their interactions with folate, homocysteine on serum lipid levels in Chinese patients with hypertension. Participants were 480 hypertensive adults that enrolled in September to December 2005 from six different Chinese hospitals (Harbin, Shanghai, Shenyang, Beijing, Xi'an, and Nanjing). Known MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genotypes were determined by PCR-RFLP methods. Serum folate was measured by chemiluminescent immunoassay, homocysteine was measured by high-performance liquid chromatography, serum lipids parameters were determined by an automatic biochemistry analyzer, low-density lipoprotein was calculated by Friedewald's equation. Unitary linear regression model was used to assess the associations of gene polymorphisms, folate and homocysteine on serum lipid profiles. Unconditional logistic regression model was applied to test the interactions of folate, homocysteine and gene polymorphisms on dyslipidemia. No correlations between gene polymorphisms and homocysteine on serum lipid profiles. Compared with normal folate patients, patients with low folate showed higher odds of hypertriglyceridemia (OR = 2.02, 95 % CI: 1.25-3.25, P = 0.004) and low levels of high-density lipoprotein cholesterol (OR = 1.88, 95 % CI: 1.07-3.28, P = 0.027). Each of four gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) combined with low folate showed higher odds of hypertriglyceridemia (P for trend: 0.049, 0.004, 0.007 and 0.005, respectively). MTHFR C677T and A1298C with low folate showed higher odds of low levels of high-density lipoprotein cholesterol (P for trend: 0.008 and 0.031). Low folate status and homocysteine

  10. 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. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Association between the MTHFR C677T polymorphism, blood folate and vitamin B12 deficiency, and elevated serum total homocysteine in healthy individuals in Yunnan Province, China.

    PubMed

    Ni, Juan; Zhang, Ling; Zhou, Tao; Xu, Wei-Jiang; Xue, Jing-Lun; Cao, Neng; Wang, Xu

    2017-03-01

    An increased serum total homocysteine (tHcy) concentration is typically associated with genetic defects involved in Hcy metabolism or related nutritional deficiencies. In this study, the combined effects of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and folate and vitamin B12 deficiency on serum total Hcy (tHcy) levels were evaluated in a healthy Chinese population in Yunnan Province, China. The MTHFR C677T polymorphism was genotyped in 330 volunteers (164 men and 166 women) using polymerase chain reaction-restriction fragment length polymorphism analysis. Folate, vitamin B12, and tHcy concentrations were determined by corpuscle immune chemiluminescence assays. The tHcy concentration was determined using an enzymatic assay. Significant negative correlations (p<0.001) were observed between the serum levels of tHcy and folate (r=-0.252) and vitamin B12 (r=-0.243). Men had significantly higher serum tHcy concentrations than women (p<0.001). Individuals with the MTHFR TT genotype had significantly higher serum tHcy concentrations than individuals with the CC and CT genotypes (p<0.001). The folate level of red blood cells was significantly increased in individuals with the TT genotype than in individuals with the CC genotype (p<0.05). Moreover, in the low vitamin group, the serum tHcy level was significantly correlated with the levels of folate (r=-0.334, p=0.001) and vitamin B12 (r=-0.212, p=0.046). The MTHFR C677T polymorphism, folate deficiency, and B12 deficiency were significantly associated with elevated serum tHcy levels. Among these three factors, folate deficiency had the greatest contribution to the serum tHcy concentration, followed by (in order of decreasing effect) MTHFR C677T and vitamin B12 deficiency. Thus, folic acid and vitamin B12 supplementation could help prevent diseases associated with tHcy accumulation, especially in individuals with the MTHFR 677TT genotype. Copyright © 2017. Published by Elsevier Taiwan LLC.

  12. 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

  13. Genotypes of the MTHFR C677T and MTRR A66G genes act independently to reduce migraine disability in response to vitamin supplementation.

    PubMed

    Menon, Saras; Lea, Rod A; Roy, Bishakha; Hanna, Michelle; Wee, Shirley; Haupt, Larisa M; Oliver, Chris; Griffiths, Lyn R

    2012-10-01

    Migraine is a chronic disabling neurovascular condition that may in part be caused by endothelial and cerebrovascular disruption induced by hyperhomocysteinaemia. We have previously provided evidence indicating that reduction of homocysteine by vitamin supplementation can reduce the occurrence of migraine in women. The current study examined the genotypic effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene variants on the occurrence of migraine in response to vitamin supplementation. This was a 6-month randomized, double-blinded placebo-controlled trial of daily vitamin B supplementation (B(6), B(9) and B(12)) on reduction of homocysteine and of the occurrence of migraine in 206 female patients diagnosed with migraine with aura. Vitamin supplementation significantly reduced homocysteine levels (P<0.001), severity of headache in migraine (P=0.017) and high migraine disability (P=0.022) in migraineurs compared with the placebo effect (P>0.1). When the vitamin-treated group was stratified by genotype, the C allele carriers of the MTHFR C677T variant showed a higher reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.01) and percentage of high migraine disability (P=0.009) compared with those with the TT genotypes. Similarly, the A allele carriers of the MTRR A66G variants showed a higher level of reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.002) and percentage of high migraine disability (P=0.006) compared with those with the GG genotypes. Genotypic analysis for both genes combined indicated that the treatment effect modification of the MTRR variant was independent of the MTHFR variant. This provided further evidence that vitamin supplementation is effective in reducing migraine and also that both MTHFR and MTRR gene variants are acting independently to influence treatment response in female migraineurs.

  14. 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

  15. MTHFR and MTRR genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from the Czech Republic.

    PubMed

    Pardini, Barbara; Kumar, Rajiv; Naccarati, Alessio; Prasad, Rashmi B; Forsti, Asta; Polakova, Veronika; Vodickova, Ludmila; Novotny, Jan; Hemminki, Kari; Vodicka, Pavel

    2011-03-18

    Polymorphic variants in genes involved in one-carbon metabolism, in particular of dietary folate, may modulate the risk for colorectal cancer through aberrant DNA-methylation and altered nucleotide synthesis and repair. In the present study, we have assessed the association of six polymorphisms and relative haplotypes in the MTHFR gene (rs1801133 and rs1801131) and in the MTRR gene (rs1801394, rs1532268, rs162036, and rs10380) with the risk for colorectal cancer in 666 patients and 1377 controls from the Czech Republic. We found that the 677 C>T polymorphism in the MTHFR gene significantly decreased the risk for colorectal cancer in homozygous carriers of the variant allele (OR, 0.58; 95% CI, 0.39-0.87). Also, we noted a significantly different distribution of genotypes between cases and controls for the 66A>G polymorphism in the MTRR gene. In particular, homozygous carriers of the G-containing allele of this polymorphism were at an increased risk for colorectal cancer (OR, 1.39; 95% CI, 1.04-1.85). Haplotype analysis of the two MTHFR polymorphisms showed a moderate difference in the distribution of the TA haplotype between cases and controls. In comparison to the most common haplotype (CA), the TA haplotype was associated with a decreased risk for colorectal cancer (OR, 0.84; 95% CI, 0.71-0.99). No difference in the distribution between cases and controls was observed for the haplotypes based on the four polymorphisms in the MTRR gene. The present study suggests that the 677TT genotype and the TA haplotype in the MTHFR gene may also have a role in colorectal cancer risk in the Czech population, indicating the importance of genes involved in folate metabolism with respect to cancer risk. For MTRR, additional studies on larger populations are needed to clarify the possible role of variation in this gene in colorectal carcinogenesis. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. 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

  17. A Single Nucleotide Polymorphism in the MTHFR Gene is Associated with Risk of Radiation Pneumonitis in Lung Cancer Patients Treated with Thoracic Radiation Therapy

    PubMed Central

    Mak, Raymond H.; Alexander, Brian M.; Asomaning, Kofi; Heist, Rebecca S.; Liu, Chen-yu; Su, Li; Zhai, Rihong; Ancukiewicz, Marek; Napolitano, Brian; Niemierko, Andrzej; Willers, Henning; Choi, Noah C.; Christiani, David C.

    2011-01-01

    Background To study the association between functional single nucleotide polymorphisms (SNPs) in candidate genes from oxidative stress pathways, and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy (RT) for locally advanced lung cancer (LC). Methods We reviewed 136 patients treated with RT for LC between 2001 and 2007, and had prior genotyping of functional SNPs in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylenetetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of grade ≥2 and grade ≥3 RP on univariate and multivariate analysis. P-values were corrected for multiple hypothesis testing. Results With a median follow-up of 21.4 months, the incidence of ≥grade 2 RP was 29% and ≥grade 3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy, and consolidation docetaxel, and lung dosimetric parameters such as V20 and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of ≥grade 2 RP (Hazard ratio [HR]: 0.37; 95% confidence interval [CI]: 0.18-0.76; p=0.006, corrected p=0.018) and ≥grade 3 RP (HR: 0.21; 95% CI: 0.06-0.70; p=0.01; corrected p=0.03). SOD2 genotype was not associated with RP. Conclusions Our study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP. PMID:22144047

  18. A single-nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy.

    PubMed

    Mak, Raymond H; Alexander, Brian M; Asomaning, Kofi; Heist, Rebecca S; Liu, Chen-yu; Su, Li; Zhai, Rihong; Ancukiewicz, Marek; Napolitano, Brian; Niemierko, Andrzej; Willers, Henning; Choi, Noah C; Christiani, David C

    2012-07-15

    This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer. A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting. With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP. This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP. Copyright © 2011 American Cancer Society.

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

    PubMed

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

    2016-12-15

    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.

  20. Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial.

    PubMed

    Nagele, Peter; Brown, Frank; Francis, Amber; Scott, Mitchell G; Gage, Brian F; Miller, J Philip

    2013-07-01

    Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C gene variant. In this randomized controlled trial, the authors sought to determine whether patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and whether this risk could be mitigated by B-vitamins. The authors randomized adult patients with cardiac risk factors undergoing noncardiac surgery, to receive nitrous oxide plus intravenous B-vitamins before and after surgery, or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I increase within the first 72 h after surgery. A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T, or A1298C gene variant (n=98; 19.6%) had no increased rate of postoperative cardiac troponin I increase compared with wild-type and heterozygous patients (11.2 vs. 14.0%; relative risk 0.96; 95% CI, 0.85-1.07; P=0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I increase compared with patients receiving placebo (13.2 vs. 13.6%; relative risk 1.02; 95% CI 0.78 to 1.32; P=0.91). Neither MTHFR C677T and A1298C gene variant, nor acute homocysteine increase are associated with perioperative cardiac troponin increase after nitrous oxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin I increase.

  1. Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults

    PubMed Central

    Lange, Leslie A.; Croteau-Chonka, Damien C.; Marvelle, Amanda F.; Qin, Li; Gaulton, Kyle J.; Kuzawa, Christopher W.; McDade, Thomas W.; Wang, Yunfei; Li, Yun; Levy, Shawn; Borja, Judith B.; Lange, Ethan M.; Adair, Linda S.; Mohlke, Karen L.

    2010-01-01

    Plasma homocysteine (Hcy) level is associated with cardiovascular disease and may play an etiologic role in vascular damage, a precursor for atherosclerosis. We performed a genome-wide association study for Hcy in 1786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP) (rs7422339, P = 4.7 × 10−13) encodes Thr1405Asn in the gene CPS1 and explained 3.0% of variation in the Hcy level. The widely studied MTHFR C677T SNP (rs1801133) was also highly significant (P = 8.7 × 10−10) and explained 1.6% of the trait variation. We also genotyped these two SNPs in 1679 CLHNS young adult offspring. The MTHFR C677T SNP was strongly associated with Hcy (P = 1.9 × 10−26) and explained ∼5.1% of the variation in the offspring. In contrast, the CPS1 variant was significant only in females (P = 0.11 in all; P = 0.0087 in females). Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with Hcy in the offspring (interaction P = 1.2 × 10−5). Furthermore, although there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring (interaction P = 0.0046), there was no significant evidence for an interaction in the mothers (P = 0.55). These data confirm a recent finding that CPS1 is a locus influencing Hcy levels in women and suggest that genetic effects on Hcy may differ across developmental stages. PMID:20154341

  2. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy

    PubMed Central

    Jongbloet, Piet Hein; Verbeek, André LM; den Heijer, Martin; Roeleveld, Nel

    2008-01-01

    Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C → T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance. PMID:18616826

  3. Influence of Nitrous Oxide Anesthesia, B-Vitamins, and MTHFR gene polymorphisms on Perioperative Cardiac Events: The Vitamins in Nitrous Oxide (VINO) Randomized Trial

    PubMed Central

    Nagele, Peter; Brown, Frank; Francis, Amber; Scott, Mitchell G.; Gage, Brian F.; Miller, J. Philip

    2013-01-01

    Background Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the MTHFR C677T or A1298C gene variant. In this randomized controlled trial we sought to determine if patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and if this risk could be mitigated by B-vitamins. Methods We randomized adult patients with cardiac risk factors undergoing noncardiac surgery to receive nitrous oxide plus intravenous B-vitamins before and after surgery or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I elevation within the first 72 hours after surgery. Results A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T or A1298C gene variant (n= 98; 19.6%) had no increased rate of postoperative cardiac troponin I elevation compared to wild-type and heterozygous patients (11.2% vs. 14.0%; relative risk 0.96, 95% CI 0.85 to 1.07, p=0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I elevation compared to patients receiving placebo (13.2% vs. 13.6%; relative risk 1.02, 95% CI 0.78 to 1.32, p=0.91). Conclusions Neither MTHFR C677T and A1298C gene variant nor acute homocysteine increase are associated with perioperative cardiac troponin elevation after nitrousoxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin elevation. PMID:23856660

  4. 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.

  5. 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. © 2013 Wiley Periodicals, Inc.

  6. 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.

  7. Meta- and Pooled Analyses of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Colorectal Cancer: A HuGE-GSEC Review

    PubMed Central

    Taioli, E.; Garza, M. A.; Ahn, Y. O.; Bishop, D. T.; Bost, J.; Budai, B.; Chen, K.; Gemignani, F.; Keku, T.; Lima, C. S. P.; Le Marchand, L.; Matsuo, K.; Moreno, V.; Plaschke, J.; Pufulete, M.; Thomas, S. B.; Toffoli, G.; Wolf, C. R.; Moore, C. G.; Little, J.

    2009-01-01

    Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations. PMID:19846566

  8. Polymorphisms in the CBS gene and homocysteine, folate and vitamin B12 levels: association with polymorphisms in the MTHFR and MTRR genes in Brazilian children.

    PubMed

    Aléssio, Ana C M; Siqueira, Lúcia H; Bydlowski, Sérgio P; Höehr, Nelci F; Annichino-Bizzacchi, Joyce M

    2008-10-15

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) and cystathionine beta-synthase (CBS) genes, involved in the intracellular metabolism of homocysteine (Hcy), can result in hyperhomocysteinemia. The objective of this study was to evaluate prevalence estimates of CBS T833C, G919A and the insertion of 68-bp (844ins68) polymorphisms and their correlation with Hcy, folate and B(12) in 220 children previously genotyped for MTHFR C677T, A1298C, and MTRR A66G. The prevalence of heterozygote children for 844ins68 was 19.5%. The T833C CBS mutation was identified in association with 844ins68 in all the carriers of the insertion. Genotyping for CBS G919A mutation showed that all the children presented the GG genotype. Analysis of Hcy, B(12) and folate, according to the combination of the different genotypes of the C677T and A1298C MTHFR, A66G MTRR, and 844ins68 CBS showed that the 677TT/1298AA/68WW genotype is associated with an increase in Hcy, when compared to the 677CC/1298AC/68WW (P = 0.033) and the 677CT/1298AA/68WW genotypes (P = 0.034). Since B(12) and folate were not different between these groups, a genetic interaction between diverse polymorphisms probably influences Hcy. Our results emphasize the role of genetic interactions in Hcy levels. 2008 Wiley-Liss, Inc.

  9. Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2.

    PubMed

    Shi, Min; Caprau, Diana; Romitti, Paul; Christensen, Kaare; Murray, Jeffrey C

    2003-08-01

    Genetic variation in enzymes involved in vitamin metabolism is a candidate for analysis in studies of how nutritional covariates may impact a disease state. The role of folate pathway genes in birth defects and cardiovascular disease in humans has been widely studied. Since incidence rates for these disorders vary by geographic origins, it is useful to know which variants are the best candidates for studies based on genotype and allele frequency, as well as linkage disequilibrium (LD) in founder populations. Six polymorphisms in five folate metabolism-related genes (MTHFR, MTHFD, MTRR, GCP2, and RFC1) were genotyped on a collection of 1064 DNA samples from populations around the world, which were made available by the Centre d'Etude du Polymorphisme Humain (CEPH) consortium for analysis. In this study we report the genotype frequencies for variants in the MTHFR, MTHFD, MTRR, GCP2, and RFC1 genes, and the LD for two variants (C677T and A1298C) in MTHFR. The rare allele frequency for each of the five genes studied varied widely. LD is strongest in Pakistani and Brazilian populations (D' = 1.0) and weakest in Mexican populations (D' = 0.45). These findings will allow the selection of variants that will provide the most power in studies of folate pathway genes involving different ancestral populations, and contribute to our knowledge of the population distribution of selected nutritional gene variants.

  10. 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. PMID:28409162

  11. [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.

  12. 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

  13. The analysis of the relationship between A1298C and C677T polymorphisms of the MTHFR gene with prostate cancer in Eskisehir population.

    PubMed

    Muslumanoglu, Muhammed H; Tepeli, Emre; Demir, Selma; Uludag, Ahmet; Uzun, Derya; Atli, Engin; Canturk, Kemal M; Ozdemir, Muhsin; Turgut, Mehmet

    2009-10-01

    Prostate cancer is the most common cause of cancer deaths in men and is a major health problem worldwide. Methylene tetrahydrofolate reductase (MTHFR) plays an important role for folate metabolism and is also an important source for DNA methylation and DNA synthesis (nucleotide synthesis). The objective of this study was to investigate the relationship between the A1298C and C677T polymorphisms of the MTHFR gene and prostate cancer in the Turkish population. In our study, 93 prostate cancer patients between the ages of 50-89 and a control group of 166 benign prostate hyperplasia patients were evaluated. C677T and A1298C polymorphism ratios were compared among these two groups, and an analysis was made to see if there is a statistically meaningful difference. In this study, it has been observed that C677T polymorphism of the MTHFR gene produces no statistically significant difference for T allele frequency and the genotype frequency in prostate cancer patients and male controls with benign prostate hyperplasia not having prostate cancer, whereas it has been observed that A1298C polymorphism produces a statistically significant difference for C allele frequency in prostate cancer patients and controls and that it also produces a statistically marginal significance for genotype frequencies.

  14. Association of the MTHFR 1298A>C (rs1801131) polymorphism with speed and strength sports in Russian and Polish athletes.

    PubMed

    Zarebska, Aleksandra; Ahmetov, Ildus I; Sawczyn, Stanislaw; Weiner, Alexandra S; Kaczmarczyk, Mariusz; Ficek, Krzysztof; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Leonska-Duniec, Agata; Klocek, Tomasz; Voronina, Elena N; Boyarskikh, Uljana A; Filipenko, Maksim L; Cieszczyk, Pawel

    2014-01-01

    It has been suggested that DNA hypomethylation because of poorer effectiveness of the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme induces muscular growth. We hypothesised that the common, functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. To test this hypothesis, we investigated the distribution of the 1298A>C variant in Polish (n = 302) and Russian (n = 842) athletes divided into four groups: endurance, strength-endurance, sprint-strength and strength-endurance, as well as in 1540 control participants. We found different genotypes (the AC heterozygote advantage) and allele distributions among sprint-strength athletes and strength athletes than the groups of sedentary controls for each nationality. In the combined study, the allelic frequencies for the 1298C variant were 35.6% in sprint-strength athletes (OR 1.18 [1.02-1.36], P = 0.024 vs. controls) and 38.6% in strength athletes (OR 1.34 [1.10-1.64], P = 0.003 vs. controls). The results of the initial and repetition studies as well as the combined analysis suggest that the functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. The presence of the C allele seems to be beneficial in sprint-strength and strength athletes. It needs to be established whether and to what extent this effect is mediated by alteration in DNA methylation status.

  15. 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

  16. The TT genotype of the MTHFR 677C > T polymorphism increases susceptibility to premature coronary artery disease in interaction with some of the traditional risk factors.

    PubMed

    Sarecka-Hujar, Beata; Zak, Iwona; Krauze, Jolanta

    2012-01-01

    The presence of several risk factors (genetic and non-genetic) has greater impact on the risk of premature coronary artery disease (CAD) than single risk factor. The aim of the study was to establish possible relations between genotypes and alleles of 677C>T polymorphism of MTHFR gene and some traditional risk factors e.g. elevated levels of lipid parameters and smoking in development of premature CAD. The groups comprised 152 patients with angiographically documented premature CAD (aged 42.9 +/- 5.5) and 121 age-matched blood donors (aged 42.3 +/- 6.5) were studied. The MTHFR 677C>T polymorphism was genotyped with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Patients with TT genotype who simultaneously smoked had increased risk of premature CAD compared to non-smoking cases with CC genotype (OR = 24.62). We also found that individuals with TT genotype and elevated LDL-cholesterol (LDL-chol.) level had significantly higher risk of CAD (OR = 9.92) than individuals with normal LDL-chol. level and CC genotype. The present study shows that simultaneous presence of MTHFR TT genotype and smoking or elevated levels of LDL-chol. influences the risk of premature CAD. This findings give interesting contribution to gene-environment interaction problem that may have clinical implications in the future.

  17. 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

  18. Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

    PubMed Central

    Verhoef, Petra; Dötsch-Klerk, Mariska; Lathrop, Mark; Xu, Peng; Nordestgaard, Børge G.; Holm, Hilma; Hopewell, Jemma C.; Saleheen, Danish; Tanaka, Toshihiro; Anand, Sonia S.; Chambers, John C.; Kleber, Marcus E.; Ouwehand, Willem H.; Yamada, Yoshiji; Elbers, Clara; Peters, Bas; Stewart, Alexandre F. R.; Reilly, Muredach M.; Thorand, Barbara; Yusuf, Salim; Engert, James C.; Assimes, Themistocles L.; Kooner, Jaspal; Danesh, John; Watkins, Hugh; Samani, Nilesh J.

    2012-01-01

    Background Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality. Methods and Findings Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases). Conclusions The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems. Please see later in the article for the Editors' Summary PMID:22363213

  19. 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

  20. 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

  1. [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).

  2. No correlation between MTHFR c.677 C > T, MTHFR c.1298 A > C, and ABCB1 c.3435 C > T polymorphisms and methotrexate therapeutic outcome of rheumatoid arthritis in West Algerian population.

    PubMed

    Boughrara, Wefa; Benzaoui, Ahmed; Aberkane, Meriem; Moghtit, Fatima Zohra; Dorgham, Samia; Lardjam-Hetraf, Aicha Sarah; Ouhaibi-Djellouli, Hadjer; Teixeira, Elisabeth Petit; Boudjema, Abdallah

    2017-06-01

    The c.677 C > T and c.1298 A > C polymorphisms of methylenetatrahydrofolate reductase (MTHFR) gene and c.3435 C > T polymorphism of ATP-Binding cassette B1 (ABCB1) gene are reported as pharmacogenetic markers, influencing the methotrexate (MTX) therapeutic outcome in rheumatoid arthritis (RA) patients. The aims of this study were to determine the relationship between these polymorphisms and clinical response and/or adverse drug reaction (ADRs) to MTX treatment. The cohort of our study was composed of 110 RA patients of the West Algerian population. The clinical response was evaluated using the disease activity score 28 (DAS28) and the ADRs were collected after physical examination of patients. All samples were genotyped for theses polymorphisms by TaqMan(®) allelic discrimination assay. Based on EULAR criteria, 59.09% RA patients were responders and ADRs were observed in 40.9% patients. The frequency distribution of these three polymorphisms was similar between the responders and the non-responders. The same result was found on ADRs study and no significant difference of distribution between the presence of ADRs group and absence of ADRs group was observed. Our study joins the results that found in others population in the world. We have demonstrated, for the first time in the West Algerian population, that these polymorphisms were not predictive for clinical response and/or ADRs to MTX therapeutic outcome.

  3. Association of folate metabolism genes MTHFR and MTRR with multiple complex congenital malformation risk in Chinese population of Shanxi

    PubMed Central

    Zhang, Qin; Bai, Baoling; Liu, Xiaozhen; Miao, Chunyue

    2014-01-01

    Birth defects are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. Low dietary folate and polymorphisms in genes of folate metabolism can influence risk for birth defects. In the present study 250 Chinese birth defects cases who suffered 1-8 types of birth defect disease phenotypes were subjected and two genetic variants in two folate metabolism key enzymes, rs1801394 of methionine synthase reductase (MTRR) and rs1801133 of methylenetetrahydrofolate reductase (MTHFR) were genotyped by using SNaPshot method. The results indicated that rs1801394 and rs1801133 were associated with multiple birth defects. According to homology of organogenesis, the disease phenotypes were classified into ectoderm-, mesoderm-, and endoderm-developed groups. Genetic analysis results displayed that as protective factors, genetic variants of rs1801133 and rs1801394 were associated with the risk of ectoderm-, and endoderm-developed malformations, but only the variant of rs1801394 was associated with the risk of mesoderm-developed malformations. Our present study first related nutrition metabolism related gene variants to germ layers and provided a novel understanding of an implication of earlier causation of birth defects pathogenesis in humans. PMID:26835343

  4. Association of folate metabolism genes MTHFR and MTRR with multiple complex congenital malformation risk in Chinese population of Shanxi.

    PubMed

    Zhang, Qin; Bai, Baoling; Liu, Xiaozhen; Miao, Chunyue; Li, Huili

    2014-07-01

    Birth defects are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. Low dietary folate and polymorphisms in genes of folate metabolism can influence risk for birth defects. In the present study 250 Chinese birth defects cases who suffered 1-8 types of birth defect disease phenotypes were subjected and two genetic variants in two folate metabolism key enzymes, rs1801394 of methionine synthase reductase (MTRR) and rs1801133 of methylenetetrahydrofolate reductase (MTHFR) were genotyped by using SNaPshot method. The results indicated that rs1801394 and rs1801133 were associated with multiple birth defects. According to homology of organogenesis, the disease phenotypes were classified into ectoderm-, mesoderm-, and endoderm-developed groups. Genetic analysis results displayed that as protective factors, genetic variants of rs1801133 and rs1801394 were associated with the risk of ectoderm-, and endoderm-developed malformations, but only the variant of rs1801394 was associated with the risk of mesoderm-developed malformations. Our present study first related nutrition metabolism related gene variants to germ layers and provided a novel understanding of an implication of earlier causation of birth defects pathogenesis in humans.

  5. 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

  6. [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.

  7. 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.

  8. Renal transplantation experience in a patient with factor V Leiden homozygous, MTHFR C677T heterozygous, and PAI heterozygous mutation.

    PubMed

    Gülhan, Bora; Tavil, Betül; Gümrük, Fatma; Aki, Tuncay F; Topaloglu, Rezan

    2015-08-01

    Vascular complications are important causes of allograft loss in renal transplantation. A two and a half-month-old boy was diagnosed with posterior urethral valve and progressed to end-stage renal disease at eight yr of age. During the HD period, a central venous catheter was replaced three times for repeated thrombosis. The boy was found to be homozygous for FVL and heterozygous for both MTHFR (C677T) and PAI. At the age of 12, renal transplantation was performed from a deceased donor. Postoperative anticoagulation therapy was initiated with continuous intravenous administration of heparin at the dose of 10 IU/kg/h. HD was performed for the first three days. By the fourth day of transplantation, his urine output had increased gradually. Heparin infusion was continued for 18 days during hospitalization at the same dosage. Thereafter, he was discharged with LMWH. On the third month after transplantation, his serum creatinine level was 1.1 mg/dL and eGFR was 75.7 mL/min/1.73 m(2). He has still been using LMWH, and his eGFR was 78.7 mL/min/1.73 m(2) eight months after transplantation. Postoperative low-dose heparin treatment is a safe strategy for managing a patient with multiple thrombotic risk factors. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. 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.

  10. 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

  11. Are polymorphisms in MTRR A66G and MTHFR C677T genes associated with congenital heart diseases in Iranian population?

    PubMed

    Noori, Noormohammad; Miri-Moghaddam, Ebrahim; Dejkam, Asieh; Garmie, Yasman; Bazi, Ali

    2017-01-01

    The 5, 10-methyleneterahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are two essential enzymes involved in folate metabolism. The relationship between genetic polymorphisms and congenital heart defects (CHDs) is inconsistent. Our aim was to investigate the association between two well-known polymorphisms of MTHFR and MTRR genes, C677T and A66G, respectively, and CHDs in Iranian patients. We enrolled 74 patients with ventricular septal defect (VSD) and 79 with tetralogy of fallot (TOF) along with 147 healthy controls. C677T and A66G polymorphisms were detected using tetra-primer ARMS (amplification refractory mutation system) PCR. Individuals carrying homozygote mutant (TT) genotype of C677T polymorphism represented the highest risk for CHDs (OR=7.3, 95% CI: 0.8-61, P=0.06). Also, significantly increased risk of VSD was observed in individuals with TT genotype (OR=10, 95% CI: 1-92.2, P=0.04). However, the frequency for variant allele (T) of C677T polymorphism was not statistically different between cases and controls (16.3% and 20.9%, respectively). For A66G polymorphism, we found that AG and GG genotypes had higher frequencies in the patients (48.4% and 21.6% respectively) than controls (42.9% and 15.6%, respectively). In line with this, combined AG+GG genotype represented with significantly elevated risk of CHDs (OR=1.6; 95% CI: 1-2.6, P=0.03). AG+GG combination was also identified as a risk factor for TOF (OR=1.8, 95% CI: 1-3.3, P=0.04). We demonstrated that C677T polymorphism of MTHFR gene was significantly associated with VSD in our patients. Our study also suggested that A66G polymorphism of MTRR gene may contribute to the development of TOF in Iranians.

  12. Are polymorphisms in MTRR A66G and MTHFR C677T genes associated with congenital heart diseases in Iranian population?

    PubMed Central

    Noori, Noormohammad; Miri-Moghaddam, Ebrahim; Dejkam, Asieh; Garmie, Yasman; Bazi, Ali

    2017-01-01

    Background: The 5, 10-methyleneterahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are two essential enzymes involved in folate metabolism. The relationship between genetic polymorphisms and congenital heart defects (CHDs) is inconsistent. Our aim was to investigate the association between two well-known polymorphisms of MTHFR and MTRR genes, C677T and A66G, respectively, and CHDs in Iranian patients. Methods: We enrolled 74 patients with ventricular septal defect (VSD) and 79 with tetralogy of fallot (TOF) along with 147 healthy controls. C677T and A66G polymorphisms were detected using tetra-primer ARMS (amplification refractory mutation system) PCR. Results: Individuals carrying homozygote mutant (TT) genotype of C677T polymorphism represented the highest risk for CHDs (OR=7.3, 95% CI: 0.8-61, P=0.06). Also, significantly increased risk of VSD was observed in individuals with TT genotype (OR=10, 95% CI: 1-92.2, P=0.04). However, the frequency for variant allele (T) of C677T polymorphism was not statistically different between cases and controls (16.3% and 20.9%, respectively). For A66G polymorphism, we found that AG and GG genotypes had higher frequencies in the patients (48.4% and 21.6% respectively) than controls (42.9% and 15.6%, respectively). In line with this, combined AG+GG genotype represented with significantly elevated risk of CHDs (OR=1.6; 95% CI: 1-2.6, P=0.03). AG+GG combination was also identified as a risk factor for TOF (OR=1.8, 95% CI: 1-3.3, P=0.04). Conclusion: We demonstrated that C677T polymorphism of MTHFR gene was significantly associated with VSD in our patients. Our study also suggested that A66G polymorphism of MTRR gene may contribute to the development of TOF in Iranians. PMID:28702146

  13. Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial.

    PubMed

    Wilson, Carol P; McNulty, Helene; Ward, Mary; Strain, J J; Trouton, Tom G; Hoeft, Birgit A; Weber, Peter; Roos, Franz F; Horigan, Geraldine; McAnena, Liadhan; Scott, John M

    2013-06-01

    Intervention with riboflavin was recently shown to produce genotype-specific lowering of blood pressure (BP) in patients with premature cardiovascular disease homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). Whether this effect is confined to patients with high-risk cardiovascular disease is unknown. The aim of this randomized trial, therefore, was to investigate the responsiveness of BP to riboflavin supplementation in hypertensive individuals with the TT genotype but without overt cardiovascular disease. From an available sample of 1427 patients with hypertension, we identified 157 with the MTHFR 677TT genotype, 91 of whom agreed to participate in the trial. Participants were stratified by systolic BP and randomized to receive placebo or riboflavin (1.6 mg/d) for 16 weeks. At baseline, despite being prescribed multiple classes of antihypertensive drugs, >60% of participants with this genotype had failed to reach goal BP (≤140/90 mm Hg). A significant improvement in the biomarker status of riboflavin was observed in response to intervention (P<0.001). Correspondingly, an overall treatment effect of 5.6±2.6 mm Hg (P=0.033) in systolic BP was observed, with pre- and postintervention values of 141.8±2.9 and 137.1±3.0 mm Hg (treatment group) and 143.5±3.0 and 144.3±3.1 mm Hg (placebo group), whereas the treatment effect in diastolic BP was not significant (P=0.291). In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the MTHFR 677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN23620802.

  14. Morphology and Progression in Primary Varicose Vein Disorder Due to 677C>T and 1298A>C Variants of MTHFR

    PubMed Central

    Wilmanns, Christoph; Cooper, Alexis; Wockner, Leesa; Katsandris, Sotirios; Glaser, Nadine; Meyer, Alexander; Bartsch, Oliver; Binder, Harald; Walter, Paul Karl; Zechner, Ulrich

    2015-01-01

    Background Clinical assessment and prognostic stratification of primary varicose veins have remained controversial and the molecular pathogenesis is unknown. Previous data have suggested a contribution of the MTHFR (methylenetetrahydrofolate reductase) polymorphism c.677C>T. Methods We collected blood and vein specimens from 159 consecutive patients undergoing varicose vein surgery, or autologous vein reconstruction for arterial occlusive disease as controls. We compared the frequencies of c.677C>T and another polymorphism of MTHFR, c.1298A>C, with morphology and types of complicated disease. Morphology was recorded as a trunk or perforator type and peripheral congestive complication was defined as chronic venous insufficiency (CEAP C3–6) associated with edema and skin manifestations. Findings Multivariate analysis of genotypes for c.677C>T and c.1298A>C indicated that c.677C>T was associated significantly with the trunk phenotype (43/53 patients, 81%, p < 0.01), while c.1298A>C was associated significantly with the perforator phenotype (18/24 patients, 75%, p < 0.01) of primary varicose veins. Accordingly, when both c.677C>T and c.1298A>C displayed a heterozygous genotype, the patients were more likely to present with both phenotypes. Additionally, c.1298A>C was found to be strongly linked to the congestive complication (34/51 patients, 67%, p < 0.01). Interpretation Both polymorphisms of MTHFR may be involved in the morphological specification of primary varicose veins and contribute to the development of complicated disease. Funding None. PMID:26137554

  15. Association between C677T polymorphism of MTHFR gene and risk of amyotrophic lateral sclerosis: Polish population study and a meta-analysis.

    PubMed

    Żur-Wyrozumska, Kamila; Pera, Joanna; Dziubek, Anna; Sado, Małgorzata; Golenia, Aleksandra; Słowik, Agnieszka; Dziedzic, Tomasz

    Genetic factors play a role in pathogenesis of amyotrophic lateral sclerosis (ALS). A few studies demonstrated that the TT genotype of C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene can increase the risk of sporadic ALS. The aim of our study was to determine the relationship between C677T polymorphism of MTHFR gene and the risk of sporadic ALS in Polish population and to perform the meta-analysis assessing the significance this polymorphism for the risk of ALS in Caucasian population. We included 251 patients with ALS and 500 control subjects recruited from Polish population and performed the meta-analysis of published data from Caucasian population. MTHFR C677T polymorphism was genotyped using a TaqMan assay and 7900HT Fast real Time PCR System. The frequency of genotypes did not differ significantly between Polish ALS patients and control subjects (CC: 45.0 vs 45.8%, CT: 48.2 vs 45.0%, TT: 6.8 vs 9.2%, P=0.46). The meta-analysis including 863 ALS patients and 1362 controls revealed that TT genotype increases the risk of sporadic ALS in Caucasian population. Although we did not find the association between C677T polymorphism of MTHRF gene and risk of ALS in Polish population, the results of meta-analysis suggest that the TT genotype can be a genetic risk factor for ALS in Caucasian population. Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  16. Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin.

    PubMed

    Russo, G T; Giandalia, A; Romeo, E L; Scarcella, C; Gambadoro, N; Zingale, R; Forte, F; Perdichizzi, G; Alibrandi, A; Cucinotta, D

    2016-03-01

    Hyperhomocysteinemia and vitamin B12 deficiency may be involved in the development of diabetic peripheral neuropathy (DPN). Metformin therapy may reduce vitamin B12 plasma levels, thus contributing to DPN. The purposes of this cross-sectional study were to assess (1) the potential associations of DPN with serum levels of homocysteine (tHcy), B-vitamins, and/or the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation; (2) the influence of chronic treatment with metformin on tHcy and B-vitamins concentrations and, finally, (3) to evaluate whether, by this influence, metformin is a risk factor for DPN in a group of type 2 diabetic outpatients. Our data showed that fasting tHcy, folate, and vitamin B12 levels and the MTHFR C677T genotype distribution were comparable between subjects with (n = 79, 30 %) and without DPN (n = 184, 70 %). Metformin-treated subjects (n = 124, 47 %) showed significantly lower levels of vitamin B12 (P < 0.001), but the prevalence of DPN was not different when compared to those not treated with this drug (33 vs. 27 %, P = NS). At univariate regression analysis, DPN was associated with age, duration of diabetes, HbA1c, creatinine levels, and the presence of coronary heart disease (CHD), and negatively with HDL-C concentrations (P < 0.05 all), but at multivariate regression analysis, high creatinine levels (P = 0.06), low HDL-C levels (P = 0.013), and a higher prevalence of CHD (P = 0.001) were the only variables independently associated with DPN in this population. In conclusion, in these type 2 diabetic outpatients circulating levels of tHcy, folate, and the MTHFR C677T mutation are not associated with DPN, which was predicted by creatinine levels, CHD, and dyslipidemia. Metformin therapy is associated with a mild vitamin B12 level reduction, but not with DPN.

  17. 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.

  18. 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

  19. 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.

  20. Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma.

    PubMed

    Lu, Cheng; Xie, Hui; Wang, Fengliang; Shen, Hongbing; Wang, Jianming

    2011-03-05

    Folic acid may affect the development of human cancers. However, few studies have evaluated the consumption of diet folate in the prognosis of patients with esophageal squamous cell carcinoma (ESCC). One hundred and twenty five ESCC patients underwent esophagectomy between January 2005 and March 2006 in the Yangzhong People's Hospital were recruited and followed up. The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms on the prognosis of ESCC were evaluated by using Cox proportional hazard regression models. Our analysis showed an inverse association between diet folate intake and the risk of death after esophagectomy. The median survival time was 3.06 years for low or moderate folate consumption and over 4.59 years for high folate consumption. After adjusting for potential confounders, the hazard ratios (95% confidence interval) [HRs (95% CI)] were 0.72 (0.36-1.46) for moderate and 0.39 (0.20-0.78) for high folate intake, respectively (P for trend = 0.007). This preventive effect was more evident in patients carrying MTHFR 677CC genotype. No significant relation was observed between aberrant DNA methylation of P16, MGMT and hMLH1 gene, as well as MTHFR C677T genetic polymorphisms and the prognosis of ESCC. Our research indicated that diet folate intake may have benefits on the prognosis of ESCC after esophagectomy. From a practical viewpoint, the findings of our study help to establish practical intervention and surveillance strategies for managements of ESCC patients and can finally decrease the disease burden.

  1. 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.

  2. The one-carbon-cycle and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state?

    PubMed

    Lok, A; Mocking, R J T; Assies, J; Koeter, M W; Bockting, C L; de Vries, G J; Visser, I; Derks, E M; Kayser, M; Schene, A H

    2014-09-01

    An important biological factor suggested in the pathophysiology of (recurrent) Major Depressive Disorder (MDD) concerns a polymorphism in a gene encoding for the MTHFR-enzyme of the one-carbon (1-C)-metabolism. Integratively investigating key 1-C-components (folate, homocysteine, vitamin B6 and B12), including the possible effects of antidepressant medication and depressive state, could provide more insight in the possible association between the MTHFR-polymorphism and recurrent MDD. We compared the MTHFR C677T-polymorphism together with the key 1-C-components in clinically ascertained patients with recurrent MDD (n=137) to age- and gender-matched healthy controls (n=73). First, patients had lower folate (t=2.25; p=.025) as compared to controls; a difference that resolved after correction for demographics (t=1.22; p=.223). Second, patients that were depressed during sampling had lower vitamin B6 (t=-2.070; p=.038) and higher homocysteine (t=2.404; p=.016) compared to those in remission. Finally, current use of antidepressants had no influence on the 1-C-components. Despite investigation of a specific recurrently depressed patient population, we found no clear associations with the 1-C-cycle, except for higher homocysteine and lower vitamin B6 during the depressed state. This suggests that 1-C-cycle alterations in MDD are state-associated, possibly resulting from high levels of acute (psychological) stress, and may provide a treatment target to reduce cardiovascular risk in this population. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Folic acid supplementation during pregnancy may protect against depression 21 months after pregnancy, an effect modified by MTHFR C677T genotype.

    PubMed

    Lewis, S J; Araya, R; Leary, S; Smith, G Davey; Ness, A

    2012-01-01

    As low folate status has been implicated in depression, high folate intake, in the form of supplements, during pregnancy might offer protection against depression during pregnancy and postpartum. We examined the association between change in self-reported depressive symptoms (Edinburgh Postnatal Depression Scale) at different timepoints during and following pregnancy and self-reported folic acid supplementation during pregnancy in a prospective cohort of 6809 pregnant women. We also tested whether there was a main effect of methylenetetrahydrofolate reductase (MTHFR) C677T genotype (which influences folate metabolism and intracellular levels of folate metabolites and homocysteine) on change in depression scores, and carried out our analysis of folic acid supplementation and depression stratifying by genotype. We found no strong evidence that folic acid supplementation reduced the risk of depression during pregnancy and up to 8 months after pregnancy. However, we did find evidence to suggest that folic acid supplements during pregnancy protected against depression 21 months postpartum, and that this effect was more pronounced in those with the MTHFR C677T TT genotype (change in depression score from 8 months to 21 months postpartum among TT individuals was 0.66 (95% CI=0.31-1.01) among those not taking supplements, compared with -1.02 (95% CI=-2.22-0.18) among those taking supplements at 18 weeks pregnancy, P(difference)=0.01). Low folate is unlikely to be an important risk factor for depression during pregnancy and for postpartum depression, but may be a risk factor for depression outside of pregnancy, especially among women with the MTHFR C677T TT genotype.

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

    PubMed

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

    2016-11-01

    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 r 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.

  5. Association study of folate-related enzymes (MTHFR, MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population

    PubMed Central

    Kurzawski, Mateusz; Wajda, Anna; Malinowski, Damian; Kazienko, Anna; Kurzawa, Rafal; Drozdzik, Marek

    2015-01-01

    Spermatogenesis is a process where an important contribution of genes involved in folate-mediated one-carbon metabolism is observed. The aim of the present study was to investigate the association between male infertility and the MTHFR (677C > T; 1298A > C), MTR (2756A > G) and MTRR (66A > G) polymorphisms in a Polish population. No significant differences in genotype or allele frequencies were detected between the groups of 284 infertile men and of 352 fertile controls. These results demonstrate that common polymorphisms in folate pathway genes are not major risk factors for non-obstructive male infertility in the Polish population. PMID:25983623

  6. Geographical distribution of MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in China: findings from 15357 adults of Han nationality.

    PubMed

    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

    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. 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. 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. 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 future researches in related fields.

  7. 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

  8. Association study of folate-related enzymes (MTHFR, MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population.

    PubMed

    Kurzawski, Mateusz; Wajda, Anna; Malinowski, Damian; Kazienko, Anna; Kurzawa, Rafal; Drozdzik, Marek

    2015-03-01

    Spermatogenesis is a process where an important contribution of genes involved in folate-mediated one-carbon metabolism is observed. The aim of the present study was to investigate the association between male infertility and the MTHFR (677C > T; 1298A > C), MTR (2756A > G) and MTRR (66A > G) polymorphisms in a Polish population. No significant differences in genotype or allele frequencies were detected between the groups of 284 infertile men and of 352 fertile controls. These results demonstrate that common polymorphisms in folate pathway genes are not major risk factors for non-obstructive male infertility in the Polish population.

  9. 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

  10. 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

  11. MTHFR (C677T) CT genotype and CT-apoE3/3 genotypic combination predisposes the risk of ischemic stroke.

    PubMed

    Vijayan, Murali; Chinniah, Rathika; Ravi, Padma Malini; Sivanadham, Ramgopal; Mosses Joseph, Arun Kumar; Vellaiappan, Neethi Arasu; Krishnan, Jeyaram Illiayaraja; Karuppiah, Balakrishnan

    2016-10-15

    The predisposition to ischemic stroke (IS) might involve interactions of several genes and environmental factors. The present study was aimed to evaluate the influence of polymorphisms in methylenetetrahydrofolate reductase (MTHFR-C677T) and apolipoprotein-E (apo-E) as risk factors for IS patients in south Indian population. 200 IS patients and 193 age and sex matched controls were genotyped for MTHFR-C677T and apoE by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Statistically significant association was observed for MTHFR CT genotype (IS-Pooled: OR=4.29; p=5.01×10(-5); IS-Males: OR=4.13; p=0.001; IS-Females: OR=8.62; p=0.027; IS-Large Vessel Disease (LVD)- Pooled: OR=4.14; p=0.0002) and T allele (IS-Pooled: OR=4.82; p=1.49×10(-5); IS-Males: OR=4.33; p=0.0002; IS-Females: OR=7.99; p=0.031; IS-LVD-Pooled: OR=4.13; p=0.0001). Further, reduced frequencies of CC genotype (IS-Pooled: OR=0.20; p=9.80×10(-6); IS-Males: OR=0.25; p=0.001; IS-Females: OR=0.12; p=0.027; IS-LVD-Pooled: OR=0.23; p=0.0001) and C allele (IS-Pooled: OR=0.21; p=1.49×10(-5); IS-Males: OR=0.23; p=0.0002; IS-Females: OR=0.13; p=0.031; IS-LVD-Pooled: OR=0.24; p=0.0001) were observed in IS patients than the controls. No association was observed for apoE genotypes/alleles in IS/LVD cases. Our study demonstrated the presence of risk for MTHFR CT genotype/T allele and 'CT-3/3' (n=33 vs. 5; OR=7.42; p=0.001) genotypic combination in the development of IS in south India. Further, follow-up study of these stroke cases i.e., in later stages of the disease whether they are developing the neurological disorders such as Alzheimer's Disease (AD) and vascular dementia (VaD) is needed to draw a fruitful conclusion in connection between neurological disorders and with these two polymorphisms, before translating it into clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. 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.

  13. Coexistence of the 677C>T and 1298A>C MTHFR polymorphisms and its significance in the population of Polish women.

    PubMed

    Wolski, Hubert; Kocięcka, Maria; Mrozikiewicz, Aleksandra E; Barlik, Magdalena; Kurzawińska, Grażyna

    2015-10-01

    The aim of the study was to evaluate the frequency of the 677C>T and 1298A>C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, as well as the coexistence of both these genetic variants in women from the Polish population. A total of 662 women from the Polish population were enrolled in the study group. The frequency of the investigated genotypes of the 677C>T and 1298A>C polymorphisms of the MTHFR gene was analyzed with the use of PCR/RFLP methods. The frequency of the 677CC, 677CT and 677TT genotypes in the studied population of women was 50.60%, 39.88% and 9.52%, respectively As to the 1298AA, 1298AC and 1298CC genotypes, the obtained results were as follows: 42.75%, 47.88% and 9.37%, respectively (Tables II and III). Simultaneous analysis revealed the most frequent coexistence of 677CC/1298AC (28.85%), 677CT/1298AA (20.85%) and 677CT/1298AC (19.03%) genotypes. The coexistence of 677CC/1298AA (12.39%), 677CC/1298CC (9.37%) and 677TT/1298AA (9.51%) genotypes was observed less frequently In the studied population of Polish women, the coexistence of 677CT/1298CC, 677TT/1298AC and 677TT/1298CC genotypes has been not observed. The frequency and coexistence of genotypes of the 677C>T and 1298A>C MTHFR gene polymorphisms in the studied population of Polish women is similar to other North-European populations. Women carriers of the mutated variants of both, 677C>T and 1298A>C polymorphisms of the MTHFR gene should receive special perinatal care in order to prevent fetal defects and thrombosis-related complications during pregnancy It is vital to emphasize the significance of proper education of folate supplementation, especially in pregnant patients and women of reproductive age.

  14. Association of vdr, cyp27b1, cyp24a1 and mthfr gene polymorphisms with oral lichen planus risk.

    PubMed

    Kujundzic, Bojan; Zeljic, Katarina; Supic, Gordana; Magic, Marko; Stanimirovic, Dragan; Ilic, Vesna; Jovanovic, Barbara; Magic, Zvonko

    2016-05-01

    The current study investigated the association between VDR EcoRV (rs4516035), FokI (rs2228570), ApaI (rs7975232) and TaqI (rs731236), CYP27B1 (rs4646536), CYP24A1 (rs2296241), and MTHFR (rs1801133) gene polymorphisms and risk of oral lichen planus (OLP) occurrence. The study group consisted of 65 oral lichen planus patients and 100 healthy blood donors in the control group. Single nucleotide polymorphisms were genotyped by real time PCR or PCR-restriction fragment length polymorphism (RFLP) method. Heterozygous as well as mutated genotype of vitamin D receptor (VDR) FokI (rs2228570) polymorphism was associated with increased oral lichen planus risk in comparison with wild type genotype (odds ratio (OR) = 3.877, p = 0.017, OR = 38.153, p = 0.001, respectively). A significantly decreased OLP risk was observed for heterozygous genotype of rs2296241 polymorphism in CYP24A1 gene compared with the wild type form (OR = 0.314, p = 0.012). VDR gene polymorphisms ApaI and TaqI were in linkage disequilibrium (D' = 0.71, r(2) = 0.22). Identified haplotype AT was associated with decreased OLP risk (OR = 0.592, p = 0.047). Our results highlight the possible important role of VDR FokI (rs2228570) and CYP24A1 rs2296241 gene polymorphisms for oral lichen planus susceptibility. Identification of new molecular biomarkers could potentially contribute to determination of individuals with OLP predisposition.

  15. Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease.

    PubMed

    Arakawa, Y; Watanabe, M; Inoue, N; Sarumaru, M; Hidaka, Y; Iwatani, Y

    2012-11-01

    To clarify the association between factors regulating DNA methylation and the prognosis of autoimmune thyroid diseases (AITDs), we genotyped single nucleotide polymorphisms in genes encoding DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), which are enzymes essential for DNA methylation. Subjects for this study included 125 patients with Hashimoto's disease (HD), including 48 patients with severe HD and 49 patients with mild HD; 176 patients with Graves' disease (GD), including 79 patients with intractable GD and 47 patients with GD in remission; and 83 healthy volunteers (control subjects). The DNMT1+32204GG genotype was more frequent in patients with intractable GD than in patients with GD in remission. Genomic DNA showed significantly lower levels of global methylation in individuals with the DNMT1+32204GG genotype than in those with the AA genotype. The MTRR+66AA genotype was observed to be more frequent in patients with severe HD than in those with mild HD. The DNMT1+14395A/G, DNMT3B-579G/T, MTHFR+677C/T and +1298A/C polymorphisms were not correlated with the development or prognosis of AITD. Our study indicates that the DNMT1+32204GG genotype correlates with DNA hypomethylation and with the intractability of GD, and that the MTRR+66AA genotype may correlate with the severity of HD. © 2012 Osaka University. Clinical and Experimental Immunology © 2012 British Society for Immunology.

  16. Lack of Association Between MTHFR, MTR, MTRR, and TCN2 Genes and Nonsyndromic CL±P in a Chinese Population: Case-Control Study and Meta-Analysis.

    PubMed

    Jiang, Chanyuan; Yin, Ningbei; Zhao, Zhenmin; Wu, Di; Wang, Yongqian; Li, Haidong; Song, Tao

    2015-09-01

    Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common congenital deformity, often associated with folate deficiency. The genes MTHFR, MTR, MTRR, and TCN2 play key roles in folate metabolism. The risk of NSCLP associated with particular variants in the folic acid pathway differs among ethnic groups. The goal of this study was to explore whether genetic variations in these four genes, as well as gene-gene interactions, are associated with NSCLP. We investigated 7 tagSNPs for MTHFR, 18 tagSNPs for MTR, 15 tagSNPs for MTRR, and 7 tagSNPs for TCN2 selected from HapMap data in a Chinese population. These single nucleotide polymorphisms (SNPs) were examined for associations with NSCLP in 204 patients and 226 controls. We then performed a meta-analysis of association between rs1801133 and NSCLP. There was a significant difference in the allele frequency and haplotype analysis of rs4077829 and rs10802565 in MTR between the NSCLP and control groups but not a significant difference after correction with 10,000 times permutations. The allele frequency, haplotype analysis, and gene-gene interactions of other SNPs did not show a significant difference. The meta-analysis results showed that no significant differences were found for allele comparison, heterozygote comparison, homozygote comparison, dominant model comparison, or recessive model comparison. The alterations of folate metabolism related to these polymorphisms are not involved in NSCLP in the Chinese population.

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

    PubMed

    Wang, Xingmin; Fu, Jinjian; Li, Qianxi; Zeng, Dingyuan

    2016-01-01

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

  18. Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease

    PubMed Central

    Arakawa, Y; Watanabe, M; Inoue, N; Sarumaru, M; Hidaka, Y; Iwatani, Y

    2012-01-01

    To clarify the association between factors regulating DNA methylation and the prognosis of autoimmune thyroid diseases (AITDs), we genotyped single nucleotide polymorphisms in genes encoding DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), which are enzymes essential for DNA methylation. Subjects for this study included 125 patients with Hashimoto's disease (HD), including 48 patients with severe HD and 49 patients with mild HD; 176 patients with Graves’ disease (GD), including 79 patients with intractable GD and 47 patients with GD in remission; and 83 healthy volunteers (control subjects). The DNMT1+32204GG genotype was more frequent in patients with intractable GD than in patients with GD in remission. Genomic DNA showed significantly lower levels of global methylation in individuals with the DNMT1+32204GG genotype than in those with the AA genotype. The MTRR+66AA genotype was observed to be more frequent in patients with severe HD than in those with mild HD. The DNMT1+14395A/G, DNMT3B−579G/T, MTHFR+677C/T and +1298A/C polymorphisms were not correlated with the development or prognosis of AITD. Our study indicates that the DNMT1+32204GG genotype correlates with DNA hypomethylation and with the intractability of GD, and that the MTRR+66AA genotype may correlate with the severity of HD. PMID:23039890

  19. 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.

  20. Analysis of the rs13306560 functional variant in the promoter region of the MTHFR gene in sporadic Parkinson´s disease.

    PubMed

    García, Silvia; Cano-Martínez, Luis Javier; Coral-Vázquez, Ramón Mauricio; Coronel-Perez, Agustín; Gómez-Díaz, Benjamín; Toledo-Lozano, Christian Gabriel; Gallegos-Arreola, Martha Patricia; Dávila-Maldonado, Luis; Jimenez-Hernández, Dulce Adeí; Alcaraz-Estrada, Sofía Lizeth; López-Hernández, Luz Berenice

    2017-08-05

    Among susceptibility genes for Sporadic Parkinson´s Disease (SPD), the MTHFR gene has been suggested as candidate. The A allele of the functional variant rs13306560 in its promoter region has been liked to decreased transactivation capacity. Therefore, we sought to determine a possible association of the rs13306560 and SPD. In total, 237 individuals were genotyped, 113 patients with SPD diagnosed according to the Queen Square Brain Bank criteria and 124 neurologically healthy controls. Genotyping was performed using TaqMan probes for the rs13306560 and real-time PCR. The A allelle was associated to protection in SPD, under the dominant model, (OR=0.22, C.I.=[0.048-1.080], p=0.04), nevertheless, after logistic regression analysis with adjustment for gender, resulted only in a trend (Exp (β)=0.211, [I.C. 95.0%, 0.042-1.057], p=0.058). Although further studies are needed, our data suggest an important role of the MTHFR gene variants in the fine-tuning regulation of one-carbon metabolism in the brain.

  1. 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.

  2. Prevalence of Factor V Leiden-G1691A and MTHFR-C677T Thrombosis Gene Modifier in Iron Deficiency Anemia: A Pathophysiological Effect in Indian Isolates.

    PubMed

    Pandey, S K; Pandey, S; Mishra, R M; Indurkar, M

    2017-03-01

    Normal iron levels are required to prevent thrombocytosis by inhibiting thrombopoiesis. Thrombocytosis is usually associated with a mild iron deficiency and is the result of a lack of inhibition of thrombopoiesis. Study participants were 430 iron deficiency anemia (IDA) patients. Ten (10) mL of venous blood were collected for the subjects. Ferritin analysis was done by ELISA method while Hemogram analysis was done by auto-analyzer. Factor V Leiden, PRTG20210A, and MTHFR C677T genotype analysis was performed by PCR-RFLP method. Among the patients, 9 were heterozygous (G>A) and 2 were homozygous (A>A) carrier of FV Leiden; while 20 were heterozygous (C>T) and 3 were homozygous (T>T) for MTHFR polymorphism. None of the patient was identified with PT mutation. Patients with thrombosis gene marker had lower hemoglobin, mean corpuscular volume, mean corpuscular haemoglobin levels, and mean corpuscular hemoglobin concentration than patients without thrombosis gene marker. Serum ferritin was elevated in subject with the absence of thrombosis gene markers. Our data suggest a high impact of inherited hypercoagulability risk factors in the pathogenesis of IDA and its complications.

  3. Frequency of the thermolabile variant C677T in the MTHFR gene and lack of association with neural tube defects in the State of Yucatan, Mexico.

    PubMed

    González-Herrera, L; García-Escalante, G; Castillo-Zapata, I; Canto-Herrera, J; Ceballos-Quintal, J; Pinto-Escalante, D; Díaz-Rubio, F; Del Angel, R M; Orozco-Orozco, L

    2002-11-01

    The C677T variant in the MTHFR gene is considered to be an associated risk factor for neural tube defects. However, the association has not been found in some ethnic groups. In order to assess the association between neural tube defects and the C677T variant, we determined the frequency of this variant in the MTHFR gene in the State of Yucatan, Mexico, where neural tube defects are highly prevalent. The study was performed on 65 subjects with spine bifida, 60 of their mothers and 110 control subjects. The presence of the C677T variant was determined by amplification and digestion with HinF1 of each subject's DNA. Genotypic and allelic frequencies were calculated for all groups. We did not observe any statistically significant difference in the genotypic or allelic frequencies between cases and controls for any of the groups studied (p > 0.05), suggesting that the thermolabile variant C677T is not an associated risk factor neither for the development of neural tube defects nor for mothers to have affected offspring in the population from Yucatan. Interestingly, the frequency of the C677T variant (54%) obtained in the Yucatan population is one of the highest reported (p < 0.01) and confirmed the high frequency of this allele throughout Mexico.

  4. Hyperhomocysteinemia and MTHFR Polymorphisms as Antenatal Risk Factors of White Matter Abnormalities in Two Cohorts of Late Preterm and Full Term Newborns

    PubMed Central

    Marseglia, Lucia M.; Nicotera, Antonio; Salpietro, Vincenzo; Giaimo, Elisa; Cardile, Giovanna; Bonsignore, Maria; Alibrandi, Angela; Caccamo, Daniela; Manti, Sara; D'Angelo, Gabriella; Mamì, Carmelo; Di Rosa, Gabriella

    2015-01-01

    Higher total homocysteine (tHcy) levels, and C677T and A1298C methylenetetrahydrofolate (MTHFR) polymorphisms, have been reported in preterm or full term newborns with neonatal encephalopathy following perinatal hypoxic-ischemic insult. This study investigated the causal role of tHcy and MTHFR polymorphisms together with other acquired risk factors on the occurrence of brain white matter abnormalities (WMA) detected by cranial ultrasound scans (cUS) in a population of late preterm and full term infants. A total of 171 newborns (81 M, 47.4%), 45 (26.3%) born <37 wks, and 126 (73.7%) born ≥37 wks were recruited in the study. cUS detected predominant WMA pattern in 36/171 newborns (21.1%) mainly characterized by abnormal periventricular white matter signal and mild-to-moderate periventricular white matter volume loss with ventricular dilatation (6/36, 16.6%). WMA resulted in being depending on tHcy levels (P < 0.014), lower GA (P < 0.000), lower Apgar score at 1 minutes (P < 0.000) and 5 minutes (P < 0.000), and 1298AC and 677CT/1298AC genotypes (P < 0.000 and P < 0.000). In conclusion, both acquired and genetic predisposing antenatal factors were significantly associated with adverse neonatal outcome and WMA. The role of A1298C polymorphism may be taken into account for prenatal assessment and treatment counseling. PMID:25829992

  5. 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

    2017-06-01

    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 38:3039-3051, 2017. © 2017 The Authors Human Brain Mapping Published Wiley by Periodicals, Inc. © 2017 The Authors Human Brain Mapping Published Wiley by Periodicals, Inc.

  6. Evaluation of maternal serum folate, vitamin B12, and homocysteine levels andfactor V Leiden, factor II g.20210G>A, and MTHFR variations in prenatallydiagnosed neural tube defects.

    PubMed

    Aydin, Hatip; Arisoy, Resul; Karaman, Ali; Erdoğdu, Emre; Çetinkaya, Arda; B Geçkinli, Bilge; Şimşek, Hasan; Demirci, Oya

    2016-02-17

    Neural tube defects (NTDs) are common congenital malformations that develop as a result of interactions between several genes and environmental factors. Many factors have been investigated in order to understand the etiology of NTDs, and many studies have identified folate intake as a common contributing factor. The exact etiology of the disease is still unknown. In this study, we compared serum folate, vitamin B12, and homocysteine levels, along with common thrombophilia-related genetic variations, including factor V Leiden, factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C, in 35 pregnant women with fetal NTDs and 38 pregnant women with healthy fetuses. A significant difference in serum vitamin B12 level and factor V Leiden frequency was detected between the two groups. On the other hand, serum folate, homocysteine levels, and factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C were not significantly different in the NTD group compared to the controls. These results indicate that vitamin B12 supplementation along with folate may help in lowering NTD frequency. In addition, this is the first study that provides evidence for a possible relationship between increased NTD risk and factor V Leiden.

  7. 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.

  8. Methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C and G1793A polymorphisms: association with risk for clear cell renal cell carcinoma and tumour behaviour in men.

    PubMed

    Safarinejad, M R; Shafiei, N; Safarinejad, S

    2012-05-01

    Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated whether MTHFR C677T, A1298C and G1793A polymorphisms modified clear cell renal cell carcinoma (CCRCC) risk independently as well as in combination with serum total homocysteine (Hcy) and folate levels. A case-control study of 152 cases (men) and 304 age-matched healthy controls was conducted in one geographical area of Iran. Genotyping of MTHFR gene polymorphisms was carried out using a polymerase chain reaction restriction fragment length polymorphism technique. Serum levels of total Hcy, folate and vitamin B12 were also determined. The MTHFR 677T and 1298C allele frequencies were 42.8 and 47.4% in cases, compared with 33.7 and 33.1% in controls. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31-3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21-2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75-8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72-6.54) for grade 3 CCRCC (both P=0.0001). After adjustment for selected variants, the MTHFR 1298AC genotype showed a significantly increased risk of CCRCC compared with the wild-type (odds ratio=3.71, 95% confidence interval=2.22-5.33; P=0.001), and the 1298C allele carrier showed a positive association with the risk of CCRCC compared with the wild-type (odds ratio=3.9, 95% confidence interval=2.55-6.02; P=0.001). Furthermore, subjects carrying at least one copy of the variant allele showed a 4.4 times

  9. Role of treatment-modifying MTHFR677C>T and 1298A > C polymorphisms in metformin-treated Puerto Rican patients with type-2 diabetes mellitus and peripheral neuropathy

    PubMed Central

    Jiménez-Ramírez, Francisco J.; Castro, Liza M.; Ortiz, Clarymar; Concepción, Jennifer; Renta, Jessicca Y.; Morales-Borges, Raúl H.; Miranda-Massari, Jorge R.; Duconge, Jorge

    2017-01-01

    Background The study was conducted to investigate potential association between MTHFR genotypes and diabetic peripheral neuropathy (DPN) in Puerto Ricans with type-2 diabetes mellitus (T2DM) treated with metformin. The prevalence of major MTHFR polymorphisms in this cohort was also ascertained. Methods DNAs from 89 metformin-treated patients with T2DM and DPN were genotyped using the PCR-based RFLP assay for MTHFR677C > T and 1298A > C polymorphisms. Frequency distributions of these variants in the study cohort were compared to those reported for three reference populations (HapMap project) and controls (400 newborn specimens). Chi-square (or Fischer’s exact) tests and odds ratios (OR) were used to assess association with DPN susceptibility risk (patients vs. controls) and biochemical markers (wild types vs. carriers). Results Sixty-seven percent (67%) of participants carry at least one of these MTHFR polymorphisms. No deviations from Hardy-Weinberg equilibrium were detected. The genotype and allele frequencies showed statistically significant differences between participants and controls (p < 0.0001 and p = 0.03, respectively). Results suggest that 1298A > C but not 677C > T is associated with DPN susceptibility in this cohort (p = 0.018). Different patterns of allelic dissimilarities are observed when comparing our cohort vs. the three parental ancestries. After sorting individuals by their carrier status, no significant associations were observed between these genetic variants (independently or combined) and any of the biochemical markers (HbA1c, folate, vitamin B12, homocysteine). Conclusions Prevalence of major MTHFR variants in Puerto Rican patients with T2DM is first time ever reported. The study provides further evidence on the use of this genetic marker as an independent risk factor for DPN. PMID:28231061

  10. Relationship between glutathione S-transferase P1 (GSTP1), X-ray repair cross complementing group 1 (XRCC1) and 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) gene polymorphisms and response to chemotherapy in advanced gastric cancer.

    PubMed

    Ji, Mei; Xu, Bin; Jiang, Jing-Ting; Wu, Jun; Li, Xiao-Dong; Zhao, Wei-Qing; Zhang, Hong-Yu; Zhou, Wen-Jie; Wu, Chang-Ping

    2013-01-01

    Our study aimed to investigate the relationship between glutathione S-transferase P1 (GSTP1), 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) and X-ray repair cross complementing group 1 (XRCC1) gene polymorphisms and the response to chemotherapy in advanced gastric cancer. 59 cases of advanced gastric cancer were enrolled. All patients were treated with the DCF regimen comprising docetaxel, cisplatin, and 5-fluorouracil. All patients' genotypes regarding GSTP1, XRCC1, and 5,10-MTHFR were analyzed by polymerase chain reaction/ligase detection reaction (PCR-LDR). There were 15 (25.42%) cases of G/G genotype, 21 (35.59%) of G/A genotype, and 23 (38.98%) of A/A genotype for GSTP1, 16 (27.12%) cases of A/A genotype, 18 (30.51%) of G/A genotype, and 25 (42.37%) of G/G genotype for XRCC1, and 21 (35.59%) cases of C/C genotype, 22 (37.29%) of C/T genotype, and 16 (27.12%) of T/T genotype for 5,10-MTHFR. After 2 cycles of chemotherapy, there were 4 cases of complete remission, 14 of partial remission, 19 of stable disease, and 22 of advanced disease, with a total effective rate of 30.51%. Better survival was shown for GSTP1 G/G genotype, XRCC1 A/A genotype, and 5,10-MTHFR T/T genotype (p < 0.05). The gene polymorphisms of GSTP1 G/G, XRCC1 A/A, and 5,10-MTHFR T/T have clinical value for predicting the response to the DCF regimen for advanced gastric cancer. © 2013 S. Karger GmbH, Freiburg.

  11. 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

  12. Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis.

    PubMed

    Wei, Loo Keat; Au, Anthony; Menon, Saras; Griffiths, Lyn R; Kooi, Cheah Wee; Irene, Looi; Zhao, Jiangyang; Lee, Chaeyoung; Alekseevna, Avdonina Maria; Hassan, Muhammad Radzi Abdul; Aziz, Zariah Abdul

    2017-11-01

    The association between ischemic stroke and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR; 677C>T and 1298A>C), endothelial nitric oxide synthase (eNOS; -786T>C, +894G>T, and variable number tandem repeat [VNTR]), phosphodiesterase 4D (PDE4D; SNPs 83 and 87), angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) 235M>T, paraoxonase 1 (PON1) 192Q>R, and apolipoprotein E (ApoE) ε2ε3ε4 remains inconclusive. Therefore, this updated meta-analysis aimed to clarify the presumed influence of genetic polymorphisms on ischemic stroke by meta-analyzing the comprehensive coverage of all individual association studies. All case-control studies published in different languages such as English, Japanese, Korean, Spanish, Chinese, Hungarian, Ukrainian, or Russian were identified from databases. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via fixed- and random-effect models. Sensitivity analysis, heterogeneity test, Hardy Weinberg Equilibrium, and Egger's regression analyses were performed in this study. A total of 490 case-control studies with 138,592 cases and 159,314 controls were included in this meta-analysis. Pooled ORs from all the genetic models indicated that MTHFR 677TT and 1298CC, eNOS +894TT and VNTR, PDE4D SNP 83, ACE DD, AGT 235TT, PON1 192RR, and ApoE ε4 polymorphisms were increasing the risks of ischemic stroke. Nevertheless, PDE4D SNP 87 and eNOS -786T>C polymorphisms are not associated with ischemic stroke risks. Hence, the evidence from this meta-analysis concluded that MTHFR (677C>T and 1298A>C), eNOS (+894G>T and VNTR), PDE4D SNP 83, ACE I/D, AGT 235M>T, PON1 192Q>R, and ApoE ε2ε3ε4 polymorphisms predispose individuals to ischemic stroke. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  13. The C677T MTHFR genotypes influence the efficacy of B9 and B12 vitamins supplementation to lowering plasma total homocysteine in hemodialysis.

    PubMed

    Achour, Ons; Elmtaoua, Sahbi; Zellama, Dorsaf; Omezzine, Asma; Moussa, Amira; Rejeb, Jihene; Boumaiza, Imene; Bouacida, Lobna; Rejeb, Nabila Ben; Achour, Abdellatif; Bouslama, Ali

    2016-10-01

    Hyperhomocysteinaemia, an independent risk factor for cardiovascular diseases, is common in hemodialysis patients (HD) and particularly in those homozygous for polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. B vitamins supplementation has been shown to lower plasma total homocysteine (tHcy), but this has been contreversed in several groups. The aim of our study was to explore the response of tHcy in hemodialysis (HD) patients to individual supplementation with folic acid (B9) and/or vitamin B12, based on carrier status for the (MTHFR) polymorphism. 132HD were randomized according to C677TMTHFR genotypes into 2 groups (AandB). The group (A) was treated initially with B9 (10mg/day orally) for 2 months (t1) and then with B12 vitamin (cyanocobalamin ampoule of 1000 μg) for the following 2 months (t2), then association of B9 and B12 for 2 months (t3). The group (B) was supplemented initially with vitamin B12 (t1), then with folic acid (t2) and then B9 + B12 for 2 months (t3). A wash-out period of 2 months followed the treatment in both groups (t4). We determined tHcy, B9 and B12 concentrations at each time. In group A, we noted that the decrease in tHcy becomes significant for CC when patients were supplemented with vit B12 only (p = 0.009). While, B9 + vit B12 supplementation did not seem to improve a significant effect compared with B12 alone. For genotypes (CT) and (TT) we noticed a significant decrease in tHcy at t1 (p = 0.038; 0.005 respectively) and at (t3; CT p = 0.024; TT p = 0.017). In group B, for genotypes CC, the decrease in tHcy became significant at t3 (vit B12 + B9; p = 0.031). For genotypes (CT) and (TT), at the replacement of vit B12 by B9, tHcy was significantly decreased (p = 0.036; 0.012, respectively). The combination of the 2 vitamins (t3) showed no difference compared to folate alone. In the 2 groups (t4), there was an significant increase of tHcy again for 3 genotypes. Supplementation with B

  14. Association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and ischemic stroke in the Chinese population: a meta-analysis.

    PubMed

    Zhu, Xiao-Yan; Hou, Rong-Yao; Pan, Xu-Dong; Wang, Yu-Chun; Zhang, Zheng-Shou; Guo, Rui-You

    2015-01-01

    The association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and ischemic stroke (IS) has been extensively studied; however, the results from genetic association studies have been inconsistent even in the Chinese population. As far as we know, there was no previous meta-analysis concerning this association in the Chinese population. Therefore, the aim of our meta-analysis was to further evaluate the association in the Chinese population. We collected all of the relevant studies from Pubmed, OVID, Embase, Chinese Wan Fang database, CNKI, Chongqing VIP database and CBM up to August 2014. The available data was analyzed by Stata (version 12.0). We used odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to present the strength of the association. Heterogeneity was evaluated by the Q-test and I(2) statistic. Different genetic models, subgroup analysis, publication bias and sensitivity analysis were used to improve the comprehensive understanding. The results showed a significant association between the MTHFR gene C677T polymorphism and IS in six genetic models (additive model: OR = 1.34, 95%CI: 1.17 ∼ 1.54, p < 0.001; dominant model: OR = 1.44, 95% CI:1.26 ∼ 1.64, p < 0.001; recessive model: OR = 1.45, 95% CI: 1.15 ∼ 1.83, p = 0.001; heterozygote model: OR = 1.35, 95% CI: 1.18 ∼ 1.55, p < 0.001; homozygote model: OR = 1.80, 95% CI: 1.34 ∼ 2.41, p < 0.001; and allelic model: OR = 1.34, 95% CI: 1.17 ∼ 1.53, p < 0.001) based on the overall population, as well as subgroup analysis. In addition, the similar results were obtained in the sensitivity analysis based on studies with the high quality. This meta-analysis presented a significant association between the MTHFR gene C677T polymorphism and IS, the T allele might be a risk factor for IS in the Chinese population.

  15. 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

  16. MTRR rs1801394 and its interaction with MTHFR rs1801133 in colorectal cancer: a case-control study and meta-analysis.

    PubMed

    Haerian, Monir Sadat; Haerian, Batoul Sadat; Molanaei, Saadat; Kosari, Farid; Sabeti, Shahram; Bidari-Zerehpoosh, Farahnaz; Abdolali, Ebrahim

    2017-07-01

    This study aims to evaluate the association between the MTRR rs1801394 alone or in interaction with the MTHFR rs1801133 and susceptibility to colorectal cancer (CRC) and its characteristics in Iranian population. Additionally, both a systematic review and meta-analysis were performed to derive a more precise assessment of this association. Genomic DNA of 2332 subjects was genotyped for rs1801394. These data were pooled with 17 eligible studies for meta-analysis. No significant association was found between the rs1801394 or rs1801394-rs1801133 and CRC risk. Meta-analysis results also demonstrated no significant relationship between the rs1801394 and CRC risk. Results of this study showed that the rs1801394 alone or together with the rs1801133 is not a risk factor for CRC in Iranian population.

  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. PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and Prothrombin 20210A in Splanchnic Vein Thrombosis: Analysis of Individual Patient Data From Three Prospective Studies.

    PubMed

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

    2016-03-01

    There are no univocal opinions on the role of genetic thrombophilia on splanchnic vein thrombosis (SVT). We defined genetic thrombophilia the presence of one of these thrombophilic genetic factors (THRGFs): PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and prothrombin 20210A. To evaluate the frequencies of these THRGFs in SVT patients, we analyzed individual data of 482 Caucasian patients, recruited from 2000 to 2014 in three prospective studies. SVT was defined as the presence of thrombosis of portal (PVT), mesenteric (MVT), splenic (SPVT), cava (CT), and hepatic vein (Budd Chiari syndrome, BCS). Pre-hepatic SVT (pre-HSVT) was defined as PVT with or without MVT/SPVT, without BCS. Post-hepatic SVT (post-HSVT) was BCS with or without PVT/MVT/SPVT. We compared 350 patients with liver cirrhosis (LC), 47 hepatocellular carcinoma (HCC), 37 myeloproliferative neoplasm (MPN), 38 associated disease (AD), 10 without any associated disease (WAD), vs 150 healthy controls (HC); 437 patients showed pre-HSVT and 45 post-HSVT. Thrombophilia was present in 294/482 (60.9%) patients: 189/350 LC (54.0%), 31/47 (66.0%) HCC, 29/39 (74.4%) MPN, 35/38 AD (92.1%), and 10/10 (100%) WAD, and 54/150 (36.0%) in HC. In the total group, we found 175 PAI-1 4G-4G, 130 MTHFR 677TT, 42V Leiden 506Q, and 27 prothrombin 20210A; 75 patients showed presence of >1 TRHGF; the more frequent association was PAI-1 4G-4G/MTHFR 677TT, in 36 patients. PAI-1 4G-4G and MTHFR 677TT were significantly more frequent in patients with SVT (P values <0.005), whereas V Leiden Q506 and prothrombin G20210A were not. PAI-1 4G-4G and MTHFR 677TT distributions deviated significantly from that expected from a population in Hardy-Weinberg equilibrium. Thrombophilia was significantly less frequent in patients with pre-HSVT (250/437, 57.2%) than in patients with post-HSVT (44/45, 97.8%). Our study shows the significant prevalence of PAI-1 4G-4G and MTHFR 677TT in SVT, mainly in post-HSVT.

  19. PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and Prothrombin 20210A in Splanchnic Vein Thrombosis: Analysis of Individual Patient Data From Three Prospective Studies

    PubMed Central

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

    2016-01-01

    Background There are no univocal opinions on the role of genetic thrombophilia on splanchnic vein thrombosis (SVT). We defined genetic thrombophilia the presence of one of these thrombophilic genetic factors (THRGFs): PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and prothrombin 20210A. Objectives To evaluate the frequencies of these THRGFs in SVT patients, we analyzed individual data of 482 Caucasian patients, recruited from 2000 to 2014 in three prospective studies. SVT was defined as the presence of thrombosis of portal (PVT), mesenteric (MVT), splenic (SPVT), cava (CT), and hepatic vein (Budd Chiari syndrome, BCS). Pre-hepatic SVT (pre-HSVT) was defined as PVT with or without MVT/SPVT, without BCS. Post-hepatic SVT (post-HSVT) was BCS with or without PVT/MVT/SPVT. Methods We compared 350 patients with liver cirrhosis (LC), 47 hepatocellular carcinoma (HCC), 37 myeloproliferative neoplasm (MPN), 38 associated disease (AD), 10 without any associated disease (WAD), vs 150 healthy controls (HC); 437 patients showed pre-HSVT and 45 post-HSVT. Results Thrombophilia was present in 294/482 (60.9%) patients: 189/350 LC (54.0%), 31/47 (66.0%) HCC, 29/39 (74.4%) MPN, 35/38 AD (92.1%), and 10/10 (100%) WAD, and 54/150 (36.0%) in HC. In the total group, we found 175 PAI-1 4G-4G, 130 MTHFR 677TT, 42V Leiden 506Q, and 27 prothrombin 20210A; 75 patients showed presence of >1 TRHGF; the more frequent association was PAI-1 4G-4G/MTHFR 677TT, in 36 patients. PAI-1 4G-4G and MTHFR 677TT were significantly more frequent in patients with SVT (P values <0.005), whereas V Leiden Q506 and prothrombin G20210A were not. PAI-1 4G-4G and MTHFR 677TT distributions deviated significantly from that expected from a population in Hardy–Weinberg equilibrium. Thrombophilia was significantly less frequent in patients with pre-HSVT (250/437, 57.2%) than in patients with post-HSVT (44/45, 97.8%). Conclusions Our study shows the significant prevalence of PAI-1 4G-4G and MTHFR 677TT in SVT, mainly in

  20. 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

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

    PubMed Central

    Zeng, Dingyuan

    2016-01-01

    Background The geographical and ethnic distributions of the polymorphic methylenetetrahydrofolate reductase (MTHFR) mutations (C677T and A1298C) and methionine synthase reductase (MTRR) mutation (A66G) remain heterogeneous in China. The goal of this study was to estimate the pooled frequencies of the alleles and associated genotypes of these gene polymorphisms among healthy populations in Mainland China. Objective and Methods We systematically reviewed published epidemiological studies on the distributions of 3 genetic variants in Chinese healthy populations living in Mainland China through a meta-analysis. The relevant electronic databases were searched. All of the raw data of the eligible citations were extracted. The frequency estimates were stratified by geography, ethnicity and sex. Results Sixty-six studies were identified with a total of 92277 study participants. The meta-analysis revealed that the frequencies of the MTHFR C677T, A1298C, and MTRR A66G gene polymorphisms varied significantly between different ethnic groups and along geographical gradients. The frequencies of the 677T allele and 677TT genotype increased along the southern-central-northern direction across Mainland China (all Pvalues≤0.001). The frequencies of the 1298C, 1298CC, 66G and 66GG genotypes decreased along the south-central-north direction across the country (all Pvalues≤0.001). Conclusions Our meta-analysis strongly indicates significant geographical and ethnic variations in the frequencies of the C677T, A1298C, and A66G gene polymorphisms in the folate metabolism pathway among Chinese populations. PMID:27089387

  3. MTHFR, MTR, and MTRR polymorphisms in relation to p16INK4A hypermethylation in mucosa of patients with colorectal cancer.

    PubMed

    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.

  4. MTHFR c.677C>T is a risk factor for non-syndromic cleft lip with or without cleft palate in Chile.

    PubMed

    Ramírez-Chau, C; Blanco, R; Colombo, A; Pardo, R; Suazo, J

    2016-10-01

    The functional variant within the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene c.677C>T, producing alterations in folate metabolism, has been associated with the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). We assessed this association in a Chilean population using a combined analysis of case-control and case-parent trio samples. Samples of 165 cases and 291 controls and 121 case-parent trios (sharing the cases) were genotyped. Odds ratio (OR) was estimated for case-control (allele and genotype frequency differences), and this result was confirmed by allele transmission distortion in trios. Due to that these samples are not independent, a combined OR was also computed. Maternal genotype effect was additionally evaluated based on a log-linear method. Borderline but not significant OR (1.28; CI 0.97-1.69) was observed for risk allele (T) in the case-control sample. However, triad sample showed a significant association (OR 1.56: CI 1.09-2.25) which was confirmed by the combined OR (1.37; CI 1.11-1.71). Maternal genotype has been also associated with the phenotype (P = 0.002). In contrast to previous reports considering Chilean subjects, our results demonstrated that the offspring and maternal genotypes for MTHFR c.677C>T variant are strongly associated with NSCL/P in this Chilean population. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. 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

  6. 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

  7. The relationship between factor V Leiden, prothrombin G20210A, and MTHFR mutations and the first major thrombotic episode in polycythemia vera and essential thrombocythemia.

    PubMed

    Trifa, Adrian P; Cucuianu, Andrei; Popp, Radu A; Coadă, Camelia A; Costache, Roxana M; Militaru, Mariela S; Vesa, Ştefan C; Pop, Ioan V

    2014-02-01

    Arterial and venous thrombosis are the most frequent complications in patients with polycythemia vera and essential thrombocythemia. We sought to demonstrate a possible contribution of the factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) 677 C > T and 1298 A > C mutations to the thrombotic risk in patients with polycythemia vera and essential thrombocythemia along with other biological features of these patients. We included 86 patients with polycythemia vera, of which 34 (39.5 %) had major thrombosis and 95 patients with essential thrombocythemia, of which 22 (23.1 %) had major thrombosis. In the whole cohort of patients, only the factor V Leiden mutation was significantly associated with both arterial and venous thrombosis in univariate and multivariate analysis (odds ratio (OR) = 4.3; 95 % confidence interval (CI) = 1.5-12.5; p = 0.008 and OR = 4.3; 95 % CI = 1.2-15.9; p = 0.02, respectively). Other factors significantly associated with thrombosis in both univariate and multivariate analysis were male sex (OR = 2.8, 95 % CI = 1.4-5.4, p = 0.002 and OR = 3.5, 95 % CI = 1.6-7.6, p = 0.002, respectively) and the JAK2 V617F mutation (OR = 5.5, 95 % CI = 2.1-15, p = 0.0001 and OR = 6.9, 95 % CI = 2.2-21.2, p = 0.001, respectively). In conclusion, among the four mutations analyzed (factor V Leiden, prothrombin G20210A, and MTHFR 677 C > T and 1298 A > C), only factor V Leiden is a major contributor to thrombosis in polycythemia vera and essential thrombocythemia.

  8. Investigation of MTHFR C677T gene polymorphism, biochemical and clinical parameters in Turkish migraine patients: association with allodynia and fatigue.

    PubMed

    Bahadir, Anzel; Eroz, Recep; Dikici, Suber

    2013-11-01

    We investigated whether there is any relationship between biochemical and clinical parameters of migraine and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism, associated with the migraine subtypes, symptoms, and gender. A total of 150 migraine patients with and without aura (MA and MO) and 107 non-sufferers were included in the study. Biochemical and clinical parameters were measured and genetic analysis was performed. The MTFHR C677T genotype was significantly higher in the migraine group (p = 0.000). The CT genotype frequency of individuals with a family history of migraine was significantly higher (p = 0.025). This genotype frequency was higher in patients who suffer from compression, allodynia, fatigue, and sleeplessness (p = 0.027, 0.023, 0.006, and 0.05, respectively). Homocysteine and total cholesterol levels were significantly higher in the migraine group than the control group (p = 0.007 and 0.010, respectively). However, the other biochemical and clinical parameters did not differ from each other (p > 0.05), with only attack frequency being significantly higher in the MO group (p = 0.005). While the folate and HDL levels were significantly higher in females (p = 0.001 and 0.000, respectively), the homocysteine and triglyceride levels were significantly higher in males (p = 0.000 for each one). BMIs were significantly lower in the control than the migraine group (p = 0.021); however, an association between the C677T variant and BMI was not found (p = 0.787) in the migraine group. An association between the MTHFR C667T polymorphism and migraine susceptibility was found. Additional studies including genetic, clinic, and biochemical parameters should be conducted to better understand the disease.

  9. 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

  10. 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

  11. Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis.

    PubMed

    Gupta, Nishi; Gupta, Saraswati; Dama, Madhukar; David, Archana; Khanna, Geeta; Khanna, Anil; Rajender, Singh

    2011-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies. We undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522) and confirmed fertile (N = 315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included 'Pubmed', 'Ovid' and 'Google Scholar'. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p = 0.0025) and genotypes (CT+TT) (p = 0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p = 0.000), 1.310 (p = 0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility. 677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.

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

    PubMed

    Matsha, Tandi E; Pheiffer, Carmen; Mutize, Tinashe; Erasmus, Rajiv T; Kengne, Andre P

    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.

  13. 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

  14. 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