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Sample records for reductase mthfr mutation

  1. A C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism and G20210A mutation in the prothrombin gene of sickle cell anemia patients from Northeast Brazil.

    PubMed

    Couto, Fbio David; Boas, Wendell Vilas; Lyra, Isa; Zanette, Angela; Dupuit, Marie France; Almeida, Mari Ney Tavares; Reis, Mitermayer Galvo; Gonalves, Marilda Souza

    2004-08-01

    The C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and the G20210A mutation at the 3' untranslated region (3'UTR) of the prothrombin gene may be considered to be genetic risk factors that contribute to the clinical heterogeneity in sickle cell disease. The current study investigated a group of sickle cell (SS) patients from Salvador-Bahia, Northeast Brazil in order to determine the prevalence of these polymorphisms, using the polymerase chain reaction (PCR) and restriction fragment length polymorphim (RFLP) techniques. Out of 69 SS patients diagnosed with the C677T MTHFR gene polymorphism, 13 (18.6%) were heterozygous and four (5.7%) homozygous. The G20210A mutation was not found in 50 SS patients investigated. These results became important once the C677T MTHFR gene polymorphism was found to be an independent risk factor for vascular disease, a common clinical event in sickle cell disease. PMID:15481892

  2. Cerebral sinovenous thrombosis associated with MTHFR A1298C mutation in the newborn: a case report.

    PubMed

    Cizmeci, Mehmet Nevzat; Kanburoglu, Mehmet Kenan; Akelma, Ahmet Zulfikar; Donmez, Ahsen; Sonmez, Fatma Mujgan; Polat, Aziz; Kosehan, Dilek; Tatli, Mustafa Mansur

    2013-02-01

    Although cerebral sinovenous thrombosis (CSVT) is a rare condition in the neonatal period, high rates of morbidity and mortality necessitate the establishment of an early diagnosis. Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and mutations of MTHFR are associated with vascular disease. While the C677T common missense mutation is the most well-defined MTHFR polymorphism, another common missense mutation, A1298C also exists. There has been no reported case of CSVT associated with MTHFR A1298C mutation in the neonatal period. Herein, we report a neonate with CSVT who was found to have MTHFR A1298C homozygosity. PMID:22797907

  3. Common Mutations of the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Non-Syndromic Cleft Lips and Palates Children in North-West of Iran

    PubMed Central

    Abdollahi-Fakhim, Shahin; Asghari Estiar, Mehrdad; Varghaei, Parizad; Alizadeh Sharafi, Mahdi; Sakhinia, Masoud; Sakhinia, Ebrahim

    2015-01-01

    Introduction: Cleft lips and cleft palates are common congenital abnormalities in children. Various chromosomal loci have been suggested to be responsible the development of these abnormalities. The present study was carried out to investigate the association between the suspected genes (methylenetetrahydrofolate reductase [MTHFR] A1298C and C677T) that might contribute into the etiology of these disorders through application of molecular methods. Materials and Methods: This cross-sectional and explanatory study was carried out on a study population of 65 affected children, 130 respective parents and 50 healthy individuals between 2009 and 2012 at Tabriz University of Medical Sciences, IR Iran. After DNA extraction, amplification refractory mutation systempolymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphism (RFLP)-PCR were used respectively to investigate the C677T and A1298C mutations for the MTHFR gene. Results: There was a significant difference in the rates of the C677T mutation when affected patients and their fathers were compared with the control group (odds ratio [OR]=0.44) (OR=0.64). However, there was no significant difference observed in the rate of this mutation between the patients mothers and the control group (OR=1.35). In addition, the abnormality rate was higher in patients with the A1298C mutation and their parents, when compared with the control group. This abnormality rate was higher for the affected children and their fathers in comparison with their mothers (Fathers, OR=0.26; Mothers, OR=0.65; Children, OR=0.55). No significant difference was seen in the rate of the polymorphism C677T in its CC, when the affected children and their parents were compared with the control group. However, there was a significant difference in the A1298C mutation. Conclusion: An association was seen between the A1298C mutation and cleft lip and cleft palate abnormalities in Iran. However, there seems to be a stronger relationship between the C67TT mutation and these abnormalities in other countries, which could be explained by racial differences. Moreover, this association was more notable between the affected children and their fathers than their mothers. The findings in this study may be helpful in future studies and screening programs. PMID:25745606

  4. [Polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR) and incidence of hyperhomocysteinemia-related diseases].

    PubMed

    Pawlak, A L; Strauss, E

    2001-01-01

    Methylenetetrahydrofolate reductase (MTHFR), is a cytosolic enzyme, the product of which is N5-metyltetrahydrofolate, the main form of folates in tissues and the carbon donor for methylation of homocysteine to methionine. In MTHFR gene a series of the pathogenic mutations is known which lead to loss of enzymatic activity as well as the two polymorphic alleles (MTHFR 677T and 1298C) with products displaying the lowered enzyme activity resulting in hyperhomocysteinaemia. These polymorphic alleles of MTHFR represent the main genetic factor contributing to hyperhomocysteinaemia. The better known allele MTHFR 677T is found in different populations with frequency between ca. 0.1 and 0.36. In persons inheriting the variant alleles of MTHFR the increase in the level of homocysteine is noted resulting in the increased susceptibility to vascular diseases and the neural tube defects in the progeny. The procedure recommended for the prevention of effects of deficiency of MTHFR activity consists of the supplementation of the diet with 0.4 mg of folic acid daily. PMID:11468972

  5. 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. PMID:25449138

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

    PubMed

    Romn, 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. PMID:26401555

  7. 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-? 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. PMID:24616178

  8. Bilateral transverse sinus thrombosis secondary to a homozygous C677T MTHFR gene mutation.

    PubMed

    Kanaan, Ziad M; Mahfouz, Rami; Taher, Ali; Sawaya, Raja A

    2008-09-01

    We describe the case of a previously healthy young man who presented with headache, diplopia, nausea, vomiting, and bilateral papilledema. Magnetic resonance venography of the brain revealed thrombosis of the right transverse sinus. Blood tests showed elevated homocysteine levels, and coagulation studies revealed a homozygous C677T mutation and a heterozygous A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. The patient had no other etiology for venous thrombosis. We recommend screening patients who present with sinus thrombosis for MTHFR gene mutations. PMID:18666857

  9. Internal jugular vein thrombosis due to heterozygote methylene tetrahydrofolate reductase (MTHFR) 1298C and Factor V G1691A mutations after a minor trauma

    PubMed Central

    Gumussoy, Murat; Arslan, Ilker B.; Cukurova, Ibrahim; Uluyol, Sinan

    2014-01-01

    Internal jugular vein thrombosis usually appears in central venous catheterization, distant malignancies, hypercoagulation, infections, or secondary to ovarian hyperstimulation syndrome. A 44-year-old female patient presented to us with sore throat, and pain and swelling on the right side of her neck. She had a history of simple neck trauma 10 days ago. Ultrasonography and computed tomography showed bilateral multiple lymphadenopathies and right internal jugular vein thrombosis. Patient was put on parenteral antibiotherapy and oral anticoagulant treatment. Genomic DNA tests for hypercoagulation revealed methylene tetrahydrofolate reductase 1298C heterozygote mutation and Factor V G1691A (Leiden) mutation. Patient has been under clinical control for 1 year and does not have any complaints. In this article, diagnosis, treatment, and the etiology of internal jugular vein thrombosis, which is a rare and potentially fatal condition, have been discussed through this case. PMID:25937730

  10. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study.

    PubMed

    Khorshied, Mervat Mamdooh; Shaheen, Iman Abdel Mohsen; Abu Khalil, Reham E; Sheir, Rania Elsayed

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene plays a pivotal role in folate metabolism. Several genetic variations in MTHFR gene as MTHFR-C677T and MTHFR-A1298C result in decreased MTHFR activity, which could influence efficient DNA methylation and explain susceptibility to different cancers. The etiology of chronic myeloid leukemia (CML) is obscure and little is known about individual's susceptibility to CML. In order to assess the influence of these genetic polymorphisms on the susceptibility to CML and its effect on the course of the disease among Egyptians, we performed an age-gender-ethnic matched case-control study. The study included 97 CML patients and 130 healthy controls. Genotyping of MTHFR-C677T and -A1298C was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results showed no statistical difference in the distribution of MTHFR-C677T and -A1298C polymorphic genotypes between CML patients and controls. The frequency of MTHFR 677-TT homozygous variant was significantly higher in patients with accelerated/blastic transformation phase when compared to those in the chronic phase of the disease. In conclusion, our study revealed that MTHFR-C677T and -A1298C polymorphisms could not be considered as genetic risk factors for CML in Egyptians. However, MTHFR 677-TT homozygous variant might be considered as a molecular predictor for disease progression. PMID:24338216

  11. Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects.

    PubMed

    Yaliwal, Laxmi V; Desai, Rathnamala M

    2012-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C?T is associated with a 2-4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A?C transition at position 1298. The 1298A?C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C?T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs. PMID:22754237

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

    PubMed

    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

  14. Association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and congenital heart disease: A meta-analysis?

    PubMed Central

    Wang, Wenju; Hou, Zongliu; Wang, Chunhui; Wei, Chuanyu; Li, Yaxiong; Jiang, Lihong

    2013-01-01

    Background Inconsistent results were reported in recent literature regarding the association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility of congenital heart disease (CHD). In this study, we performed a meta-analysis to investigate the associations by employing multiple analytical methods. Methods Literature search was performed and published articles were obtained from PubMed, Embase and CNKI databases based on the exclusion and inclusion criteria. Data were extracted from eligible studies and the crude odds ratios and their corresponding 95% confidence intervals (CIs) were calculated using random or fix effects model to evaluate the associations between the MTHFR C677T/A1298C polymorphisms and CHD development. Subgroup based analysis was performed by HardyWeinberg equilibrium, ethnicity, types of CHD, source of control and sample size. Results Twenty-four eligible studies were included in this meta-analysis. Significant association was found between fetal MTHFR C677T polymorphism and CHD development in all genetic models. The pooled ORs and 95% CIs in all genetic models indicated that MTHFR C677T polymorphism was significantly associated with CHD in Asian, but not Caucasian in subgroup analysis. The maternal MTHFR C677T polymorphism was not associated with CHD except for recessive model. Moreover, neither maternal nor fetal MTHFR A1298C polymorphism was associated with CHD. Conclusion The fetal MTHFR C677T polymorphism may increase the susceptibility to CHD. Fetal MTHFR C677T polymorphism was more likely to affect Asian fetus than Caucasian. The MTHFR A1298C polymorphism may not be a risk of congenital heart disease. PMID:25606381

  15. Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia.

    PubMed

    Vares, Maria; Saetre, Peter; Deng, Hong; Cai, Guiqing; Liu, Xiehe; Hansen, Thomas; Rasmussen, Henrik B; Werge, Thomas; Melle, Ingrid; Djurovic, Srdjan; Andreassen, Ole A; Agartz, Ingrid; Hall, Hkan; Terenius, Lars; Jnsson, Erik G

    2010-03-01

    Different lines of evidence indicate that methylenetetrahydrofolate reductase (MTHFR) functional gene polymorphisms, causative in aberrant folate-homocysteine metabolism, are associated with increased vulnerability to several heritable developmental disorders. Opposing views are expressed considering the possible association between MTHFR and susceptibility for schizophrenia. In order to evaluate if age of onset could explain some of this discrepancy we investigated the relationship between two functional MTHFR gene polymorphisms and age at onset in this disorder. Scandinavian patients (n = 820) diagnosed with schizophrenia, schizoaffective disorder, and schizophreniform disorder were investigated. Two functional MTHFR single nucleotide polymorphisms (SNPs; rs1801131 and rs1801133) were genotyped and the effect of MTHFR polymorphisms on the age of onset was examined with survival analysis. In an attempt to replicate the findings from the Scandinavian sample, the association between rs1801133 and age at onset was also analyzed in Chinese high-risk families, with two or more affected siblings (n = 243). Among the Scandinavian patients the functional MTHFR SNP rs1801133 (C677T) significantly affected age at onset of schizophrenia in a dose-dependent manner (P = 0.0015), with lower age of onset with increasing numbers of the mutant T-allele. There was no evidence of rs1801131 (A1298C) affecting age of onset in schizophrenia. Within the Chinese high-risk families carriers of the MTHFR 677T allele showed earlier age at onset than siblings being homozygous for the wild-type allele (P = 0.008). The MTHFR C677T polymorphism may play a role as a modifying factor for age of onset in schizophrenia. PMID:19746410

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  17. Effect of methotrexate on the survival of human lymphocyte cultures carrying MTHFR 677 (C>T) and MTHFR 1298 (A>C) mutations.

    PubMed

    Al-Refai, Ekhlas A; Sadiq, May F; Khassawneh, Mohammad Y; Amjad D, Al-Nasser

    2009-01-01

    The correlations between the presence of MTHFR 677 (C>T) and MTHFR 1298 (A>C) mutations in human lymphocytes and the sensitivity of lymphocytes to methotrexate (MTX) were examined in cultures derived from 82 unrelated women, genotyped for these mutations by polymerase chain reaction-restriction fragment length polymorphism. Lymphocytes heterozygous for the mutant allele, MTHFR 677T, were significantly more sensitive to methotrexate than those carrying the homozygous wild-type allele, MTHFR677C, and those carrying either the mutant or the wild-type alleles in the polymorphic MTHFR 1298 site. In addition, the lymphocyte cultures carrying the mutant MTHFR 1298C allele were not different in their sensitivity to MTX from those cultures carrying the wild-type allele, MTHFR 1298A. This demonstrated that the polymorphic site MTHFR C677, but not MTHFR1298, could be considered as a useful pharmacogenetic determinant in planning and designing the effective personal MTX chemotherapeutic doses and regimes. PMID:19514945

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

    PubMed

    Ucar, V B; Nami, B; Acar, H; Kilin, 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. PMID:24456105

  19. 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 Mller 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-?-synthase (Cbs) reported earlier. The data support the hypothesis that hyperhomocysteinemia may be causative in certain retinal neurovasculopathies. PMID:25766590

  20. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R.

    1995-05-01

    5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

  1. Retrospective approach to methylenetetrahydrofolate reductase mutations in children.

    PubMed

    zer, I??l; zetin, Mustafa; Karaer, Hatice; Kurt, Semiha G; ?ahin, ?emsettin

    2011-07-01

    Methylenetetrahydrofolate reductase reduces methyltetrahydrofolate, a cosubstrate in the remethylation of homocysteine, from methylenetetrahydrofolate. Congenital defects, hematologic tumors, and intrauterine growth retardation can occur during childhood. This study evaluated clinical and laboratory treatment approaches in children diagnosed with methylenetetrahydrofolate reductase mutations. Our group included 23 boys and 14 girls, aged 103.4 70.8 months S.D. Clinical findings of patients and homocysteine, vitamin B12, folate, hemogram, electroencephalography, cranial magnetic resonance imaging, and echocardiography data were evaluated in terms of treatment approach. Our patients' findings included vitamin B12 at 400.4 224.6 pg/mL S.D. (normal range, 300-700 pg/mL), folate at 10.1 4.5 ng/mL S.D. (normal range, 1.8-9 ng/mL), and homocysteine at 8.4 4.7 ?mol/L S.D. (normal range, 5.5-17 ?mol/L). Eighty-eight percent of patients demonstrated clinical findings. In comparisons involving categorical variables between groups, ?(2) tests were used. No relationship was evident between mutation type, laboratory data, and clinical severity. All mothers who had MTHFR mutations and had babies with sacral dimples had taken folate supplements during pregnancy. To avoid the risk of neural tube defects, pregnant women with a MTHFR mutation may require higher than normally recommended doses of folic acid supplementation for optimum health. PMID:21723457

  2. 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?=?0.720.95; CT vs. CC: P?=?0.05, OR?=?0.83, 95% CI?=?0.691.00; TT vs. CC: P?=?0.05, OR?=?0.73, 95% CI?=?0.531.00). 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?=?0.991.49) and AC vs. AA (P?=?0.09, OR?=?1.21, 95% CI?=?0.971.51). 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 polymorphisms and the susceptibility to cervical cancer requires a further study. PMID:23285018

  3. Neonatal and Fetal Methylenetetrahydrofolate Reductase Genetic Polymorphisms: An Examination of C677T and A1298C Mutations

    PubMed Central

    Isotalo, Phillip A.; Wells, George A.; Donnelly, James G.

    2000-01-01

    Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy. Folate sufficiency is thought to play an integral role in the phenotypic expression of MTHFR mutations. Samples of neonatal cord blood (n=119) and fetal tissue (n=161) were analyzed for MTHFR C677T and A1298C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis revealed that all possible MTHFR genotype combinations were represented in the fetal group, demonstrating that 677T and 1298C alleles could occur in both cis and trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contain three and four mutant alleles, respectively, were not observed in the neonatal group (P=.0402). This suggests decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This is the first report that describes the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrates their potential role in compromised fetal viability. PMID:10958762

  4. 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 ? 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

  5. Evidence of Paternal N5, N10 - Methylenetetrahydrofolate Reductase (MTHFR) C677T Gene Polymorphism in Couples with Recurrent Spontaneous Abortions (RSAs) in Kolar District- A South West of India

    PubMed Central

    Vanilla, Shiny; Kotur, Pushpa F; Kutty, Moideen A; Vegi, Pradeep Kumar

    2015-01-01

    Introduction: Recurrent spontaneous abortion (RSA) is a multifactorial clinical obstetrics complication commonly occurring in pregnancy. Many research studies have noted the mutations such as C677T in N5, N10 - Methylenetetrahydrofolate reductase (MTHFR)gene which is regarded as RSA risk factor. This study was carried out to determine the occurrence of frequency of C677T of the MTHFR gene mutations with RSA. Aim: The purpose of present study is to determine the frequency of MTHFR C677T polymorphisms in couples with recurrent pregnancy loss and the impact of paternal polymorphisms of MTHFR C677T in recurrent pregnancy loss in population of couples living in Kolar district of Karnataka with RSA. Design: A total of 15 couples with a history of two or more unexplained RSA were enrolled as subjects in the study and a total of 15 couples with normal reproductive history, having two or more children and no history of miscarriages were enrolled as controls. Materials and Methods: DNA extraction from samples case and control group couples and its quantification by Agarose gel electrophoresis, assessment of DNA purity, MTHFR C 677T gene mutation detection by PCR-RFLP method. Statistical analysis: Carried out by web based online SPSS tool. Results: The frequency of C677T genotype showed homozygous wild type CC (80%), heterozygous CT type (13.3%) and homozygous mutation TT type (6.67%) observed in males. Similarly from females homozygous wild type CC (86.6%), heterozygous type (13.3%), and homozygous type mutations TT (0%) was recorded. In couple control groups, we observed homozygous wild type CC (86.6%), heterozygous CT type (13.3%) and homozygous type mutations TT type (0%). Conclusion: We noticed a high frequency of MTHFR specifically T allele associated with paternal side.Therefore, the present study indicated the impact of paternal gene polymorphism of MTHFR C677T on screening in couples with recurrent pregnancy loss. PMID:25859445

  6. 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

    2011-01-01

    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. PMID:21732284

  7. Severe arterial thrombophilia associated with a homozygous MTHFR gene mutation (A1298C) in a young man with Klinefelter syndrome.

    PubMed

    Ozbek, Mustafa; Oztrk, M Akif; Ureten, Kemal; Ceneli, Ozcan; Erdogan, Mehmet; Haznedaroglu, Ibrahim C

    2008-07-01

    Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It may be associated with an increased risk for venous thrombosis and thromboembolism, which is partially explained by hypofibrinolysis due to androgen deficiency. Additional genetic or acquired thrombophilic states have been shown in KS patients complicated with venous thrombosis as isolated case reports. Arterial thrombotic events had not been previously reported in KS. In this study, a young man with KS who developed acute arterial thrombosis during testosterone replacement therapy is presented. He was homozygous for the A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. PMID:18160591

  8. Serum Folate and Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Adjusted for Folate Intake

    PubMed Central

    Nishio, Kazuko; Goto, Yasuyuki; Kondo, Takaaki; Ito, Shimon; Ishida, Yoshiko; Kawai, Sayo; Naito, Mariko; Wakai, Kenji; Hamajima, Nobuyuki

    2008-01-01

    Background Serum folate concentration is lower in individuals with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype than in those with the MTHFR 677CC or 677CT genotypes. Since studies considering folate intake are limited, we examined the association between folate intake and serum folate levels, according to the genotype. Methods The subjects comprised 170 Japanese persons (74 males and 96 females) aged 20-75 years who visited a clinic to test for Helicobacter pylori infection. Folate intake was estimated using a semiquantitative food-frequency questionnaire, and serum folate was measured in the residual fasting blood samples of the subjects. MTHFR C677T was genotyped using polymerase chain reaction. Results The geometric means of serum folate level were 6.19, 6.20, and 5.17 ng/mL among the 60 participants with the 677CC genotype, 90 participants with the 677CT genotype, and 20 participants with the 677TT genotype, respectively. No difference was noted in the mean folate intake estimated using the food-frequency questionnaire. Regression analysis showed that loge(serum folate) adjusted for age, sex, and loge(folate intake) was significantly lower among those with the 677TT genotype than among those with the 677CT or 677CC genotypes (p = 0.01). The adjusted reduction in serum folate was 20.2% (95% confidence interval, 5.4-32.6%) in the case of the 677TT genotype relative to the levels in the case of the 677CC/677CT genotypes. When folate intake was adjusted for total energy intake, using the residual method, the slope of the regression line for 677TT was smaller than those of the regression lines for 677CC and 677CT. Conclusion Individuals with the 677TT genotype may need to consume more folate to maintain serum folate levels similar to those found in individuals with the 677CC/677CT genotypes. PMID:18480590

  9. 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. PMID:19825918

  10. Association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and carotid intima medial thickness progression in post ischaemic stroke patient

    PubMed Central

    Faradz, Sultana M.H.; Sari, Stefani; Hadisaputro, Soeharyo

    2015-01-01

    Background Hyperhomocysteinemia is associated with an increased risk of atherosclerosis. The main cause of elevated levels of homocysteine is 677T allele, the gene encoded by methylenetetrahydrofolate reductase (MTHFR). Carotid atherosclerosis progression, which can be measured by examination of carotid intima-media thickness (C-IMT), is a predictor of recurrent ischemic stroke. The objective of this study was to determine a relationship between MTHFR polymorphism, homocysteine ??levels, and increased C-IMT in post- ischemic stroke patients. Methods This was an epidemiological prospective observational cohort study involving 71 patients with post-ischemic stroke subject of the first (onset 1 month) admitted in the Neurology Clinic of Kariadi Hospital during 2012 to 2013. C-IMT was examined using carotid duplex ultrasound at 1st, 6th, and 12th month after stroke onset. MTHFR gene polymorphism was examined using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Homocysteine level was measured using Axis Homocysteine EIA. Results We found 3 categories of MTHFR gene variation, i.e., 677T/T, 677T/C, and 677C/C. The most frequent allele was MTHFR 677C (88.9%), while the MTHFR 677T allele frequency was 11.1%. The majority allele of the subject population was 677C/C, however, there were 3 subjects (4.2%) who had 677T/T allele. The 677T/T allele group had normal homocysteine level and the lowest mean C-IMT among others. Conclusions This study supports that the MTHFR 677T allele polymorphism is not associated with hyperhomocysteinemia as well as an increase in C-IMT in post ischemic stroke patients. PMID:26734634

  11. Seven novel mutations at the 5,10-methylenetetrahydrofolate reductase locus

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen, R.

    1994-09-01

    5,10-methylenetetrahydrofolate reductase (MTHFR), a flavoprotein, catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cofactor for methionine synthase in the methylation of homocysteine to methionine. Severe MTHFR deficiency, which causes homocysteinemia, is an autosomal recessive disorder with variable clinical features; developmental delay, perinatal death, mental retardation and asymptomatic individuals have been observed. A milder deficiency has been reported in patients with cardiovascular disease. We have recently described the isolation of a cDNA for MTHFR and the identification of 2 mutations in patients with severe MTHFR deficiency. We report here the characterization of 7 additional mutations at this locus: 5 missense mutations and 2 splicing mutations. Mutation analysis was performed by SSCP on PCR products generated either from reverse transcription-PCR of patients` total fibroblast RNA or from PCR of patients` genomic DNA. The 5 missense mutations are as follows: 1 Arg to Cys substitution in a hydrophilic segment proposed to be the hinge region that connects the catalytic and regulatory domains, 2 different Arg to Cys substitutions in 2 patients whose enzymatic thermolability is responsive to FAD, 1 Thr to Met substitution affecting an evolutionarily-conserved residue and a Pro to Leu substitution. The 2 splicing mutations affect the 5{prime} splice site and the 3{prime} splice site of 2 introns, respectively. The 5{prime} splice site mutation generates a 57 bp in-frame deletion of the RNA through the utilization of a cryptic 5{prime} splice site within the coding sequence. The identification of 9 mutations at this locus has allowed us to make preliminary correlations between genotype and phenotype and to contribute to a structure:function analysis of the enzyme.

  12. 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 ?mol/L while each MTHFR 677T-allele contributed to 4.63 ?mol/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. PMID:24449370

  13. 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. PMID:22847291

  14. The methylene tetrahydrofolate reductase (C677T) mutation as a potential risk factor for avascular necrosis in sickle cell disease.

    PubMed

    Kutlar, A; Kutlar, F; Turker, I; Tural, C

    2001-05-01

    Avascular necrosis (AVN) of the humeral and femoral heads is a frequent and debilitating complication of sickle cell disease. Some of the risk factors for AVN are alpha-thalassemia and age. Recently, newly discovered thrombophilia mutations have been associated with AVN in patients without sickle cell disease. We studied the frequency of the thermolabile methylene tetrahydrofolate reductase (MTHFR) variant (C677T) in adult sickle cell patients with and without AVN. The frequency of the MTHFR mutation was 35.6% in patients with AVN and 12.9% in those without AVN (p = 0.006). These data suggest that the thermolabile MTHFR variant may be a contributing risk factor for AVN in some populations with sickle cell disease. PMID:11480782

  15. Association study of methylenetetrahydrofolate reductase A1298C mutation with cerebral venous thrombosis risk in an Iranian population

    PubMed Central

    Habib, Ghaznavi; Zahra, Soheili; Shahram, Samiei; Soltanpour, Mohammad Soleiman

    2015-01-01

    Background: Cerebral venous thrombosis (CVT) is an uncommon condition characterized by severe clinical manifestations and high mortality rate. There is limited data on the role of methylenetetrahydrofolate reductase (MTHFR) A1298C mutation as a risk factor for CVT development in Iranians. Aim: The aim was to investigate a possible association between fasting plasma homocysteine (Hcy) levels, MTHFR A1298C mutation, and CVT in Iranian population. Materials and Methods: The study population consisted of 50 patients with a diagnosis of CVT (2063 years old) and 75 healthy subjects (1865 years old) as control. Genotyping of the MTHFR A1298C mutation and Hcy measurement was carried out by polymerase chain reaction-restriction fragment length polymorphism technique and enzyme immunoassay method, respectively. Results: Fasting plasma total Hcy levels were significantly higher in CVT patients than controls (P = 0.015). No significant differences were observed in the MTHFR A1298C genotypes frequency between CVT patients and controls (P > 0.05). The frequency of the 1298C allele was 36% and 37.5% in CVT patients and controls, respectively and did not differ significantly between the two groups (P = 0.16). Conclusions: Our study demonstrated that MTHFR A1298Cmutation is not a significant risk factor for CVT. PMID:26539365

  16. [Neonatal renal vein thrombosis in a heterozygous carrier of both factor V Leiden and the MTHFR gene mutation].

    PubMed

    Wannes, S; Soua, H; Ghanmi, S; Braham, H; Hassine, M; Hamza, H A; Ben Hamouda, H; Sfar, M-T

    2012-04-01

    Renal vein thrombosis (RVT) is a rare but potentially serious neonatal disease. Its epidemiology and its clinical and biological expression are currently well known, but its etiological exploration, like that of venous thromboembolism, is increasingly complex. Perinatal risk factors such as prematurity, dehydration, and birth asphyxia have lost their direct accountability at the expense of their interaction with constitutional disorders of hemostasis. We report a case of RVT in a newborn who was a heterozygous carrier of both factor V Leiden and the methylene tetrahydrofolate reductase (MTHFR) gene mutation. We recall the clinical and epidemiological characteristics. A search for inborn blood coagulation disorders should be systematic in the newborn infant with venous thrombosis because of the risk of recurrence, taking into account perinatal factors and maternal thrombophilia (especially if RVT is established during the prenatal period). PMID:22361411

  17. Cerebral venous sinus thrombosis presenting as transient ischemic attacks in a case with homozygous mutations of MTHFR A1298C and CG677T.

    PubMed

    Yildiz, Ozlem Kayim; Cevik, Seyda; Cil, Gulsum; Oztoprak, Ibrahim; Bolayir, Ertugrul; Topaktas, Suat

    2012-01-01

    We report a case with recurrent, transient attacks of slurred speech, weakness, and numbness of the right half of the face and the right arm without seizure activity, accompanied by headache and double vision. Neurologic examination revealed bilateral papilledema and right abducens palsy. Brain magnetic resonance imaging revealed thrombosis of the dural venous sinuses and the cortical veins, with no evidence of parenchymal lesion. Homozygous mutations were found for methylenetetrahydrofolate reductase (MTHFR) A1298C and MTHFR CG677T. Anticoagulation with heparin and warfarin resulted in prompt cessation of the transient attacks, as well as the signs and symptoms of increased intracranial pressure. This report documents that, although rare, transient ischemic attacks can result from cerebral venous thrombosis. PMID:20833086

  18. 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.; OConnor, 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

  19. 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

    2015-01-01

    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. PMID:25966188

  20. Acute renal infarction associated with homozygous methylenetetrahydrofolate reductase mutation C677T and IgA beta-2-glycoprotein antibodies.

    PubMed

    Vlachostergios, Panagiotis J; Dufresne, Franois

    2015-07-01

    Arterial thrombosis of the kidney(s) is a rare clinical entity usually presenting as a result of cardioembolic disease, though rare inherited hypercoagulable states have also been implicated. Within this context, both hyperhomocysteinemia triggered by a mutated methylenetetrahydrofolate reductase (MTHFR) gene product and the presence of antiphospholipid antibodies have been separately associated with arterial thrombotic events, including renal artery embolism. We present a case of combined homozygous MTHFR C677T mutation and IgA beta-2-glycoprotein antibody positivity resulting in acute renal infarction and previous silent myocardial infarction. An acute and otherwise unexplained thrombotic event of unusual location always warrants further investigation, which should include testing for hereditary thrombophilic disorders. PMID:25828971

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

    PubMed

    B?nescu, 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. PMID:25510667

  2. High prevalence of hyperhomocysteinemia in chronic alcoholism: the importance of the thermolabile form of the enzyme methylenetetrahydrofolate reductase (MTHFR).

    PubMed

    de la Vega, M J; Santolaria, F; Gonzlez-Reimers, E; Alemn, M R; Milena, A; Martnez-Riera, A; Gonzlez-Garca, C

    2001-10-01

    Alcoholism is related to malnutrition and low levels of several vitamins that take part in the metabolism of homocysteine. The objective of the study was to analyze the prevalence of hyperhomocysteinemia in patients with heavy alcohol intake and the factors on which it depends. Included in the study were 103 hospitalized heavy drinkers (i.e., patients with an intake of alcohol greater than 80 g per day). Serum homocysteine, folate, and vitamin B(12) levels, plasma vitamin B(6) levels, and CT677 polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were determined. We also recorded the intensity of alcoholism, the status of nutrition, and the existence of liver cirrhosis. Determination of biochemical data was repeated after 15 days of withdrawal. Serum homocysteine levels were found to be significantly elevated, whereas serum folate and plasma B(6) levels were significantly decreased. Serum homocysteine levels were significantly higher in those heavy drinkers who showed the TT polymorphism of MTHFR, with a prevalence of hyperhomocysteinemia of 84.2% in the homozygote TT, 54.3% in the heterozygote CT, and 31.6% in the normal CC genotype. Serum homocysteine inversely correlated with serum folate, serum B(12), and plasma B(6) levels. We did not find any relation between serum homocysteine and intensity of alcoholism, nutritional status, or liver cirrhosis. Serum folate levels were significantly decreased in heavy drinkers, mainly depending on irregular feeding and malnutrition. After 15 days of withdrawal, serum homocysteine levels significantly decreased, whereas folate, B(12), and B(6) levels significantly increased. The conclusion is that heavy drinkers show a high prevalence of hyperhomocysteinemia related to low levels of folate, B(6), and B(12) and to the TT polymorphism of MTHFR. PMID:11747974

  3. Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida.

    PubMed

    Johnson, W G; Stenroos, E S; Heath, S C; Chen, Y; Carroll, R; McKoy, V V; Chatkupt, S; Lehner, T

    1999-12-22

    Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found. PMID:10594879

  4. 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 the g.2244A>G and g.2264A>G SNPs. The current study evaluated these SNPs as potential genetic markers in goats, with potential applications in breeding programs. PMID:26186555

  5. 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

  6. MTHFR 677C/T and 1298A/C mutations and non-alcoholic fatty liver disease.

    PubMed

    Kasapoglu, Benan; Turkay, Cansel; Yalcin, Kadir Serkan; Kosar, Ali; Bozkurt, Alper

    2015-06-01

    Common genetic mutations encountered in folate metabolism may result in increased homocysteine (Hcy) levels. It has been reported that increased serum Hcy levels may affect the intracellular fat metabolism and may cause enhanced fatty infiltration in the liver resulting in non-alcoholic fatty liver disease (NAFLD). In total, 150 patients diagnosed with FLD by ultrasound examination and 136 healthy control patients that do not have any fatty infiltration in the liver were included in the study. Patients were grouped as mild (n = 88), moderate (n = 38) or severe (n = 24) according to the stage of fatty liver in ultrasound. Serum liver function tests, Hcy, folic acid and vitamin B12 levels of the patients were studied. The genetic MTHFR C677T and A1298C polymorphisms of the patients were also evaluated. Although there was no significant difference in vitamin B12 and folic acid levels, in the severe group, Hcy levels were significantly higher than that of control and mild groups (p<0.001). By contrast, there was no significant difference in heterozygote MTHFR 677C/T and 1298A/C mutations, both MTHFR 677C/T and MTHFR 1298A/C mutations were more common in NAFLD groups compared with the control patients (p<0.001). We have determined increased Hcy levels and increased prevalence of homozygote MTHFR 677C/T and MTHFR 1298A/C mutations in patients with NAFLD compared with healthy controls. Larger studies are warranted to clarify the etiological role of the MTHFR mutations and Hcy levels in FLD. PMID:26031974

  7. Myocardial infarction in a newborn heterozygous for the MTHFR C677T mutation.

    PubMed

    Clark, Amy B; Stokes, Theophil A; Krous, Henry F; Carbine, Douglas N

    2012-01-01

    Neonatal myocardial infarction secondary to congenital heart disease, anomalous coronary artery anatomy, thromboembolism, coagulopathy, birth asphyxia, and unknown causes has been previously reported. We now report an infant who suffered a massive myocardial infarction during birth, requiring extensive resuscitation and aggressive management. A thrombus, the origin of which was not detected on autopsy, was found occluding the proximal left coronary artery several hours after birth. Genetic studies revealed a single copy variant of the MTHFR C677T mutation that we speculate may have predisposed the infant to coronary thrombosis. PMID:22339112

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

    PubMed

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

    2015-10-01

    The incidence of congenital heart defects is higher in infants with mutation of methylenetetrahydrofolate reductase (MTHFR) gene. The MTHFR C677T gene decreases the bioavailability of folate and increases plasma homocysteine, a risk factor for thrombosis. There have been no reported cases in the literature on the clinical implications of this procoagulable state in the setting of cyanotic heart disease, which itself has prothrombotic predisposition. Two patients with hypoplastic left heart syndrome developed postoperative thrombotic complications, both were homozygous for MTHFR C677T. We present these cases and highlight the implications of MTHFR mutation in the management of complex congenital heart disease. PMID:26467879

  9. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease

    SciTech Connect

    Kluijtmans, L.A.J.; Heuvel, L.P.W.J. van den; Stevens, E.M.B.

    1996-01-01

    Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine P-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T{yields}C (1278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C{yields}T; A{yields}V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHFR activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T{yields}C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-{yields}T mutation in the MTHFR gene was found in 9 (15%) of 60 cardiovascular patients and in only 6 ({approximately}5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.21]). Because of both the high prevalence of the 833T-{yields}C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease. 35 refs., 3 figs., 1 tab.

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

    PubMed Central

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

    2012-01-01

    Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.102.04 and HR 2.16, 95%CI 1.243.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. PMID:22669161

  11. Recurrent cerebral venous thrombosis associated with heterozygote methylenetetrahydrofolate reductase C677T mutation and sickle cell trait without homocysteinemia: an autopsy case report and review of literature.

    PubMed

    Ali, Z; Troncoso, J C; Fowler, D R

    2014-09-01

    Elevated blood homocysteine concentration and certain genetic mutations have been associated with increased risk for developing arterial and venous thrombosis. A common mutation of methylenetetrahydrofolate reductase, MTHFR C677T, has been associated with elevated homocysteine concentration and increased risk for developing thrombosis in homozygote carriers. Heterozygote carriers for this gene mutation, if associated with other major or minor risk factors for thrombophilia, appear to be prone to develop thrombosis. A postmortem genetic testing for common mutations resulting in thrombophilia should be performed in all individuals who die as a result of thrombosis, regardless of predisposing risk factors, to determine the true prevalence of mutations in these individuals, and to assess the true role of a certain mutation, such as heterozygote MTHFR C677T, in the pathogenesis of thrombosis. Postmortem genetic testing for common mutations associated with thrombophilia in selected cases has potentially life-saving importance to surviving family members. We report a case of recurrent cerebral venous thrombosis in a 19 year old male with history of sickle cell trait, obesity, and high normal blood homocysteine, who was heterozygote for MTHFR C677T mutation. PMID:25074331

  12. The Prevalence of Factor V Leiden (G1691A) and Methylenetetrahydrofolate Reductase C677T Mutations in Sickle Cell Disease in Western India.

    PubMed

    Kangne, Harshada K; Jijina, Farah F; Italia, Yazdi M; Jain, Dipti L; Nadkarni, Anita H; Ghosh, Kanjaksha K; Colah, Roshan B

    2015-03-01

    The prevalence of the Factor V Leiden (FVL; G1691A) mutation and the methylenetetrahydrofolate reductase (MTHFR; C677T) mutation was determined in 180 patients with sickle cell (SS) disease (126 sickle homozygous and 54 sickle ?-thalassaemia--age 1-47 years) and in 130 healthy controls. The FVL mutation in the heterozygous state was present in only 3 patients with SS disease and was absent in the controls. Genotyping of MTHFR 677C > T revealed increased frequency of the C allele than the T allele in patients as well as in controls. This suggests that these genetic markers may not be major risk factors for a hypercoagulable state in Indian patients with SS disease. PMID:23869056

  13. Association of methylenetetrahytrofolate reductase (MTHFR) C677T and A1298C polymorphisms with the susceptibility of childhood acute lymphoblastic leukaemia (ALL) in Chinese population

    PubMed Central

    2014-01-01

    Background The aim of this study was to investigate the relationship between the polymorphisms of the methylenetetrahytrofolate reductase (MTHFR) gene and susceptibility to childhood acute lymphoblastic leukemia (ALL). Methods A casecontrol study was conducted among 98 children with ALL and 93 age- and sex- matched non-ALL controls. Genotyping of MTHFR C677T and A1298C polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) of MTHFR genotypes were used to assess the associations of these polymorphisms with childhood ALL susceptibility. Results No significant differences were observed for frequencies of the 677CC, 677CT and 677TT genotypes between patients and controls. Frequencies of the 1298AA, 1298AC and 1298CC genotypes between the two groups were significantly different. The risk of ALL with the 1298C allele carriers (AC?+?CC) was elevated by 1.1 times compared with the AA genotype [OR?=?2.100; 95% CI (1.149; 3.837); P?=?0.015]. Conclusions The MTHFR A1298C polymorphism is associated with susceptibility to childhood ALL in the Chinese population. PMID:24476575

  14. 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; Coad?, Camelia A; Costache, Roxana M; Militaru, Mariela S; Vesa, ?tefan 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. PMID:23828072

  15. Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in 200 healthy Jordanians.

    PubMed

    Eid, Suhair S; Rihani, Ghada

    2004-01-01

    Thrombophilia is now considered a multi-causal condition, with interplay of acquired genetic risk factors. In order to estimate the frequency of the factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in the Jordanian population, we screened 200 healthy Jordanian individuals. 40% were females. Mean age was 32.1 years for males and 30.0 years for female participants. A PCR method detected 15.0% factor V Leiden (87% heterozygous, 13% homozygous), 2% prothrombin G20210A (100% heterozygous), and 24% MTHFR C677T (67% heterozygous, 33% homozygous). We conclude that the prevalence of factor V Leiden and MTHFR C677T is elevated in this population of Jordanians. However the incidence of G20210A is relatively low. Quantification of these genetic thrombosis risk factors in various populations will contribute to a better understanding of the interaction of genetic and environmental risk factors. PMID:15559724

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

    PubMed

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

    2014-08-01

    Because a number of data studies include some controversial results about Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Down syndrome (DS), we performed a meta-analysis to determine a more precise estimation of this association. Studies were searched on PubMed, EMBASE and Lilacs-Scielo, up to April 2013, and they were eligible if they included case mothers (DSM) that have gave birth to children with DS, and controls mothers (CM) that have gave birth to healthy children without chromosomal abnormality, syndrome or malformation. The combined odds ratio with 95% confidence intervals was calculated by fixed or random effects models to assess the strength of associations. Potential sources of heterogeneity between studies were evaluated using Q test and the I(2). Publication bias was estimated using Begg's test and Egger's linear regression test. Sensitivity analyses were performed by using allelic, dominant, recessive and codominant genetic models, Hardy-Weinberg equilibrium (HWE) and ethnicity. Twenty-two studies with 2,223 DSM and 2,807 CM were included for MTHFR C677T and 15 studies with 1,601 DSM and 1,849 CM were included for MTHFR A1298C. Overall analysis suggests an association of the MTHFR C677T polymorphism with maternal risk for DS. Moreover, no association between the MTHFR A1298C polymorphism and maternal risk for DS was found. There is also evidence of higher heterogeneity, with I(2) test values ranging from 8 to 89%. No evidence of publication bias was found. Taken together, our meta-analysis implied that the T allele carriers might carry an increased maternal risk for DS. PMID:24913031

  17. A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE IS ASSOCIATED WITH QUANTITATIVE ULTRASOUND IN THOSE WITH LOW PLASMA FOLATE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bo...

  18. 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. PMID:24123968

  19. Elevated total plasma homocysteine and 667C{r_arrow}T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease

    SciTech Connect

    De Franchis, R.; Sebastio, G.; Andria, G.

    1996-07-01

    Moderate elevation of total plasma homocysteine (tHcy) has been reported as an independent risk factor for thrombotic vascular disease, a well-known multifactorial disorder. Possible genetic causes of elevated tHcy include defects of the sulfur-containing amino acids metabolism due to deficiencies of cystathionine {Beta}-synthase, of 5,10-methylenetetrahydrofolate reductase (MTHFR), and of the enzymes of cobalamin metabolism. An impaired activity of MTHFR due to a thermolabile form of the enzyme has been observed in {le}28% of hyperhomocysteinemic patients with premature vascular disease. More recently, the molecular basis of such enzymatic thermolability has been related to a common mutation of the MTHFR gene, causing a C-to-T substitution at nt 677 (677C{r_arrow}T). This mutation was found in 38% of unselected chromosomes from 57 French Canadian individuals. The homozygous state for the mutation was present in 12% of these subjects and correlated with significantly elevated tHcy. Preliminary evidence indicates that the frequency of homozygotes for the 677C{r_arrow}T mutation may vary significantly in populations from different geographic areas. 5 refs., 2 tabs.

  20. 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

    2016-04-01

    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. PMID:26273990

  1. Folate intake, serum homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T genotype are not associated with oral cancer risk in Puerto Rico.

    PubMed

    Weinstein, Stephanie J; Gridley, Gloria; Harty, Lea C; Diehl, Scott R; Brown, Linda M; Winn, Deborah M; Bravo-Otero, Eleuterio; Hayes, Richard B

    2002-04-01

    We examined the relationships between folate and methionine intake, serum homocysteine levels (as a biomarker for folate metabolism), and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism genotype and risk of oral cancer in a population-based, case-control study in Puerto Rico. Structured questionnaires were used to collect information on demographic factors, usual adult diet, and tobacco and alcohol use. Oral epithelial cells and blood samples were collected from a subset of subjects. Analyses were conducted by logistic regression, adjusting for age, sex, lifetime smoking and lifetime alcohol intake, with the following numbers of cases/controls, respectively: dietary data (341/521); MTHFR genotype (148/149); and homocysteine (60/90). Although increased folate intake was associated with decreased oral cancer risk [adjusted odds ratio (OR) in highest vs. lowest quartile = 0.6, 95% confidence interval (CI): 0.4, 1.0, P(trend) = 0.05)], this finding was due almost entirely to folate intake from fruit (adjusted OR = 0.4, 95% CI: 0.2, 0.6; P(trend) = 0.0001), whereas other dietary folate sources showed no clear association. Methionine intake and serum homocysteine levels were not associated with oral cancer risk. Subjects with the MTHFR C677T homozygous variant (TT) genotype had a nonsignificantly lower risk, and risk patterns tended to differ by level of folate, methionine, alcohol intake and smoking, although the power to detect significant associations in subgroups of these variables was low. Risks for oral cancer are not folate specific; preventive recommendations for this disease should emphasize the importance of a healthy diet, including substantial intake of fruits. PMID:11925474

  2. 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 (<28weeks of gestation, n=22), very preterm (2832weeks of gestation, n=43) and moderate preterm (3237weeks 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

  3. Methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and G1793A genotypes, and the relationship between maternal folate intake, tibia lead and infant size at birth

    PubMed Central

    Kordas, Katarzyna; Ettinger, Adrienne S.; Lamadrid-Figueroa, Hctor; Tellez-Rojo, Martha M.; Hrnandez-Avila, Mauricio; Hu, Howard; Wright, Robert O.

    2011-01-01

    Small size at birth continues to be a problem worldwide and many factors, including reduced folate intake and Pb exposure, are associated with it. However, single factors rarely explain the variability in birth weight, suggesting a need for more complex explanatory models. We investigated environmentgene interactions to understand whether folate intake and maternal Pb exposure were associated with smaller newborn size in 474 women with uncomplicated pregnancies delivering term infants in Mexico City. We examined if folate intake modified the negative effects of maternal Pb burden on birth size. We also asked if maternal and infant methylenetetrahydrofolate reductase (MTHFR) genotypes (C677T, A1298C and G1793A) modified the effects of folate intake or Pb exposure on birth size. Women were aged 246 (SD 51) years; 435 % were primiparous. Maternal blood Pb at delivery was 86 (SD 42) ?g/l, with 267 % having levels ?100 ?g/l. Tibia Pb level was 99 (SD 98) ?g/g. Of the women, 353 % had folate intakes <400 ?g/d. Birth weight was 3170 (SD 422) g. In covariate-adjusted regressions, higher folate intake was associated with higher birth weight (? 004; P<005). Higher bone Pb was associated with lower birth weight (? ?49; P<005). Folate intake did not modify the effects of Pb on birth size, nor did MTHFR modify the association between Pb or folate intake on birth size. Although modest, the relationship between maternal nutrition, Pb burden and birth size does underscore the importance of environmental exposures to child health because patterns of fetal growth may affect health outcomes well into adulthood. PMID:19338708

  4. Recurrent ischemic strokes in a young celiac woman with MTHFR gene mutation

    PubMed Central

    Fabbri, Elisa; Rustignoli, Lisa; Muscari, Antonio; Puddu, Giovanni M; Guarino, Maria; Rinaldi, Rita; Minguzzi, Elena; Caio, Giacomo; Zoli, Marco; Volta, Umberto

    2012-01-01

    Celiac disease (CD) is frequently associated with neurological disorders, but very few reports concern the association with ischemic stroke. A 26-year-old woman affected by CD with secondary amenorrhea, carrier of a homozygous 5,10-methylenetetrahydrofolate reductase mutation with hyperhomocysteinemia, was affected by two occipital ischemic strokes within a period of 5 mo. At the time of the second stroke, while she was being treated with folic acid, acetylsalicylic acid and a gluten-free diet, she had left hemianopsia, left hemiparesthesias, and gait imbalance. Brain magnetic resonance imaging showed a subacute right occipital ischemic lesion, which was extended to the dorsal region of the right thalamus and the ipsilateral thalamo-capsular junction. Antitransglutaminase and deamidated gliadin peptide antibodies were no longer present, while antinuclear antibodies, antineuronal antibodies and immune circulating complexes were only slightly elevated. Since the patient was taking folic acid, her homocysteine ??levels were almost normal and apparently not sufficient alone to explain the clinical event. A conventional cerebral angiography showed no signs of vasculitis. Finally, rare causes of occipital stroke in young patients, such as Fabrys disease and mitochondrial myopathy, encephalomyopathy, lactic acidosis and stroke-like symptoms, were also excluded by appropriate tests. Thus, the most probable cause for the recurrent strokes in this young woman remained CD, although the mechanisms involved are still unknown. The two main hypotheses concern malabsorption (with consequent deficiency of vitamins known to exert neurotrophic and neuroprotective effects) and immune-mediated mechanisms. CD should be kept in mind in the differential diagnosis of ischemic stroke in young patients. PMID:22807619

  5. Prevalence of MTHFR C677T single nucleotide polymorphism in genetically isolated populations in Jordan.

    PubMed

    Dajani, Rana; Fathallah, Raja; Arafat, Ala; AbdulQader, Mohammed Emad; Hakooz, Nancy; Al-Motassem, Yousef; El-Khateeb, Mohammad

    2013-10-01

    Methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism is a major inherited risk factor of venous thromboembolism. We sought to determine its prevalence in genetically isolated populations of Chechens and Circassians in Jordan. The MTHFR C677T mutation was analyzed from blood samples taken from 120 random unrelated Chechens and 72 Circassians. The prevalence of the MTHFR mutation in the Chechen population was 27.5% (allele frequency 15%); the prevalence among the Circassians was 50% (allele frequency 29.2%). The prevalence in the Chechen population is similar to that in Jordan and other world populations, but it is higher in the Circassian population. This study will contribute to understanding the interaction between genetic and environmental risk factors underlying thrombosis and will be useful in deciding which genetic variants should be tested in a clinical genetic testing service. PMID:23749065

  6. [Relationship of MTHFR gene polymorphisms with infertility].

    PubMed

    Guo, Kai-min; Tian, Run-hui; Wang, Hong-liang

    2016-02-01

    The folate metabolic pathway plays important roles in cellular physiology by participating in nucleotide synthesis, DNA repair and methylation, and maintenance and stability of the genome. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme involved in folate metabolism. Polymorphisms of MTHFR may change the level of homocysteine and affect DNA synthesis and methylation, leading to an increased oxidative stress and disturbed methylation reactions and consequently affecting reproductive function. This article presents an overview on MTHFR gene polymorphisms, proposing that multicentered, large-sample and long-term prospective studies are needed to reveal the relationship between MTHFR gene polymorphisms and infertility. PMID:26939404

  7. Factor V-Leiden, prothrombin G20210A, and MTHFR C677T mutations among patients with sickle cell disease in Eastern Saudi Arabia.

    PubMed

    Fawaz, Naglaa A; Bashawery, Layla; Al-Sheikh, Iman; Qatari, Ahlam; Al-Othman, Sara S; Almawi, Wassim Y

    2004-07-01

    The prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations were investigated among 87 Saudi sickle cell disease (SCD) patients (38 males and 49 females) and 105 healthy controls (65 males and 40 females). The prevalences of factor V Leiden (P = 0.174) and PRT G20210A (P = 0.397) were not different between patients and controls, thereby giving no support to an association of either single-point mutation with SCD. However, an increased prevalence of the MTHFR 677 T/T genotype was seen among patients (8/87) compared to controls (4/105), but this was not statistically significant (P = 0.217; OR = 2.56). This suggested a low impact of inherited hypercoagulability risk factors in the pathogenesis of SCD and/or its complications. PMID:15224376

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

    PubMed

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

    2014-01-01

    In this study, we examined the distribution of genotype and allele frequencies of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase gene (MTHFR) in two ethnic groups in the State of Guerrero, Mexico, which were compared with those of the Mestizo population of the region. A comparative study was conducted on 455 women from two ethnic groups and a group of Mestizo women of the State of Guerrero, Mexico: 135 Nahuas, 124 Mixtecas, and 196 Mestizas. Genotyping of both polymorphisms were performed by using polymerase chain reaction-restriction fragment length polymorphism methods. We found that the 677TT genotype was more frequent in Nahua and Mixteca women compared to Mestiza women (P = 0.008), and the most prevalent genotype in both ethnic groups was the 1298AA genotype (P < 0.001). We also compared the 677T allele frequency obtained from the groups studied with the frequencies reported in other ethnic groups of Mexico (Huichol, Tarahumara, and Purepecha). There were significant differences between the three ethnic groups compared to Nahuas (Huicholes, P = 0.004; Tarahumaras, P < 0.001; Purepechas, P = 0.042). Our results indicated significant differences in the frequencies of the C677T and A1298C polymorphisms between the two ethnic groups and the Mestizo population of the State of Guerrero. In addition, we found strong differences with other ethnic groups in Mexico. These results could be useful for future studies investigating diseases related to folate metabolism, and could help the government to design specific nutrition programs for different ethnic groups. PMID:25299110

  9. Mutationally altered ribonucleotide reductase from Escherichia coli: characterization of mutations isolated on multicopy plasmids.

    PubMed Central

    Platz, A; Sjberg, B M

    1984-01-01

    The Escherichia coli ribonucleotide reductase genes (nrd genes) were mutagenized at random. Point mutations were introduced in vitro into a recombinant nrd plasmid. Transformants were initially screened for altered tolerance toward the drug hydroxyurea and further characterized by enzymatic and immunological methods. The screening procedure could pick out defects in either of the two subunits of ribonucleotide reductase. Cells carrying the nrd plasmid pPS2 were earlier shown to have levels of ribonucleotide reductase molecules that were 10 to 20 times higher than those in wild-type cells. We now demonstrate that the enzymatic activity in gently lysed pPS2-containing cells on cellophane disks is six times higher than in wild-type cells. Supplementation of the pPS2-containing lysates with a purified thioredoxin system results in a further 4.5-fold stimulation of the enzymatic activity, which implies a functional shortage of the electron donor system(s) for ribonucleotide reduction in pPS2-containing cells. PMID:6389503

  10. Massive pulmonary embolism associated with Factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase gene mutations in a young patient on oral contraceptive pills: a case report.

    PubMed

    Charafeddine, Khalil M; Mahfouz, Rami A; Ibrahim, Georges Y; Taher, Ali T; Hoballah, Jamal J; Taha, Assad M

    2010-10-01

    Factor V Leiden (Factor V G1691A), prothrombin gene mutation G20210A, and homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene are known to predispose venous thromboembolism (VTE). We present herein a rare case of a young woman heterozygous for these mutations and taking oral contraceptive pills for less than 2 months, diagnosed to have massive deep venous thrombosis and bilateral pulmonary embolism. The patient was managed for 10 days in the hospital and discharged home on oral anticoagulants. This case suggests that screening for these factors in people with family history of thrombosis and in relatives of patients with these mutations is highly recommended to prevent fatal consequences. In addition, a new guideline for treatment and prophylaxis with anticoagulant for these patients and others who are at risk of developing VTE (American College of Chest Physicians [ACCP] guidelines-Chest 2008) has been published recently. Our recommendation is to promote for the internationally published algorithms through their application, where necessary, to prevent any future thrombotic morbidity or mortality incidents. PMID:19520679

  11. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.

    PubMed

    Waterham, H R; Wijburg, F A; Hennekam, R C; Vreken, P; Poll-The, B T; Dorland, L; Duran, M; Jira, P E; Smeitink, J A; Wevers, R A; Wanders, R J

    1998-08-01

    Smith-Lemli-Opitz syndrome is a frequently occurring autosomal recessive developmental disorder characterized by facial dysmorphisms, mental retardation, and multiple congenital anomalies. Biochemically, the disorder is caused by deficient activity of 7-dehydrocholesterol reductase, which catalyzes the final step in the cholesterol-biosynthesis pathway-that is, the reduction of the Delta7 double bond of 7-dehydrocholesterol to produce cholesterol. We identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the database of expressed sequence tags with the amino acid sequence for the Arabidopsis thaliana sterol Delta7-reductase and isolated the remaining 5' sequence by the "rapid amplification of cDNA ends" method, or 5'-RACE. The cDNA has an open reading frame of 1,425 bp coding for a polypeptide of 475 amino acids with a calculated molecular weight of 54.5 kD. Heterologous expression of the cDNA in the yeast Saccharomyces cerevisiae confirmed that it codes for 7-dehydrocholesterol reductase. Chromosomal mapping experiments localized the gene to chromosome 11q13. Sequence analysis of fibroblast 7-dehydrocholesterol reductase cDNA from three patients with Smith-Lemli-Opitz syndrome revealed distinct mutations, including a 134-bp insertion and three different point mutations, each of which was heterozygous in cDNA from the respective parents. Our data demonstrate that Smith-Lemli-Opitz syndrome is caused by mutations in the gene coding for 7-dehydrocholesterol reductase. PMID:9683613

  12. Antifolates and MTHFR.

    PubMed

    Trachtman, Joseph N; Pagano, Vincent

    2015-12-01

    We describe a patient who developed symptoms of headache, fatigue, and dizziness after administration of terbinafine (Lamisil). Laboratory tests revealed that he is heterozygous for the C677T variation of the methylenetetrahydrofolate reductase genetic mutation. The prescription of Deplin (L-methylfolate) greatly reduced the symptoms. It was later noted that Lamisil's mechanism of action interferes with cells' methylation cycle, which we suspect compromises cellular function in people with the methylenetetrahydrofolate reductase genetic mutation. PMID:25929315

  13. Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder

    PubMed Central

    Gokcen, Cem; Kocak, Nadir; Pekgor, Ahmet

    2011-01-01

    Objective: The purpose of this study was to evaluate the relationship between 5,10- methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Turkish children. Study Design: MTHFR gene polymorphisms were assessed in 40 patients with ADHD and 30 healty controls. Two mutations in the MTHFR gene were investigated using polymerase chain reactions and restriction fragment length polymorphisms. Results: Although there were no statistically significant differences in genotype distributions of the C677T alleles between the ADHD and the control groups (p=0,678) but the genotypic pattern of the distributions of the A1298C alleles was different between the ADHD patients and the controls (p=0,033). Conclusions: Preliminary data imply a possible relationship between A1298C MTHFR polymorphisms and the ADHD. PMID:21897766

  14. Association study between methylenetetrahydrofolate reductase gene polymorphisms and Graves' disease.

    PubMed

    Mao, Renfang; Fan, Yihui; Zuo, Lulu; Geng, Dongfeng; Meng, Fantao; Zhu, Jing; Li, Qiang; Qiao, Hong; Jin, Yan; Bai, Jing; Fu, Songbin

    2010-10-01

    5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides, which are essential for DNA synthesis and methylation. It is highly polymorphic, and its variant genotypes result in lower enzymatic activity and higher plasma homocysteine. Previous studies have provided evidence that a high prevalence of MTHFR gene polymorphisms is frequently detected in patients with autoimmune disease, suggesting a novel genetic association with autoimmune disorders. However, the genetic association between MTHFR and Graves' disease (GD), one of the most common autoimmune diseases, has not been studied. Here, we designed a clinic-based case-control study including 199 GD cases and 235 healthy controls to examine the associations between three common MTHFR polymorphisms (i.e., C677T, A1298C, and G1793A) and GD. Surprisingly, logistic regression analysis shows MTHFR 677CT?+?TT genotypes are associated with an approximately 42% reduction in the risk of GD in women (adjusted OR?=?0.58, 95% CI?=?0.3-0.9), compared to the CC genotype, indicating a significant protective effect of 677CT?+?TT genotypes. Our result provides epidemiological evidence that MTHFR mutation (C677T) protects women from GD. The protective effect, possibly obtained by influencing DNA methylation, should be confirmed in a large number of cohorts. PMID:20941748

  15. Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks.

    PubMed

    Jakubowska, Anna; Gronwald, Jacek; Menkiszak, Janusz; Grski, Bohdan; Huzarski, Tomasz; Byrski, Tomasz; Edler, Lutz; Lubi?ski, Jan; Scott, Rodney J; Hamann, Ute

    2007-09-01

    Methylenetetrahydrofolate reductase (MTHFR), a key regulatory enzyme in the metabolism of folate, is suspected to play a role in the etiology of cancer, via its effects on DNA methylation and nucleotide synthesis. In this study we have investigated the effect of two functional polymorphisms of the MTHFR gene, MTHFR_677_C > T and MTHFR_1298_A > C, on breast and ovarian cancer risk in Polish BRCA1 mutation carriers. The study included 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Odds ratios (OR) were calculated using univariate and multivariate logistic regression taking into account a series of confounding variables that potentially could have biased any association. The results revealed that the MTHFR_677_C > T change was associated with an increased risk of breast and ovarian cancer. The MTHFR_1298_A > C polymorphism was only associated with a decrease in breast cancer risk. Together, it appears that functional polymorphisms in the MTHFR gene modify the risk of breast and may potentially alter the risk of ovarian cancer in women with an inherited predisposition. PMID:17063264

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

    PubMed

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

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine. PMID:24461181

  17. 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 2875 were enrolled in this study from September 2005December 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

  18. 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

    2015-08-01

    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

  19. Evaluation of Gestational Diabetes Mellitus Risk in South Indian Women Based on MTHFR (C677T) and FVL (G1691A) Mutations

    PubMed Central

    Khan, Imran Ali; Shaik, Noor Ahmad; Kamineni, Vasundhara; Jahan, Parveen; Hasan, Qurratulain; Rao, Pragna

    2015-01-01

    We aimed to scrutinize the extent to which single amino acid substitutions in the MTHFR and factor V Leiden (FVL) genes affect the risk of gestational diabetes mellitus (GDM) in pregnant women of South Indian descendant. This casecontrol study was implemented once the ethical approval has been obtained. Overall, 237 women were recruited in this study: 137 had been diagnosed with GDM and the remaining 100 women were used as normal controls or non-GDM. The diagnosis of GDM was confirmed with biochemical analysis, i.e., GCT and oral glucose tolerance tests. Five milliliters of peripheral blood was collected and used for biochemical and molecular analyses. DNA was isolated, and genotyping for MTHFR (C677T) and FVL (G1691A) mutations was performed using PCRRFLP. FVL (G1691A) locus was not polymorphic in the investigated sample. There was no significant difference in the allele and genotype frequencies of C677T polymorphism between GDM and non-GDM women (p?=?0.8892). PMID:26000264

  20. MTHFR gene polymorphisms in bladder cancer in the Turkish population.

    PubMed

    Izmirli, Muzeyyen; Inandiklioglu, Nihal; Abat, Deniz; Alptekin, Davut; Demirhan, Osman; Tansug, Zuhtu; Bayazit, Yildirim

    2011-01-01

    Bladder cancer is the 9th most common cancer and is responsible for malignancy related death all on the world. Folate and folate related enzyme polymorphisms related to the cancer risk. The methylene tethrahydrofolate reductase (MTHFR) enzyme is folate related and association of bladder cancer and MTHFR gene. Our purpose was to assess the prevalence of MTHFR gene 677 CT and 1298 AC polymorphisms and Bladder cancer in Turkey. We intended that bladder cancer patients and controls and we used the Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) methods. The MTHFR gene C677T and A1298C polymorphisms were associated with an increased risk of bladder cancer in our population (For the MTHFR gene C677T polymorphism and A1298C polymorphism; p=0.036<0.05; p=0.278>0.05 respectively). Consequently, the MTHFR gene C677T polymorphism augments the risk of bladder cancer in Turkey. PMID:22126575

  1. The clinical impact of MTHFR polymorphism on the vascular complications of sickle cell disease.

    PubMed

    Moreira Neto, F; Loureno, D M; Noguti, M A E; Morelli, V M; Gil, I C P; Beltro, A C S; Figueiredo, M S

    2006-10-01

    Sickle cell disease (SCD) is one of the most common inherited diseases in the world and the patients present notorious clinical heterogeneity. It is known that patients with SCD present activation of the blood coagulation and fibrinolytic systems, especially during vaso-occlusive crises, but also during the steady state of the disease. We determined if the presence of the factor V gene G1691A mutation (factor V Leiden), the prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may be risk factors for vascular complications in individuals with SCD. We studied 53 patients with SCD (60% being women), 29 with SS (sickle cell anemia; 28 years, range: 13-52 years) and 24 with SC (sickle-hemoglobin C disease; 38.5 years, range: 17-72 years) hemoglobinopathy. Factor V Leiden, MTHFR C677T polymorphism, and prothrombin G20210A variant were identified by PCR followed by further digestion of the PCR product with specific endonucleases. The following vascular complications were recorded: stroke, retinopathy, acute thoracic syndrome, and X-ray-documented avascular necrosis. Only one patient was heterozygous for factor V Leiden (1.8%) and there was no prothrombin G20210A variant. MTHFR 677TT polymorphism was detected in 1 patient (1.8%) and the heterozygous form 677TC was observed in 18 patients (34%, 9 with SS and 9 with SC disease), a prevalence similar to that reported by others. No association was detected between the presence of the MTHFR 677T allele and other genetic modulation factors, such as alpha-thalassemia, beta-globin gene haplotype and fetal hemoglobin. The presence of the MTHFR 677T allele was associated with the occurrence of vascular complications in SCD, although this association was not significant when each complication was considered separately. In conclusion, MTHFR C677T polymorphism might be a risk factor for vascular complications in SCD. PMID:16906320

  2. 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

  3. [Genetic variant C677T in the MTHFR in women with recurrent early fetal loss].

    PubMed

    Ivanov, P; Kovacheva, K; Komsa-Penkova, R; Konova, E; Simeonova, M; Popov, I; Gecheva, S; Bozhinova, S; Tanchev, S; Tsafarov, M

    2007-01-01

    The aim of this study was to evaluate correlation of carrier status for thrombophilic gene mutation--C677T in the methylenetetrahydrofolate reductase (MTHFR) and recurrent early pregnancy loss. Recently inherited thrombophilia was discussed as a predisposed factor for early recurrent fetal loss (ERFL). We investigated carrier status for C677T genetic variant in 54 women with ERFL before 10 week of gestation and 67 women with one or more successful pregnancy. It was found significant prevalence of C677T genetic variant in MTHFR in women with ERFL compared with controls (p = 0.005). The significant high prevalence of C677T genetic variant in women with ERFL suggests that thrombophilia have an increased risk of early pregnancy loss and possibly, although the definition of the magnitude of risk will require prospective longitudinal studies. PMID:17974190

  4. A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy

    PubMed Central

    Krebs, Stefan; Medugorac, Ivica; Rther, Susanne; Strsser, Katja; Frster, Martin

    2007-01-01

    The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketodihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle. PMID:17420465

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

    PubMed

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

    2015-01-01

    Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessively inherited inborn error of folate metabolism. We report a new patient with severe MTHFR deficiency who presented at age 4 months with early onset severe scoliosis associated with severe hypotonia. Markedly decreased MTHFR enzyme activity (0.3 nmoles CHO/mg protein/h; reference range>9) and compound heterozygous mutations (c. 1304T>C; p.Phe435Ser and c.1539dup; p.Glu514Argfs∗24) in the MTHFR gene confirmed the diagnosis. She was treated with vitamin B12, folic acid and betaine supplementation and showed improvements in her developmental milestones and hypotonia. To the best of our knowledge, this is the first patient with MTHFR deficiency reported with severe early onset scoliosis. Despite the late diagnosis and treatment initiation, she showed favorable short-term neurodevelopmental outcome. This case suggests that homocysteine measurement should be included in the investigations of patients with developmental delay, hypotonia and scoliosis within first year of life prior to organizing genetic investigations. PMID:24726568

  6. 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

  7. Inherited prothrombotic risk factors in Turkish children with acute lymphoblastic leukemia: significance of concomitant genetic mutation.

    PubMed

    Torun, Yasem'n Altuner; Patiroglu, Turkan; Ozdemir, Mehmet Akif; Ozkul, Yusuf; Ekici, Arzu; Karakukcu, Musa

    2012-01-01

    Our study was designed to prospectively evaluate the role of the methylenetetrahydrofolate reductase (MTHFR) TT677 genotype, the prothrombin (PT) 620210A mutation, the factor V G1691A mutation in leukemic Turkish children treated according to modified BFM 95 study protocols with respect to the onset at thromboembolic events. Eighty-two consecutive leukemic children investigated had are established inherited prothrombotic risk factor: 29 children showed the MTHFR genotype (heterozygous, n = 22; homozygous, n = 7); 3 showed the heterozygous PT G20210A variant; 16 were carriers of the factor V mutation (heterozygous). In addition, combined prothrombotic defects were found in a further 11 patients the MTHFR mutation was combined with the F V mutation (n = 7), the PT G20210A variant (n = 2). In 7 (8.5%) of these 82 patients, venous thromboembolism occurred. In conclusion, the presence of inherited thrombophilia with Turkish children treated acute lymphoblastic leukemia may be useful for designing targeted primary prevention strategies. PMID:21873357

  8. Mutations in the dihydrofolate reductase gene of trimethoprim-resistant isolates of Streptococcus pneumoniae.

    PubMed Central

    Adrian, P V; Klugman, K P

    1997-01-01

    Streptococcus pneumoniae isolates resistant to several antimicrobial agent classes including trimethoprim-sulfamethoxazole have been reported with increasing frequency throughout the world. The MICs of trimethoprim, sulfamethoxazole, and trimethoprim-sulfamethoxazole (1:19) for 259 clinical isolates from South Africa were determined, and 166 of these 259 (64%) isolates were resistant to trimethoprim-sulfamethoxazole (MICs > or =20 mg/liter). Trimethoprim resistance was found to be more strongly correlated with trimethoprim-sulfamethoxazole resistance (correlation coefficient, 0.744) than was sulfamethoxazole resistance (correlation coefficient, 0.441). The dihydrofolate reductase genes from 11 trimethoprim-resistant (MICs, 64 to 512 microg/ml) clinical isolates of Streptococcus pneumoniae were amplified by PCR, and the nucleotide sequences were determined. Two main groups of mutations to the dihydrofolate reductase gene were found. Both groups shared six amino acid changes (Glu20-Asp, Pro70-Ser, Gln81-His, Asp92-Ala, Ile100-Leu, and Leu135-Phe). The first group included two extra changes (Lys60-Gln and Pro111-Ser), and the second group was characterized by six additional amino acid changes (Glu14-Asp, Ile74-Leu, Gln91-His, Glu94-Asp, Phe147-Ser, and Ala149-Thr). Chromosomal DNA from resistant isolates and cloned PCR products of the genes encoding resistant dihydrofolate reductases were capable of transforming a susceptible strain of S. pneumoniae to trimethoprim resistance. The inhibitor profiles of recombinant dihydrofolate reductase from resistant and susceptible isolates revealed that the dihydrofolate reductase from trimethoprim-resistant isolates was 50-fold more resistant (50% inhibitory doses [ID50s], 3.9 to 7.3 microM) than that from susceptible strains (ID50s, 0.15 microM). Site-directed mutagenesis experiments revealed that one mutation, Ile100-Leu, resulted in a 50-fold increase in the ID50 of trimethoprim. The resistant dihydrofolate reductases were characterized by highly conserved redundant changes in the nucleotide sequence, suggesting that the genes encoding resistant dihydrofolate reductases may have evolved as a result of inter- or intraspecies recombination by transformation. PMID:9371341

  9. 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

  10. Mutational analysis of the nor gene cluster which encodes nitric-oxide reductase from Paracoccus denitrificans.

    PubMed

    de Boer, A P; van der Oost, J; Reijnders, W N; Westerhoff, H V; Stouthamer, A H; van Spanning, R J

    1996-12-15

    The genes that encode the hc-type nitric-oxide reductase from Paracoccus denitrificans have been identified. They are part of a cluster of six genes (norCBQDEF) and are found near the gene cluster that encodes the cd1-type nitrite reductase, which was identified earlier [de Boer, A. P. N., Reijnders, W. N. M., Kuenen, J. G., Stouthamer, A. H. & van Spanning, R. J. M. (1994) Isolation, sequencing and mutational analysis of a gene cluster involved in nitrite reduction in Paracoccus denitrificans, Antonie Leeu wenhoek 66, 111-127]. norC and norB encode the cytochrome-c-containing subunit II and cytochrome b-containing subunit I of nitric-oxide reductase (NO reductase), respectively. norQ encodes a protein with an ATP-binding motif and has high similarity to NirQ from Pseudomonas stutzeri and Pseudomonas aeruginosa and CbbQ from Pseudomonas hydrogenothermophila. norE encodes a protein with five putative transmembrane alpha-helices and has similarity to CoxIII, the third subunit of the aa3-type cytochrome-c oxidases. norF encodes a small protein with two putative transmembrane alpha-helices. Mutagenesis of norC, norB, norQ and norD resulted in cells unable to grow anaerobically. Nitrite reductase and NO reductase (with succinate or ascorbate as substrates) and nitrous oxide reductase (with succinate as substrate) activities were not detected in these mutant strains. Nitrite extrusion was detected in the medium, indicating that nitrate reductase was active. The norQ and norD mutant strains retained about 16% and 23% of the wild-type level of NorC, respectively. The norE and norF mutant strains had specific growth rates and NorC contents similar to those of the wild-type strain, but had reduced NOR and NIR activities, indicating that their gene products are involved in regulation of enzyme activity. Mutant strains containing the norCBQDEF region on the broad-host-range vector pEG400 were able to grow anaerobically, although at a lower specific growth rate and with lower NOR activity compared with the wild-type strain. PMID:9022686

  11. Frequency of the MTHFR C677T polymorphism in Yemeni children with sickle cell disease.

    PubMed

    Al-Saqladi, Abdul-Wahab M; Harper, Greg; Delpisheh, Ali; Fijnvandraat, Karin; Bin-Gadeem, Hassan A; Brabin, Bernard J

    2010-01-01

    The frequency of the methylenetetrahydrofolate reductase enzyme (MTHFR) C677T mutation was determined using polymerase chain reaction (PCR) and with measurement of plasma total homocysteine (tHcy), folate, vitamins B6, B12 and disease severity in 102 SS children from Yemen. The homozygous TT genotype for MTHFR C677T was present in 2% (2/102), and heterozygous CT in 10.8% (11/102), giving an allele frequency of 7.35%. The T allele was not associated with raised plasma tHcy or increased disease severity. The mean [+/-SD (standard deviation)] tHcy was 2.8 +/- 1.7 micromol/L, increased with age and was highest in children >10 years (3.6 +/- 2.5 vs. 2.5 +/- 1.2 micromol/L, p <0.05). Whole blood folate and plasma vitamin B12 levels were normal or elevated, and 4% had vitamin B6 deficiency. In Yemeni children with sickle cell disease the frequency of the MTHFR C677T mutation was not higher than expected in the general population and was not associated with disease severity. PMID:20113291

  12. Study on Environmental Causes and SNPs of MTHFR, MS and CBS Genes Related to Congenital Heart Disease

    PubMed Central

    Liu, Yan; Huang, Peng; Lin, Ning; Sun, Xiaoru; Yu, Rongbin; Zhang, Yuanyuan; Qin, Yuming; Wang, Lijuan

    2015-01-01

    Purpose Congenital heart diseases (CHD) are among the most common birth defects in China. Environmental causes and folate metabolism changes may alter susceptibility to CHD. The aim of this study is to evaluate the relevant risk-factors of children with CHD and their mothers. Methods 138 children with CHD and 207 normal children for controls were recruited. Their mothers were also enlisted in this study and interviewed following a questionnaire about their pregnant history and early pregnancy situation. Five single nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS) and cystathionine β-synthase (CBS) of mothers and children were genotyped. Results There were significant differences in the gender of children, occupation of mothers, family history with CHD, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHD group and control group ( P < 0.05). Logistic regression analyses showed that after adjustment for above factors, MTHFR rs1801131 were significantly associated with their offspring CHD risk in mothers. Compared with the mothers whose MTHFR were rs1801131 AA and AC genotypes, the mothers who got a mutation of MTHFR rs1801131 CC genotypes had a 267% increase in risk of given birth of a CHD children (OR=3.67,95%CI=1.12-12.05). Meanwhile, MTHFR rs1801131 were significantly associated with CHD susceptibility in children (OR = 1.42, 95% CI = 1.00-2.44 in additive model). Conclusions Besides mothers’ social and fertility characteristics, our results suggested that the genetic variants in folate metabolism pathway might be one of the most related risk-factors of CHD. MTHFR rs1801131 were identified as loci in Chinese population that were involved in CHD. PMID:26035828

  13. [Population study of frequency of methylenetetrahydrofolate reductase C677T gene polymorphism in Yakutia].

    PubMed

    Spiridonova, M G; Stepanov, V A; Maksimova, N R; Puzyrev, V P

    2004-05-01

    The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyzes synthesis of 5'-methylenehydrofolate, which is the methyl donor for the conversion of homocysteine to methionine. According to the numerous literature data, polymorphic variant of the MTHFR-encoding gene, C677T, is associated with hyperhomocysteinemia, vascular pathologies, neural tube defects, dementia, perinatal mortality, mental disorders, long-term neurodegenerative disorders, lens displacement, arachnodactyly, and venous thromboses. The present study was focused on the analysis of the C677T polymorphism (missence mutation leading to the replacement of cytosine by thymine at position 677) of the MTHFR gene in three indigenous populations of the Republic of Sakha (Yakutia), living in the settlements of Cheriktei, Byadi, and Dyupsya. Comparison of the genotype and allele frequencies revealed no substantial differences between the three Yakut populations, as well as between Yakuts and other Mongoloid ethnic groups. PMID:15272569

  14. Free-floating thrombus of the carotid artery with a homozygous methylenetetrahydrofolate reductase gene mutation: a case report.

    PubMed

    Colak, Necmettin; Nazli, Yunus; Kosehan, Dilek; Alpay, Mehmet Fatih; Cakir, Omer

    2013-02-01

    Free-floating thrombus (FFT) of the carotid artery is a rare condition of currently unknown etiology. We describe a symptomatic patient with an FFT in the left common carotid artery. A duplex ultrasonography scan showed the presence of a mobile floating thrombus moving in cyclical motion with the cardiac cycles in the left common carotid artery. During emergency surgery, an FFT was seen at this location and removed. No underlying wall defect was seen at the time of surgery. In a genetic screening test, TT homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms was detected. The patient recovered uneventfully, with no neurogical events. Lifelong anticoagulant therapy was recommended. An aggressive surgical approach is recommended in the patient to prevent embolic episodes. PMID:22101856

  15. Frequency of the 677 C-->T mutation of the methylenetetrahydrofolate reductase gene among Kuwaiti sickle cell disease patients.

    PubMed

    Adekile, A D; Kutlar, F; Haider, M Z; Kutlar, A

    2001-04-01

    Sickle cell disease (SCD) is relatively mild among Kuwaiti Arabs. However, an atypical subset of patients exists with frequent, severe vaso-occlusive crisis and osteonecrosis. The thermolabile variant of MTHFR, resulting from a C-->T mutation at nucleotide 677, has been shown to be associated with hyperhomocysteinemia, which is an important risk factor for premature vascular disease. We have screened an unselected group of 41 Kuwaiti SCD patients (33 SS and 8 Sbeta(0)-thal) attending the Hematology Clinic of Kuwait University Teaching Hospital for the MTHFR mutation, using a PCR-RFLP method. The patients were aged 2-41 years (mean of 12.8 +/- 8.6). One (2.4%) individual was homozygous for the mutation while 15 (36.6%) were heterozygous, giving an allele frequency of 20.7%. Twenty-one patients (14 SS and 7 Sbeta(0)-thal) were screened for osteonecrosis using MRI of the hip (spin-echo T1- and T2-weighted images). Seven (33.3%) had varying degrees of osteonecrosis, among whom the frequency of the 677 C-->T allele was 21.4%. The frequency was identical among those without osteonecrosis. Although the allele frequency is higher among our patients compared to American SS patients, our results do not suggest an association with osteonecrosis. PMID:11279637

  16. Correlation of the C677T MTHFR genotype with homocysteine levels in children with sickle cell disease.

    PubMed

    Balasa, V V; Gruppo, R A; Gartside, P S; Kalinyak, K A

    1999-01-01

    Recently, a mild to moderate elevation in the plasma homocysteine (Hcy) level has been found to be an important risk factor for stroke. Homozygosity for a common mutation (C677T) in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) involved in Hcy metabolism has been associated with increased levels of Hcy. To determine the role of hyperhomocysteinemia in the pathogenesis of stroke in children with sickle cell disease (SCD), Hcy levels and C677T MTHFR genotype were determined in 40 patients homozygous for hemoglobin SS and compared with 197 healthy children. Eleven of 40 patients with SCD had a history of stroke. The prevalence of homozygosity for the C677T MTHFR variant was 5% in the patients with SCD. The median Hcy level was 5.8 micromol/L in the patients versus 5.4 micromol/L in the controls (Fisher's, P > 0.05). There was no correlation of Hcy levels with the MTHFR genotype in patients with SCD. In patients with SCD and stroke, the median Hcy level was 4.8 micromol/L versus 6.0 micromol/L in those without stroke (P = 0.44, Mann-Whitney rank sum test). There was no difference in the proportion of patients with SCD with or without stroke who were homozygous for the C677T MTHFR mutation (0/11 versus 2/29; Fisher's, P = 1.000). In conclusion, this study failed to demonstrate an elevation in plasma Hcy levels in children with SCD compared with normal controls. Furthermore, hyperhomocysteinemia did not seem to be a significant factor in the pathogenesis of stroke in children with SCD. PMID:10524453

  17. A foreign dihydrofolate reductase gene in transgenic mice acts as a dominant mutation.

    PubMed Central

    Gordon, J W

    1986-01-01

    We have produced 17 lines of transgenic mice by microinjecting a full-length cDNA clone of an altered dihydrofolate reductase (dhfr) gene. The protein specified by this gene carries a point mutation which triples its Km for dihydrofolate and reduces substrate turnover 20-fold relative to the wild-type enzyme. Transgenic mice from different pedigrees, several of which carry a single copy of this gene in different integration sites, manifest an array of similar developmental abnormalities including growth stunting, reduced fertility, pigmentation changes, and skeletal defects. These defects appear in animals heterozygous for the foreign gene. RNA analyses demonstrate significant expression of the cDNA in newborn mice and adult tissues. These findings show that the additional dhfr gene exerts its mutational effects in a dominant fashion, and therefore the data indicate that transgenic mice can serve as models for elucidating mechanisms of dominant mutagenesis. Images PMID:3785192

  18. 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 contributes to the sensitivity of As embryotoxicity. • Fetal Mthfr genotype does not affect the reproductive outcome after As exposure.

  19. Mutation in Pyrroline-5-Carboxylate Reductase 1 Gene in Families with Cutis Laxa Type 2

    PubMed Central

    Guernsey, Duane L.; Jiang, Haiyan; Evans, Susan C.; Ferguson, Meghan; Matsuoka, Makoto; Nightingale, Mathew; Rideout, Andrea L.; Provost, Sylvie; Bedard, Karen; Orr, Andrew; Dub, Marie-Pierre; Ludman, Mark; Samuels, Mark E.

    2009-01-01

    Autosomal-recessive cutis laxa type 2 (ARCL2) is a multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin, joint laxity, and a general developmental delay. Cutis laxa includes a family of clinically overlapping conditions with confusing nomenclature, generally requiring molecular analyses for definitive diagnosis. Six genes are currently known to mutate to yield one of these related conditions. We ascertained a cohort of typical ARCL2 patients from a subpopulation isolate within eastern Canada. Homozygosity mapping with high-density SNP genotyping excluded all six known genes, and instead identified a single homozygous region near the telomere of chromosome 17, shared identically by state by all genotyped affected individuals from the families. A putative pathogenic variant was identified by direct DNA sequencing of genes within the region. The single nucleotide change leads to a missense mutation adjacent to a splice junction in the gene encoding pyrroline-5-carboxylate reductase 1 (PYCR1). Bioinformatic analysis predicted a pathogenic effect of the variant on splice donor site function. Skipping of the associated exon was confirmed in RNA from blood lymphocytes of affected homozygotes and heterozygous mutation carriers. Exon skipping leads to deletion of the reductase functional domain-coding region and an obligatory downstream frameshift. PYCR1 plays a critical role in proline biosynthesis. Pathogenicity of the genetic variant in PYCR1 is likely, given that a similar clinical phenotype has been documented for mutation carriers of another proline biosynthetic enzyme, pyrroline-5-carboxylate synthase. Our results support a significant role for proline in normal development. PMID:19576563

  20. MTHFR polymorphisms in gastric cancer and in first-degree relatives of patients with gastric cancer.

    PubMed

    De Re, Valli; Cannizzaro, R; Canzonieri, V; Cecchin, E; Caggiari, L; De Mattia, E; Pratesi, C; De Paoli, P; Toffoli, G

    2010-01-01

    Two common mutations, 677 C-->T and a1298 A-->C, in the methylenetetrahydrofolate reductase gene (MTHFR) reduce the activity of MTHFR and folate metabolism. Familial aggregation in a variable but significant proportion of gastric cancer (GC) cases suggests the importance of genetic predisposition in determining risk. In this study, we evaluate MTHFR polymorphisms in 57 patients with a diagnosis of GC, in 37 with a history of GC in first-degree relatives (GC-relatives), and in 454 blood donors. Helicobacter pylori (HP) infection was also determined. An increased risk was found for 677TT in GC patients with respect to blood donors (odds ratio (OR) = 1.98), and statistical significance was sustained when we compared sex-age-matched GC patients and donors (OR = 2.37). The 677TT genotype association with GC was found in women (OR = 3.10), while a reduction in the 667C allele frequency was present in both the sex. No statistically significant association was detected when 677-1298 genotype was stratified by sex and age. Men of GC-relatives showed a higher 1298C allele frequency than donors (OR = 4.38). Between GC and GC-relatives, HP infection frequency was similar. In conclusion, overall findings support the hypothesis that folate plays a role in GC risk. GC-relatives evidence a similar 677TT frequency to that found in the general population. PMID:20237899

  1. Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typology.

    PubMed

    Benyamina, Amine; Saffroy, Raphal; Blecha, Lisa; Pham, Patrick; Karila, Laurent; Debuire, Brigitte; Lemoine, Antoinette; Reynaud, Michel

    2009-09-01

    Prior studies have associated 677C-T Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with decreased enzymatic activity and modified homocysteine regulation. This study determines and compares MTHFR 677C-T distribution and examines its consequences on homocysteine metabolism and alcohol dependence in alcoholic patients classified according to the Babor and Lesch typologies. MTHFR TT genotype was more prevalent in AD patients with milder alcohol dependence (Babor type A) and with Lesch type 3, associated with depression. MTHFR TT was also associated with hyperhomocysteinemia. Determining MTHFR 677C-T genotype, folate and vitamin B12 levels could assist physicians in identifying type 3 patients and improve addictions management. PMID:19650814

  2. Relationship of MTHFR gene polymorphisms with renal and cardiac disease

    PubMed Central

    Trovato, Francesca M; Catalano, Daniela; Ragusa, Angela; Martines, G Fabio; Pirri, Clara; Buccheri, Maria Antonietta; Di Nora, Concetta; Trovato, Guglielmo M

    2015-01-01

    AIM: To investigate the effects of different methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism and hyperhomocysteinemia for the development of renal failure and cardiovascular events, which are controversial. METHODS: We challenged the relationship, if any, of MTHFR 677C>T and MTHFR 1298A>C polymorphisms with renal and heart function. The present article is a reappraisal of these concepts, investigating within a larger population, and including a subgroup of dialysis patients, if the two most common MTHFR polymorphisms, C677T and A1298C, as homozygous, heterozygous or with a compound heterozygous state, show different association with chronic renal failure requiring hemodialysis. MTHFR polymorphism could be a favorable evolutionary factor, i.e., a protective factor for many ominous conditions, like cancer and renal failure. A similar finding was reported in fatty liver disease in which it is suggested that MTHFR polymorphisms could have maintained and maintain their persistence by an heterozygosis advantage mechanism. We studied a total of 630 Italian Caucasian subject aged 54.60 16.35 years, addressing to the increased hazard of hemodialysis, if any, according to the studied MTHFR genetic polymorphisms. RESULTS: A favorable association with normal renal function of MTHFR polymorphisms, and notably of MTHFR C677T is present independently of the negative effects of left ventricular hypertrophy, increased Intra-Renal arterial Resistance and hyperparathyroidism. CONCLUSION: MTHFR gene polymorphisms could have a protective role on renal function as suggested by their lower frequency among our dialysis patients in end-stage renal failure; differently, the association with left ventricular hypertrophy and reduced left ventricular relaxation suggest some type of indirect, or concurrent mechanism. PMID:25664255

  3. A distal mutation perturbs dynamic amino acid networks in dihydrofolate reductase.

    PubMed

    Boehr, David D; Schnell, Jason R; McElheny, Dan; Bae, Sung-Hun; Duggan, Brendan M; Benkovic, Stephen J; Dyson, H Jane; Wright, Peter E

    2013-07-01

    Correlated networks of amino acids have been proposed to play a fundamental role in allostery and enzyme catalysis. These networks of amino acids can be traced from surface-exposed residues all the way into the active site, and disruption of these networks can decrease enzyme activity. Substitution of the distal Gly121 residue in Escherichia coli dihydrofolate reductase results in an up to 200-fold decrease in the hydride transfer rate despite the fact that the residue is located 15 Å from the active-site center. In this study, nuclear magnetic resonance relaxation experiments are used to demonstrate that dynamics on the picosecond to nanosecond and microsecond to millisecond time scales are changed significantly in the G121V mutant of dihydrofolate reductase. In particular, picosecond to nanosecond time scale dynamics are decreased in the FG loop (containing the mutated residue at position 121) and the neighboring active-site loop (the Met20 loop) in the mutant compared to those of the wild-type enzyme, suggesting that these loops are dynamically coupled. Changes in methyl order parameters reveal a pathway by which dynamic perturbations can be propagated more than 25 Å across the protein from the site of mutation. All of the enzyme complexes, including the model Michaelis complex with folate and nicotinamide adenine dinucleotide phosphate bound, assume an occluded ground-state conformation, and we do not observe sampling of a higher-energy closed conformation by (15)N R2 relaxation dispersion experiments. This is highly significant, because it is only in the closed conformation that the cofactor and substrate reactive centers are positioned for reaction. The mutation also impairs microsecond to millisecond time scale fluctuations that have been implicated in the release of product from the wild-type enzyme. Our results are consistent with an important role for Gly121 in controlling protein dynamics critical for enzyme function and further validate the dynamic energy landscape hypothesis of enzyme catalysis. PMID:23758161

  4. A distal mutation perturbs dynamic amino acid networks in dihydrofolate reductase

    PubMed Central

    Bae, Sung-Hun; Duggan, Brendan M.; Benkovic, Stephen J.; Dyson, H. Jane; Wright, Peter E

    2013-01-01

    Correlated networks of amino acids have been proposed to play a fundamental role in allostery and enzyme catalysis. These networks of amino acids can be traced from surface-exposed residues all the way into the active site, and disruption of these networks can decrease enzyme activity. Substitution of the distal Gly121 residue in E.coli dihydrofolate reductase results in up to a 200-fold decrease in the hydride transfer rate despite the fact that the residue is located 15 Å from the active-site center. In the present study, NMR relaxation experiments are used to demonstrate that dynamics on the ps-ns and μs-ms timescales are changed significantly in the G121V mutant of dihydrofolate reductase. In particular, ps-ns timescale dynamics are decreased in the FG loop (containing the mutated residue 121) and the neighboring active-site loop (the Met20 loop) in the mutant compared to wild-type enzyme, suggesting that these loops are dynamically coupled. Changes in methyl order parameters reveal a pathway by which dynamic perturbations can be propagated more than 25 Å across the protein from the site of mutation. All of the enzyme complexes, including the model Michaelis complex with folate and NADP+ bound, assume an occluded ground state conformation, and we do not observe sampling of a higher energy closed conformation by 15N R2 relaxation dispersion. This is highly significant, since it is only in the closed conformation that the cofactor and substrate reactive centers are positioned for reaction. The mutation also impairs μs - ms timescale fluctuations that have been implicated in product release from the wild type enzyme. Our results are consistent with an important role for Gly121 in controlling protein dynamics critical for enzyme function and further validate the dynamic energy landscape hypothesis of enzyme catalysis. PMID:23758161

  5. Prevalence of thromogenic gene mutations in women with recurrent miscarriage: A retrospective study of 1,507 patients

    PubMed Central

    Hilali, Nese Gul; Camuzcuoglu, Aysun; Camuzcuoglu, Hakan; Akbas, Halit; Kilic, Avni; Vural, Mehmet

    2014-01-01

    Objective Thromogenic gene mutations has been thought to be associated with recurrent pregnancy loss in women in Turkey. The aim of this study was to investigate the prevalence of thromogenic gene mutations such as factor V Leiden (FVL, G1691T), prothrombin (G20210A), and the methylene tetrahydrofolate reductase (MTHFR, C677T) mutation in women with recurrent pregnancy loss. Methods This descriptive study was carried out in the Department of Obstetrics and Gynaecology, Harran University School of Medicine, and included a total of 1,507 women with histories of recurrent pregnancy loss between January 2010 and June 2013. The mutations were assessed by using the polymerase chain reaction. Results The homozygous mutation frequencies of FVL, prothrombin, and MTHFR were found to be 3 (0.20%), 0 and 125 (8.29%), and the heterozygous mutation frequencies were 83 (5.51%), 61 (4.05%), and 612 (40.61%), respectively. Among the 86 FVL mutation patients, 38 also had accompanying prothrombin and MTHFR mutations. Conclusion Since the homozygous forms of the FVL-prothrombin gene mutations have low incidences and MTHFR mutation is similar to a healthy population, preconceptional thromogenic gene mutations screening seems to be controversial. PMID:25469341

  6. Identification of ribonucleotide reductase mutation causing temperature-sensitivity of herpes simplex virus isolates from whitlow by deep sequencing

    PubMed Central

    Daikoku, Tohru; Oyama, Yukari; Yajima, Misako; Sekizuka, Tsuyoshi; Kuroda, Makoto; Shimada, Yuka; Takehara, Kazuhiko; Miwa, Naoko; Okuda, Tomoko; Sata, Tetsutaro; Shiraki, Kimiyasu

    2015-01-01

    Key Clinical Message Herpes simplex virus 2 caused a genital ulcer, and a secondary herpetic whitlow appeared during acyclovir therapy. The secondary and recurrent whitlow isolates were acyclovir-resistant and temperature-sensitive in contrast to a genital isolate. We identified the ribonucleotide reductase mutation responsible for temperature-sensitivity by deep-sequencing analysis. PMID:26185649

  7. Thioredoxin Reductase 2 (TXNRD2) Mutation Associated With Familial Glucocorticoid Deficiency (FGD)

    PubMed Central

    Prasad, Rathi; Chan, Li F.; Hughes, Claire R.; Kaski, Juan P.; Kowalczyk, Julia C.; Savage, Martin O.; Peters, Catherine J.; Nathwani, Nisha; Clark, Adrian J. L.; Metherell, Louise A.

    2014-01-01

    Context: Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis. Objective: We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD. Design: Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis. Setting: The study was conducted on patients from three pediatric centers in the United Kingdom. Patients: Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study. Interventions: There were no interventions. Main Outcome Measure: Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured. Results: A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line. Conclusion: In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans. PMID:24601690

  8. Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice.

    PubMed

    Chew, Tina W; Jiang, Xinyin; Yan, Jian; Wang, Wei; Lusa, Amanda L; Carrier, Bradley J; West, Allyson A; Malysheva, Olga V; Brenna, J Thomas; Gregory, Jesse F; Caudill, Marie A

    2011-08-01

    Choline and folate are interrelated in 1-carbon metabolism, mostly because of their shared function as methyl donors for homocysteine remethylation. Folate deficiency and mutations of methylenetetrahydrofolate reductase (MTHFR) reduce the availability of a major methyl donor, 5-methyltetrahydrofolate, which in turn may lead to compensatory changes in choline metabolism. This study investigated the hypothesis that reductions in methyl group supply, either due to dietary folate deficiency or Mthfr gene deletion, would modify tissue choline metabolism in a sex-specific manner. Mthfr wild type (+/+) or heterozygous (+/-) knockout mice were randomized to a folate-deficient or control diet for 8 wk during which time deuterium-labeled choline (d9-choline) was consumed in the drinking water (~10 ?mol/d). Mthfr heterozygosity did not alter brain choline metabolite concentrations, but it did enhance their labeling in males (P < 0.05) and tended to do so in females (P < 0.10), a finding consistent with greater turnover of dietary choline in brains of +/- mice. Dietary folate deficiency in females yielded 52% higher (P = 0.027) hepatic glycerophosphocholine, which suggests that phosphatidylcholine (PtdCho) degradation was enhanced. Labeling of the hepatic PtdCho in d3 form was also reduced (P < 0.001) in females, which implies that fewer of the dietary choline-derived methyl groups were used for de novo PtdCho biosynthesis under conditions of folate insufficiency. Males responded to folate restriction with a doubling (P < 0.001) of hepatic choline dehydrogenase transcripts, a finding consistent with enhanced conversion of choline to the methyl donor, betaine. Collectively, these data show that several adaptations in choline metabolism transpire as a result of mild perturbations in folate metabolism, presumably to preserve methyl group homeostasis. PMID:21697299

  9. C677T methylenetetrahydrofolate reductase and plasma homocysteine levels among Thai vegans and omnivores.

    PubMed

    Kajanachumpol, Saowanee; Atamasirikul, Kalayanee; Tantibhedhyangkul, Phieuvit

    2013-01-01

    Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) mol/L vs. 8.53 (8.12 - 8.95) mol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 mol/L, 20.4 mol/L, and 30.0 mol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia. PMID:24491881

  10. Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients.

    PubMed

    Burda, Patricie; Schfer, Alexandra; Suormala, Terttu; Rummel, Till; Brer, Cline; Heuberger, Dorothea; Frapolli, Michele; Giunta, Cecilia; Sokolov, Jitka; Vlkov, Hana; Koich, Viktor; Koch, Hans Georg; Fowler, Brian; Froese, D Sean; Baumgartner, Matthias R

    2015-06-01

    5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations. PMID:25736335

  11. 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

  12. In human alleles specific variation of MTHFR C677T and A1298C associated "risk factor" for the development of ovarian cancer.

    PubMed

    Singh, Anupama; Pandey, S; Pandey, L K; Saxena, Ajit K

    2015-01-01

    Etiopathology of tumor biology is highly complex and ovarian cancer is one of the important gynaecological neoplasia associated with high risk of mortality rate. Methlenetetrahydrofolate reductase (MTHFR) mutation are commonly linked to folate metabolism with increased risk factor for the development of neural tube defects, recurrent pregnancy loss and development of several type of cancer but genetic interaction between two alleles of MTHFR has been poorly defined in ovarian cancer in India. Hence, present study becomes imperative with the aim to assess the alleles frequency of MTHFR (C677T & A1298C) gene polymorphism using PCR based RFLP analysis. The O.R at 95% confidence interval (C.I.) was computed between cases and their respective controls to determine "risk factor". Interestingly, our findings reveals highly significant (p < 0.001) difference in heterozygous (CT) condition of C677T allele by computing odd ratio (0.12 at 95% C.I, 0.021-0.0428; P for trend = 0.001) in controls and (0.34 at 95% C.I, 0.074-1.530; P for trend = 0.198) cases, suggesting that three time increase the "risk factor" for genetic susceptibility of MTHFR "T" allele for the development of ovarian carcinoma. PMID:26259392

  13. [Resistance to acenocoumarol revealing a missense mutation of the vitamin K epoxyde reductase VKORC1: a case report].

    PubMed

    Mboup, M C; Dia, K; Ba, D M; Fall, P D

    2015-02-01

    A significant proportion of the interindividual variability of the response to vitamin K antagonist (VKA) treatment has been associated with genetic factors. Genetic variations affecting the vitamin K epoxide reductase complex subunit 1 (VKORC1) are associated with hypersensitivity or rarely with resistance to VKA. We report the case of a black women patient who presents a resistance to acenocoumarol. Despite the use of high doses of acenocoumarol (114 mg/week) for the treatment of recurrent pulmonary embolism, the International Normalized Ratio was below the therapeutic target. This resistance to acenocoumarol was confirmed by the identification of a missense mutation Val66Met of the vitamin K epoxide reductase. PMID:24095214

  14. Prevalence of factor V Leiden G1691A, MTHFR C677T, and prothrombin G20210A among Asian Indian sickle cell patients.

    PubMed

    Pandey, Sanjay Kumar; Meena, Arvind; Kishor, Kamal; Mishra, R M; Pandey, Sweta; Saxena, Renu

    2012-06-01

    The prevalence of factor V (FV) Leiden G1691A, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations were investigated among 90 sickle trait, 61 sickle homozygous, 75 sickle beta thalassemia, and 15 HbSD Asian Indian sickle cell patients. In all, 297 healthy controls were evaluated to compare the polymorphism frequency. The prevalence of FV Leiden heterozygous G>A were significant in the group (P = .02), while PRT G20210A polymorphism was not seen among patients as well as controls. However, an increased frequency of the MTHFR 677 C>T genotype was seen among patients as well as controls, but this was not statistically significant (P = .13). This suggested a low impact of inherited hypercoagulability risk factors in the pathogenesis of sickle cell disease and/or its complications. PMID:22084413

  15. Polymorphisms of methylenetetrahydrofolate reductase gene as the genetic predispositions of coronary artery diseases in eastern India

    PubMed Central

    Dhar, Soujatya; Chatterjee, Sumana; Ray, Saumitra; Dutta, Anjanlal; Sengupta, Bani; Chakrabarti, Shila

    2010-01-01

    Background: Geneenvironment interaction is an important aspect in the development of coronary artery disease (CAD). The mutation (677C-T) of methylenetetrahydrofolate reductase (MTHFR) gene results in a decrease of the enzyme activity that leads to mild hyperhomocysteinemia. Elevated plasma level of homocysteine has been recognized as an independent risk factor for cardiovascular disease. A casecontrol study was designed to assess whether the prevalence of some MTHFR gene polymorphisms have any role in the development of CAD. Materials and Methods: The study included unrelated 217 cases with CAD and 255 healthy controls. DNA was extracted from peripheral blood. MTHFR genotypes were identified by seeing the presence or absence of 677C?T mutation obtained by PCR followed by Hinf1 restriction digestion. Multiple logistic regression analysis was carried out to find association between studied genotypes and lifestyle as well as biochemical risk factors. Results: The T allele was found to be associated with the disease. Significant associations were found with smoking, hypertension, diabetes, and family history of CAD. Conclusion: The results indicate that MTHFR 677C-T polymorphism has significant association with CADs in the population of eastern India. PMID:21187870

  16. Multiple origins of resistance-conferring mutations in Plasmodium vivax dihydrofolate reductase

    PubMed Central

    Hawkins, Vivian N; Auliff, Alyson; Prajapati, Surendra Kumar; Rungsihirunrat, Kanchana; Hapuarachchi, Hapuarachchige C; Maestre, Amanda; O'Neil, Michael T; Cheng, Qin; Joshi, Hema; Na-Bangchang, Kesara; Sibley, Carol Hopkins

    2008-01-01

    Background In order to maximize the useful therapeutic life of antimalarial drugs, it is crucial to understand the mechanisms by which parasites resistant to antimalarial drugs are selected and spread in natural populations. Recent work has demonstrated that pyrimethamine-resistance conferring mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) have arisen rarely de novo, but spread widely in Asia and Africa. The origin and spread of mutations in Plasmodium vivax dhfr were assessed by constructing haplotypes based on sequencing dhfr and its flanking regions. Methods The P. vivax dhfr coding region, 792 bp upstream and 683 bp downstream were amplified and sequenced from 137 contemporary patient isolates from Colombia, India, Indonesia, Papua New Guinea, Sri Lanka, Thailand, and Vanuatu. A repeat motif located 2.6 kb upstream of dhfr was also sequenced from 75 of 137 patient isolates, and mutational relationships among the haplotypes were visualized using the programme Network. Results Synonymous and non-synonymous single nucleotide polymorphisms (SNPs) within the dhfr coding region were identified, as was the well-documented in-frame insertion/deletion (indel). SNPs were also identified upstream and downstream of dhfr, with an indel and a highly polymorphic repeat region identified upstream of dhfr. The regions flanking dhfr were highly variable. The double mutant (58R/117N) dhfr allele has evolved from several origins, because the 58R is encoded by at least 3 different codons. The triple (58R/61M/117T) and quadruple (57L/61M/117T/173F, 57I/58R/61M/117T and 57L/58R/61M/117T) mutant alleles had at least three independent origins in Thailand, Indonesia, and Papua New Guinea/Vanuatu. Conclusion It was found that the P. vivax dhfr coding region and its flanking intergenic regions are highly polymorphic and that mutations in P. vivax dhfr that confer antifolate resistance have arisen several times in the Asian region. This contrasts sharply with the selective sweep of rare antifolate resistant alleles observed in the P. falciparum populations in Asia and Africa. The finding of multiple origins of resistance-conferring mutations has important implications for drug policy. PMID:18442404

  17. The prevalence of folate-remedial MTHFR enzyme variants in humans

    PubMed Central

    Marini, Nicholas J.; Gin, Jennifer; Ziegle, Janet; Keho, Kathryn Hunkapiller; Ginzinger, David; Gilbert, Dennis A.; Rine, Jasper

    2008-01-01

    Studies of rare, inborn metabolic diseases establish that the phenotypes of some mutations in vitamin-dependent enzymes can be suppressed by supplementation of the cognate vitamin, which restores function of the defective enzyme. To determine whether polymorphisms exist that more subtly affect enzymes yet are augmentable in the same way, we sequenced the coding region of a prototypical vitamin-dependent enzyme, methylenetetrahydrofolate reductase (MTHFR), from 564 individuals of diverse ethnicities. All nonsynonymous changes were evaluated in functional in vivo assays in Saccharomyces cerevisiae to identify enzymatic defects and folate remediability of impaired alleles. We identified 14 nonsynonymous changes: 11 alleles with minor allele frequencies <1% and 3 common alleles (A222V, E429A, and R594Q). Four of 11 low-frequency alleles affected enzyme function, as did A222V. Of the five impaired alleles, four could be restored to normal functionality by elevating intracellular folate levels. All five impaired alleles mapped to the N-terminal catalytic domain of the enzyme, whereas changes in the C-terminal regulatory domain had little effect on activity. Impaired activity correlated with the phosphorylation state of MTHFR, with more severe mutations resulting in lower abundance of the phosphorylated protein. Significantly, diploid yeast heterozygous for mutant alleles were impaired for growth, particularly with lower folate supplementation. These results suggested that multiple less-frequent alleles, in aggregate, might significantly contribute to metabolic dysfunction. Furthermore, vitamin remediation of mutant enzymes may be a common phenomenon in certain domains of proteins. PMID:18523009

  18. Impact of thrombophilic genes mutations on thrombosis risk in Egyptian nonmetastatic cancer patients.

    PubMed

    Wahba, Mona Ahmed; Ismail, Mona Ahmed; Saad, Abeer Attia; Habashy, Deena Mohamed; Hafeez, Zeinab Mohamed Abdel; Boshnak, Noha Hussein

    2015-04-01

    Venous thromboembolism (VTE) is a common complication in cancer patients. Several genetic risk factors related to thrombophilia are known; however, their contributions to thrombotic tendency in cancer patients have conflicting results. We aimed to determine the prevalence of factor V Leiden (FVL), prothrombin (PTH) G20210A and methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphisms in Egyptian nonmetastatic cancer patients and their influence on thrombosis risk in those patients. Factor V Leiden, PTH G20210A and MTHFR C677T polymorphisms were detected in 40 cancer patients with VTE (group 1) and 40 cancer patients with no evidence of VTE (group 2) by PCR-based DNA analysis. Factor V and MTHFR mutations were higher in group 1 than in group 2 (factor V heterozygous mutation: 20 vs. 7.5%, homozygous mutation: 10 vs. 2.5%; MTHFR heterozygous mutation: 40 vs. 25%, homozygous mutation 5 vs. 0%, respectively) (P?=?0.03). Mortality rate was higher in group 1 (75%) than in group 2 (25%; P?mutation (P?=?1). Mortality rate was higher in the presence of homozygous and heterozygous factor V mutation (100 and 82%, respectively) compared to the wild type (41%) (P?=?0.0006). Having any of the three studied gene mutations worsened the overall survival (P?=?0.0003). Cox regression proved that both thrombosis and presence of factor V mutation are independent factors affecting survival in cancer patients (P?MTHFR mutations and risk of VTE in Egyptian cancer patients. Thrombosis and presence of factor V mutation are independent factors that influence survival in those patients. PMID:25565385

  19. MTHFR polymorphic variant C677T is associated to vascular complications in sickle-cell disease.

    PubMed

    Hatzlhofer, Betnia L D; Bezerra, Marcos Andr C; Santos, Magnun N N; Albuquerque, Dulcinia M; Freitas, Elizabete M; Costa, Fernando F; Arajo, Aderson S; Muniz, Maria Tereza C

    2012-09-01

    Vaso-occlusion is a determinant for most signs and symptoms of sickle-cell anemia (SCA). The mechanisms involved in the pathogenesis of vascular complications in SCA remain unclear. It is known that genetic polymorphisms associated with thrombophilia may be potential modifiers of clinical features of SCA. The genetic polymorphisms C677T and A1298C relating to the enzyme methylenetetrahydrofolate reductase (MTHFR), a clotting Factor V Leiden mutation (1691G?A substitution of Factor V Leiden), and the mutant prothrombin 20210A allele were analyzed in this study. The aim was to find possible correlations with vascular complications and thrombophilia markers in a group of SCA patients in Pernambuco, Brazil. The study included 277 SCA patients, divided into two groups: one consisting of 177 nonconsanguineous SCA patients who presented vascular manifestations of stroke, avascular necrosis, leg ulcers, priapism, and acute chest syndrome (group 1); and the other consisting of 100 SCA patients without any reported vascular complication (group 2). Molecular tests were done using either polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR techniques. Comparisons between the groups were made using the ?(2) test. The 677 CT and TT genotypes showed a significant risk of vascular complications (p=0.015). No significant associations between the groups were found when samples were analyzed for the MTHFR A1298C allele (p=0.913), Factor V G1691 (p=0.555), or prothrombin G20210A mutation (p=1.000). The polymorphism MTHFR C677T seemed to be possibly predictive for the development of some vascular complications in SCA patients among this population. PMID:22924497

  20. 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 strategies should consider a combination of genotyping with drug regimens. PMID:20813139

  1. Prospective study of MTHFR genetic polymorphisms as a possible etiology of male infertility.

    PubMed

    Li, S-S; Li, J; Xiao, Z; Ren, A-G; Jin, L

    2014-01-01

    The aim of this study was to explore the relationship between 2 genetic polymorphisms of the methylenetetrahydrofolate reductase gene (MTHFR), C677T and A1298C, and determine the long-term reproductive outcome in infertile men. This was a prospective study conducted in an andrology clinic. Men with a 1-year history of infertility were assessed for the MTHFR polymorphisms at a 5-year follow-up. We compared the MTHFR C677T and A1298C polymorphisms by polymerase chain reaction-restriction fragment length polymorphism between men who did and did not bear children during follow-up. Of the 215 men who were infertile at 1 year, 82 (38.1%) remained infertile and 133 (61.9%) achieved natural conception during the 5-year follow-up, with the highest rate in the first year (32.6%). The MTHFR 677TT genotype (homozygote) was associated with a substantially increased risk of infertility during follow-up [odds ratio (OR) = 10.242; 95% confidence interval (CI) = 1.257-83.464] relative to the MTHFR 677CC genotype (wild-type). Risk of infertility was not increased by the MTHFR A1298C polymorphism alone, but was increased by the combination of polymorphisms MTHFR C677T and MTHFR A1298C (OR = 11.818; 95%CI = 1.415-98.674). The homozygous MTHFR C677T genotype was a risk factor for male infertility during 5-year follow-up, whereas a correlation between MTHFR A1298C and infertility was not observed. The MTHFR C677T and MTHFR A1298C polymorphisms had additive effects on male infertility. PMID:24737513

  2. The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk.

    PubMed

    Arslan, Sulhattin; Karadayi, Sule; Yildirim, Malik Ejder; Ozdemir, Ozturk; Akkurt, Ibrahim

    2011-02-01

    This study aimed to determine the relation between methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism and lung cancer risk and the frequency of this polymorphism. The study involved 64 lung cancer patients (the study group) with definitive diagnosis and 61 noncancerous subjects (the control group). MTHFR C677T and A1298C mutation analysis was made using DNA isolated from peripheric blood and multiplex PCR and reverse hybridization strip test. Eighty-four percent of the patients were male. The age, gender, and history of alcohol use of the patients and control group were statistically similar. While MTHFR 677T and 677C allele frequency was 0.33 and 0.67 in the patients respectively, it was 0.29 and 0.71 in the control group. The frequencies of MTHFR 1298C and 1298A were 0.33 and 0.67 in the patients, and it was 0.31 and 0.69 in the control group respectively. When MTHFR 677TT and 677CT genotypes were compared with 677CC genotype, lung cancer risk was 2.4 times higher in the 677TT genotype. When MTHFR 1298AC and 1298CC genotypes were compared with 1298AA genotype, lung cancer risk was 1.5 times higher in 1298CC genotype. According to the results, allele frequency of homozygote T and C was high in lung cancer patients. It was 3.05 and 1.29 times higher in smokers than in non-smokers, and 3.05 and 1.64 times higher in males than in females; 3.0 and 2.44 times higher in those with non-small cell lung cancer than in those with small-cell lung cancer. PMID:20532637

  3. Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase

    SciTech Connect

    Pandey, Amit V.; Flueck, Christa E.; Mullis, Primus E.

    2010-09-24

    Research highlights: {yields} Mutations in POR identified from patients lead to reduced HO-1 activities. {yields} POR mutation Y181D affecting FMN binding results in total loss of HO-1 activity. {yields} POR mutations A287P, C569Y and V608F, lost 50-70% activity. {yields} Mutations in FAD binding domain, R457H, Y459H and V492E lost all HO-1 activity. {yields} POR polymorphisms P228L, R316W, G413S, A503V and G504R have normal activity. -- Abstract: Human heme oxygenase-1 (HO-1) carries out heme catabolism supported by electrons supplied from the NADPH through NADPH P450 reductase (POR, CPR). Previously we have shown that mutations in human POR cause a rare form of congenital adrenal hyperplasia. In this study, we have evaluated the effects of mutations in POR on HO-1 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified HO-1 to measure heme degradation in a coupled assay using biliverdin reductase. Here we show that mutations in POR found in patients may reduce HO-1 activity, potentially influencing heme catabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had total loss of HO-1 activity, while POR mutations A287P, C569Y and V608F lost 50-70% activity. The POR variants P228L, R316W and G413S, A503V and G504R identified as polymorphs had close to WT activity. Loss of HO-1 activity may result in increased oxidative neurotoxicity, anemia, growth retardation and iron deposition. Further examination of patients affected with POR deficiency will be required to assess the metabolic effects of reduced HO-1 activity in affected individuals.

  4. Association of MTHFR genetic polymorphisms with venous thromboembolism in Uyghur population in Xinjiang, China

    PubMed Central

    Li, Zhao; Yadav, Umesh; Mahemuti, Ailiman; Tang, Bao-Peng; Upur, Halmurat

    2015-01-01

    Background: The aim of this study was to reveal the association between Methylene tetrahydrofolate reductase (MTHFR) gene mutations (C677T, A1298C and C1317T) and risk of venous thromboembolism (VTE) in Han and Uyghur population in Xinjiang. Material and method: We conducted a case control study composed of 246 cases, including 86 Uyghur and 160 Han ethnic diagnosed VTE were admitted in the First Affiliated Hospital of Xinjiang Medical University between January 2008 to December 2012, and 292 population including 122 Uyghur ethnic and 170 Han ethnic were studied as controls. To detect the polymorphism of MTHFR gene C677T, A1298T, and C1317T, Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied. Fluorescence polarization immunoassay was adopted to determine the plasma levels Homocysteine (Hcy), folic acid and vitaminB12 (VitB12). The association of the polymorphism of MTHFR and levels Hcy, folic acid and VitB12 with VTE was analyzed. Results: The MTHFR gene C677T genotypes distribution in Uyghur VTE patients and control groups were: TT (27.91% vs. 12.29%), CT (41.86% vs. 52.46%) and CC (30.23% vs. 35.25%), respectively; and in Han VTE patients and control groups were: TT (27.49% vs. 14.71%), CT (44.38% vs. 53.53%) and CC (28.13% vs. 31.76%), respectively, and there were significant differences in TT genotype of MTHFRC677T between VTE patients and controls in both Uyghur and Han ethnic (Uyghur: x2=8.070, P=0.005; Han: x2=8.159, P=0.004). However, there were no significant differences in the MTHFR gene A1298T and C1317T genotyping distribution frequency in Uygur and Han ethnic between VTE patients and controls (P>0.05). Plasma levels of Hcy in MTHFR gene TT genotype were statistically higher than CT and CC genotype (P<0.05). After adjusting for age, gender, smoking, hypertension, hyperlipidemia, diabetes and MTHFR genotype for plasma Hcy levels, multifactor logistic regression analysis showed (OR=1.025, 95% CI 1.003-1.046, P=0.024) and obesity (OR=4.660, 95% CI 1.417-15.324, P=0.011) were independent risk factors for Uygur ethnic with VTE while plasma Hcy levels (OR=1.020, 95% CI 1.006-1.034, P=0.004) and smoking (OR=2.867, 95% CI 1.062-6.586, P=0.024) were independent risk factors for Han ethnic with VTE. Conclusions: Our finding supports significant role of MTHFR gene in VTE and evidence of genetically determined HHcy contribute a risk for VTE, and a smoker with tHcy has positive association with a risk of VTE. PMID:26770360

  5. Increased susceptibility to mild neonatal stress in MTHFR deficient mice.

    PubMed

    Kezurer, N; Galron, D; Golan, H M

    2013-09-15

    Early life stress is shown to have a life-span outcome on human and animal behavior, increasing the risk for psychopathology. The gene methylenetetrahydrofolate reductase (MTHFR), which encodes for a key enzyme in one carbon metabolism, shows a high prevalence of polymorphism in patients with developmental disorders. Here we examined the hypothesis that MTHFR deficiency results in an increased susceptibility of the developing brain to mild neonatal stress (NS). Mild NS failed to alter corticosterone levels in young and adult Wt mice. However, an elevated level of corticosterone was found in the MTHFR deficient-NS female, exemplifying enhanced sensitivity to NS. Behavioral phenotyping of Wt and MTHFR deficient mice provides evidence that the effect of mild NS may be amplified by the MTHFR deficient genotype. Distinct behavioral characteristics were altered in male and female mice. In general, three patterns of influence on mice behavior were observed: (1) an additive suppressive effect of NS and MTHFR deficiency on exploration and activity was evident in females; (2) stress related parameters were significantly sensitive to genotype in females, presenting an interaction between genotype and sex; (3) various aspects of behavior in a social setting were modified preferably in males by genotype, NS and the interaction between the two, while females exhibited a smaller effect that was restricted to NS with no genotype effect. Overall, our results support an interaction between mild NS, the MTHFR genotype and sex. We suggest using this animal model to study the molecular mechanism linking these two risk factors and their involvement in neurodevelopmental disorders such as schizophrenia and autism. PMID:23896051

  6. Staying green postharvest: how three mutations in the Arabidopsis chlorophyll b reductase gene NYC1 delay degreening by distinct mechanisms.

    PubMed

    Jibran, Rubina; Sullivan, Kerry L; Crowhurst, Ross; Erridge, Zoe A; Chagn, David; McLachlan, Andrew R G; Brummell, David A; Dijkwel, Paul P; Hunter, Donald A

    2015-11-01

    Stresses such as energy deprivation, wounding and water-supply disruption often contribute to rapid deterioration of harvested tissues. To uncover the genetic regulation behind such stresses, a simple assessment system was used to detect senescence mutants in conjunction with two rapid mapping techniques to identify the causal mutations. To demonstrate the power of this approach, immature inflorescences of Arabidopsis plants that contained ethyl methanesulfonate-induced lesions were detached and screened for altered timing of dark-induced senescence. Numerous mutant lines displaying accelerated or delayed timing of senescence relative to wild type were discovered. The underlying mutations in three of these were identified using High Resolution Melting analysis to map to a chromosomal arm followed by a whole-genome sequencing-based mapping method, termed 'Needle in the K-Stack', to identify the causal lesions. All three mutations were single base pair changes and occurred in the same gene, NON-YELLOW COLORING1 (NYC1), a chlorophyll b reductase of the short-chain dehydrogenase/reductase (SDR) superfamily. This was consistent with the mutants preferentially retaining chlorophyll b, although substantial amounts of chlorophyll b were still lost. The single base pair mutations disrupted NYC1 function by three distinct mechanisms, one by producing a termination codon, the second by interfering with correct intron splicing and the third by replacing a highly conserved proline with a non-equivalent serine residue. This non-synonymous amino acid change, which occurred in the NADPH binding domain of NYC1, is the first example of such a mutation in an SDR protein inhibiting a physiological response in plants. PMID:26261268

  7. Prothrombotic polymorphisms, mutations, and their association with pediatric non-cardioembolic stroke in Asian-Indian patients.

    PubMed

    Biswas, Arijit; Tiwari, Arun Kumar; Ranjan, Ravi; Meena, Arvind; Akhter, Mohammad Suhail; Yadav, Birendra Kumar; Behari, Madhuri; Saxena, Renu

    2009-05-01

    Genes involved in the hemostatic mechanism are logical candidate genes for association studies in prothrombotic conditions such as stroke. Since the underlying etiology in pediatric strokes is different than adults, looking for genetic causes would be the logical thing to do in the pediatric stroke population. Fifty-eight Asian-Indian stroke patients below 15 years of age and equal number of age- and sex-matched healthy controls were the subjects for the study. The subjects were screened for 13 polymorphisms and three mutations spread across seven different candidate genes involved in the hemostatic system. Of the 13 polymorphisms and three mutations studied, four polymorphisms, HPA-I, TAFI 147Ala>Thr, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, and MTHFR 1298 A>C, showed significant association with the disease phenotype. MTHFR 677 C>T showed the strongest association and therefore may have a strong predisposing role for pediatric strokes. Gene-gene interaction studies showed a strong interaction between HPA-I and MTHFR 677 C>T polymorphism. The wild type of both these polymorphisms synergistically showed a strong protective effect [p < 0.0001, O.R: 10.06(4.26-23.71)]. Polymorphisms in HPA-I and MTHFR may have important predisposing roles in the development of pediatric stroke. PMID:18836720

  8. Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations.

    PubMed

    Dianzani, I; de Sanctis, L; Smooker, P M; Gough, T J; Alliaudi, C; Brusco, A; Spada, M; Blau, N; Dobos, M; Zhang, H P; Yang, N; Ponzone, A; Armarego, W L; Cotton, R G

    1998-01-01

    Dihydropteridine reductase (DHPR) is an enzyme involved in recycling of tetrahydrobiopterin (BH4), the cofactor of the aromatic amino acid hydroxylases. Its deficiency is characterized by hyperphenylalaninemia due to the secondary defect of phenylalanine hydroxylase and depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases. The DHPR cDNA has been cloned and mapped on 4p15.3. In the present study we report the genomic structure of the DHPR gene (QDPR). This gene includes seven exons within a range of 84-564 bp; the corresponding introns are flanked by canonic splice junctions. We also present a panel of PCR primers complementary to intronic sequences that greatly facilitates amplification of the gene and provides a genomic DNA approach for mutation detection. We have used this approach to study six patients with DHPR deficiency. Four known mutations (G23D, H158Y, IVS5G+ 1A, R221X) and two new mutations (Y150C and G218ins9bp) were found. The Y150C mutation was found in compound heterozygosity with G23D, a mutation always associated with a severe phenotype in homozygous patients. This patient has an intermediate phenotype (good response to monotherapy with BH4). The mutant enzyme for Y150C was expressed in an E. coli system. Comparison of its kinetic parameters with those of the G23D mutant enzyme showed that it is not as effective as the wild-type enzyme, but is more active than the G23D mutant. This patient's intermediate phenotype is thus due to the mild DHPR mutation Y150C. Correlations between genotypes and phenotypes were also found for the other mutations. PMID:9744478

  9. Factor V Leiden, factor V Cambridge, factor II GA20210, and methylenetetrahydrofolate reductase in cerebral venous and sinus thrombosis: A case-control study

    PubMed Central

    Saadatnia, Mohammad; Salehi, Mansour; Movahedian, Ahmad; Shariat, Seyed Ziaeddin Samsam; Salari, Mehri; Tajmirriahi, Marzieh; Asadimobarakeh, Elham; Salehi, Rasoul; Amini, Gilda; Ebrahimi, Homa; Kheradmand, Ehsan

    2015-01-01

    Background: Factor V G1691A (FV Leiden), FII GA20210, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations are the most common genetic risk factors for thromboembolism in the Western countries. However, there is rare data in Iran about cerebral venous and sinus thrombosis (CVST) patients. The aim of this study was to evaluate the frequency of common genetic thrombophilic factors in CVST patients. Materials and Methods: Forty consequently CVST patients from two University Hospital in Isfahan University of Medical Sciences aged more than 15 years from January 2009 to January 2011 were recruited. In parallel, 51 healthy subjects with the same age and race from similar population selected as controls. FV Leiden, FII GA20210, MTHFR C677T, and FV Cambridge gene mutations by polymerase chain reaction technique were evaluated in case and control groups. Results: FV Leiden, FII GA20210, and FV Cambridge gene mutations had very low prevalence in both case (5%, 2%, 0%) and control (2.5%, 0%, 0%) and were not found any significant difference between groups. MTHFR C677T mutations was in 22 (55%) of patients in case group and 18 (35.5%) of control group (P = 0.09). Conclusion: This study showed that the prevalence of FV Leiden, FII GA20210, and FV Cambridge were low. Laboratory investigations of these mutations as a routine test for all patients with CVST may not be cost benefit. PMID:26600830

  10. Association of methylene tetrahydrofolate reductase C677T genotype with type 2 diabetes mellitus patients with and without renal complications.

    PubMed

    Movva, Sireesha; Alluri, Ravindra V; Venkatasubramanian, Sambasivan; Vedicherla, Bhavani; Vattam, Kiran K; Ahuja, Yog R; Hasan, Qurratulain

    2011-04-01

    Diabetes is gradually getting the status of a global epidemic, with India projected as the capital of type 2 diabetes mellitus (T2DM). Nephropathy is an important complication of diabetes and a major cause of end-stage renal disease. Studies from different parts of the world have given controversial results regarding the association of methylene tetrahydrofolate reductase (MTHFR) gene variation with T2DM and diabetic nephropathy (DN). This case-control study assessed the association of MTHFR C677T mutation in T2DM and DN cases. Genotyping of MTHFR was carried out for 236 T2DM cases with diabetes diagnosed for >8 years, having either normoalbuminuria (n=100) or established DN (n=136). One hundred age- and sex-matched healthy individuals with normal blood sugars and no family history of T2DM were selected as controls. This first report from India gives a highly significant odds ratio of 4.0423 (95% confidence interval=1.8753-8.7133), indicating that the MTHFR 677T allele confers a fourfold risk of developing DM in our population. The frequency of the T allele in both the DM and DN groups was similar (i.e., 0.16 and 0.11, respectively), showing no association with the initiation or progression of DN. Individuals with a family history of diabetes or with risk factors such as obesity, hypertension, and impaired glucose tolerance should be screened for MTHFR C677T mutation and may be prescribed folic acid, vitamin B6, and vitamin B12 to assess if this helps in delaying the onset of diabetes. PMID:21186995

  11. Genetic and epigenetic variants in the MTHFR gene are not associated with non-Hodgkin lymphoma

    PubMed Central

    Bradshaw, Gabrielle; Sutherland, Heidi G.; Camilleri, Emily T.; Lea, Rodney A.; Haupt, Larisa M.; Griffiths, Lyn R.

    2015-01-01

    The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme which plays a key role in the pathway of folate and methionine metabolism. Polymorphisms of genes in this pathway affect its regulation and have been linked to lymphoma. In this study we examined whether we could detect an association between two common non-synonymous MTHFR polymorphisms, 677C>T (rs1801133) and 1298A>C (rs1801131), and susceptibility to non-Hodgkin lymphoma (NHL) in an Australian casecontrol cohort. We found no significant differences between genotype or allele frequencies for either polymorphisms between lymphoma cases and controls. We also explored whether epigenetic modification of MTHFR, specifically DNA methylation of a CpG island in the MTHFR promoter region, is associated with NHL using blood samples from patients. No difference in methylation levels was detected between the case and control samples suggesting that although hypermethylation of MTHFR has been reported in tumour tissues, particularly in the diffuse large B-cell lymphoma subtype of NHL, methylation of this MTHFR promoter CpG island is not a suitable epigenetic biomarker for NHL diagnosis or prognosis in peripheral blood samples. Further studies into epigenetic variants could focus on genes that are robustly associated with NHL susceptibility. PMID:26629414

  12. Genetic and epigenetic variants in the MTHFR gene are not associated with non-Hodgkin lymphoma.

    PubMed

    Bradshaw, Gabrielle; Sutherland, Heidi G; Camilleri, Emily T; Lea, Rodney A; Haupt, Larisa M; Griffiths, Lyn R

    2015-12-01

    The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme which plays a key role in the pathway of folate and methionine metabolism. Polymorphisms of genes in this pathway affect its regulation and have been linked to lymphoma. In this study we examined whether we could detect an association between two common non-synonymous MTHFR polymorphisms, 677C>T (rs1801133) and 1298A>C (rs1801131), and susceptibility to non-Hodgkin lymphoma (NHL) in an Australian case-control cohort. We found no significant differences between genotype or allele frequencies for either polymorphisms between lymphoma cases and controls. We also explored whether epigenetic modification of MTHFR, specifically DNA methylation of a CpG island in the MTHFR promoter region, is associated with NHL using blood samples from patients. No difference in methylation levels was detected between the case and control samples suggesting that although hypermethylation of MTHFR has been reported in tumour tissues, particularly in the diffuse large B-cell lymphoma subtype of NHL, methylation of this MTHFR promoter CpG island is not a suitable epigenetic biomarker for NHL diagnosis or prognosis in peripheral blood samples. Further studies into epigenetic variants could focus on genes that are robustly associated with NHL susceptibility. PMID:26629414

  13. MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer.

    PubMed

    Reeves, Stuart G; Meldrum, Cliff; Groombridge, Claire; Spigelman, Allan D; Suchy, Janina; Kurzawski, Grzegorz; Lubinski, Jan; McElduff, Patrick; Scott, Rodney J

    2009-05-01

    Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is characterized by inactivating germline mutations in DNA mismatch repair genes resulting in an increased risk of developing an epithelial malignancy. There is considerable variability in disease expression observed in this syndrome, which is thought to be due to a combination of genetic and environmental factors. Alterations in the kinetics of methylene tetrahydrofolate reductase (MTHFR) due to the presence of polymorphisms in the MTHFR gene have been associated with an increased risk of colorectal cancer (CRC). Two common single nucleotide polymorphisms (SNPs) located within the MTHFR gene, 677 C>T and 1298 A>C, that alter the function of the encoded protein have been the focus of many studies on CRC risk outside the context of an inherited predisposition to disease. In this report, a total of 417 HNPCC participants were genotyped for the 677 C>T and 1298 A>C SNPs to determine whether there exists an association with the age of disease onset of CRC. Genotyping of both SNPs was performed by TaqMan(R) assay technology. Associations in disease risk were further investigated using Kaplan-Meier survival analysis and Cox hazard regression. The average ages of disease diagnosis were found to be different between individuals harbouring either one of the MTHFR polymorphisms. Both Kaplan-Meier and Cox hazard regression analyses revealed a more complex relationship between the two polymorphisms and the age of CRC onset. The Kaplan-Meier survival analysis revealed that compound heterozygotes for the two SNPs developed CRC 10 years later compared with those carrying only wild-type alleles. PMID:19156174

  14. Coronary heart disease among Circassians in Israel is not associated with mutations in thrombophilia genes.

    PubMed

    Falik-Zaccai, Tzipora C; Haron, Yafa; Eilat, Danny; Harash, Bakky; Golinker, Ekaterina; Hussein, Osamah; Eisikovits, Rivka; Borochowitz, Zvi; Linn, Shai

    2003-02-01

    The Muslim Circassian community in Israel represents a unique ethnic community that has never been genetically and medically studied. One hundred and fifty-three randomly selected individuals (91 men and 62 women, ages 35 and older), both healthy or with a history of cardiovascular disease (14 men and 7 women), were studied in a cross-sectional descriptive study for mutations in three genes known to be associated with hypercoagulation. Their medical records were reviewed for risk factors and history of cardiovascular disease (CVD) and thromboembolic events. The mutation FV 1691G --> A in the gene for factor V (FV 1691G --> A), the mutation MTHFR 677C --> T in the gene 5,10-methylenetetrahydrofolate reductase, and the allele G20210A in the gene for prothrombin (PT 20210G --> A) were studied. The mutation FV 1691G --> A was observed in a heterozygous form in 1.3% of 153 studied individuals, while the PT 20210G --> A allele was identified in a heterozygous form in 6.5%. No individual was found homozygous for either of these two mutations. The MTHFR C677T mutation was present in 42.8% of the studied population in a heterozygous form and in 8.6% in a homozygous form. Serum homocysteine, folate, and B12 levels were studied among individuals heterozygous and homozygous for the MTHFR C677T mutation. There was no significant difference in the prevalence of all three mutations between individuals affected with CVD or other forms of thromboembolic disease and healthy individuals. This is the first report of a medical condition and its genetic background among Circassians. The high prevalence of CVD among Circassians was found to be etiologically unrelated to the three mutations studied in the genes for factor V, MTHFR, and prothrombin. PMID:12713146

  15. 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…

  16. 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

  17. 5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects

    SciTech Connect

    Ou, C.Y.; Brown, V.K.; Khoury, M.J.

    1996-06-28

    Persons with a thermolabile form of the enzyme 5,10 methylenetetrahydrofolate reductase (MTHFR) have reduced enzyme activity and increased plasma homocysteine which can be lowered by supplemental folic acid. Thermolability of the enzyme has recently been shown to be caused by a common mutation (677C{sup {r_arrow}}T) in the MTHFR gene. We studied 41 fibroblast cultures from NTD-affected fetuses and compared their genotypes with those of 109 blood specimens from individuals in the general population. 677C{sup {r_arrow}}T homozygosity was associated with a 7.2 fold increased risk for NTDs (95% confidence interval: 1.8-30.3; p value: 0.001). These preliminary data suggest that the 677C{sup {r_arrow}}T polymorphism of the MTHFR gene is a risk factor for spina bifida and anencephaly that may provide a partial biologic explanation for why folic acid prevents these types of NTD. 13 refs., 1 fig., 1 tab.

  18. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss.

    PubMed

    Kumar, K S D; Govindaiah, V; Naushad, S E; Devi, R R; Jyothy, A

    2003-01-01

    Hyperhomocysteinaemia, a risk factor for recurrent pregnancy loss, is related either to a hereditary defect within the methionine-homocysteine pathway or it might be acquired as a result of deficiencies of vitamin B(12) and folate (B(9)). Because hyperhomocysteinaemia seems to be determined by both genetic and environmental factors, the current study was undertaken to find out the interactions between folate status and MTHFR mutation on the homocysteine concentration in 24 women experiencing unexplained three or more consecutive recurrent pregnancy losses. The median fasting total plasma homocysteine concentration in the study group was 10.23 micro mol/l compared to 8.95 micro mol/l; P = 0.096 in the controls. Elevated homocysteine levels > 18 micro mol/l, which was considered to be a risk factor for recurrent early pregnancy loss, was found in four women in the study group and none among the controls. Lower red cell folate levels (normal range >/= 160 ng/ml) were observed in nine (37.5%) women among the study group, compared to five (20.84%) women among controls. The mean +/- SD red cell folate levels in the study group was found to be 154.37 +/- 37.07, while in the controls it was 159.0 +/- 28.97. In the present study six women in the study group and two among controls were found to be carriers for the C677T MTHFR mutation. None were homozygous for the mutant (TT) allele. The highest values of homocysteine concentration were found in women experiencing recurrent pregnancy loss with both the CT genotype and folate deficiency. Identification of hyperhomocysteinaemia in women with recurrent pregnancy loss may help in therapeutic normalisation and might permit a normal birth. PMID:12623486

  19. Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility

    PubMed Central

    Eloualid, Abdelmajid; Abidi, Omar; Charif, Majida; El houate, Brahim; Benrahma, Houda; Louanjli, Noureddine; Chadli, Elbakkay; Ajjemami, Maria; Barakat, Abdelhamid; Bashamboo, Anu; McElreavey, Ken; Rhaissi, Houria; Rouba, Hassan

    2012-01-01

    The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR?=?3.372, 95% confidence interval CI?=?1.278.238; p?=?0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants. PMID:22457816

  20. MTHFR genotype and colorectal adenoma recurrence: data from a double blind placebo controlled clinical trial

    PubMed Central

    Levine, A. Joan; Wallace, Kristin; Tsang, Shirley; Haile, Robert W.; Saibil, Fred; Ahnen, Dennis; Cole, Bernard F.; Barry, Elizabeth L.; Munroe, David J; Ali, Iqbal U; Ueland, Per; Baron, John A.

    2009-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We ssessed the association between two common MTHFR variants, 677C>T and 1298A>C, and adenoma recurrence in the context of a randomized double blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% CIs for recurrence, adjusting for age, sex, clinical center, follow-up time, and treatment status. Neither MTHFR polymorphism was associated with overall or advanced adenoma recurrence. Compared to those with 2 wild type alleles, the relative risk for advanced adenoma was 0.75 (95% CI 0.36 to 1.55), for the MTHFR 677 TT genotype and 1.16 (95% CI 0.582.33) for the MTHFR 1298 CC genotype. The effect of folate supplementation on recurrence risk did not differ by genotype. Our findings indicate that MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk. PMID:18768511

  1. Genetic variations in MTHFR and gastric cardia adenocarcinoma susceptibility in the Chinese Han population

    PubMed Central

    Wang, Yafeng; Chen, Shuchen; Kang, Mingqiang; Tang, Weifeng; Gu, Haiyong; Yin, Jun; Huang, Ziyang

    2015-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms are associated with many types of cancers. The purpose of our study was to evaluate the effect of MTHFR single nucleotide polymorphisms (SNPs) on gastric cardia adenocarcinoma (GCA). We conducted a hospital-based case-control study. Three hundred and thirty cases with GCA and 608 controls were recruited. The ligation detection reaction (LDR) method was used to determine genotypes. The genotype MTHFR rs1801133 TT was significantly more frequent in cases than in controls (adjusted odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.04-2.05, P = 0.029) in a recessive model, after adjusting for age, sex and smoking and alcohol use. The haplotype MTHFR Grs4845882Ars4846048Trs1801133Crs9651118Ars3753584 was more frequent in cases than in controls (crude OR = 5.32, 95% CI = 2.34-12.10, P < 0.001). No association between other genotypes and haplotypes was observed. Our results suggest that the genotype MTHFR rs1801133 TT and the MTHFR Grs4845882Ars4846048Trs1801133Crs9651118Ars3753584 haplotype may be associated with susceptibility to GCA. Further studies are needed to confirm these findings. PMID:26770518

  2. Association of the MTHFR A1298C variant with unexplained severe male infertility.

    PubMed

    Eloualid, Abdelmajid; Abidi, Omar; Charif, Majida; El Houate, Brahim; Benrahma, Houda; Louanjli, Noureddine; Chadli, Elbakkay; Ajjemami, Maria; Barakat, Abdelhamid; Bashamboo, Anu; McElreavey, Ken; Rhaissi, Houria; Rouba, Hassan

    2012-01-01

    The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR?=?3.372, 95% confidence interval CI?=?1.27-8.238; p?=?0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants. PMID:22457816

  3. Hyperhomocysteinemia and the compound heterozygous state for methylene tetrahydrofolate reductase are independent risk factors for deep vein thrombosis among South Indians.

    PubMed

    Naushad, Sm; Jamal, Nurul Jain; Angalena, R; Prasad, C Krishna; Devi, A Radha Rama

    2007-03-01

    To investigate the role of methylene tetrahydrofolate reductase (MTHFR) (677 C-->T and 1298 A-->C), factor V (1691 G-->A), factor II (20210 G-->A) genetic polymorphisms and hyperhomocysteinemia in the aetiology of deep vein thrombosis (DVT) in 163 cases and 163 controls. Polymerase chain reaction-restriction fragment length polymorphism was used for genotyping, reverse-phase high-performance liquid chromatography for plasma homocysteine, and Student's t-test and Fisher exact tests were used for statistical analysis. Elevated mean plasma homocysteine levels were observed in DVT cases irrespective of gender differences. Homocysteine elevation above the 95th percentile of the control group associated with 9.4-fold and 7.6-fold increased risk for DVT in men and women, respectively. Genotyping showed the MTHFR 677CT/1298AC genotype (i.e. compound heterozygosity) is associated with 3.5-fold risk for thrombosis. The factor V Leiden mutation frequency was higher in DVT cases, but not statistically significant; however, genetic predisposition to this mutation was associated with early age of DVT onset. Factor II mutation was absent in cases and controls. Co-segregation of two or more risk factors was associated with 11.7-fold increased risk for thrombosis. This study projects that hyperhomocysteinemia and compound heterozygous state for MTHFR are independent risk factors for DVT among South Indians. PMID:17287626

  4. Role of folate status and methylenetetrahydrofolate reductase genotype on the toxicity and outcome of induction chemotherapy in children with acute lymphoblastic leukemia.

    PubMed

    Roy Moulik, Nirmalya; Kumar, Archana; Agrawal, Suraksha; Awasthi, Shally; Mahdi, Abbas Ali; Kumar, Ashutosh

    2015-05-01

    The effect of serum folate levels and methylenetetrahydrofolate reductase (MTHFR) genotype on complications and outcome of induction chemotherapy in 150 children with acute lymphoblastic leukemia (ALL) was studied. Folate deficiency in 26% at baseline was more common in children with MTHFR 677 mutations. Folate deficient children had a higher incidence of neutropenia (p = 0.03), thrombocytopenia (p = 0.02) and febrile neutropenia (p = 0.01) and higher transfusion requirement during induction compared to folate sufficient children. Sepsis related induction deaths were more frequent in folate deficient children (p = 0.02) during induction. Children with 677 and 1298 mutations had a higher incidence of cytopenias (p = 0.01) and mucositis (p = 0.007), the risks of which increased with concomitant folate deficiency. A significant fall in folate levels was observed post-induction (p = 0.02), most markedly in mutant 677 genotypes. Multivariate analysis revealed associations of baseline folate deficiency with low counts at day 14 (p = 0.001) and MTHFR 1298 mutations with mucositis (p = 0.02). PMID:25065700

  5. Evaluation of GenoFlow Thrombophilia Array Test Kit in Its Detection of Mutations in Factor V Leiden (G1691A), Prothrombin G20210A, MTHFR C677T and A1298C in Blood Samples from 113 Turkish Female Patients

    PubMed Central

    Aytekin, Ebru; Ergun, Sezen Guntekin; Percin, Ferda E.

    2014-01-01

    Thrombophilia is a heritable blood disease characterized by an increased tendency to form abnormal blood clots that can block blood vessels. In obstetrics and gynecology, it has been shown by a number of reports that a proportion of recurrent miscarriages involve thrombophilia-related mutations, in particular, Factor V G1691A, prothrombin G20210A, and MTHFR C677T and A1298C. In this study, we examined the frequency of these four mutations in 113 female Turkish patients who had prior complications in pregnancy, using the DiagCor GenoFlow Thrombophilia Array Test kit. Heterozygous MTHFR C677T and A1298C mutations were detected in 46% of the patients, and among these patients, 60% of them carried double heterozygous mutations. In contrast, the heterozygous Factor V G1691A and prothrombin G20210A were detected only in a smaller number of patients, respectively, 13% and 3%. The GenoFlow kit demonstrated 100% concordance with results from Sanger sequencing, which can be translated into sensitivity and specificity both at 100% within this series of patients. PMID:25153695

  6. Evaluation of GenoFlow Thrombophilia Array Test Kit in its detection of mutations in Factor V Leiden (G1691A), prothrombin G20210A, MTHFR C677T and A1298C in blood samples from 113 Turkish female patients.

    PubMed

    Aytekin, Ebru; Ergun, Sezen Guntekin; Ergun, Mehmet Ali; Percin, Ferda E

    2014-11-01

    Thrombophilia is a heritable blood disease characterized by an increased tendency to form abnormal blood clots that can block blood vessels. In obstetrics and gynecology, it has been shown by a number of reports that a proportion of recurrent miscarriages involve thrombophilia-related mutations, in particular, Factor V G1691A, prothrombin G20210A, and MTHFR C677T and A1298C. In this study, we examined the frequency of these four mutations in 113 female Turkish patients who had prior complications in pregnancy, using the DiagCor GenoFlow Thrombophilia Array Test kit. Heterozygous MTHFR C677T and A1298C mutations were detected in 46% of the patients, and among these patients, 60% of them carried double heterozygous mutations. In contrast, the heterozygous Factor V G1691A and prothrombin G20210A were detected only in a smaller number of patients, respectively, 13% and 3%. The GenoFlow kit demonstrated 100% concordance with results from Sanger sequencing, which can be translated into sensitivity and specificity both at 100% within this series of patients. PMID:25153695

  7. Pneumocystis jirovecii infection and the associated dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) mutations in HIV-positive individuals from Pune, India.

    PubMed

    Mane, Arati; Gujar, Pankaj; Chandra, Jipsi; Lokhande, Rahul; Dhamgaye, Tilak; Ghorpade, Shivhari; Risbud, Arun

    2015-02-01

    The present study was undertaken to detect Pneumocystis jirovecii infection among HIV-positive patients presenting with symptoms of lower respiratory tract infection and analyze the associated dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) mutations. P. jirovecii infection was detected in 12.6% cases. We did not find DHPS gene mutations at the commonest positions of codon 55 and 57; however, mutation at codon 171 was detected in two cases. No mutations in DHFR gene were detected. The results indicate low prevalence of DHPS and DHFR mutations in Indian P. jirovecii isolates, suggesting that the selective pressure of sulfa drugs on the local strains has probably not reached the levels found in developed nations. PMID:25266324

  8. Methylenetetrahydrofolate reductase gene polymorphisms in 13 Chinese ethnic populations.

    PubMed

    Mao, Renfang; Fan, Yihui; Chen, Feng; Sun, Donglin; Bai, Jing; Fu, Songbin

    2008-04-01

    It has been shown that the polymorphisms of Methylenetetrahydrofolate reductase (MTHFR) gene are associated with susceptibility to several disorders including hyperhomocysteinemia, vascular disease, birth defect, and certain cancers, and exhibit great diversities among various populations. The aim of this study was to investigate the prevalence of two common non-synonymous single nucleotide polymorphisms (i.e., C677T and A1298C) at MTHFR gene in 13 Chinese populations. A total of 1015 healthy individuals from 13 populations distributed widely from north to south in China were studied. DNA samples were isolated from peripheral blood samples and genotyped using polymerase chain reaction-restriction fragment length polymorphism. For C677T polymorphism, the frequency in Chinese of CC homozygous was 42.4%; CT heterozygous was 49.8%; and TT homozygous was 7.9%. For A1298C, AA homozygous was 39.2%; AC heterozygous was 38.6%; and CC homozygous was 22.2%. The allelic frequency of 677T and 1298C was 32.8 and 41.5%, respectively, and each allele frequency had significant variance in 13 Chinese populations. The frequency of the 677T allele among southern populations was 30.7% compared to 38.0% among northeastern and 30.5% among northwestern populations. The difference was statistically significant (p < 0.01). The frequency of 1298C mutation in southerns was 58.9% whereas in northeasterns it was 24.0% and 37.6% in northwesterns. This was also statistically significant (p < 0.01). The MTHFR C677T and A1298C sites were in linkage disequilibrium in the Chinese population revealed by our data. PMID:18098118

  9. Quantitative assessment of the association between MTHFR rs1801131 polymorphism and risk of liver cancer.

    PubMed

    Liang, Tie-Jun; Liu, Hui; Zhao, Xiao-Qian; Tan, Yan-Rong; Jing, Kai; Qin, Cheng-Yong

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes for folate metabolism which plays a key role in cell metabolism. MTHFR rs1801131 (A1298C) polymorphism can decrease in vitro MTHFR enzyme activity and has been hypothesized to be associated with liver cancer risk. This study aimed to quantify the strength of the association between MTHFR rs1801131 polymorphism and liver cancer risk by performing a meta-analysis. We searched the PubMed and Wanfang databases for studies relating on the association between MTHFR rs1801131 polymorphism and risk of liver cancer. Seven studies with 2,030 cases of liver cancer and 3,096 controls were finally included into the meta-analysis. Meta-analysis of a total of seven studies showed that the homozygote genotype CC of MTHFR rs1801131 polymorphism was significantly associated with decreased risk of liver cancer (for CC versus AA: odds ratio (OR)?=?0.65, 95% confidence interval (CI) 0.47-0.89, P?=?0.007; for CC versus AA?+?AC: OR?=?0.65, 95% CI 0.48-0.89, P?=?0.006). Subgroup by race showed that the homozygote genotype CC of MTHFR rs1801131 polymorphism was significantly associated with decreased risk of liver cancer in Asians (CC versus AA: OR?=?0.64, 95% CI 0.46-0.90, P?=?0.010; for CC versus AA?+ AC: OR?=?0.63, 95% CI 0.45-0.88, P?=?0.007). However, the association in Caucasians was still unclear owing to the limited data available now. Thus, Asian individuals with the homozygote genotype CC of MTHFR rs1801131 polymorphism are significantly associated with decreased risk of liver cancer. The association in Caucasians needs further studies. PMID:24014085

  10. Targeted Mutations of Bacillus anthracis Dihydrofolate Reductase Condense Complex Structure-Activity Relationships

    SciTech Connect

    J Beierlein; N Karri; A Anderson

    2011-12-31

    Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogues, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogues remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.

  11. A New Strategy to Produce a Defensin: Stable Production of Mutated NP-1 in Nitrate Reductase-Deficient Chlorella ellipsoidea

    PubMed Central

    Chen, Yu-Hong; Niu, Li-Li; Sun, Yong-Ru; Zhao, Shi-Min; Yang, Fu-Quan; Wang, Richard R.-C.; Wu, Qing; Zhang, Xiang-Qi; Hu, Zan-Min

    2013-01-01

    Defensins are small cationic peptides that could be used as the potential substitute for antibiotics. However, there is no efficient method for producing defensins. In this study, we developed a new strategy to produce defensin in nitrate reductase (NR)-deficient C. ellipsoidea (nrm-4). We constructed a plant expression vector carrying mutated NP-1 gene (mNP-1), a mature α-defensin NP-1 gene from rabbit with an additional initiator codon in the 5′-terminus, in which the selection markers were NptII and NR genes. We transferred mNP-1 into nrm-4 using electroporation and obtained many transgenic lines with high efficiency under selection chemicals G418 and NaNO3. The mNP-1 was characterized using N-terminal sequencing after being isolated from transgenic lines. Excitingly, mNP-1 was produced at high levels (approximately 11.42 mg/l) even after 15 generations of continuous fermentation. In addition, mNP-1 had strong activity against Escherichia coli at 5 µg/ml. This research developed a new method for producing defensins using genetic engineering. PMID:23383016

  12. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination

    PubMed Central

    Nakayama, Tojo; Al-Maawali, Almundher; El-Quessny, Malak; Rajab, Anna; Khalil, Samir; Stoler, Joan M.; Tan, Wen-Hann; Nasir, Ramzi; Schmitz-Abe, Klaus; Hill, R. Sean; Partlow, Jennifer N.; Al-Saffar, Muna; Servattalab, Sarah; LaCoursiere, Christopher M.; Tambunan, Dimira E.; Coulter, Michael E.; Elhosary, Princess C.; Gorski, Grzegorz; Barkovich, A. James; Markianos, Kyriacos; Poduri, Annapurna; Mochida, Ganeshwaran H.

    2015-01-01

    Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated genes have yet to be identified. Here, we report mutations in PYCR2, which encodes an enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Linkage mapping and whole-exome sequencing identified homozygous mutations (c.355C>T [p.Arg119Cys] and c.751C>T [p.Arg251Cys]) in PYCR2 in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in the amount of PYCR2. When mutant cDNAs were transfected into HEK293FT cells, both variant proteins retained normal mitochondrial localization but had lower amounts than the wild-type protein, suggesting that the variant proteins were less stable. A PYCR2-deficient HEK293FT cell line generated by genome editing with the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to apoptosis under oxidative stress. Morpholino-based knockdown of a zebrafish PYCR2 ortholog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2’s isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development. PMID:25865492

  13. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination.

    PubMed

    Nakayama, Tojo; Al-Maawali, Almundher; El-Quessny, Malak; Rajab, Anna; Khalil, Samir; Stoler, Joan M; Tan, Wen-Hann; Nasir, Ramzi; Schmitz-Abe, Klaus; Hill, R Sean; Partlow, Jennifer N; Al-Saffar, Muna; Servattalab, Sarah; LaCoursiere, Christopher M; Tambunan, Dimira E; Coulter, Michael E; Elhosary, Princess C; Gorski, Grzegorz; Barkovich, A James; Markianos, Kyriacos; Poduri, Annapurna; Mochida, Ganeshwaran H

    2015-05-01

    Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated genes have yet to be identified. Here, we report mutations in PYCR2, which encodes an enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Linkage mapping and whole-exome sequencing identified homozygous mutations (c.355C>T [p.Arg119Cys] and c.751C>T [p.Arg251Cys]) in PYCR2 in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in the amount of PYCR2. When mutant cDNAs were transfected into HEK293FT cells, both variant proteins retained normal mitochondrial localization but had lower amounts than the wild-type protein, suggesting that the variant proteins were less stable. A PYCR2-deficient HEK293FT cell line generated by genome editing with the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to apoptosis under oxidative stress. Morpholino-based knockdown of a zebrafish PYCR2 ortholog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2's isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development. PMID:25865492

  14. The MET13 Methylenetetrahydrofolate Reductase Gene Is Essential for Infection-Related Morphogenesis in the Rice Blast Fungus Magnaporthe oryzae

    PubMed Central

    Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J.; Wang, Zhengyi

    2013-01-01

    Methylenetetrahydrofolate reductases (MTHFRs) play a key role in the biosynthesis of methionine in both prokaryotic and eukaryotic organisms. In this study, we report the identification of a novel T-DNA-tagged mutant WH672 in the rice blast fungus Magnaporthe oryzae, which was defective in vegetative growth, conidiation and pathogenicity. Analysis of the mutation confirmed a single T-DNA insertion upstream of MET13, which encodes a 626-amino-acid protein encoding a MTHFR. Targeted gene deletion of MET13 resulted in mutants that were non-pathogenic and significantly impaired in aerial growth and melanin pigmentation. All phenotypes associated with Δmet13 mutants could be overcome by addition of exogenous methionine. The M. oryzae genome contains a second predicted MTHFR-encoding gene, MET12. The deduced amino acid sequences of Met13 and Met12 share 32% identity. Interestingly, Δmet12 mutants produced significantly less conidia compared with the isogenic wild-type strain and grew very poorly in the absence of methionine, but were fully pathogenic. Deletion of both genes resulted in Δmet13Δmet12 mutants that showed similar phenotypes to single Δmet13 mutants. Taken together, we conclude that the MTHFR gene, MET13, is essential for infection-related morphogenesis by the rice blast fungus M. oryzae. PMID:24116181

  15. Population- and family-based studies associate the MTHFR gene with idiopathic autism in simplex families.

    PubMed

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

    2011-07-01

    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 677TT genotype and higher frequencies of the 677T-1298A haplotype and double homozygous 677TT/1298AA genotype in affected individuals relative to controls. Family-based association testing demonstrated significant preferential transmission of the 677T and 1298A alleles and the 677T-1298A haplotype to affected offspring. The results were not replicated in MPX families. The results associate the MTHFR gene with autism in SPX families only, suggesting that reduced MTHFR activity is a risk factor for autism in these families. PMID:21069446

  16. Association of MTHFR gene polymorphisms with breast cancer survival

    PubMed Central

    Martin, Damali N; Boersma, Brenda J; Howe, Tiffany M; Goodman, Julie E; Mechanic, Leah E; Chanock, Stephen J; Ambs, Stefan

    2006-01-01

    Background Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women. Methods African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease-specific survival. Results We observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 (A/C or C/C) had reduced survival when compared to homozygous carriers of the common A allele [Hazard ratio (HR) = 2.05; 95% confidence interval (CI), 1.054.00]. In contrast, breast cancer patients with the variant allele at codon 677 (C/T or T/T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/C genotype (HR = 0.65; 95% CI, 0.311.35). The effects were stronger in patients with estrogen receptor-negative tumors (HR = 2.70; 95% CI, 1.176.23 for A/C or C/C versus A/A at codon 1298; HR = 0.36; 95% CI, 0.121.04 for C/T or T/T versus C/C at codon 677). Interactions between the two MTHFR genotypes and race/ethnicity on breast cancer survival were also observed (A1298C, pinteraction = 0.088; C677T, pinteraction = 0.026). Conclusion We found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ethnicity modified the association between the two SNPs and breast cancer survival. PMID:17069650

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

    ERIC Educational Resources Information Center

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

    2012-01-01

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

  18. 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…

  19. 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

  20. 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

  1. Frequency of APOE, MTHFR and ACE polymorphisms in the Zambian population

    PubMed Central

    2014-01-01

    Background Polymorphisms within the apolipoprotein-E (APOE), Methylenetetrahydrofolate reductase (MTHFR) and Angiotensin I-converting enzyme (ACE) genes has been associated with cardiovascular and cerebrovascular disorders, Alzheimers disease and other complex diseases in various populations. The aim of the study was to analyze the allelic and genotypic frequencies of APOE, MTHFR C677T and ACE I/D gene polymorphisms in the Zambian population. Results The allele frequencies of APOE polymorphism in the Zambian populations were 13.8%, 59.5% and 26.7% for the ?2, ?3 and ?4 alleles respectively. MTHFR C677T and ACE I/D allele frequencies were 8.6% and 13.8% for the T and D minor alleles respectively. The ?2?2 genotype and TT genotype were absent in the Zambian population. The genetic distances between Zambian and other African and non-African major populations revealed an independent variability of these polymorphisms. Conclusion We found that the APOE ?3 allele and the I allele of the ACE were significantly high in our study population while there were low frequencies observed for the MTHFR 677T and ACE D alleles. Our analysis of the APOE, MTHFR and ACE polymorphisms may provide valuable insight into the understanding of the disease risk in the Zambian population. PMID:24679048

  2. MTHFR C677T polymorphism and anatomopathological characteristics with prognostic significance in sporadic colorectal cancer.

    PubMed

    Delgado-Plasencia, Luciano; lvarez-Argelles, Hugo; Salido-Ruiz, Eduardo; Castro-Peraza, M Elisa; Bravo-Gutirrez, Alberto; Fernndez-Peralta, Antonia; Gonzlez-Aguilera, Juan; Alarc-Hernndez, Antonio; Medina-Arana, Vicente

    2015-12-01

    Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair and synthesis. The MTHFR C677T polymorphism is associated with decreased risk of CRC and increased sensitivity to 5-FU treatment. The present study addressed the relationship between this polymorphism and histopathological and immunohistochemical characteristics of prognostic significance in 50 patients from the Canary Islands. No differences were found between the MTHFR C677T genotypes with respect to tumor budding, tumor necrosis, desmoplastic fibrosis and tumoral eosinophilia. No significant differences were found in Ki-67, bcl-2 (cytoplasmic and nuclear), CD31, CD3+ T lymphocytes (both stromal and intraepithelial) and peritumoral CD20+ B lymphocytes. In carriers of the MTHFR CC variant, tumor margins were infiltrative more frequently (68.7%) than in CT+TT carriers (33.3%, p=0.03). In addition, wild-type CC genotype showed stromal CD20+ B lymphocytes (68.8%) more often than CT+TT carriers (33.3%, p=0.03). Both parameters indicate a better tumor prognosis when the MTHFR 677T variant is present. PMID:26564107

  3. 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. PMID:25855017

  4. Association of the MTHFR rs1801131 and rs1801133 variants in sporadic Parkinson's disease patients.

    PubMed

    Yuan, Lamei; Song, Zhi; Deng, Xiong; Xiong, Wei; Yang, Zhijian; Deng, Hao

    2016-03-11

    Parkinson's disease (PD) is a common age-dependent neurodegenerative movement disorder related to multiple factors, and genetic factors play an important role in the pathogenesis of PD. Variants in the methylenetetrahydrofolate reductase gene (MTHFR), a gene encoding a folate-dependent enzyme that is involved in homocysteine metabolism, have been reported to be associated with PD. To explore the role of the MTHFR gene in the development of PD in Chinese Han population, we analyzed two MTHFR variants (rs1801131 and rs1801133) in a patient cohort consisting of 512 patients with PD from mainland China and a control cohort consisting of 512 age, gender and ethnicity matched normal subjects. Statistically significant differences in genotypic and allelic frequencies were detected in the MTHFR variant rs1801133 (P=0.022 and 0.007, respectively; odds ratio=0.780, 95% confidence interval=0.651-0.934). In addition, the A-T haplotype of rs1801131-rs1801133 showed a protective role against PD development (P=0.007, odds ratio=0.779, 95% confidence interval=0.650-0.933). Our results suggested that the T allele of rs1801133 variant and A-T haplotype of rs1801131-rs1801133 in the MTHFR gene may decrease the risk of developing PD in Chinese Han population from mainland China. PMID:26806866

  5. Try235Phe homozygous mutation of the steroid 5-a reductase type 2 (SRD5A2) gene in a Turkish patient.

    PubMed

    Parlak, Mesut; Durmaz, Erdem; Gursoy, Semin; Bircan, Iffet; Akcurin, Sema

    2014-01-01

    Steroid 5-a reductase type 2 isoenzyme (SRD5A2) deficiency is a male-limited autosomal recessive disorder that results in decreased conversion of testosterone to dihydrotestosterone with various de.gree of incomplete virilization in affected 46, XY infants. No clear genotype-phenotype relationship has been reported till date; moreover, the same mutation can result in considerable heterogeneity in clinical manifestations. Of 6 documented cases with Try235Phe homozygous mutation of the SRD5A2 gene, 3 patients had predominantly female external genitalia whereas the other 3 had predominantly male phenotype. We report Try235Phe homozygous mutation of the SRD5A2 gene in a Turkish patient who was initially assigned as a girl because of the predominantly female appearance of the external genitalia. PMID:25266188

  6. Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell disease.

    PubMed

    Zimmerman, S A; Ware, R E

    1998-12-01

    Thrombosis may play an important role in the pathophysiology of certain complications of sickle cell disease (SCD), including stroke and avascular necrosis (AVN). Currently there is no laboratory or clinical parameter that can identify patients who are at highest risk of developing these thrombotic complications. We hypothesized that some patients with SCD have an inherited hypercoagulable state that results in an increased risk of developing stroke or AVN. We examined the role of two common inherited thrombophilic mutations that, in other populations, have been associated with arterial and venous thrombosis and are amenable to screening with DNA restriction enzyme analysis. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the C1565T mutation in the platelet glycoprotein IIIa (GPIIIa) gene were evaluated. We analyzed genomic DNA from 86 children and adults with SCD, including 16 patients with a history of a clinical stroke and 14 patients with AVN, for the presence of these mutations. The C677T MTHFR mutation was found in 19% of patients with stroke, 14% of patients with AVN, and 14% of patients with neither complication (P = NS). The C1565T GPIIIa mutation was found in 25% of patients with stroke, 14% of patients with AVN, and 18% of patients with neither complication (P = NS). Although each of these mutations is relatively common in patients with SCD, neither is independently associated with an increased risk of developing stroke or AVN. PMID:9840906

  7. Prothrombin mutant, factor V Leiden, and thermolabile variant of methylenetetrahydrofolate reductase among patients with sickle cell disease in Brazil.

    PubMed

    Andrade, F L; Annichino-Bizzacchi, J M; Saad, S T; Costa, F F; Arruda, V R

    1998-09-01

    The prevalence of the prothrombin gene variant (allele 20.210 A), factor V Leiden mutation, and homozygosity for transition 677C-->T in the methylenetetrahydrofolate reductase (MTHFR) gene was determined among patients with sickle cell disease (SCD). The group included 73 patients with median age of 32.3 years with a diagnosis of sickle cell anemia in 53 patients, hemoglobinopathy SC in 16 patients, and four with S/beta(0) thalassemia. Vascular complications such as ischemic stroke or deep vein thrombosis were diagnosed in nine patients. Heterozygosity for the prothrombin gene variant or factor V Leiden mutation was identified in four patients. However, only one patient, who developed ischemic stroke, was identified as a carrier of factor V Leiden mutation. None of the patients presented homozygosity for the thermolabile variant of the MTHFR. These data suggest a low clinical impact of inherited hypercoagulability risk factors in developing thrombosis, occlusive stroke, or mortality data among patients with SCD in Brazil. PMID:9723576

  8. Lack of association between MTHFR C677T polymorphism and breast cancer risk in Ahvaz, west south-Iran

    PubMed Central

    Mohammadzadeh, Ghorban; Karimi, Maryam; Bazyar, Mohammad; Hosseini, Seyed-Mohammad

    2016-01-01

    Background: Association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism and DNA methylation, and breast cancer risk are inconsistent. We investigated in a case-control study, possible effect of the common MTHFR C677T polymorphism on breast cancer risk in a sample of Iranian patients. Materials and Methods: The study subjects comprised of 123 breast cancer cases and 110 cancer-free control, who were matched for age and body mass index (BMI). C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Lipid profile was measured in all subjects by standard method. Results: The genotypes distributions (CC, CT, and TT) were 55.3, 39, and 5.7% in breast cancer cases and 51.8, 44.5, and 3.6% in controls. Chi square analysis revealed that there was no significant association between breast cancer risk and MTHFR genotypes and alleles. Additionally, no significant association was observed between C677T genotypes and biochemistry parameters. A multinomial logistic regression model with MTHFR genotypes, lipid profiles, BMI and age as covariates revealed that there is no significant association between MTHFR genotypes and risk of breast cancer, but higher values of LDL and HDL significantly increase risk of breast cancer. Conclusions: Our findings do not support the hypothesis that genetic variation in the MTHFR C677T polymorphism is implicated in the breast cancer risk in a sample of Iranian patients. PMID:27014653

  9. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation.

    PubMed

    De Mattia, Elena; Toffoli, Giuseppe

    2009-05-01

    Pharmacogenetics represents an exciting, new promising tool for the individualisation of therapy. Several genetic polymorphisms and haplotypes have been considered in an attempt to optimise therapy with specific drugs but, up to now, their clinical applications remain limited. 5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme of one-carbon metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were described for the MTHFR gene and associated with a decreased enzymatic activity and an alteration of intracellular folate distribution. Other MTHFR polymorphisms with marginal impact on enzymatic activity were also reported. Several published clinical studies have investigated the potential predictive role of C677T and A1298C genetic variants on toxicity and efficacy of antifolate and fluoropyrimidine agents, such as methotrexate (MTX), 5-fluorouracil (5-FU) and raltitrexed. Many of these studies show significant associations with MTHFR variants, but others report neither association nor opposite results. A significant interaction between MTHFR polymorphisms and nutrient/environmental factors (i.e. folate status) as well as the ethnicity was reported. Finally, a haplotype approach and the combined analysis of multiple folate pathway gene variants seem to provide a more comprehensive strategy compared to single-locus investigations. The aim of this review is to critically analyse the available data on the importance of MTHFR polymorphisms in modulating the clinical outcome of antifolate and fluoropyrimidine therapies. PMID:19144510

  10. In-Depth Dissection of the P133R Mutation in Steroid 5?-Reductase (AKR1D1): A Molecular Basis of Bile Acid Deficiency.

    PubMed

    Chen, Mo; Jin, Yi; Penning, Trevor M

    2015-10-20

    Human steroid-5?-reductase (aldo-keto reductase 1D1, AKR1D1) stereospecifically reduces ?(4)-3-ketosteroids to 5?-dihydrosteroids and is essential for steroid hormone metabolism and bile acid biosynthesis. Genetic defects in AKR1D1 cause bile acid deficiency that leads to life threatening neonatal hepatitis and cholestasis. The disease-associated P133R mutation caused significant decreases in catalytic efficiency with both the representative steroid (cortisone) and the bile acid precursor (7?-hydroxycholest-4-en-3-one) substrates. Pro133 is a second shell residue to the steroid binding channel and is distal to both the cofactor binding site and the catalytic center. Strikingly, the P133R mutation caused over a 40-fold increase in Kd values for the NADP(H) cofactors and increased the rate of release of NADP(+) from the enzyme by 2 orders of magnitude when compared to the wild type enzyme. By contrast the effect of the mutation on Kd values for steroids were 10-fold or less. The reduced affinity for the cofactor suggests that the mutant exists largely in the less stable cofactor-free form in the cell. Using stopped-flow spectroscopy, a significant reduction in the rate of the chemical step was observed in multiple turnover reactions catalyzed by the P133R mutant, possibly due to the altered position of NADPH. Thus, impaired NADPH binding and hydride transfer is the molecular basis for bile acid deficiency in patients with the P133R mutation. Results revealed that optimal cofactor binding is vulnerable to distant structural perturbation, which may apply to other disease-associated mutations in AKR1D1, all of which occur at conserved residues and are unstable. PMID:26418565

  11. Association of the methylenetetrahydrofolate reductase A1298C but not the C677T single nucleotide polymorphism with sickle cell disease in Bahrain.

    PubMed

    Al-Absi, Iman K; Al-Subaie, Abeer M; Ameen, Ghada; Mahdi, Najat; Mohammad, Akbar Mohsin; Fawaz, Naglaa A; Almawi, Wassim Y

    2006-01-01

    The association of methylenetetrahydrofolate reductase (MTHFR) gene mutations, C677T and A1298C, together with changes in homocysteine (Hcy) levels was investigated in 106 sickle cell disease patients and 156 healthy controls from Bahrain. The mutation analysis was done by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). While the frequencies of the mutant alleles C677T and A1298C were comparable between patients and controls, the frequency of the A1298C (C/C) (p = 0.03) but not C677T (T/T) (p = 0.67) genotype, and of the 677T/1298C haplotype were significantly higher in the patients (p = 0.05). Homocysteine levels were normal in all subjects. This suggests that the A1298C, but not C677T, mutation is associated with the genotype of sickle cell disease. PMID:16987799

  12. Significant impact of MTHFR C677T polymorphism on plasma homovanillic acid (HVA) levels among alcohol-dependent patients.

    PubMed

    Lutz, Ulrich C; Batra, Anil; Wiatr, Gerlinde; Machicao, Fausto; Kolb, Werner; Maurer, Sandra; Buchkremer, Gerhard; Khnke, Michael D

    2007-03-01

    The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate. It plays a critical role in homocysteine metabolism. A high impact of MTHFR C677T polymorphism on plasma homocysteine levels has been observed among alcoholics. Recent studies indicate that homocysteine has toxic effects on dopaminergic neurons. Thus it lowers levels of homovanillic acid (HVA) in the striatal region in rats. Alcoholics had significantly lower plasma HVA concentrations compared with healthy controls. Aim of this study is to elucidate whether HVA plasma levels in alcoholics are influenced by MTHFR C677T polymorphism. A total of 142 alcohol-dependent patients and 101 healthy controls were examined regarding plasma HVA concentration and MTHFR C677T genotype. Blood samples of alcoholics were obtained after a minimum of 22 days of abstinence. Among alcohol-dependent patients MTHFR C677T polymorphism was significantly associated with plasma HVA levels: carriers of MTHFR C677T T-allele had significantly lower HVA plasma levels compared with homozygote carriers of C-allele: 11.9 ng/ml versus 14.4 ng/ml (chi2: 5.39; P = 0.02). In healthy control subjects plasma HVA levels did not differ significantly between MTHFR C677T T-allele carriers and homozygote carriers of C-allele: 15.1 ng/ml versus 15.3 ng/ml (chi2: 0.04; P = 0.82). The data suggest an influence of MTHFR C677T polymorphism on plasma HVA among alcohol-dependent patients. This might be due to neurotoxic effects of homocysteine on the dopaminergic system or direct impairment of monoamine metabolism. Future studies should try to elucidate whether this effect is reversible during alcohol abstinence. PMID:17407503

  13. 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 deficiency in neurodevelopmental disorders. PMID:21490592

  14. Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and ?-aminobutyric acid in brain tissue

    PubMed Central

    Jadavji, N.M.; Wieske, F.; Dirnagl, U.; Winter, C.

    2015-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is an enzyme key regulator in folate metabolism. Deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAM). In the brain, SAM donates methyl groups to catechol-O-methyltransferase (COMT), which is involved in neurotransmitter analysis. Using the MTHFR-deficient mouse model the purpose of this study was to investigate levels of monoamine neurotransmitters and amino acid levels in brain tissue. MTHFR deficiency affected levels of both glutamate and ?-aminobutyric acid in within the cerebellum and hippocampus. Mthfr?/? mice had reduced levels of glutamate in the amygdala and ?-aminobutyric acid in the thalamus. The excitatory mechanisms of homocysteine through activation of the N-methyl-d-aspartate receptor in brain tissue might alter levels of glutamate and ?-aminobutyric acid.

  15. Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City1234

    PubMed Central

    Hu, Howard; Wright, Robert O; Kordas, Katarzyna; Ettinger, Adrienne S; Snchez, Brisa N; Cantonwine, David; Lazarus, Alicia L; Cantoral, Alejandra; Schnaas, Lourdes; Tllez-Rojo, Martha Maria; Hernndez-Avila, Mauricio

    2010-01-01

    Background: Maternal folate nutritional status and prenatal lead exposure can influence fetal development and subsequent health. The methylenetetrahydrofolate reductase (MTHFR) gene is important for folate metabolism, and 2 common polymorphisms, C677T and A1298C, reduce enzymatic activity; C677T is present at high penetrance in Mexican populations. Objective: The objective of this study was to examine potential links between maternal and child MTHFR polymorphisms and child neurodevelopment in a lead-exposed population. Design: Data regarding MTHFR polymorphisms C677T and A1298C, peri- and postnatal lead measures, and Bayley Mental Development Index at 24 mo of age (MDI-24) scores were available for 255 mother-child pairs who participated in the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) study during 19941995. Results: In covariate-adjusted regression models, maternal MTHFR 677 genotype predicted MDI-24 scores, in which each copy of the maternal MTHFR 677T variant allele was associated with lower MDI-24 scores (? = ?3.52; 95% CI: ?6.12, ?0.93; P = 0.004). Maternal MTHFR haplotype also predicted MDI-24 scores (mean SE: 93.3 1.2 for 677C-1298A compared with 89.9 0.8 for 677T-1298A; P < 0.05). MDI-24 scores were not associated with maternal MTHFR 1298 genotype or child MTHFR genotypes. We did not observe significant MTHFR genotype lead interactions with respect to any of the subject biomarkers of lead exposure. Conclusions: The maternal MTHFR 677T allele is an independent predictor of poorer child neurodevelopment at 24 mo. These results suggest that maternal genetic variations in folate metabolism during pregnancy may program offspring neurodevelopment trajectories. Further research is warranted to determine the generalizability of these results across other populations. PMID:20504979

  16. Deep Sequencing Study of the MTHFR Gene to Identify Variants Associated with Myelomeningocele

    PubMed Central

    Aneji, Chiamaka U; Northrup, Hope; Au, Kit Sing

    2012-01-01

    INTRODUCTION Neural tube defects (NTDs) are congenital anomalies caused by a combination of genetic and environmental influences. A defect below the head region resulting in protuberance of meninges and nervous tissue is termed myelomeningocele (MM). MM, the most common NTD compatible with survival, occurs in approximately 1 in 1,000 births worldwide. Maternal pre- and periconceptional folate supplementation reduces the risk of NTDs by up to 70%. A key enzyme in folate metabolism is 5, 10-methylene-tetrahydrofolate reductase (MTHFR). OBJECTIVES Sequence the 12 exons of the MTHFR gene among 96 subjects with MM to identify variants potentially contributing to the disease trait. METHODS Exons were amplified by polymerase chain reaction and the products were sequenced by Sanger method to reveal sequence variants compared to MTHFR reference sequences. Association of variants was examined by Fishers test. RESULTS A novel variant c.171+3G>T was identified in intron 1 in one affected subject. The variant was not found in the subjects unaffected mothers DNA and the unaffected fathers DNA was unavailable. We found significant differences in allele frequencies for seven SNPs in MM subjects compared to ethnically matched reference populations reported in the single nucleotide polymorphism (SNP) database (dbSNP). CONCLUSION We identified a novel variant c.171+3G>T in the MTHFR gene that potentially affects splicing in an affected subject. Also, we observed five SNPs (rs13306561, rs2274976, rs2066462, rs12121543, and rs1476413) in the MTHFR gene not previously shown to associate with MM. The current study provides additional evidence that multiple variations in the MTHFR gene are associated with MM. PMID:22241680

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

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Gabriel, Marcin; Zapalski, Stanis?aw; 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. PMID:12590185

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

    PubMed Central

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

    2013-01-01

    Background: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have recently raised the interest as a possible thrombophilic factors. Aims: We aimed to assess the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in idiopathic venous thromboembolism (VTE) in a Romanian population and the associated risk of VTE. Study Design: We performed a case-control transversal study including 90 patients diagnosed with VTE and 75 sex- and age-matched controls. Methods: MTHFR C677T and A1298C polymorphisms were detected using PCR-RFLP method. Results: The homozygous MTHFR 677TT genotype, present in 18.8% of patients with VTE versus 6.6% of controls, was significantly associated with VTE (p= 0.021, OR= 3.26, 95%CI (1.1419.313)). The heterozygous MTHFR A1298C genotype, presenting the highest prevalence in the VTE group (34.4%) as well as in controls (37.3%), was not associated with VTE (p=0.7). No associations were found for heterozygous MTHFR C677T (with a frequency of 32.2% in VTE and 37.3% in controls, p=0.492), respective homozygous MTHFR A1298C genotype (with a frequency of 1.1% in VTE and 2.6% in controls, p=0.456). Conclusion: Among MTHFR polymorphisms, only homozygosity for MTHFR 677TT may be considered a risk factor for VTE; the MTHFR A1298C polymorphism is not significantly associated with an increased risk of VTE. PMID:25207100

  19. MTHFR genetic polymorphism increases the risk of preterm delivery

    PubMed Central

    Nan, Yanrong; Li, Hongmei

    2015-01-01

    Aims: This study aimed to investigate the association between the methylene tetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and premature delivery susceptibility. Methods: With matched age and gender, 108 premature delivery pregnant women as cases and 108 healthy pregnant women as controls were recruited in this case-control study. The cases and controls had same gestational weeks. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was adopted to analyze C677T and A1298C polymorphisms of the participants. Linkage disequilibrium (LD) and haplotype analysis were conducted by Haploview software. The differences for frequencies of gene type, allele and haplotypes in cases and controls were tested by chi-square test. The relevant risk of premature delivery was represented by odds ratios (ORs) with 95% confidence intervals (95% CIs). Results: TT gene type frequency of C677T polymorphsim was higher in cases than the controls (P=0.004, OR=3.077, 95% CI=1.469-6.447), so was allele T (P=0.002, OR=1.853, 95% CI=1.265-2.716). Whereas, CC gene type of A1298C polymorphism had a lower distribution in cases than the controls (P=0.008, OR=0.095, 95% CI=0.012-0.775), so was allele C (P=0.047, OR=0.610, 95% CI=0.384-0.970). Haplotype analysis and linkage disequilibrium test conducted on the alleles of two polymorphisms in MTHFR gene, we discovered that haplotype T-A had a higher distribution in cases, which indicated that susceptible haplotype T-A was the candidate factor for premature delivery. Conclusions: Gene type TT of MTHFR C677T polymorphism might make premature delivery risk rise while gene type CC of A1298C polymorphism might have protective influence on premature delivery. PMID:26261642

  20. 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-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient. PMID:25733650

  1. Quantitative proteomics reveals differentially expressed proteins in murine preneoplastic intestine in a model of intestinal tumorigenesis induced by low dietary folate and MTHFR deficiency.

    PubMed

    Leclerc, Daniel; Dejgaard, Kurt; Mazur, Alexander; Deng, Liyuan; Wu, Qing; Nilsson, Tommy; Rozen, Rima

    2014-11-01

    Colorectal cancer risk is increased when dietary folate intake is low, with or without a deficiency in methylenetetrahydrofolate reductase (MTHFR). We have observed that intestinal tumors are induced in mice fed low-folate diets, and that tumor incidence is increased when these mice also have MTHFR deficiency. This study was undertaken to identify differentially expressed proteins in conditions favoring initial steps of murine carcinogenesis in normal preneoplastic intestine. We compared the proteome of BALB/c normal intestine in Mthfr(+/+) mice fed control diets for 1 year (low susceptibility to tumorigenesis) with the proteome of Mthfr(+/-) animals fed low folate diets (higher tumor susceptibility). Our data suggest that the NuRD complex, KRAS-related proteins, the protein synthetic machinery, and fatty acid-related metabolic proteins are upregulated in the early stages of tumorigenesis. These proteins may serve as biomarkers or targets for colorectal cancer diagnosis or therapy. PMID:25081070

  2. The Association of the MTHFR c.1625A>C Genetic Variant with the Risk of Congenital Heart Diseases in the Chinese

    PubMed Central

    Wang, Yuting; Sun, Lei; Du, Weina; Song, Shuang; Wang, Shuo; Jiang, Weiju; Huang, Tianchu

    2015-01-01

    The purpose of this study is to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the risk of congenital heart diseases (CHD). The genotypes of the MTHFR genetic variant were determined by the polymerase chain reactionrestriction fragment length polymorphism and DNA sequencing methods. Our data suggested that the allelic and genotypic frequencies of CHD patients were significantly different from non-CHD controls. The MTHFR c.1625A>C genetic variant was significantly associated with the increased risk of CHD (CC vs. AA: odds ratio [OR]=2.29, 95% confidence interval [CI] 1.154.53, p=0.016; C vs. A: OR=1.47, 95% CI 1.111.96, p=0.008). Results from this study indicate that the MTHFR c.1625A>C genetic variant influences the risk of CHD in the studied population. PMID:25494855

  3. Association study of methylenetetrahydrofolate reductase C677T mutation with cerebral venous thrombosis in an Iranian population.

    PubMed

    Ghaznavi, Habib; Soheili, Zahra; Samiei, Shahram; Soltanpour, Mohammad S

    2015-12-01

    There are limited data on the role of methylenetetrahydrofolate reductase C677T polymorphism and hyperhomocysteinemia as risk factors for cerebral venous thrombosis in Iranian population. We examined a possible association between fasting plasma homocysteine levels, methylenetetrahydrofolate reductase C677T polymorphism, and cerebral venous thrombosis in 50 patients with a diagnosis of cerebral venous thrombosis (20-63 years old) and 75 healthy controls (18-65 years old). Genotyping of the methylenetetrahydrofolate reductase C677T gene polymorphism was performed by PCR-restriction fragment length polymorphism analysis, and homocysteine levels were measured by enzyme immunoassay. Fasting plasma homocysteine levels were significantly higher in cerebral venous thrombosis patients than in controls (P?=?0.015). Moreover, plasma homocysteine levels were significantly higher in methylenetetrahydrofolate reductase 677TT genotype compared to 677CT and 677CC genotypes in both cerebral venous thrombosis patients (P?=?0.01) and controls (P?=?0.03). Neither 677CT heterozygote genotype [odds ratio (OR) 1.35, 95% confidence interval (CI) 0.64-2.84, P?=?0.556] nor 677TT homozygote genotype (OR 1.73, 95% CI 0.32-9.21, P?=?0.833) was significantly associated with cerebral venous thrombosis. Additionally, no significant differences in the frequency of 677T allele between cerebral venous thrombosis patients and controls were identified (OR 1.31, 95% CI 0.69-2.50, P?=?0.512). In conclusion, our study demonstrated that elevated plasma homocysteine levels are significant risk factors for cerebral venous thrombosis. Also, methylenetetrahydrofolate reductase 677TT genotype is not linked with cerebral venous thrombosis, but is a determinant of elevated plasma homocysteine levels. PMID:26083986

  4. Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease

    PubMed Central

    Cario, Holger; Smith, Desire E.C.; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

    2011-01-01

    The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. PMID:21310277

  5. MTHFR polymorphisms involved in vitamin B12 deficiency associated with atrophic gastritis.

    PubMed

    Palladino, Mariangela; Chiusolo, Patrizia; Reddiconto, Giovanni; Marietti, Sara; De Ritis, Daniela; Leone, Giuseppe; Sica, Simona

    2009-10-01

    Genetic polymorphisms affecting methylentetrahydrofolate reductase (MTHFR) activity may influence hematological and neurological dysfunction in cobalamin-deficient patients. We studied the prevalence of C677T and A1298C polymorphisms by analyzing genomic DNA in 30 cobalamin-deficient patients. No significant difference was found in 677 and 1298 genotype distribution with respect to hematological parameters, B12 and folate levels, and neurological symptoms. The two MTHFR polymorphisms were not protective against anemia or neurological dysfunction in patients with cobalamin deficiency; however, we found evidence of a significant increase in atrophic gastritis in the 677TT group (P = 0.009) but not for the 1298CC genotype. Based on observations that inadequate cobalamin intake and reduced MTHFR activity might be significant risk factors for gastric cancer, and the increased risk of gastric cancer shown in patients affected by atrophic gastritis, we speculate that concomitant atrophic gastritis and impaired MTHFR function could have a role in the development of gastric cancer. PMID:19521764

  6. Defining the role of mutations in Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene using an episomal Plasmodium falciparum transfection system.

    PubMed

    Auliff, Alyson M; Adams, John H; O'Neil, Michael T; Cheng, Qin

    2010-09-01

    Plasmodium vivax resistance to antifolates is prevalent throughout Australasia and is caused by point mutations within the parasite dihydrofolate reductase (DHFR)-thymidylate synthase. Several unique mutations have been reported in P. vivax DHFR, and their roles in resistance to classic and novel antifolates are not entirely clear due, in part, to the inability to culture P. vivax in vitro. In this study, we use a homologous system to episomally express both wild-type and various mutant P. vivax dhfr (pvdhfr) alleles in an antifolate-sensitive line of P. falciparum and to assess their influences on the susceptibility of the recipient P. falciparum line to commonly used and new antifolate drugs. Although the wild-type pvdhfr-transfected P. falciparum line was as susceptible to antifolate drugs as the P. falciparum parent line, the single (117N), double (57L/117T and 58R/117T), and quadruple (57L/58R/61M/117T) mutant pvdhfr alleles conferred a marked reduction in their susceptibilities to antifolates. The resistance index increased with the number of mutations in these alleles, indicating that these mutations contribute to antifolate resistance directly. In contrast, the triple mutant allele (58R/61M/117T) significantly reversed the resistance to all antifolates, indicating that 61M may be a compensatory mutation. These findings help elucidate the mechanism of antifolate resistance and the effect of existing mutations in the parasite population on the current and new generation of antifolate drugs. It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax. PMID:20566761

  7. Defining the Role of Mutations in Plasmodium vivax Dihydrofolate Reductase-Thymidylate Synthase Gene Using an Episomal Plasmodium falciparum Transfection System?

    PubMed Central

    Auliff, Alyson M.; Adams, John H.; O'Neil, Michael T.; Cheng, Qin

    2010-01-01

    Plasmodium vivax resistance to antifolates is prevalent throughout Australasia and is caused by point mutations within the parasite dihydrofolate reductase (DHFR)-thymidylate synthase. Several unique mutations have been reported in P. vivax DHFR, and their roles in resistance to classic and novel antifolates are not entirely clear due, in part, to the inability to culture P. vivax in vitro. In this study, we use a homologous system to episomally express both wild-type and various mutant P. vivax dhfr (pvdhfr) alleles in an antifolate-sensitive line of P. falciparum and to assess their influences on the susceptibility of the recipient P. falciparum line to commonly used and new antifolate drugs. Although the wild-type pvdhfr-transfected P. falciparum line was as susceptible to antifolate drugs as the P. falciparum parent line, the single (117N), double (57L/117T and 58R/117T), and quadruple (57L/58R/61M/117T) mutant pvdhfr alleles conferred a marked reduction in their susceptibilities to antifolates. The resistance index increased with the number of mutations in these alleles, indicating that these mutations contribute to antifolate resistance directly. In contrast, the triple mutant allele (58R/61M/117T) significantly reversed the resistance to all antifolates, indicating that 61M may be a compensatory mutation. These findings help elucidate the mechanism of antifolate resistance and the effect of existing mutations in the parasite population on the current and new generation of antifolate drugs. It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax. PMID:20566761

  8. 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 mol/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-?-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 1860 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 [?(SE ?), 2.01(0.63) and 16.19(1.8) mol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [?(SE ?), ?0.56(0.58) and ?0.83(0.99) mol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was ?1.88(0.81) mol/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(3.628.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.340.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in folate and vitamin B12 deficiencies and high blood lead (p value <0.05) level. Conclusions Gene polymorphism (especially MTHFR C677T transition), folate and vitamin B12 deficiencies, male gender and high blood lead level appear to be contributing towards the development of hyperhomocysteinemia in a Pakistani population. PMID:22470444

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  11. AB068. Association between MTHFR C677T and carotid intima medial thickness progression in post-ischemic stroke patient

    PubMed Central

    Pramukarso, Dodik Tugasworo; Faradz, Sultana MH; Sari, Stefani Harum; Hadisaputro, Suharyo

    2015-01-01

    Background and objective Substitution of c.677C > T in methylenetetrahydrofolate reductase (MTHFR) gene contributes to increase blood level of homocysteine (Hcy). Hyperhomocysteinemia is believed to have association with vascular damage leads to atherosclerosis. Defect MTHFR may influence vascular progression in post ischemic stroke. Carotid intima media thickness (c-IMT) has been known as vascular marker for atherosclerosis and predictor for ischemic stroke. The study aims to determine association between MTHFR C677T and c-IMT progression in post-ischemic stroke patients. Methods Seventy one of post-ischemic stroke patients were included in epidemiological prospective observational cohort study. Genotyping MTHFR gene polymorphism was done using PCR-RFLP with HinfI restriction enzyme. Blood Hcy level was determined using enzyme immunoassay (EIA) method. Carotid duplex ultrasound was used to evaluate c-IMT in 1st, 6th, and 12th month after the onset of stroke. Results The genotype distribution of MTHFR C677T in samples was CC (81.9%), CT (13.9%) and TT (4.2%). No significant differences in mean Hcy levels between genotype TT and others (CT and CC) were identified (P=0.250). Mean c-IMT showed no significant differences between genotype TT and others at evaluation in 1st month (P=0.979), 6th month (P=0.670) and 12th month (P=0.770). All samples with genotype TT were observed to have increase c-IMT level at evaluation in 1st, 6th and 12th month. Conclusions The presence of homozygote TT of MTHFR C677T may contribute to increase c-IMT level. However, this study found no association between MTHFR C677T with hyperhomocysteinemia as well as an increase in c-IMT in post-ischemic stroke patients.

  12. Polymorphisms in the MTHFR gene are associated with breast cancer risk and prognosis in a Chinese population.

    PubMed

    Lu, Qing; Jiang, Ke; Li, Qiong; Ji, Ya-Jie; Chen, Wei-Li; Xue, Xiao-Hong

    2015-05-01

    Breast cancer is the most common cancer affecting women in China and the world. Folate supplementation is proven to be effective in reducing the risk of breast cancer or improving its prognosis. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. This study aims to examine whether single nucleotide polymorphisms (SNP) in the MTHFR gene are associated with risk and survival of breast cancer and serum folate levels in healthy controls. We genotyped nine tagging SNPs in the MTHFR gene in a case-control study, including 560 breast cancer cases and 560 healthy controls in China. We found that TT genotype of rs1801133 had significant increased risk of breast cancer [adjusted odds ratio (OR)?= 1.60, 95 % confidence interval (CI) 1.12-2.28] compared with CC genotype, and CC genotype of rs9651118 conferred significant reduced risk of breast cancer (adjusted OR = 0.65, 95 % CI 0.45-0.95) compared to TT genotype. Haplotype analysis also showed that MTHFR CACCAA and AGTCAC haplotypes (rs12121543-rs13306553-rs9651118-rs1801133-rs4846048-rs1801131) had significant reduced risk of breast cancer (adjusted OR = 0.70, 95 % CI 0.58-0.86; adjusted OR = 0.57, 95 % CI 0.40-0.80) compared with CATTAA haplotype. Besides, MTHFR rs9651118 CC genotype was significantly associated with survival in breast cancer cases (adjusted hazard ratio (HR)?= 0.63, 95 % CI 0.40-0.99). But none of the SNPs in the MTHFR gene was associated with serum folate level in healthy controls. These findings suggest that variants in the MTHFR gene may influence the risk and prognosis of breast cancer. PMID:25566964

  13. Infants' MTHFR polymorphisms and nonsyndromic orofacial clefts susceptibility: a meta-analysis based on 17 case-control studies.

    PubMed

    Pan, Yongchu; Zhang, Weibing; Ma, Junqing; Du, Yifei; Li, Dandan; Cai, Qi; Jiang, Hongbing; Wang, Meilin; Zhang, Zhengdong; Wang, Lin

    2012-09-01

    Methylenetetrahydrofolate reductase (MTHFR), an important enzyme in folate metabolism, is thought to be involved in the development of nonsyndromic orofacial clefts (NSOC). However, conflicting results have been achieved when evaluating the associations between infants' MTHFR C677T and A1298C polymorphisms and the risk of NSOC. To obtain more precise estimations of these associations, a meta-analysis recruiting 17 case-control studies was performed. Among Asians we found that CT heterozygote, TT homozygote, and CT/TT of infants' MTHFR C677T variant could contribute to elevated risks of NSOC, compared with CC wild-type homozygote (OR=1.741, 95% CI=1.043-2.907 for CT vs. CC, OR=2.311, 95% CI=1.313-4.041 for TT vs. CC, and OR=1.740, 95% CI=1.051-2.882 for CT/TT vs. CC, respectively). Similar effect was also observed on MTHFR 677T T allele, when using C allele as a reference in Asians (OR=1.420, 95% CI=1.191-1.693, for T allele vs. C allele). Furthermore, in stratified analysis by types of disease, CT/CC was suggested to confer decreased susceptibility to CL/P under recessive genetic model (OR=0.854, 95% CI=0.730-1.000). For MTHFR A1298C, the MTHFR 1298C allele in the case group of Caucasians was significantly lower than that in the control group, suggesting a protective effect against NSOC in Caucasian populations (OR=0.711, 95% CI=0.641-0.790, for C allele vs. A allele). In conclusion, the meta-analysis provided confirmative evidences that infants' MTHFR C677T and A1298C polymorphisms were involved in the development of NSOC. PMID:22847888

  14. Molecular Determination of Point Mutation Haplotypes in the Dihydrofolate Reductase and Dihydropteroate Synthase of Plasmodium falciparum in Three Districts of Northern Tanzania

    PubMed Central

    Pearce, Richard J.; Drakeley, Chris; Chandramohan, Daniel; Mosha, Frank; Roper, Cally

    2003-01-01

    The antimalarial combination of sulfadoxine and pyrimethamine (SP) was introduced as first-line treatment for uncomplicated malaria in Tanzania during 2001 following 18 years of second-line use. The genetic determinants of in vitro resistance to the two drugs individually are shown to be point mutations at seven sites in the dihydrofolate reductase gene (dhfr) conferring resistance to pyrimethamine and five sites in the dihydropteroate synthase (dhps) gene conferring resistance to sulfadoxine. Different combinations of mutations within each gene confer differing degrees of insensitivity, but information about the frequency with which allelic haplotypes occur has been lacking because of the complicating effects of multiple infection. Here we used a novel high-throughput sequence-specific oligonucleotide probe-based approach to examine the present resistance status of three Plasmodium falciparum populations in northern Tanzania. By using surveys of asymptomatic infections and screening for the presence of all known point mutations in dhfr and dhps genes, we showed that just five dhfr and three dhps allelic haplotypes are present. High frequencies of both triple-mutant dhfr and double-mutant dhps mutant alleles were found in addition to significant interregional heterogeneity in allele frequency. In vivo studies have shown that the cooccurrence of three dhfr mutations and two dhps mutations in an infection prior to treatment is statistically predictive of treatment failure. We have combined data for both loci to determine the frequency of two-locus genotypes. The triple-dhfr/double-dhps genotype is present in all three regions with frequencies ranging between 30 and 63%, indicating that treatment failure rates are likely to be high. PMID:12654669

  15. Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia

    PubMed Central

    Imwong, Mallika; William, Timothy; Bird, Elspeth; Piera, Kim A.; Aziz, Ammar; Boonyuen, Usa; Drakeley, Christopher J.; Cox, Jonathan; White, Nicholas J.; Cheng, Qin; Yeo, Tsin W.; Auburn, Sarah; Anstey, Nicholas M.

    2016-01-01

    Background Malaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine-pyrimethamine (SP) as a potential marker of H-H transmission. Methods The P. knowlesi dihdyrofolate-reductase (pkdhfr) gene was sequenced from 449 P. knowlesi malaria cases from Sabah (Malaysian Borneo) and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the pvdhfr template was used to assess the effect of pkdhfr mutations on the pyrimethamine binding pocket. Results Fourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2%) and R34L (10.0%), resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the P. knowlesi infections were with pkdhfr mutants; 145 (32%) patients had single mutants and 14 (3%) had double-mutants. In contrast, among the 47 P. falciparum isolates sequenced, three pfdhfr genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with pkdhfr genotypes. There was no association between pkdhfr mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in P. falciparum were not mutated in pkdhfr. Subsequent homology modelling of pkdhfr revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449 P. knowlesi isolates. Conclusion Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans. PMID:26930493

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

    PubMed Central

    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 0.415.01, 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. PMID:26317030

  17. MTHFR Gene Polymorphisms and the Risk of Acute Lymphoblastic Leukemia in Adults and Children: A Case Control Study in India.

    PubMed

    Sazawal, Sudha; Chaubey, Rekha; Kaur, Pawandeep; Chikkara, Sunita; Kumar, Bijender; Bakshi, Sameer; Arya, L S; Raina, Vinod; Das Gupta, Alakananda; Saxena, Renu

    2014-12-01

    Genetic polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene have been associated with the development of acute leukemias and various malignancies. The role of MTHFR polymorphism in the development of pediatric acute lymphoblastic leukemia (ALL) has been extensively studied among north Indians in various settings, yet its association with acute leukemias remains unresolved. To evaluate the relationship between functional MTHFR polymorphisms, C677T and A1298C and possible effect on risk of ALL in adults and children in North Indian population by comparing them with healthy controls. DNA was isolated from peripheral blood of 184 ALL patients (33 adults, 151 children) and 155 controls and analyzed by a PCR-restriction fragment length polymorphism assay. The frequency of MTHFR 677CT and 1298 AC genotypes were significantly lower among adult ALL cases when compared to the controls. We found a 1.74-fold reduced risk of ALL in individuals with 1298AC polymorphic variant and a 9.17-fold decreased risk of adult ALL. However, no statistically significant difference was evident between the above polymorphisms and susceptibility to ALL in children. Polymorphisms in the MTHFR gene possibly modulate risk of ALL in north Indian adults but not in children, although larger studies are needed. PMID:25435717

  18. A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder.

    PubMed

    Wang, Liang-Jen; Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Chen, Kao Chin; Lee, I Hui; Wang, Tzu-Yun; Yang, Yen Kuang; Lu, Ru-Band

    2015-01-01

    Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under-recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction effect of the COMT Val158Met Val/Val genotype and the MTHFR C677T C/T + T/T genotype (P = 0.039) for the protective effect on the odds of developing BP-II. Our findings support preliminary evidence that the COMT and MTHFR genes interact in BP-II, and they imply the connection of both dopaminergic pathways and methylation pathways in the pathogenesis of BP-II. PMID:25744938

  19. A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder

    PubMed Central

    Wang, Liang-Jen; Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Chen, Kao Chin; Lee, I. Hui; Wang, Tzu-Yun; Yang, Yen Kuang; Lu, Ru-Band

    2015-01-01

    Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under-recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction effect of the COMT Val158Met Val/Val genotype and the MTHFR C677T C/T + T/T genotype (P = 0.039) for the protective effect on the odds of developing BP-II. Our findings support preliminary evidence that the COMT and MTHFR genes interact in BP-II, and they imply the connection of both dopaminergic pathways and methylation pathways in the pathogenesis of BP-II. PMID:25744938

  20. A nonsense mutation in S-antigen (p.Glu306*) causes Oguchi disease

    PubMed Central

    Waheed, Nadia K.; Qavi, Ahmed H.; Malik, Sarah N.; Maria, Maleeha; Riaz, Moeen; Cremers, Frans P. M.; Azam, Maleeha

    2012-01-01

    Purpose Genetic studies were performed to identify the causative mutation in a 15-year-old girl diagnosed with congenital stationary night blindness (CSNB) presenting Mizuo-Nakamura phenomenon, a typical Oguchi disease symptom. The patient also had dural sinus thrombosis (DST), thrombocytopenia, and systemic lupus erythematosus (SLE). Methods Mutation analysis was done by sequencing two candidate genes, S-antigen (SAG; arrestin 1), associated with Oguchi type 1, and rhodopsin kinase (GRK1), associated with Oguchi type 2. In addition, the C677T variation in the methylenetetrahydrofolate reductase (MTHFR) gene was also screened in the family, to determine its probable association with hyperhomocysteinemia in the patient. Results Sequencing of the SAG and GRK1 resulted in identifying a novel homozygous nonsense mutation (c.916G>T; p.Glu306*) in SAG, which in unaffected siblings either was present in a heterozygous state or absent. The C677T heterozygous allele in the MTHFR gene was found to be associated with hyperhomocysteinemia in the patient and other family members. Conclusions This is the first report of Oguchi type 1 in a Pakistani patient due to a nonsense mutation (c.916G>T; p.Glu306*) in SAG. The neurologic and hematological abnormalities likely are not associated with the SAG variant. PMID:22665972

  1. Malaria treatment failure with novel mutation in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) gene in Kolkata, West Bengal, India.

    PubMed

    Das, Sabyasachi; Chakraborty, Subhankari Prasad; Hati, AmiyaKumar; Roy, Somenath

    2013-05-01

    The aim of this work was to define the cause of sulfadoxine/pyrimethamine (SP) treatment failure in Plasmodium falciparum infections in a malaria-endemic zone of India. Samples were collected from 176 patients in Kolkata from November 2008 to July 2009. In vitro susceptibility testing was performed on all isolates. Parasite DNA was extracted, and PCR and restriction fragment length polymorphism (RFLP) analysis of different codons of the dhfr gene (16, 51, 59, 108 and 164) and dhps gene (436, 437, 540, 581 and 613) were performed. Finally, sequencing of the products was performed to confirm the mutations. The in vivo treatment response to SP among the 176 patients was determined. A novel mutation of isoleucine was observed at codon 108 of the dhfr gene, which was highly correlated with in vitro SP resistance as well as early treatment failure. A double dhfr mutation (108I+51I) was observed in 77.3% of isolates, and triple mutation of the dhps gene was observed in 18.2% of isolates. In this endemic zone, SP treatment failure is due to a novel dhfr mutation (108I+51I) and any one of the dhps mutations (S436A, A437G, A581G or A613T/S). An increase in these mutations was highly correlated with SP resistance (P < 0.0001). PMID:23428313

  2. 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. PMID:25547204

  3. Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis.

    PubMed

    Lee, Young Ho; Seo, Young Ho; Kim, Jae-Hoon; Choi, Sung Jae; Ji, Jong Dae; Song, Gwan Gyu

    2015-11-01

    We examined whether methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) polymorphisms are associated with susceptibility to multiple sclerosis (MS). We performed a meta-analysis on the association between MS and the following genotypes: MTHFR C677T, A1298C, and GSTP1 A313G polymorphisms, and GSTM1 and GSTT1 null alleles. Fifteen comparisons involving 2,486 patients and 2,861 controls were considered. Meta-analysis of all study subjects considered together showed no association between MS and the MTHFR 677 T allele (OR=1.014, 95% CI 0.803-1.280, p=0.909). Stratification by ethnicity showed no similar association in Caucasian and Arab populations. Likewise, no link was found between MS and the MTHFR 1298 C allele in the total data (OR=2.477, 95% CI 0.507-12.10, p=0.263), nor when it was stratified by ethnicity. No association with MS was observed in relation to the GSTM1 null genotype in Caucasian populations (OR=1.229, 95% CI 0.693-2.181, p=0.481), nor with the GSTP1 A313G polymorphism (OR for G allele=1.133, 95% CI 0.903-1.421, p=0.281). However, there was an association between MS and the GSTT1 null genotype in data obtained from Caucasian populations (OR=1.945, 95% CI 1.452-2.605, p=8.6נ10(-7)). GSTT1 null genotype is associated with MS in Caucasian populations; however, no association was found between MS and polymorphisms of MTHFR, GSTM1, and GSTP1. PMID:26150166

  4. 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. PMID:26485042

  5. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.

    PubMed

    Pu, Danhua; Shen, Yiping; Wu, Jie

    2013-10-01

    Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. PMID:23653228

  6. MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins?

    PubMed

    Reilly, R; McNulty, H; Pentieva, K; Strain, J J; Ward, M

    2014-02-01

    Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme which requires riboflavin as its co-factor. A common polymorphism (677C?T) in the MTHFR gene results in reduced MTHFR activity in vivo which in turn leads to impaired folate metabolism and elevated homocysteine concentrations. Homozygosity for this polymorphism (TT genotype) is associated with an increased risk of a number of conditions including heart disease and stroke, but there is considerable variability in the extent of excess risk in various reports. The present review will explore the evidence which supports a role for this polymorphism as a risk factor for a number of adverse health outcomes, and the potential modulating roles for B-vitamins in alleviating disease risk. The evidence is convincing in the case which links this polymorphism with hypertension and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, elevated blood pressure was found to be highly responsive to riboflavin intervention specifically in individuals with the MTHFR 677TT genotype. Future intervention studies targeted at these genetically predisposed individuals are required to further investigate this novel gene-nutrient interaction. This polymorphism has also been associated with an increased risk of neural tube defects (NTD) and other adverse pregnancy outcomes; however, the evidence in this area has been inconsistent. Preliminary evidence has suggested that there may be a much greater need for women with the MTHFR 677TT genotype to adhere to the specific recommendation of commencing folic acid prior to conception for the prevention of NTD, but this requires further investigation. PMID:24131523

  7. 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.

  8. Mutations in the Escherichia coli fnr and tgt genes: control of molybdate reductase activity and the cytochrome d complex by fnr.

    PubMed Central

    Frey, B; Jnel, G; Michelsen, U; Kersten, H

    1989-01-01

    In eubacteria, the tRNA transglycosylase (Tgt) in specific tRNAs exchanges a guanine in the anticodon for 7-aminomethyl-7-deazaguanine, which is finally converted to queuosine. The tgt gene of Escherichia coli has been mapped at 9 min on the genome, and mutant pairs containing an intact or mutated tgt allele were obtained after transduction of the tgt locus by P1 bacteriophages into a genetically defined E. coli strain (S. Noguchi, Y. Nishimura, Y. Hirota, and S. Nishimura, J. Biol. Chem. 257:6544-6550, 1982). These tgt mutants grew anerobically with fumarate as an electron acceptor, while nitrate or trimethylamine N-oxide could not be reduced. Furthermore, molybdate reductase activity was almost lacking and the characteristic absorption maxima, corresponding to cytochrome a1 and the cytochrome d complex, were not detectable in low-temperature reduced-minus-oxidized difference spectra in anaerobically grown cells. Transduction of the mutated tgt locus into another E. coli recipient resulted in tgt mutants without anaerobic defects. Transformation of the original tgt mutants with an fnr gene-containing plasmid reversed the anaerobic defects. Clearly, the original tgt mutants harbor a second mutation, affecting the anaerobic regulator protein Fnr. The results suggest that fnr is involved in anaerobic control of components of the cytochrome d complex and of the redox system that transfers electrons to molybdate. F' plasmids containing a fused lacI-lacZ gene with the nonsense codon UAG at different positions in the lacI part were transferred to E. coli strains with a mutated or nonmutated tgt locus but intact in fnr. A twofold increase in the frequency of incorrect readthrough of the UAG codon, dependent on the codon context, was observed in the tgt mutant and is suggested to be caused by a tRNA(Tyr) with G in place of queuosine. PMID:2537821

  9. Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population.

    PubMed

    Li, H; Xu, W L; Shen, H L; Chen, Q Y; Hui, L L; Long, L L; Zhu, X L

    2011-01-01

    Methylenetetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, C677T and A1298C have been associated with several diseases, including cancer. We made a case-control study to analyze a possible association of MTHFR gene polymorphisms C677T and A1298C with risk for colorectal cancer in an eastern Chinese Han population of 137 patients with a confirmed histopathological diagnosis of CRC and 145 age- and gender-matched controls with no history of cancer. DNA was isolated from peripheral blood samples and the genotypes were determined by PCR-RFLP. The concentrations of folate in plasma were measured by chemiluminescence immunoassay. The MTHFR 677TT genotype had a protective effect against colorectal cancer, with an odds ratio (OR) = 0.467 (95% confidence interval (CI) = 0.225-0.966). The 1298CC genotype was significantly correlated with a reduced risk of colorectal cancer (OR = 0.192; 95%CI = 0.040-0.916). Compared with the MTHFR 677CC and MTHFR 1298 AA genotypes, for individuals who carried both MTHFR 677CC and 1298CC genotypes, the OR of colorectal cancer was 0.103 (95%CI = 0.012-0.900); among individuals who carried both MTHFR 677TT and 1298AC genotypes, the OR for risk of colorectal cancer was 0.169 (95%CI = 0.044-0.654). MTHFR 677TT+CT genotypes had a significantly lower plasma folate concentration than those with the MTHFR 677CC genotype. MTHFR 1298AC+CC genotypes had a lower plasma folate concentration than those with the MTHFR 1298AA genotype (P < 0.05). In conclusion, subjects with the MTHFR 677TT and MTHFR 1298CC genotypes appeared to have a significantly lower risk for colorectal cancer. MTHFR haplotypes 677CC/1298CC and 677TT/1298AC were less common in cases than in controls. These haplotypes, when compared to the most common haplotype 677CC/1298AA, were associated with a decreased risk for colorectal cancer. We conclude that plasma folate level is influenced by MTHFR genotypes. PMID:22194208

  10. Identification of three new mutations in the NADH-cytochrome b5 reductase gene responsible for recessive congenital methemoglobinemia type II

    SciTech Connect

    Mota-Vieira, L.; Kaplan, J.C.; Kahn, A.; Leroux, A.

    1994-09-01

    Recessive congenital methemoglobinemia (RCM; McKusick N{degrees}25800) due to NADH-cytochrome b5 reductase (cytb5r) deficiency leads to two different types of diseases: in type I form, cyanosis is the only symptom and the enzyme is only defective in red blood cells; in type II form, cyanosis is associated with severe mental retardation and neurological impairment and the enzyme defect is systemic. We have identified three new molecular defects in two unrelated patients with type II RCM. A homozygous C{r_arrow}T transition in codon 218 (Arg) was detected in the cDNA of one patient, resulting in a premature stop codon (TGA) in exon 8. Restriction enzyme analysis of genomic DNA confirmed the homozygosity of the propositus and heterozygosity for an identical defect in both parents. The second patient was found to be a compound heterozygote, carrying two different mutant alleles in the cyb5r gene. One allele presented a missense mutation (T{r_arrow}C) with substitution of Cys-203 (TGC) by Arg (CGC) in exon 7. The second allele showed a 3 bp deletion of nucleotides 815-817 of the cDNA. The CTG ATG sequence at position 814-819 in exon 9 coding for Leu-271 and Met-272 was replaced by the CTG triplet, with conservation of the Leu-271 and loss of the Met-272. To our knowledge, these are the first examples of a homozygous nonsense mutation and of a compound heterozygous mutation detected in the cytb5r gene. This finding supports the diversity of genetic defects in the cytb5r gene leading to the severe form of the disease.

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

    PubMed

    de Cssia Carvalho Barbosa, Rita; da Costa, Dbora 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. PMID:23155246

  12. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and nonsyndromic orofacial clefts susceptibility in a southern Chinese population.

    PubMed

    Han, Yue; Pan, Yongchu; Du, Yifei; Tong, Na; Wang, Meilin; Zhang, Zhengdong; Wan, Linzhong; Wang, Lin

    2011-12-01

    Nonsyndromic orofacial clefts (NSOC) are one of the most common congenital anomalies in humans. Great efforts have been taken to unravel its genetic background. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and two of its functional polymorphisms, MTHFR C677T and MTHFR A1298C, might be associated with NSOC susceptibility. The aim of the present study was to investigate their associations with risks of NSOC in a southern Chinese population. We found that MTHFR 677 TT and 677 CT/TT were associated with increased risk of cleft lip with or without cleft palate; meanwhile, MTHFR 1298 AC and 1298 AC/CC had protective effects against cleft lip with or without cleft palate. In further stratified analysis, we found that MTHFR 677 CT contributed to elevated risk of cleft lip only, as did MTHFR 677 CT/TT. On the contrary, MTHFR 1298 AC and 1298 AC/CC appeared to be protective against cleft lip with cleft palate. These results suggested that these two polymorphisms were involved in the development of NSOC in a southern Han Chinese population. PMID:21612398

  13. Short Communication: Lack of association between MTHFR gene polymorphisms and response to methotrexate treatment in Pakistani patients with rheumatoid arthritis.

    PubMed

    Iqbal, Mohammad Perwaiz; Ali, Azra Arif; Mehboobali, Naseema; Iqbal, Khalida

    2015-09-01

    Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with response to methotrexate (MTX) in certain populations of patients with rheumatoid arthritis (RA). This study aims at investigating any relationship of two single nucleotide polymorphisms (SNPs) in MTHFR gene, C677T and A1298C with response to therapy with MTX in Pakistani RA patients. Allelic frequencies of the two polymorphisms (C677T and A1298C) were determined in 67 RA patients (9 males and 58 females; mean age 42.87 13.5 years) who had previously participated in a prospective clinical trial. Fifty-one patients had received MTX and were followed up for response up to 6 months. Genotyping of the two MTHFR polymorphisms was carried out using PCR-RFLP, while fasting concentration of plasma homocysteine was determined using a kit method. Twenty-eight patients were found to be "good responders", while twenty-three were "poor responders". MTHFR 1298C and MTHFR 677T alleles' frequencies in "good responders" were not different from frequencies in "poor responders" (0.574 vs. 0.521; p=0.6 and 0.197 vs. 0.196; p=0.75, respectively). Plasma homocysteine levels in female RA patients were significantly higher compared to general population in Karachi (13.1 6.7 mol/l vs. 11.4 5.3 mol/l; p<0.001). MTHFR C677T and A1298C polymorphisms are not associated with response to MTX in a population of Pakistani RA patients. PMID:26408898

  14. Interaction of MTHFR 1298C with ACE D allele augments the risk of diabetic nephropathy in Western Iran.

    PubMed

    Rahimi, Zohreh; Hasanvand, Ali; Felehgari, Vahid

    2012-04-01

    The aim of the current study was to examine the influence of interaction between polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C with angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism on the risk of diabetic nephropathy (DN). In a case control study using polymerase chain reaction (PCR)- and PCR-restriction fragment length polymorphism (RFLP), the presence of three polymorphisms in 140 patients with type 2 diabetes mellitus (T2DM) with nephropathy including patients with micro- and macro-albuminuria and 72 patients with normoalbuminuria from Western Iran were investigated. In the presence of both MTHFR 677 T and ACE D alleles, there was a trend toward increased risk of DN 2.68-fold (p=0.054). The possession of both MTHFR 677 T and ACE D alleles increased the risk of macro-albuminuria four times (p=0.035). The concomitant presence of both MTHFR 1298 C and ACE D alleles increased the risk of macro-albuminuria 7.8-fold (p=0.012). In addition, the risk of progression from micro- to macro-albuminuria in the presence of both alleles tended to be increased (4.1-fold, p=0.09). Our study for the first time demonstrated a synergistic effect between ACE I/D with either MTHFR C677T or A1298C polymorphism on the increased risk of DN among patients with T2DM. We found that MTHFR 1298 C strongly interacts with the ACE D allele and augments the risk of DN in our population. PMID:21942443

  15. 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: 1.231.46) and random effects models (CT+TT vs. CC: OR = 1.39, 95% CI: 1.191.62). 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

  16. 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 affecting MTHFR enzyme activity and tHcy levels. PMID:26689687

  17. High homocysteine and epistasis between MTHFR and APOE: association with cognitive performance in the elderly.

    PubMed

    Polito, Letizia; Poloni, Tino Emanuele; Vaccaro, Roberta; Abbondanza, Simona; Mangieri, Michela; Davin, Annalisa; Villani, Simona; Guaita, Antonio

    2016-04-01

    High total homocysteine (tHcy) is associated with cognitive impairment in the elderly. The impact of high tHcy on different cognitive domains deserves further investigation, as does the role of the C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene. A cross-sectional analysis of 903 subjects from the population-based "InveCe.Ab" study was performed. The participants had no psychosis or active neurological disorders. They underwent a neuropsychological assessment. Principal component analysis allowed cognitive performance to be condensed into two components: executive functions and memory. Novel components were evaluated for association with tHcy, controlling for potential confounders. Regression models showed that high serum tHcy was associated with lower executive functions, but not with memory. MTHFR C677T TT was associated with higher tHcy but did not affect cognitive performance per se. However, when combined with the apolipoprotein E (APOE)-ε4 allele, it was a risk factor for lower executive performance, independently of tHcy levels. In summary, high tHcy per se, or MTHFR C677T TT in combination with the APOE-ε4 allele, might be associated primarily with executive dysfunctions rather than memory loss. PMID:26774227

  18. MTHFR gene polymorphism and risk of myeloid leukemia: a meta-analysis.

    PubMed

    Dong, Song; Liu, Yueling; Chen, Jieping

    2014-09-01

    An increasing body of evidence has shown that the amino acid changes at position 1298 might eliminate methylenetetrahydrofolate reductase (MTHFR) enzyme activity, leading to insufficient folic acid and subsequent human chromosome breakage. Epidemiological studies have linked MTHFR single-nucleotide polymorphism (SNP) rs1801131 to myeloid leukemia risk, with considerable discrepancy in their results. We therefore were prompted to clarify this issue by use of a meta-analysis. The search terms were used to cover the possible reports in the MEDLINE, Web of Knowledge, and China National Knowledge Infrastructure (CNKI) databases. Odds ratios were estimated to assess the association of SNP rs1801131 with myeloid leukemia risk. Statistical heterogeneity was detected using the Q-statistic and I (2) metric. Subgroup analysis was performed by ethnicity, histological subtype, and Hardy-Weinberg equilibrium (HWE). This meta-analysis of eight publications with a total of 1,114 cases and 3,227 controls revealed no global association. Nor did the subgroup analysis according to histological subtype and HWE show any significant associations. However, Asian individuals who harbored the CC genotype were found to have 1.66-fold higher risk of myeloid leukemia (odds ratio, 1.66; 95 % confidence interval, 1.10 to 2.49; P h?=?0.342; I (2)?=?0.114). Our meta-analysis has presented evidence supporting a possible association between the CC genotype of MTHFR SNP rs1801131 and myeloid leukemia in Asian populations. PMID:24894669

  19. Sequence variation of the methylene tetrahydrofolate reductase gene (677C>T and 1298?A>C) and traditional risk factors in a South Indian population.

    PubMed

    Dayakar, Seetha; Goud, Kalal Iravathy; Reddy, Thavanati Parvathi Kumara; Rao, Seshagiri P; Sesikeran, Shyamala B; Sadhnani, Muralidhar

    2011-11-01

    Methylene tetrahydrofolate reductase (MTHFR) plays a significant role in the metabolism of methionine. MTHFR deficiency is an autosomal recessive trait that could be a significant risk factor for a number of defects, for example, vascular events, due to lower dietary folate intake among South Indians. To find the incidence of 677 C>T and 1298?A>C in MTHFR gene single nucleotide polymorphisms (SNPs) among the south Indian population, polymerase chain reaction and restriction fragment length polymorphism were employed among 152 patients with myocardial infarction and 167 controls. The MTHFR 677CT genotype was found among 35 (22.4%) cases and 08 (4.8%) controls, the MTHFR 677CC allele was found among 115 (73.7%) cases and 159 (94.6%) controls. Also, the analysis of the MTHFR 1298A>C SNP identified the MTHFR 1298CC genotype among 16 (10.3%) cases and 01 (0.6%) control, the MTHFR 1298AC genotype was found in 56 (35.9%) cases and 27 (16.2%) controls, and the MTHFR 1298AA genotype was observed in 80 (51.3%) cases and 139 (82.6%) controls. The C vs. A allele also showed significantly higher frequency among the patients in comparison with the controls (p<0.0001). The results of this study indicate that the MTHFR A1298C SNP is more prevalent among south Indians compared with the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases. PMID:21749215

  20. Mutation of the Light-Induced Yellow Leaf 1 Gene, Which Encodes a Geranylgeranyl Reductase, Affects Chlorophyll Biosynthesis and Light Sensitivity in Rice

    PubMed Central

    Yuan, Yuan; Zhu, Jinyan; Wang, Man; Yuan, Fuhai; Wu, Shujun; Wang, Zhiqin; Yi, Chuandeng; Xu, Tinghua; Ryom, MyongChol; Gu, Minghong; Liang, Guohua

    2013-01-01

    Chlorophylls (Chls) are crucial for capturing light energy for photosynthesis. Although several genes responsible for Chl biosynthesis were characterized in rice (Oryza sativa), the genetic properties of the hydrogenating enzyme involved in the final step of Chl synthesis remain unknown. In this study, we characterized a rice light-induced yellow leaf 1-1 (lyl1-1) mutant that is hypersensitive to high-light and defective in the Chl synthesis. Light-shading experiment suggested that the yellowing of lyl1-1 is light-induced. Map-based cloning of LYL1 revealed that it encodes a geranylgeranyl reductase. The mutation of LYL1 led to the majority of Chl molecules are conjugated with an unsaturated geranylgeraniol side chain. LYL1 is the firstly defined gene involved in the reduction step from Chl-geranylgeranylated (ChlGG) and geranylgeranyl pyrophosphate (GGPP) to Chl-phytol (ChlPhy) and phytyl pyrophosphate (PPP) in rice. LYL1 can be induced by light and suppressed by darkness which is consistent with its potential biological functions. Additionally, the lyl1-1 mutant suffered from severe photooxidative damage and displayed a drastic reduction in the levels of ?-tocopherol and photosynthetic proteins. We concluded that LYL1 also plays an important role in response to high-light in rice. PMID:24058671

  1. A mutated xylose reductase increases bioethanol production more than a glucose/xylose facilitator in simultaneous fermentation and co-fermentation of wheat straw

    PubMed Central

    2011-01-01

    Genetically engineered Saccharomyces cerevisiae strains are able to ferment xylose present in lignocellulosic biomass. However, better xylose fermenting strains are required to reach complete xylose uptake in simultaneous saccharification and co-fermentation (SSCF) of lignocellulosic hydrolyzates. In the current study, haploid Saccharomyces cerevisiae strains expressing a heterologous xylose pathway including either the native xylose reductase (XR) from P. stipitis, a mutated variant of XR (mXR) with altered co-factor preference, a glucose/xylose facilitator (Gxf1) from Candida intermedia or both mXR and Gxf1 were assessed in SSCF of acid-pretreated non-detoxified wheat straw. The xylose conversion in SSCF was doubled with the S. cerevisiae strain expressing mXR compared to the isogenic strain expressing the native XR, converting 76% and 38%, respectively. The xylitol yield was less than half using mXR in comparison with the native variant. As a result of this, the ethanol yield increased from 0.33 to 0.39 g g-1 when the native XR was replaced by mXR. In contrast, the expression of Gxf1 only slightly increased the xylose uptake, and did not increase the ethanol production. The results suggest that ethanolic xylose fermentation under SSCF conditions is controlled primarily by the XR activity and to a much lesser extent by xylose transport. PMID:21906329

  2. Mutation of the Inducible ARABIDOPSIS THALIANA CYTOCHROME P450 REDUCTASE2 Alters Lignin Composition and Improves Saccharification1[W][OPEN

    PubMed Central

    Sundin, Lisa; Vanholme, Ruben; Geerinck, Jan; Goeminne, Geert; Höfer, René; Kim, Hoon; Ralph, John; Boerjan, Wout

    2014-01-01

    ARABIDOPSIS THALIANA CYTOCHROME P450 REDUCTASE1 (ATR1) and ATR2 provide electrons from NADPH to a large number of CYTOCHROME P450 (CYP450) enzymes in Arabidopsis (Arabidopsis thaliana). Whereas ATR1 is constitutively expressed, the expression of ATR2 appears to be induced during lignin biosynthesis and upon stresses. Therefore, ATR2 was hypothesized to be preferentially involved in providing electrons to the three CYP450s involved in lignin biosynthesis: CINNAMATE 4-HYDROXYLASE (C4H), p-COUMARATE 3-HYDROXYLASE1 (C3H1), and FERULATE 5-HYDROXYLASE1 (F5H1). Here, we show that the atr2 mutation resulted in a 6% reduction in total lignin amount in the main inflorescence stem and a compositional shift of the remaining lignin to a 10-fold higher fraction of p-hydroxyphenyl units at the expense of syringyl units. Phenolic profiling revealed shifts in lignin-related phenolic metabolites, in particular with the substrates of C4H, C3H1 and F5H1 accumulating in atr2 mutants. Glucosinolate and flavonol glycoside biosynthesis, both of which also rely on CYP450 activities, appeared less affected. The cellulose in the atr2 inflorescence stems was more susceptible to enzymatic hydrolysis after alkaline pretreatment, making ATR2 a potential target for engineering plant cell walls for biofuel production. PMID:25315601

  3. The MTHFR 677T Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer's Disease in an Egyptian Population

    PubMed Central

    Elhawary, Nasser Attia; Hewedi, Doaa; Arab, Arwa; Teama, Salwa; Tayeb, Mohammed Taher; Bogari, Neda

    2013-01-01

    Objective. We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimer's disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Methods. Forty-three Alzheimer's cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. Results. No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls (P = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; P = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. Conclusions. The MTHFR 677C>T polymorphismespecially the presence of one copy of the T alleleappears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker. PMID:24223459

  4. Contribution of GSTM1, GSTT1, and MTHFR polymorphisms to end-stage renal disease of unknown etiology in Mexicans.

    PubMed

    Gutiérrez-Amavizca, B E; Orozco-Castellanos, R; Ortíz-Orozco, R; Padilla-Gutiérrez, J; Valle, Y; Gutiérrez-Gutiérrez, N; García-García, G; Gallegos-Arreola, M; Figuera, L E

    2013-11-01

    Oxidative stress is increased in chronic kidney disease, owing to an imbalance between the oxidative and antioxidant pathways as well as a state of persistent hyperhomocysteinemia. The enzymes glutathione S-transferases (GSTs) and methylenetetrahydrofolate reductase (MTHFR) are implicated in the regulation of these pathways. This study investigates the association between polymorphisms in the Glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), and MTHFR genes and end-stage renal disease (ESRD) of unknown etiology in patients in Mexico. A Case-control study included 110 ESRD patients and 125 healthy individuals. GSTM1 and GSTT1 genotypes were determined using the multiplex polymerase chain reaction (PCR). The MTHFR C677T polymorphism was studied using a PCR/restriction fragment length polymorphism method. In ESRD patients, GSTM1 and GSTT1 null genotype frequencies were 61% and 7% respectively. GSTM1 genotype frequencies differed significantly between groups, showing that homozygous deletion of the GSTM1 gene was associated with susceptibility to ESRD of unknown etiology (P = 0.007, odds ratios = 2.05, 95% confidence interval 1.21-3.45). The MTHFR C677T polymorphism genotype and allele distributions were similar in both groups (P > 0.05), and the CT genotype was the most common genotype in both groups (45.5% and 46.6%). Our findings suggest that the GSTM1 null polymorphism appears to be associated with the ESRD of unknown etiology in patients in Mexico. PMID:24339523

  5. 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. PMID:22147263

  6. Risk association of meningiomas with MTHFR C677T and GSTs polymorphisms: a meta-analysis.

    PubMed

    Ding, Hao; Liu, Wei; Yu, Xinyuan; Wang, Lei; Shao, Lingmin; Yi, Wei

    2014-01-01

    Previous studies have shown that the single nucleotide polymorphisms (SNPs) in Methylenetetrahydrofolate reductase (MTHFR) and Glutathione S-transferases (GSTs, including GSTM1, GSTT1) genes play an important role in determining the response of an individual to environmental pathogenesis and significantly relate to incidences of various human tumors, including brain tumors. However, these genes' polymorphisms on meningioma risk remains poorly understood. The relevant inferences from previous studies are hindered by their limited statistical power and conflicting results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association between these polymorphisms and human meningioma risk. A literature search for eligible studies published before January 1, 2014 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. Pooled odds ratios (OR) with their corresponding 95% confidence intervals (95% CI) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. Heterogeneity and publication bias were evaluated. All statistical analyses were conducted by using the software of STATA 12.0 (STATA Corporation, College Station, TX, USA). For MTHFR C677T (dbSNP: rs1801133) (C T) polymorphism, 9 individual case-control studies from six publications with 1,615 cases and 1,909 controls were obtained. For GSTM1 null polymorphism, there were 4 studies with 417 cases and 1,735 controls. For GSTT1 null polymorphism, there were 4 studies with 405 cases and 1,622 controls. The combined results for the MTHFR C677T show that carriers of the CT genotype may be associated with a higher meningioma risk (OR = 1.20, 95% CI 1.05-1.38, P = 0.009). Stratified analyses show that Caucasians have significantly higher risk if they carry the CT genotype of MTHFR (OR = 1.31, 95% CI 1.05-1.63, P = 0.02). Risk of Caucasians carrying TT + CT genotype is also significantly higher (OR = 1.27, 95% CI 1.02-1.58, P = 0.03). Risk of Caucasians carrying TT genotype is not significantly different compared to control population (OR = 0.96, 95% CI 0.69-1.34, P = 0.82). All of the enrolled studies about GSTM1/GSTT1 are on Caucasians. The pooled ORGSTM1 and ORGSTT1 were not significant in Caucasian population. These results indicate SNPs of MTHFR C677T are related to meningioma risk with ethnic differences. Caucasians carrying CT genotype of MTHFR C677T have significantly higher meningioma susceptibility. SNPs of GSTM1/GSTT1 are not related to meningioma risk. PMID:25550898

  7. Significant Impact of the MTHFR Polymorphisms and Haplotypes on Male Infertility Risk

    PubMed Central

    Gupta, Nishi; Sarkar, Saumya; David, Archana; Gangwar, Pravin Kumar; Gupta, Richa; Khanna, Gita; Sankhwar, Satya Narayan; Khanna, Anil; Rajender, Singh

    2013-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate and affects the activity of cellular cycles participating in nucleotide synthesis, DNA repair, genome stability, maintenance of methyl pool, and gene regulation. Genetically compromised MTHFR activity has been suggested to affect male fertility. The objective of the present study was to find the impact on infertility risk of c.203G>A, c.1298A>C, and c.1793G>A polymorphisms in the MTHFR gene. Methods PCR-RFLP and DNA sequencing were used to genotype the common SNPs in the MTHFR gene in 630 infertile and 250 fertile males. Chi-square test was applied for statistical comparison of genotype data. Linkage disequilibrium between the SNPs and the frequency of common haplotypes were assessed using Haploview software. Biochemical levels of total homocysteine (tHcy) and folic acid were measured. Meta-analysis on c.1298A>C polymorphism was performed using data from ten studies, comprising 2734 cases and 2737 controls. Results c.203G>A and c.1298A>C were found to be unrelated to infertility risk. c.1793G>A was protective against infertility (P?=?0.0008). c.677C>T and c.1793G>A were in significant LD (D?=?0.9). Folic acid and tHcy level did not correlate with male infertility. Pooled estimate on c.1298A>C data from all published studies including our data showed no association of this polymorphism with male infertility (Odds ratio?=?1.035, P?=?0.56), azoospermia (Odds ratio?=?0.97, P?=?0.74), or oligoasthenoteratozoospermia (Odds ratio?=?0.92, p?=?0.29). Eight haplotypes with more than 1% frequency were detected, of which CCGA was protective against infertility (p?=?0.02), but the significance of the latter was not seen after applying Bonferroni correction. Conclusion Among MTHFR polymorphisms, c.203G>A and c.1298A>C do not affect infertility risk and c.1793G>A is protective against infertility. Haplotype analysis suggested that risk factors on the MTHFR locus do not extend too long on the DNA string. PMID:23874907

  8. Correlation between MTHFR gene methylation and pre-eclampsia, and its clinical significance.

    PubMed

    Ge, J; Wang, J; Zhang, F; Diao, B; Song, Z F; Shan, L L; Wang, W; Cao, H J; Li, X Q

    2015-01-01

    We investigated the correlation between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene methylation and pre-eclampsia, and its clinical significance, by comparing methylation in the MTHFR gene promoter of the placenta and peripheral venous blood in pre-eclampsia and normal gravidas. We enrolled 259 gravidas from the People's Liberation Army 202nd Hospital, China, between January 2011 and September 2011, including 127 pre-eclampsia and 132 nor-mal gravidas. Methylation levels of the MTHFR gene in placentas in two sets of gravidas were detected by methylation-specific polymerase chain reaction, plasma homocysteine levels were detected by enzyme-linked immunosorbent assay, and folic acid and vitamin B12 levels were detected by electrochemiluminescence. The chi-square test results were analyzed using the SPSS19.0 statistical software. In placentas, the methylation indices were 26.8% (34/127) and 15.2% (20/132) in the pre-eclampsia and normal groups, respectively (?(2) = 5.30, P < 0.05, odds ratio (OR) = 2.04, 95% confidence interval (95%CI) = 1.10-3.73). In peripheral venous blood, the methylation indices were 22.8% (29/127) and 12.1% (16/132) in pre-eclampsia and normal groups, respectively (?(2) = 5.17, P < 0.05, OR = 2.15, 95%CI = 1.11-4.15). The plasma methylation level of the pre-eclampsia group was consistent with the normal group. The plasma homocysteine level in the pre-eclampsia group was higher than in the normal group (P < 0.05). Levels of folic acid and vitamin B12 in the pre-eclampsia and normal groups were not statistically significant (P > 0.05). Patients with pre-eclampsia have hypermethylation in the MTHFR gene promoter, which may be one of its causes. PMID:26214484

  9. The MTHFR C677T Polymorphism and Risk of Intracerebral Hemorrhage in a Chinese Han Population

    PubMed Central

    Hu, Xin; Tao, Chuanyuan; Xie, Zhiyi; Li, Yunke; Zheng, Jun; Fang, Yuan; Lin, Sen; Li, Hao; You, Chao

    2016-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been speculated to be and extensively investigated as a risk factor for various vascular diseases, including intracerebral hemorrhage (ICH). However, results from published studies regarding the role of C677T polymorphism in ICH risk in Chinese populations were contradictory rather than conclusive. Material/Methods In this study, a total of 180 ICH patients and 180 matched controls of Chinese Han ethnicity were enrolled. The MTHFR C677T polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). A meta-analysis was conducted by combining our data with previous relevant studies in Chinese populations. Results In our case-control study, similar allele frequency (p=0.492) and genotype distribution (p=0.748) of MTHFR C677T polymorphism were detected between ICH patients and controls. Further analysis based on hematoma location did not show a significant association. When combined with previous studies, however, C677T polymorphism was found to be significantly associated with an increased risk for ICH in Chinese populations (recessive model: OR=1.57, 95%CI=1.29–1.91). When focusing on the Han ethnicity, carriers of the TT genotype had an increased risk of ICH (recessive model: OR=1.36, 95%CI=1.05–1.75). Conclusions In this case-control study we did not observe that the MTHFR C677T polymorphism was associated with ICH risk in people of Chinese Han ethnicity. However, when combined with previous published studies, a significant association of C677T polymorphism with an increased risk of ICH was detected in Chinese populations, and also in the subgroup analysis focusing on Han ethnicity. PMID:26757363

  10. The Association between MTHFR Gene Polymorphisms and Hepatocellular Carcinoma Risk: A Meta-Analysis

    PubMed Central

    Deng, Yan; Huang, Shan; Xu, Juanjuan; Li, Haiwei; Li, Shan; Zhao, Jinmin

    2013-01-01

    Background The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and hepatocellular carcinoma (HCC) risk was inconsistent and underpowered. To clarify the effects of MTHFR gene polymorphisms on the risk of HCC, a meta-analysis of all available studies relating C677T and/or A1298C polymorphisms of MTHFR gene to the risk of HCC was conducted. Methods The authors searched PubMed, EMBASE, Cochrane Library, Web of Science, and Chinese Biomedical Literature database (CBM) for the period up to July 2012. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. Results Finally, 12 studies with 2,351 cases and 4,091 controls were included for C677T polymorphism and 6 studies with 1,333 cases and 1,878 controls were included for A1298C polymorphism. With respect to A1298C polymorphism, significantly decreased HCC risk was found in the overall population (CC vs. AA: OR?=?0.660, 95%CI 0.4600.946, P?=?0.024; recessive model: OR?=?0.667, 95%CI?=?0.4700.948, P?=?0.024). In subgroup analyses, significantly decreased HCC risk was found in Asian population (CC vs. AA: OR?=?0.647, 95%CI?=?0.4350.963; P?=?0.032) and population-based studies (CC vs. AA: OR?=?0.519, 95%CI?=?0.3270.823; P?=?0.005). With respect to C677T polymorphism, no significant association with HCC risk was demonstrated in overall and stratified analyses. Conclusions We concluded that MTHFR A1298C polymorphism may play a protective role in the carcinogenesis of HCC. Further large and well-designed studies are needed to confirm this association. PMID:23457501

  11. The MTHFR C677T Polymorphism and Risk of Intracerebral Hemorrhage in a Chinese Han Population.

    PubMed

    Hu, Xin; Tao, Chuanyuan; Xie, Zhiyi; Li, Yunke; Zheng, Jun; Fang, Yuan; Lin, Sen; Li, Hao; You, Chao

    2016-01-01

    BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been speculated to be and extensively investigated as a risk factor for various vascular diseases, including intracerebral hemorrhage (ICH). However, results from published studies regarding the role of C677T polymorphism in ICH risk in Chinese populations were contradictory rather than conclusive. MATERIAL AND METHODS In this study, a total of 180 ICH patients and 180 matched controls of Chinese Han ethnicity were enrolled. The MTHFR C677T polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). A meta-analysis was conducted by combining our data with previous relevant studies in Chinese populations. RESULTS In our case-control study, similar allele frequency (p=0.492) and genotype distribution (p=0.748) of MTHFR C677T polymorphism were detected between ICH patients and controls. Further analysis based on hematoma location did not show a significant association. When combined with previous studies, however, C677T polymorphism was found to be significantly associated with an increased risk for ICH in Chinese populations (recessive model: OR=1.57, 95%CI=1.29-1.91). When focusing on the Han ethnicity, carriers of the TT genotype had an increased risk of ICH (recessive model: OR=1.36, 95%CI=1.05-1.75). CONCLUSIONS In this case-control study we did not observe that the MTHFR C677T polymorphism was associated with ICH risk in people of Chinese Han ethnicity. However, when combined with previous published studies, a significant association of C677T polymorphism with an increased risk of ICH was detected in Chinese populations, and also in the subgroup analysis focusing on Han ethnicity. PMID:26757363

  12. 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

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

    PubMed Central

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

    2015-01-01

    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. PMID:26759827

  14. 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. PMID:26759827

  15. Mutation for Nonsyndromic Mental Retardation in the trans-2-Enoyl-CoA Reductase TER Gene Involved in Fatty Acid Elongation Impairs the Enzyme Activity and Stability, Leading to Change in Sphingolipid Profile*

    PubMed Central

    Abe, Kensuke; Ohno, Yusuke; Sassa, Takayuki; Taguchi, Ryo; al??kan, Minal; Ober, Carole; Kihara, Akio

    2013-01-01

    Very long-chain fatty acids (VLCFAs, chain length >C20) exist in tissues throughout the body and are synthesized by repetition of the fatty acid (FA) elongation cycle composed of four successive enzymatic reactions. In mammals, the TER gene is the only gene encoding trans-2-enoyl-CoA reductase, which catalyzes the fourth reaction in the FA elongation cycle. The TER P182L mutation is the pathogenic mutation for nonsyndromic mental retardation. This mutation substitutes a leucine for a proline residue at amino acid 182 in the TER enzyme. Currently, the mechanism by which the TER P182L mutation causes nonsyndromic mental retardation is unknown. To understand the effect of this mutation on the TER enzyme and VLCFA synthesis, we have biochemically characterized the TER P182L mutant enzyme using yeast and mammalian cells transfected with the TER P182L mutant gene and analyzed the FA elongation cycle in the B-lymphoblastoid cell line with the homozygous TER P182L mutation (TERP182L/P182L B-lymphoblastoid cell line). We have found that TER P182L mutant enzyme exhibits reduced trans-2-enoyl-CoA reductase activity and protein stability, thereby impairing VLCFA synthesis and, in turn, altering the sphingolipid profile (i.e. decreased level of C24 sphingomyelin and C24 ceramide) in the TERP182L/P182L B-lymphoblastoid cell line. We have also found that in addition to the TER enzyme-catalyzed fourth reaction, the third reaction in the FA elongation cycle is affected by the TER P182L mutation. These findings provide new insight into the biochemical defects associated with this genetic mutation. PMID:24220030

  16. The binding sites on human heme oxygenase-1 for cytochrome p450 reductase and biliverdin reductase.

    PubMed

    Wang, Jinling; de Montellano, Paul R Ortiz

    2003-05-30

    Human heme oxygenase-1 (hHO-1) catalyzes the NADPH-cytochrome P450 reductase-dependent oxidation of heme to biliverdin, CO, and free iron. The biliverdin is subsequently reduced to bilirubin by biliverdin reductase. Earlier kinetic studies suggested that biliverdin reductase facilitates the release of biliverdin from hHO-1 (Liu, Y., and Ortiz de Montellano, P. R. (2000) J. Biol. Chem. 275, 5297-5307). We have investigated the binding of P450 reductase and biliverdin reductase to truncated, soluble hHO-1 by fluorescence resonance energy transfer and site-specific mutagenesis. P450 reductase and biliverdin reductase bind to truncated hHO-1 with Kd = 0.4 +/- 0.1 and 0.2 +/- 0.1 microm, respectively. FRET experiments indicate that biliverdin reductase and P450 reductase compete for binding to truncated hHO-1. Mutation of surface ionic residues shows that hHO-1 residues Lys18, Lys22, Lys179, Arg183, Arg198, Glu19, Glu127, and Glu190 contribute to the binding of cytochrome P450 reductase. The mutagenesis results and a computational analysis of the protein surfaces partially define the binding site for P450 reductase. An overlapping binding site including Lys18, Lys22, Lys179, Arg183, and Arg185 is similarly defined for biliverdin reductase. These results confirm the binding of biliverdin reductase to hHO-1 and define binding sites of the two reductases. PMID:12626517

  17. Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Kennedy, Deborah A.; Stern, Seth J.; Matok, Ilan; Moretti, Myla E.; Sarkar, Moumita; Adams-Webber, Thomasin; Koren, Gideon

    2012-01-01

    Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms folic acid, folate, colorectal cancer, methylenetetrahydrofolate reductase, MTHFR. Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.951.10) and for 677TT versus CC was 0.88 (95% CI 0.800.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.560.89) and the 677TT genotype 0.63 (95% CI 0.410.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes. PMID:23125859

  18. 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

    2015-08-01

    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 deficits in the offspring of dams with MTHFR deficiency or dietary deficiencies of critical methyl donors. We suggest that deficiencies in maternal one-carbon metabolism during pregnancy can contribute to hippocampal dysfunction in offspring through apoptosis or altered choline metabolism. PMID:25956258

  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 MTHFR C677T and A1298C Polymorphisms and NSCL/P Risk in Asians: A Meta-Analysis

    PubMed Central

    Zhao, Mengmeng; Ren, Yangwu; Shen, Li; Zhang, Yue; Zhou, Baosen

    2014-01-01

    Objective Several studies have reported the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and nonsyndromic cleft lip with or without palate (NSCL/P) in Asian populations. However, findings have been conflicting. In order to investigate the association, a meta-analysis was performed. Methods We searched Pubmed, MedLine and EmBase database to selected eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated using fixed effects model or random effects model to assess the association between MTHFR polymorphisms and NSCL/P in both Asian children and mothers. Results Finally, nine case-control studies were included. Overall, the MTHFR C677T polymorphism and NSCL/P showed pooled ORs (95%CI) of 1.41(1.231.61) in Asian children, and 1.70(1.192.42) in Asian mothers. Subgroup analyses by geographical locations further identified the association in Eastern Asian children, Western/Central Asian children and mothers, but not in Eastern Asian mothers. However, no significant relationship between MTHFR A1298C polymorphism and NSCL/P was found in this meta-analysis. Conclusions The MTHFR 677T allele was associated with an increased risk of NSCL/P in Asian populations. PMID:24658649

  1. Quantitative assessment of the associations between MTHFR C677T and A1298C polymorphisms and risk of fractures: a meta-analysis.

    PubMed

    Bai, Rui; Liu, Wanlin; Zhao, Aiqing; Zhao, Zhenqun; Jiang, Dianming

    2013-03-01

    Many studies have investigated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and risk of fractures, but the impact of MTHFR polymorphisms on fractures risk is unclear owing to the obvious inconsistence among those studies. This study aims to quantify the strength of association between MTHFR C677T and A1298C polymorphisms and risk of fractures. We searched the PubMed, Embase and Wanfang databases for articles relating the association between MTHFR C677T and A1298C polymorphisms and risk of fractures in humans. We estimated summary odds ratios (ORs) with their confidence intervals (CIs) to assess the associations. Meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of any site fractures (for T vs. C, OR = 1.17, 95 % CI 1.03-1.32; for TT vs. CC, OR = 1. 31, 95 % CI 1.11-1.54; for TT vs. CT, OR = 1.22, 95 % CI 1.04-1.43; for TT vs. CT/CC, OR = 1.31, 95 % CI 1.13-1.51). Besides, MTHFR A1298C polymorphism was also associated with increased risk of any site fractures. Subgroup meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of vertebral fractures under three genetic contrast modes (for TT vs. CC, OR = 1.43, 95 % CI 1.05-1.95; for TT vs. CT, OR = 1.36, 95 % CI 1.01-1.85; for TT vs. CT/CC, OR = 1.50, 95 % CI 1.17-1.91), but there was no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures (all P values were more than 0.05). Thus, individuals with homozygote genotype TT of MTHFR C677T have obviously increased risk of vertebral fractures compared those with heterozygote genotype CT or homozygote genotype CC. There is no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures. PMID:23229495

  2. The C677T polymorphism of the methylenetetrahydrofolate reductase gene in Mexican mestizo neural-tube defect parents, control mestizo and native populations.

    PubMed

    Dávalos, I P; Olivares, N; Castillo, M T; Cantú, J M; Ibarra, B; Sandoval, L; Morán, M C; Gallegos, M P; Chakraborty, R; Rivas, F

    2000-01-01

    The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene, associated with the thermolabile form of the enzyme, has reportedly been found to be increased in neural-tube defects (NTD), though this association is still unclear. A group of 107 mestizo parents of NTD children and five control populations: 101 mestizo (M), 50 Huichol (H), 38 Tarahumara (T), 21 Purepecha (P) and 20 Caucasian (C) individuals were typed for the MTHFR C677T variant by the PCR/RFLP (HinfI) method. Genotype frequencies were in agreement with the Hardy-Weinberg expectations in all six populations. Allele frequency (%) of the C677T variant was 45 in NTD, 44 in M, 56 in H, 36 in T, 57 in P, 35 in C. Pairwise inter-population comparisons of allele frequency disclosed a very similar distribution between NTD and M groups (exact test, P=0.92). Among controls, differences between M and individual native groups were NS (0.06MTHFR C677T genotypes. Thus, the C677T variant cannot be regarded as a major genetic risk factor for NTD in Mexican mestizo parents. Otherwise, C677T in Mexico is very frequent, especially in Huichol and Purepecha natives, as compared with other groups world wide. PMID:10998450

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

    PubMed

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

    2016-02-01

    Several studies have evaluated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and psoriasis. However, the results remain inconclusive. The objective of the present study was to conduct a qualitative and quantitative meta-analysis investigating the associations between MTHFR C677T and psoriasis. A published work search of PubMed, Embase, Web of Science and Chinese National Knowledge Infrastructure database were conducted to identify all publications concerning MTHFR C677T polymorphism and psoriasis on 1 October 2014. The principal outcome measure for evaluating the strength of the association was crude odds ratios along with their corresponding 95% confidence intervals. Data were extracted and statistical analyses were implemented using STATA version 12.0 software. A total of 1179 psoriatic cases and 937 controls from five case-control studies concentrating on the association between MTHFR C677T polymorphism and psoriasis were included in this qualitative meta-analysis. Pooled analysis revealed that there is no association between this polymorphism and susceptibility to psoriasis in dominant, recessive, allele and additive models under a random-effect model. However, a marginal significant association was found in the overdominant model under fixed-effect model. Subgroup analysis of ethnicity demonstrated that there is no association between MTHFR C677T polymorphism and either Asian or European psoriatic patients. In conclusion, MTHFR C677T polymorphism, qualitatively, is not a genetic factor for the pathogenesis of psoriasis but could quantitatively reflect the severity of psoriasis to some extent. PMID:26212228

  4. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population.

    PubMed

    Guo, Tianyou; Chen, Hong; Liu, Bing; Ji, Weidong; Yang, Chuang

    2012-08-01

    Causes of autism are still unknown. Some studies have shown that autism might be associated with metabolic abnormalities in the folate/homocysteine pathway, which is involved in DNA methylation, thus altering gene expression. The association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms and the risk of autism is still controversial and ambiguous. The purpose of this study was to examine the effect of the MTHFR C677T polymorphism on the autism risk in the Chinese Han population. A population-based case-control study was conducted in 186 children with autism and 186 controls. The MTHFR C677T polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of genotype MTHFR 677TT in children with autism (16.1%) was significantly higher (odds ratio [OR]=2.04; 95% confidence interval [CI]=1.07, 3.89; p=0.03] than those in controls (8.6%). When stratifying by select-item scores on the Autism Diagnostic Interview-Revised, it was found that children with current overactivity had a significantly higher frequency of the MTHFR 677TT genotype (OR=2.77, 95% CI=1.17, 6.60; p=0.02) than those without. This study suggested that MTHFR C677T is a risk factor of autism in Chinese Han children. PMID:22775456

  5. Association between epidermal growth factor receptor mutations and the expression of excision repair cross-complementing protein 1 and ribonucleotide reductase subunit M1 mRNA in patients with non-small cell lung cancer

    PubMed Central

    XU, CHUN-WEI; WANG, GANG; WANG, WU-LONG; GAO, WEN-BIN; HAN, CHUAN-JUN; GAO, JING-SHAN; LI, YANG; WANG, LIN; ZHANG, LI-YING; ZHANG, YU-PING; TIAN, YU-WANG; FANG, JIN-NV

    2015-01-01

    The present study aimed to investigate the association between epidermal growth factor receptor (EGFR) gene mutations and excision repair cross-complementing protein 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) mRNA expression in non-small cell lung cancer (NSCLC) tissue. The quantitative polymerase chain reaction was used to detect EGFR mutations, and ERCC1 and RRM1 mRNA expression in 257 cases of NSCLC. In the NSCLC samples the EGFR mutation rate was 49.03% (126/257). The rate was higher in females and non-smoking patients (P<0.05). High expression of ERCC1 mRNA was observed in 47.47% of the samples (122/257), while a high RRM1 mRNA expression was observed in 61.87% of the samples (159/257). In comparison with patients with NSCLC without EGFR mutations, patients with EGFR mutations had significantly lower levels of ERCC1 mRNA expression (P<0.05); however, EGFR mutations and expression levels of RRM1 mRNA were not correlated in NSCLC tissues (P>0.05). In addition, ERCC1 mRNA expression was not correlated with the expression levels of RRM1 mRNA (P>0.05). In conclusion, patients with NSCLC with EGFR mutations tend to have a low expression of ERCC1 mRNA and may potentially benefit from platinum-based chemotherapy. PMID:25667646

  6. Association of MTHFR C677T with total homocysteine plasma levels and susceptibility to Parkinson's disease: a meta-analysis.

    PubMed

    Zhu, Ying; Zhu, Rui-Xia; He, Zhi-Yi; Liu, Xu; Liu, He-Nan

    2015-06-01

    The C677T single-nucleotide polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) may elevate homocysteine (Hcy) levels and increase the risk of Parkinson's disease (PD); however, results are conflicting. Our aim was to resolve contradictions in the literature and to determine whether MTHFR C677T has a significant role in regulating Hcy levels and/or is a significant risk factor for PD. MEDLINE, EMBASE, the Cochrane Library, China Biological Medicine Database and Google Scholar were searched until May 2014. Strict selection and exclusion criteria were determined, and odds ratios (ORs)/weighted mean differences (WMDs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. Statistical analyses were performed using STATA 12.0. Fifteen studies that together assessed 2690 PD cases and 8465 controls were included. Meta-analysis showed that no significant difference in the distribution of MTHFR C677T between PD cases and controls was found. While stratifying for ethnicity, significant association was revealed in Europeans (T vs. C, OR = 1.17, 95 % CIs 1.04-1.31) but not in Asians. Significant association between the T allele and increased Hcy levels was found in PD cases and controls; Hcy levels were higher in PD cases and controls carrying the MTHFR T677 allele than in non-carriers (TT vs. CC, PD WMD = 6.50, 95 % CIs 6.20-6.80; controls WMD = 4.52, 95 % CIs 4.24-4.80). Other within-group comparisons showed similar results. This meta-analysis suggests that MTHFR C667T may confer PD susceptibility in Europeans. The T allele may be an independent risk factor for elevated Hcy levels in PD patients. PMID:25564416

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

    PubMed Central

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

    2015-01-01

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

  8. A case of vascular parkinsonism associated with hyperhomocysteinemia and methylenetetrahydrofolate reductase gene variant (C677T).

    PubMed

    Hara, Kenju; Onda, Keigo; Ouchi, Haruka; Shibano, Ken; Ishiguro, Hideaki

    2016-03-01

    A 56-year-old man, who presented with 6 years history of difficulty in walking, was diagnosed as having vascular parkinsonism on the basis of the clinical findings of parkinsonism, pyramidal sign and the brain MRI findings of multiple lacunar infarction. Although he did not have hypertension, he had hyperhomocysteinemia and homozygous methylenetetrahydrofolate reductase (MTHFR) gene variant (C677T) as risk factors for ischemic stroke. Recent studies have shown that hyperhomocysteinemia and MTHFR gene variant are associated with small-vessel disease, suggesting that these risk factors may underlie vascular parkinsonism, particularly in patients lacking hypertension and in those with a relatively younger age at onset of this disease. PMID:26797478

  9. The association between methylenetetrahydrofolate reductase gene C677T polymorphisms and breast cancer risk in Chinese population.

    PubMed

    Wang, Yadong; Yang, Haiyan; Gao, Huiyan; Wang, Haiyu

    2015-12-01

    With great interest, we read the recent article entitled "Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case-control studies" published online in Tumor Biology, 2014, 35: 1695-1701. This article suggests that methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was significantly associated with breast cancer risk in Chinese population. The result is encouraging. Nevertheless, three key issues in this meta-analysis are worth noticing. PMID:26537580

  10. 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. PMID:25331073

  11. MTHFR C677T Polymorphism is Associated with Tumor Response to Preoperative Chemoradiotherapy: A Result Based on Previous Reports

    PubMed Central

    Zhao, Yue; Li, Xingde; Kong, Xiangjun

    2015-01-01

    Background Preoperative chemoradiotherapy (pRCT) followed by surgery has been widely practiced in locally advanced rectal cancer, esophageal cancer, gastric cancer and other cancers. However, the therapy also exerts some severe adverse effects and some of the patients show poor or no response. It is very important to develop biomarkers (e.g., gene polymorphisms) to identify patients who have a higher likelihood of responding to pRCT. Recently, a series of reports have investigated the association of the genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and epidermal growth factor receptor (EGFR) genes with the tumor response to pRCT; however, the results were inconsistent and inconclusive. Material/Methods A systematic review and meta-analysis was performed by searching relevant studies about the association of MTHFR and EGFR polymorphisms with the tumor regression grade (TRG) in response to pRCT in databases of PubMed, EMBAS, Web of science, Chinese National Knowledge Infrastructure, and Wanfang database up to March 30, 2015. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were calculated to assess the strength of the association under 5 genetic models. Results A total of 11 eligible articles were included in the present meta-analysis, of which 8 studies were performed in rectal cancer and 3 studies were performed in esophageal cancer. We finally included 8 included studies containing 839 cases for MTHFR C677T, 5 studies involving 634 cases for MTHFR A1298C, 3 studies containing 340 cases for EGFR G497A, and 4 studies containing 396 cases for EGFR CA repeat. The pooled analysis results indicated that MTHFR C677T might be correlated with the tumor response to pRCT under the recessive model (CC vs. CTTT) in overall analysis (OR=1.426(1.0741.894), P=0.014), rectal cancer (OR=1.483(1.1021.996), P=0.009), and TRG 12 vs. 35 group (OR=1.423(1.0461.936), P=0.025), while other polymorphism including MTHFR A1298C, EGFR G497A, and EGFR CA repeat polymorphisms exerted significant association under all genetic models in overall analysis or subgroup analysis. Conclusions MTHFR C677T might be correlated with the tumor response to pRCT. Further well-designed, larger-scale epidemiological studies are needed to validate our results. PMID:26456456

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  13. Pulmonary Embolism in a Sarcoidosis Patient Double Heterozygous for Methylenetetrahydrofolate Reductase Gene Polymorphisms and Factor V Leiden and Homozygous for the D-Allele of Angiotensin Converting Enzyme Gene

    PubMed Central

    El-Majzoub, Nadim; Mahfouz, Rami; Kanj, Nadim

    2015-01-01

    Sarcoidosis is a multisystem granulomatous disease of unknown etiology and pathogenesis. It presents in patients younger than 40 years of age. The lungs are the most commonly affected organ. Till the present day, there is no single specific test that will accurately diagnose sarcoidosis; as a result, the diagnosis of sarcoidosis relies on a combination of clinical, radiologic, and histologic findings. Patients with sarcoidosis have been found to have an increased risk of pulmonary embolism compared to the normal population. MTHFR and factor V Leiden mutations have been reported to increase the risk of thrombosis in patients. We hereby present a case of a middle aged man with sarcoidosis who developed a right main pulmonary embolism and was found to be double heterozygous for methylenetetrahydrofolate reductase gene polymorphisms and factor V Leiden and homozygous for the D-allele of the angiotensin converting enzyme gene. PMID:26347783

  14. Polymorphisms of glutathione S-transferase and methylenetetrahydrofolate reductase genes in Moldavian patients with ulcerative colitis: Genotype-phenotype correlation

    PubMed Central

    Varzari, Alexander; Deyneko, Igor V.; Tudor, Elena; Turcan, Svetlana

    2015-01-01

    Background Glutathione S-transferases (GSTM1, GSTT1, and GSTP1) and methylenetetrahydrofolate reductase (MTHFR) are important enzymes for protection against oxidative stress. In addition, MTHFR has an essential role in DNA synthesis, repair, and methylation. Their polymorphisms have been implicated in the pathogenesis of ulcerative colitis (UC). The aim of the present study was to investigate the role of selected polymorphisms in these genes in the development of UC in the Moldavian population. Methods In a case-control study including 128 UC patients and 136 healthy individuals, GSTM1 and GSTT1 genotypes (polymorphic deletions) were determined using multiplex polymerase chain reaction (PCR). The GSTP1 rs1695 (Ile105Val), MTHFR rs1801133 (C677T), and MTHFR rs1801131 (A1298C) polymorphisms were studied with restriction fragment length polymorphism (RFLP) analysis. Genotype–phenotype correlations were examined using logistic regression analysis. Results None of the genotypes, either alone or in combination, showed a strong association with UC. The case-only sub-phenotypic association analysis showed an association of the MTHFR rs1801133 polymorphism with the extent of UC under co-dominant (p corrected = 0.040) and recessive (p corrected = 0.020; OR = 0.15; CI = 0.04–0.63) genetic models. Also, an association between the MTHFR rs1801131 polymorphism and the severity of UC was reported for the over-dominant model (p corrected = 0.023; coefficient = 0.32; 95% CI = 0.10–0.54). Conclusion The GST and MTHFR genotypes do not seem to be a relevant risk factor for UC in our sample. There was, however, evidence that variants in MTHFR may influence the clinical features in UC patients. Additional larger studies investigating the relationship between GST and MTHFR polymorphisms and UC are required. PMID:26862484

  15. MTHFR C677T polymorphism is associated with hyperlipidemia in women with polycystic ovary syndrome

    PubMed Central

    Jain, Madhu; Pandey, Priyanka; Tiwary, Narendra K; Jain, Shuchi

    2012-01-01

    CONTEXT: Women with polycystic ovary syndrome (PCOS) are prone for coronary artery disease (CAD), and hyperhomocysteinemia is an independent risk factor for CAD. MTHFR deficiency is the most common cause of hyperhomocysteinemia, thereby provoking a possible association between PCOS and MTHFR C677T polymorphism. AIMS: The aim of this study was to investigate an association of MTHFR C677T polymorphism with PCOS. SETTINGS AND DESIGN: 92 women with PCOS (Rotterdam criteria) and 95 age-matched controls were compared with respect to MTHFR C677T polymorphism. The 2 genotypes (CC and CT) obtained were compared with clinical and laboratory parameters in women with PCOS. MATERIALS AND METHODS: In a case-control study, clinical, biochemical, hormonal and genetic analysis (PCR-RFLP of peripheral leucocytes) was carried out on all women with PCOS as well as controls. STATISTICAL ANALYSIS: Student t test for quantitative and Chi-square test for nominal variables was used. For estimation of risk, odds ratio and 95% confidence interval were calculated. RESULTS: The odds ratio of bearing a heterozygous genotype (CT) was 1.32 in women with PCOS as compared to controls (P = 0.48). No homozygous mutation (TT) was found in the study population. Serum cholesterol was more in heterozygous (CT) genotype (215.48 25.56 mg/dl) as compared to normal (CC) genotype (203.29 16.35 mg/dl) in women with PCOS (P = 0.01). Similarly, serum triglyceride was more in heterozygous (CT) genotype (95.86 37.34 mg/dl) as compared to normal (CC) genotype (82.36 20.88 mg/dl) in women with PCOS (P = 0.04). CONCLUSIONS: Although not statistically significant, there is a slightly higher prevalence of heterozygous (CT) genotype in women with PCOS. MTHFR C677T polymorphism when present may confer an increased susceptibility to develop hyperlipidemia in women with PCOS. More prospective studies are needed to confirm whether this hyperlipidemia due to MTHFR C677T polymorphism clinically manifests into CAD in long term in women with PCOS. PMID:22870016

  16. 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.

  17. A Functional Role for the Conformationally Mobile Phenylalanine 223 in the Reaction of Methylenetetrahydrofolate Reductase from E. coli

    PubMed Central

    Lee, Moon N.; Takawira, Desire; Nikolova, Andriana P.; Ballou, David P.; Furtado, Vivek C.; Phung, Ngoc L.; Still, Brady R.; Thorstad, Melissa K.; Tanner, John J.; Trimmer, Elizabeth E.

    2009-01-01

    The flavoprotein methylenetetrahydrofolate reductase from Escherichia coli catalyzes the reduction of 5,10-methylenetetrahydrofolate (CH2-H4folate) by NADH via a ping-pong reaction mechanism. Structures of the reduced enzyme in complex with NADH and of the oxidized Glu28Gln enzyme in complex with CH3-H4folate [Pejchal, R., Sargeant, R., and Ludwig, M. L. (2005) Biochemistry 44, 11447-11457] have revealed Phe223 as a conformationally mobile active site residue. In the NADH complex, the NADH adopts an unusual hairpin conformation and is wedged between the isoalloxazine ring of the FAD and the side chain of Phe223. In the folate complex, Phe223 swings out from its position in the NADH complex in order to stack against the p-aminobenzoate ring of the folate. Although Phe223 contacts each substrate in E. coli MTHFR, this residue is not invariant; for example, a leucine occurs at this site in the human enzyme. To examine the role of Phe223 in substrate binding and catalysis, we have constructed mutants Phe223Ala and Phe223Leu. As predicted, our results indicate that Phe223 participates in the binding of both substrates. The Phe223Ala mutation impairs NADH and CH2-H4folate binding each 40-fold, yet slows catalysis of both half-reactions less than 2-fold. Affinity for CH2-H4folate is unaffected by the Phe223Leu mutation, and the variant catalyzes the oxidative half-reaction 3-fold faster than the wild-type enzyme. Structures of ligand-free Phe223Leu and Phe223Leu/Glu28Gln MTHFR in complex with CH3-H4folate have been determined at 1.65 and 1.70 resolution, respectively. The structures show that the folate is bound in a catalytically competent conformation, and Leu223 undergoes a conformational change similar to that observed for Phe223 in the Glu28Gln-CH3-H4folate structure. Taken together, our results suggest that Leu may be a suitable replacement for Phe223 in the oxidative half-reaction of E. coli MTHFR. PMID:19610625

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

    PubMed Central

    Wang, Yadong; Yang, Haiyan; Duan, Guangcai

    2015-01-01

    Objectives: 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. Methods: Systematic searches were performed through the database of Medline/PubMed, Science Direct, Elsevier, CNKI and Wanfang Medical Online. Results: 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. Conclusions: 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.

  19. 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. PMID:26380869

  20. The effect of 677C>T and 1298A>C MTHFR polymorphisms on sulfasalazine treatment outcome in rheumatoid arthritis.

    PubMed

    Pawlik, A; Kurzawski, M; Gawronska-Szklarz, B; Gornik, W; Dziedziejko, V; Safranow, K; Juzyszyn, Z; Drozdzik, M

    2009-07-01

    Despite the availability of several new agents for the treatment of rheumatoid arthritis (RA), sulfasalazine remains the mainstay because of both cost and experience with its use. Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and several polymorphisms have been described in the MTHFR gene. Of these, the 677C>T and 1298A>C polymorphisms have been associated with altered enzyme activity. To examine the association between 677C>T and 1298A>C MTHFR polymorphisms and sulfasalazine efficacy for the treatment of RA, a total of 117 RA patients treated with sulfasalazine (1 g daily; duration of treatment 17 +/- 5 months) were analyzed. The 677C>T and 1298 A>C polymorphisms were detected using a PCR-RFLP method. RA was diagnosed according to the criteria of the American College of Rheumatology (ACR). The remission of RA symptoms was evaluated according to the ACR 20% response criteria. Allele and genotype frequencies were compared by the two-sided Fisher exact test. The frequency of remission was 47.2% and 44.6% in carriers of 677T and 1298C alleles, compared to 40.7% and 42.0% in carriers of 677C and 1298A alleles, respectively. These differences were statistically non-significant. When the multivariate analysis was additionally adjusted for patients' age, gender and RA duration, the association of the MTHFR 677T allele with increased frequency of remission was statistically significant. Although RA remission rate in carriers of the MTHFR 677T and 1298C alleles was more frequently observed, it does not seem that 677C>T and 1298A>C MTHFR polymorphisms have a major influence on treatment outcome in RA patients treated with sulfasalazine. PMID:19578646

  1. 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. PMID:26235956

  2. MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients.

    PubMed

    Naghibalhossaini, Fakhraddin; Mokarram, Pooneh; Khalili, Islam; Vasei, Mohammad; Hosseini, Seyed Vahid; Ashktorab, Hassan; Rasti, Mozhgan; Abdollahi, Kourosh

    2010-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. We aimed to test the hypothesis that C677T and A1298C variants of MTHFR predispose to microsatellite instable (MSI) colorectal cancer. We determined MTHFR genotypes in 175 sporadic colorectal cancer patients and a total of 231 normal controls in Shiraz, Southern Iran. Among the genotypes found in our samples, MTHFR CT and CT+TT were associated with increased risk for CRC incidence [odds ratio (OR)=2.4, 95% confidence interval (95%CI)=1.8-4.4; OR=2.4, 95%CI=1.6-3.6, respectively]. Double heterozygotes 677CT/1298AC and double homozygote 677TT/1298AA and 677CC/1298CC genotypes also showed a significantly increased risk of developing CRC compared with the wild-type 677CC/1298AA genotypes of the controls. Among the 151 tumors tested, 36 (23.8%) were MSI+. MSI was more common in proximal tumors (OR=10.4; 95%CI=3.9-27.8) and in smokers (OR=2.9; 95%CI=1.3-6.7). In a case-control comparison, the MTHFR 677CT+TT genotype was strongly associated with MSI (OR=2.6; 95%CI=1.3-5.3). Hypermethylation of mismatch repair genes was positively related with MSI incidence in these tumor series (P=0.00). Our data suggest that the MTHFR 677CT+TT variant genotype may be a risk factor for MSI+ cancer. PMID:20193847

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

    PubMed Central

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

    2015-01-01

    Background: Atherosclerosis is a complex multifocal arterial disease involving interactions between multiple genetic and environmental factors. Objectives: 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. Patients and Methods: 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). Results: 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. Conclusions: 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. PMID:26878010

  4. Deep venous thrombosis and thrombophilic mutations in western Iran: association with factor V Leiden.

    PubMed

    Rahimi, Zohreh; Mozafari, Hadi; Shahriari-Ahmadi, Ali; Alimogaddam, Kamran; Ghavamzadeh, Ardeshir; Aznab, Mozafar; Mansouri, Kamran; Rezaei, Mansour; Parsian, Abbas

    2010-07-01

    The aim of present study was to investigate the prevalence of factor V Leiden (FVL) c.1691G>A, prothrombin g.20210G>A and methylenetetrahydrofolate reductase (MTHFR) c.677C>T in deep vein thrombosis (DVT) patients and their possible association with DVT in western Iran. Eighty DVT patients with the mean age of 42.07 +/- 13.0 years including 44 women and 36 men and 100 sex-matched healthy individuals with the mean age of 37.63 +/- 13.3 years from Kermanshah Province of Iran with ethnic background of Kurd were studied for FVL c.1691G>A, prothrombin g.20210G>A and MTHFR c.677C>T by PCR-restriction fragment length polymorphism (RFLP) method using MnlI, HindIII and HinfI restriction enzymes, respectively. Prevalence of FVL was 11.4% in patients and 2% in control group. A significant association was found between FVL mutation and DVT with odds ratio (OR) of 6.3 [95% confidence interval (CI) = 1.32-30.05; P = 0.012]. The prevalence of prothrombin g.20210G>A variant in patients (3.8%) was nonsignificantly higher than control individuals (1.0%; OR 3.8; 95% CI = 0.39-37.81; P = 0.32). The prevalence of MTHFR c.677C>T in patients was 38.7% that was not statistically different from control group (44% P = 0.12). Venous thrombosis in legs was the most frequent clinical manifestation (n = 75), corresponding to 93.8% of the thromboembolism, followed by pulmonary thromboembolism (6.2%). We have, for the first time, determined the prevalence of inherited thrombophilia in a homogenous ethnic group of DVT patients and shown that FVL may be a risk factor for DVT in western Iran. PMID:20479641

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

    PubMed Central

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

    2016-01-01

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

  6. Might erectile dysfunction be due to the thermolabile variant of methylenetetrahydrofolate reductase?

    PubMed

    Lombardo, F; Sgr, P; Gandini, L; Dondero, F; Jannini, E A; Lenzi, A

    2004-10-01

    Hyperhomocysteinemia is considered one of the most important cardiovascular risk factors increasing considerably the risk of stroke and myocardial infarction. With respect to endothelial function, direct effects of hyperhomocysteinemia on vascular endothelial cells have been demonstrated through the reduction of endothelial nitric oxide production. In this paper, we report the case of a young man with homozygote genotype mutated with 5-methylenetetrahydrofolate reductase (MTHFR) thermolabile variant who, in the absence of relational stress, developed an erectile dysfunction (ED) refractory to the vasoactive type-V phosphodiesterase (PDE5) inhibitor therapy. After one month of treatment with 5 mg/day folic acid and 1000 microg/day cyanocobalamin, the patient restarted the assumption of 50 mg sildenafil, obtaining satisfying erections during sexual intercourse. We suggest that hyperhomocysteinemia may interfere with penile blood supply and, thus, be responsible for ED. If this relationship is confirmed, plasma levels and urinary homocysteine (HCy) should be evaluated in selected young patients with vascular ED. Furthermore, careful attention should be given to the risk of ED when dealing with this metabolic disturbance. PMID:15648556

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

    PubMed

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

    2014-01-01

    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 Bfida del Hospital Infantil Virgen del Roco (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. PMID:24737468

  8. The MTHFR C677T polymorphism contributes to increased risk of Alzheimer's disease: evidence based on 40 case-control studies.

    PubMed

    Peng, Qiliu; Lao, Xianjun; Huang, Xiuli; Qin, Xue; Li, Shan; Zeng, Zhiyu

    2015-01-23

    The association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and Alzheimer's Disease (AD) risk has been widely reported with inconsistent results. We performed an updated meta-analysis of all available studies to clarify this situation. We conducted a comprehensive literature search in PubMed Alzgene, Embase, and Chinese Biomedical Literature database (CBM) for the period up to June 2014. Finally, a total of 40 case-control studies with 4503 AD cases and 5767 controls were included. Overall, significant increased AD risk was found, when all studies were pooled into the meta-analysis. In subgroup analyses stratified by ethnicity, age of onset, and APOE ?4 status, significant increased AD risk was found in Asians, late-onset AD, and APOE ?4 carriers, but not in Caucasians, early-onset AD, and non-APOE ?4 carriers. The present meta-analysis suggested that the MTHFR is a candidate gene for AD susceptibility. The MTHFR C677T polymorphism may be a risk factor for AD in Asians, APOE ?4 carriers, and late-onset AD. Further, investigations taking the potential gene-gene and gene-environmental interactions into consideration for the MTHFR C677T polymorphism should be conducted. PMID:25486592

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

    PubMed

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

    2015-12-01

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

  10. Association between MTHFR polymorphisms and congenital heart disease: a meta-analysis based on 9,329 cases and 15,076 controls.

    PubMed

    Xuan, Chao; Li, Hui; Zhao, Jin-Xia; Wang, Hong-Wei; Wang, Yi; Ning, Chun-Ping; Liu, Zhen; Zhang, Bei-Bei; He, Guo-Wei; Lun, Li-Min

    2014-01-01

    The aim of our study was to evaluate the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk for congenital heart disease (CHD). Electronic literature databases were searched to identify eligible studies published before Jun, 2014. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI). The publication bias was explored using Begg's test. Sensitivity analysis was performed to evaluate the stability of the crude results. A total of 35 studies were included in this meta-analysis. For the MTHFR C677T polymorphism, we detected significant association in all genetic models for Asian children and the maternal population. Significant association was also detected in T vs. C for a Caucasian paediatric population (OR = 1.163, 95% CI: 1.008-1.342) and in both T vs. C (OR = 1.125, 95% CI: 1.043-1.214) and the dominant model (OR = 1.216, 95% CI:b1.096-1.348) for a Caucasian maternal population. For the MTHFR A1298C polymorphism, the association was detected in CC vs. AC for the Caucasian paediatric population (OR = 1.484, 95% CI: 1.035-2.128). Our results support the MTHFR -677T allele as a susceptibility factor for CHD in the Asian maternal population and the -1298 C allele as a risk factor in the Caucasian paediatric population. PMID:25472587

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

    PubMed Central

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

    2015-01-01

    Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material/Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.791.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.801.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.841.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.731.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.811.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility. PMID:25761797

  12. MTHFR C677T polymorphism contributes to prostate cancer risk among Caucasians: A meta-analysis of 3511 cases and 2762 controls.

    PubMed

    Bai, Jian-Ling; Zheng, Ming-Hua; Xia, Xian; Ter-Minassian, Monica; Chen, Yong-Ping; Chen, Feng

    2009-05-01

    Published data regarding the association between 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and prostate cancer risk have been conflicting. 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 C677T and A1298C polymorphisms and prostate cancer risk. Six studies including 3511 cases and 2762 controls described C677T genotypes, among which four articles totalling 838 cases and 1121 controls described A1298C genotypes, were involved in this meta-analysis. Overall meta-analysis indicated that the 677T allele was more likely to exert a protective effect on prostate cancer risk (OR=0.81, 95% CI: 0.68-0.98) with a recessive genetic model. No association was found for the 677CT genotype and the 677TT mutant homozygote with prostate cancer risk compared with 677CC, with OR=1.13 (95% CI: 0.88-1.45) and OR=0.85 (95% CI: 0.71-1.03), respectively. No evidence of an association of MTHFR A1298C polymorphism with prostate cancer was found. This meta-analysis supports that the C677T of the MTHFR gene is a low-penetrance susceptibility gene for prostate cancer, and might provide protective effects against prostate cancer risk. PMID:19223177

  13. Association Between MTHFR Polymorphisms and Congenital Heart Disease: A Meta-analysis based on 9,329 cases and 15,076 controls

    PubMed Central

    Xuan, Chao; Li, Hui; Zhao, Jin-Xia; Wang, Hong-Wei; Wang, Yi; Ning, Chun-Ping; Liu, Zhen; Zhang, Bei-Bei; He, Guo-Wei; Lun, Li-Min

    2014-01-01

    The aim of our study was to evaluate the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk for congenital heart disease (CHD). Electronic literature databases were searched to identify eligible studies published before Jun, 2014. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI). The publication bias was explored using Begg's test. Sensitivity analysis was performed to evaluate the stability of the crude results. A total of 35 studies were included in this meta-analysis. For the MTHFR C677T polymorphism, we detected significant association in all genetic models for Asian children and the maternal population. Significant association was also detected in T vs. C for a Caucasian paediatric population (OR = 1.163, 95% CI: 1.0081.342) and in both T vs. C (OR = 1.125, 95% CI: 1.0431.214) and the dominant model (OR = 1.216, 95% CI:b1.0961.348) for a Caucasian maternal population. For the MTHFR A1298C polymorphism, the association was detected in CC vs. AC for the Caucasian paediatric population (OR = 1.484, 95% CI: 1.0352.128). Our results support the MTHFR -677T allele as a susceptibility factor for CHD in the Asian maternal population and the -1298C allele as a risk factor in the Caucasian paediatric population. PMID:25472587

  14. The methylenetetrahydrofolate reductase C677T polymorphism influences risk of esophageal cancer in Chinese.

    PubMed

    Qu, Hong-Hong; Cui, Li-Hong; Wang, Ke; Wang, Peng; Song, Chun-Hua; Wang, Kai-Juan; Zhang, Jian-Ying; Dai, Li-Ping

    2013-01-01

    Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. This study with 381 esophageal cancer patients and 432 healthy controls was conducted to examine the association of MTHFR C677T and A1298C polymorphisms with susceptibility to esophageal cancer (EC) in a Chinese population. Compared with the CC genotype of MTHFR C677T, subjects carrying homozygote TT and variant genotypes (CT+TT) demonstrated reduced risk of EC with adjusted ORs (95% CI) of 0.44 (0.28-0.71) and 0.57 (0.37-0.88), respectively. However, no association was found between the MTHFR A1298C polymorphism and the risk of EC. Comparing to haplotype CA, haplotypes TA and TC could reduce the susceptibility to EC with adjusted ORs (95% CI) of 0.61(0.47-0.79) and 0.06 (0.01-0.43), respectively. In conclusion, the present study suggested that the MTHFR C677T polymorphism can markedly influence the risk of EC in Chinese. PMID:23803097

  15. Significant association between the MTHFR A1298C polymorphism and hepatocellular carcinoma risk: a meta-analysis.

    PubMed

    Chang, W; Meng, Q; Liu, J H; Wu, L X; Chen, Y; Chen, S D

    2015-01-01

    The A1298C polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been reported to be associated with hepatocellular carcinoma (HCC), but there are conflicting results from previous studies. The present study aimed to investigate the association between this polymorphism and the risk of HCC using a meta-analysis of the published studies. Published literature from PubMed and Embase databases was systematically searched to identify relevant studies before October 2014. The Begg test was used to measure publication bias. Sensitivity analyses were performed to ensure the authenticity of the outcome. The meta-analysis results showed significant association between the MTHFR A1298C polymorphism and HCC risk (CC vs AA: OR = 0.52, 95%CI = 0.33-0.81; CC vs AC: OR = 0.50, 95%CI = 0.32-0.79; dominant model: OR = 1.94, 95%CI = 1.24-3.02; recessive model: OR = 1.00, 95%CI = 0.84-1.18). In the subgroup analysis, significant associations between the MTHFR A1298C polymorphism and HCC risk were found in Asians (CC vs AA: OR = 0.46, 95%CI = 0.27-0.78; CC vs AC: OR = 0.41, 95%CI = 0.24-0.71; dominant model: OR = 2.27, 95%CI = 1.33-3.86; recessive model: OR = 1.03, 95%CI = 0.86-1.24). Our results suggest that the MTHFR A1298C polymorphism might be related to increased risk of HCC in Asians. Further large and well-designed studies are needed to confirm these conclusions. PMID:26662389

  16. 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

  17. MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt.

    PubMed

    Aly, Rabab M; Taalab, Mona M; Ghazy, Hayam F

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR=2.513, 95% CI: 0.722-4.086, P=0.025). No such association was shown for heterozygous 677CT (OR=1.010, 95% CI: 0.460-2.218, P=0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR=1.1816, 95% CI: 0.952-3.573, P=0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR=1.046, 95% CI: 0.740-1.759, P=0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR=1.849, 95% CI: 0.935-2.540, P=0.024; OR=1.915, 95% CI: 1.202-3.845, P=0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P=0.001, P=0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy. PMID:24966971

  18. Characterization and site-directed mutation of a novel aldo-keto reductase from Lodderomyces elongisporus NRRL YB-4239 with high production rate of ethyl (R)-4-chloro-3-hydroxybutanoate.

    PubMed

    Wang, Qiuyan; Ye, Tingting; Ma, Zhuanzhuan; Chen, Rong; Xie, Tian; Yin, Xiaopu

    2014-11-01

    A novel aldo-keto reductase (LEK) from Lodderomyces elongisporus NRRL YB-4239 (ATCC 11503) was discovered by genome database mining for carbonyl reduction. LEK was overexpressed in Escherichia coli BL21 (DE3), purified to homogeneity and the catalytic properties were studied. Among the substrates, ethyl 4-chloro-3-oxobutanoate was converted to ethyl (R)-4-chloro-3- hydroxybutanoate ((R)-CHBE), an important pharmaceutical intermediate, with an excellent enantiomeric excess (e.e.) (>99 %). The mutants W28A and S209G obtained by site-directed mutation were identified with much higher molar conversion yields and lower Km values. Further, the constructed coenzyme regeneration system with glucose as co-substrate resulted in a yield of 100 %, an enantioselectivity of >99 %, and the calculated production rate of 56.51 mmol/L/H. These results indicated the potential of LEK for the industrial production of (R)-CHBE and other valuable chiral alcohols. PMID:25189809

  19. 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

  20. 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. PMID:24535549

  1. 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

    2015-01-01

    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. PMID:26782572

  2. The methylenetetrahydrofolate reductase gene C677T polymorphism in patients with homozygous sickle cell disease and stroke.

    PubMed

    Cumming, A M; Olujohungbe, A; Keeney, S; Singh, H; Hay, C R; Serjeant, G R

    1999-12-01

    Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism may cause hyperhomocysteinaemia, a recognized risk factor for stroke, in individuals with folate deficiency. Homozygous sickle cell (SS) disease is associated both with increased demands for folic acid and a tendency to develop stroke. We therefore investigated a possible role of the MTHFR C677T polymorphism in SS disease patients with stroke. Investigation of the frequency of the polymorphism in 48 patients with stroke and in 48 age-, sex- and racially-matched SS controls without stroke failed to reveal a difference between the groups (Fisher exact test, P = 0.99). Homozygosity for the MTHFR C677T polymorphism is unlikely to be a risk factor for stroke in this population with SS disease. PMID:10583261

  3. Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study.

    PubMed

    Shen, H; Spitz, M R; Wang, L E; Hong, W K; Wei, Q

    2001-04-01

    Previous studies have suggested that low folate intake is associated with increased risk of lung cancer. Methylene-tetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Therefore, we hypothesized that these variant genotypes may play a role in the etiology of lung cancer. To test this hypothesis, we investigated the association between two common MTHFR polymorphisms (C677T and A1298C) and risk of lung cancer in a non-population-based case-control study of 550 histologically confirmed lung cancer cases and 554 healthy controls. The subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (+ or -5 years), sex, and smoking status (ever or never). Folate intake and alcohol consumption were estimated from a self-administered food-frequency questionnaire. The cases consumed significantly less folate (162 microg/day/1000 kcal) than the controls did (172 microg/day/1000 kcal; P = 0.033). However, we found no evidence for an association between the MTHFR C677T and A1298C polymorphisms and risk of lung cancer in either all of the subjects or the low folate intake subgroup; nor did we find evidence for an interaction between these two MTHFR polymorphisms and dietary folate intake or alcohol use. In multivariate logistic regression analysis, the adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 1.1 (0.8-1.4) for 677CT versus 677CC wild type and 1.1 (0.7-1.7) for 677TT versus 677CC, and for MTHFR A1298C, they were 1.0 (0.8-1.3) for 1298AC versus 1298AA wild type and 1.1 (0.7-1.8) for 1298CC versus 1298AA. These results suggest that the MTHFR C677T and A1298C polymorphisms by themselves do not play an important role in the etiology of lung cancer. PMID:11319182

  4. Sex Differences in Ethanol’s Anxiolytic Effect and Chronic Ethanol Withdrawal Severity in Mice With a Null Mutation of the 5α-Reductase Type 1 Gene

    PubMed Central

    Tanchuck-Nipper, Michelle A.; Ford, Matthew M.; Hertzberg, Anna; Beadles-Bohling, Amy; Cozzoli, Debra K.; Finn, Deborah A.

    2015-01-01

    Manipulation of endogenous levels of the GABAergic neurosteroid allopregnanolone alters sensitivity to some effects of ethanol. Chronic ethanol withdrawal decreases activity and expression of 5α-reductase-1, an important enzyme in allopregnanolone biosynthesis encoded by the 5α-reductase-1 gene (Srd5a1). The present studies examined the impact of Srd5a1 deletion in male and female mice on several acute effects of ethanol and on chronic ethanol withdrawal severity. Genotype and sex did not differentially alter ethanol-induced hypothermia, ataxia, hypnosis, or metabolism, but ethanol withdrawal was significantly lower in female versus male mice. On the elevated plus maze, deletion of the Srd5a1 gene significantly decreased ethanol’s effect on total entries versus wildtype (WT) mice and significantly decreased ethanol’s anxiolytic effect in female knockout (KO) versus WT mice. The limited sex differences in the ability of Srd5a1 genotype to modulate select ethanol effects may reflect an interaction between developmental compensations to deletion of the Srd5a1 gene with sex hormones and levels of endogenous neurosteroids. PMID:25355320

  5. Rat lens aldehyde reductase.

    PubMed

    Sato, S; Kador, P F

    1989-07-01

    Aldehyde reductase (E.C. 1.1.1.2) has been purified to apparent homogeneity from rat lens and its properties have been compared to those of both rat lens aldose reductase and rat kidney aldehyde reductase. The purification was accomplished by ammonium sulfate fractionation, Sephadex G-75 chromatography, affinity chromatography on Amicon Matrex Gel Orange A and chromatofocusing. The purified enzyme is distinct from rat lens aldose reductase but appears similar to rat kidney aldehyde reductase in molecular weight, immunological properties and substrate specificities. Rat lens aldehyde reductase is inhibited by a number of aldose reductase inhibitors; however, its susceptibility to inhibition is more similar to rat kidney aldehyde reductase than to rat lens aldose reductase. PMID:2501231

  6. The role of the polymorphic genes apolipoprotein E and methylene- tetrahydrofolate reductase in the development of dementia of the Alzheimer type.

    PubMed

    Regland, B; Blennow, K; Germgrd, T; Koch-Schmidt, A C; Gottfries, C G

    1999-01-01

    The gene for apolipoprotein E (APOE) is polymorphic, and its variant APOE4 is a major risk factor for the development of Alzheimer-type dementia (AD). Another risk factor for AD appears to be negative cobalamin balance, which is very common in elderly people. Cobalamin and folate are interdependent and essential components of the one-carbon metabolism. Another important component is methylenetetrahydrofolate reductase (MTHFR), the gene for which is also polymorphic. Thermolabile MTHFR (tMTHFR), a gene variant that reduces the activity of its enzyme, is common in the general population. In the present study, 75% of 140 AD patients had at least one APOE4 allele. The numbers of APOE4 and tMTHFR alleles correlated significantly with the serum folate levels, however, in opposite directions. The significance of this was augmented by an inverse correlation between APOE4 and tMTHFR. Thus, not only MTHFR but also APOE appears to be related to the one-carbon metabolism, suggesting that APOE4 and insufficient one-carbon metabolism may be synergistic risk factors for AD. PMID:10364640

  7. Association of Methylenetetrahydrofolate Reductase C677T Polymorphism with Hyperhomocysteinemia and Deep Vein Thrombosis in the Iranian Population

    PubMed Central

    Ghaznavi, Habib; Soheili, Zahra; Samiei, Shahram; Soltanpour, Mohammad Soleiman

    2015-01-01

    Purpose: Deep venous thrombosis (DVT) is a common but elusive condition characterized by a high morbidity and mortality rate. The aim of the present study was to investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with plasma total homocysteine (tHcy) levels and DVT risk in an Iranian population. Materials and Methods: Our study population consisted of 67 patients with a diagnosis of DVT and 67 healthy subjects as controls. Genotyping of MTHFR C677T polymorphism was performed by the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) and measurement of tHcy levels was done by enzyme immunoassay method. Results: Plasma tHcy levels were significantly higher in DVT patients than controls (18.09±7.6 vs. 10.5±4.3, P=0.001). Also, plasma tHcy levels were significantly higher in MTHFR 677TT genotypes compared to 677CC genotypes in both DVT patients (P=0.016) and controls (P=0.03). Neither heterozygote nor homozygote genotypes of MTHFR C677T polymorphism was significantly correlated with DVT (P>0.05). The distribution of MTHFR C677T genotypes was similar between men and women in both DVT patients and controls (P>0.05). Moreover, the frequency of mutant 677T allele did not differ significantly between the two groups (28.3% vs. 21.6%, P=0.15). Conclusion: Based on this study, we propose that hyperhomocysteinemia but not homozygosity for MTHFR C677T polymorphism is a significant risk factor for DVT in the Iranian population. Also, MTHFR 677TT genotype is a determinant of elevated plasma tHcy levels. PMID:26719836

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

    PubMed

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

    2014-05-01

    An imbalance in folate metabolism can adversely affect DNA synthesis and methylation systems which can lead to susceptibility to non-Hodgkin lymphoma (NHL). Whether single nucleotide polymorphisms (SNPs) and their haplotypes in the methylenetetrahydrofolate reductase (MTHFR) are associated with NHL, remain inconclusive. We investigated the association between MTHFR C677T and A1298C SNPs and NHL risk in a population which is made up of Malay, Chinese and Indian ethnic subgroups. A total of 372 NHL patients and 722 controls were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects failed to demonstrate significant association between the MTHFR C677T and A1298C SNPs with NHL and its subtypes. The results were in agreement with the previous meta-analyses. In the Indian ethnic subgroup however, single locus analysis of MTHFR A1298C appears to confer risk to NHL (Odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.22-3.00, P=0.006). The risk is almost doubled in homozygous carrier of MTHFR 1298CC (OR 4.03, 95% CI 1.56-10.43, P=0.004). Haplotype analysis revealed higher frequency of CC in the Indian NHL patients compared with controls (OR 1.86, 95% CI 1.18-2.93, P=0.007). There is lack of evidence to suggest an association between MTHFR C677T and A1298C with the risk of NHL in the Malays and Chinese. In the Indians however, the MTHFR A1298C confers risk to NHL. This study suggests ethnicity modifies the relationship between polymorphisms in the folate-metabolizing gene and NHL. PMID:24646728

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2014-01-01

    The midribs of maize brown midrib (bm) mutants exhibit a reddish-brown color associated with reductions in lignin concentration and alterations in lignin composition. Here, we report the mapping, cloning, and functional and biochemical analyses of the bm2 gene. The bm2 gene was mapped to a small region of chromosome 1 that contains a putative methylenetetrahydrofolate reductase (MTHFR) gene, which is down-regulated in bm2 mutant plants. Analyses of multiple Mu-induced bm2-Mu mutant alleles confirmed that this constitutively expressed gene is bm2. Yeast complementation experiments and a previously published biochemical characterization show that the bm2 gene encodes a functional MTHFR. Quantitative RT-PCR analyses demonstrated that the bm2 mutants accumulate substantially reduced levels of bm2 transcript. Alteration of MTHFR function is expected to influence accumulation of the methyl donor S-adenosyl-l-methionine (SAM). Because SAM is consumed by two methyltransferases in the lignin pathway (Ye et al., 1994), the finding that bm2 encodes a functional MTHFR is consistent with its lignin phenotype. Consistent with this functional assignment of bm2, the expression patterns of genes in a variety of SAM-dependent or -related pathways, including lignin biosynthesis, are altered in the bm2 mutant. Biochemical assays confirmed that bm2 mutants accumulate reduced levels of lignin with altered composition compared to wild-type. Hence, this study demonstrates a role for MTHFR in lignin biosynthesis. PMID:24286468

  11. Mutation of the Heme Axial Ligand of Escherichia coli Succinate-Quinone Reductase: Implications for Heme Ligation in Mitochondrial Complex II from Yeast

    PubMed Central

    Maklashina, Elena; Rajagukguk, Sany; McIntire, William S.; Cecchini, Gary

    2010-01-01

    A b-type heme is conserved in membrane-bound complex II enzymes (SQR, succinate-ubiquinone reductase). The axial ligands for the low spin heme b in Escherichia coli complex II are SdhC His84 and SdhD His71. E. coli SdhD His71 is separated by 10 residues from SdhD Asp82 and Tyr83 which are essential for ubiquinone catalysis. The same His-10x-AspTyr motif dominates in homologous SdhD proteins, except for Saccharomyces cerevisiae where a tyrosine is at the axial position (Tyr-Cys-9x-AspTyr). Nevertheless, the yeast enzyme was suggested to contain a stoichiometric amount of heme, however, with the Cys ligand in the aforementioned motif acting as heme ligand. In this report, the role of Cys residues for heme coordination in the complex II family of enzymes is addressed. Cys was substituted to the SdhD-71 position and the yeast Tyr71Cys72 motif also recreated. The Cys71 variant retained heme, although it was high spin, while the Tyr71Cys72 mutant lacked heme. Previously the presence of heme in S. cerevisiae was detected by a spectral peak in fumarate-oxidized, dithionite-reduced mitochondria. Here it is shown that this method must be used with caution. Comparison of bovine and yeast mitochondrial membranes shows that fumarate induced reoxidation of cytochromes in both SQR and the bc1 complex (ubiquinol-cytochrome c reductase). Thus, this report raises a concern about the presence of low spin heme b in S. cerevisiae complex II. PMID:20100456

  12. ABO blood group but not haemostasis genetic polymorphisms significantly influence thrombotic risk: a study of 180 homozygotes for the Factor V Leiden mutation.

    PubMed

    2006-12-01

    Limited data exist on the impact of additional genetic risk factors on the clinical manifestations of factor (F) V Leiden homozygotes. A retrospective multi-centre cohort study was performed to assess the role of the FII G20210A gene mutation, the protein C (PC) promoter CG haplotype, the combination of two PC polymorphisms (A-1641G, C-1654T), the FXIII Val34Leu polymorphism, two thrombin-activatable fibrinolysis inhibitor polymorphisms (Thr325Ile, Ala147Thr), two plasminogen activator inhibitor-1 polymorphisms (-675 4G/5G, A-844G), the methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism and the ABO blood group on the thrombotic phenotype in FV Leiden homozygotes. 127 subjects with venous thrombosis and 53 asymptomatic subjects were analysed. The T allele of MTHFR C677T was more frequent in symptomatic subjects than in asymptomatic ones (68% vs. 45%, P = 0.02; odds ratio (OR) 2.8, 95% CI 1.3-5.8, after adjustment for potential confounders). For the other polymorphisms, no difference was observed between symptomatic and asymptomatic subjects. The non-O blood group was more frequent among symptomatic carriers (84% vs. 57%, P = 0.0002; OR 4.1, 95% CI 1.7-9.7). In conclusion, except for the ABO blood group, none of the polymorphisms studied contribute strongly to the thrombotic risk in FV Leiden homozygotes. PMID:17107352

  13. Conversion of Human Steroid 5[beta]-Reductase (AKR1D1) into 3[beta]-Hydroxysteroid Dehydrogenase by Single Point Mutation E120H: Example of Perfect Enzyme Engineering

    SciTech Connect

    Chen, Mo; Drury, Jason E.; Christianson, David W.; Penning, Trevor M.

    2012-10-10

    Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5{beta}-reduction of {Delta}{sup 4}-3-ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His120 (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5{beta}-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5{alpha}-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3{beta}-HSD as opposed to a 3{alpha}-HSD. The catalytic efficiency achieved for 3{beta}-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5{beta}-dihydrotestosterone, and {Delta}{sup 4}-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the {Delta}{sup 4}-double bond and confers 3{beta}-HSD activity on the 5{beta}-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its {alpha}-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.

  14. [Association between methylene-tetrahydrofolate reductase gene polymorphisms and chronic myeloid leukemia].

    PubMed

    Dorgham, Samia; Aberkane, Meriem; Boughrara, Wefa; Antar Soltan, Badra; Mehalhal, Nemra; Touhami, Hadj; Sidimansour, Noureddine; Merad Boudia, Nadia; Louhibi, Lotfi; Boudjema, Abdallah

    2014-09-01

    Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolism. Few studies were reported about its relationship with chronic myeloid leukemia (CML). We conducted a case-control study analyzing the prevalence of the polymorphisms MTHFR C677T and MTHFR A1298C in Algerians CML patients. Using TaqMan() allelic discrimination assay, we investigate MTHFR C677T and A1298C polymorphism distribution in 90 cases of CML and 100 healthy subjects. The frequencies of 677T alleles and genotypes 677TT and 677CT were significantly higher in cases than in control (P?=?1E-6; OR?=?6.77 [4.22-10.86]) and (P?=?1E-6; OR?=?10.38 [4.56-23.6]) respectively. Also, the frequencies of 1298C alleles and genotypes 1298CC and 1298AC were higher in cases (P?=?9 E-6; OR?=?2.65 [1.71-4.10]) and (P?=?0.008; OR?=?2.22 [1.21-4.06]) respectively. We report also the higher significance of the haplotype 677T/1298A and 677T/1298C in cases (P?=?0.007; OR?=?2.57 [1.26-5.24]) and (P?=?5 E-6, OR?=?6.91 [2.7646-17.2899]) respectively. Our results demonstrate that 677T and 1298C alleles are both associated with an increased risk of CML in Algeria. PMID:25036376

  15. Methylenetetrahydrofolate reductase gene polymorphisms and skin cancer risk: a meta-analysis.

    PubMed

    Deng, Feng; Gao, Ying; L V, Ju-hong; Gao, Jian-min

    2014-01-01

    We sought to determine whether the methylenetetrahydrofolate reductase (MTHFR) A1298C and C677T polymorphisms are associated with increased skin cancer risk. We performed literature searches of the PubMed, BIOSIS Previews, and Web of Science databases to identify eligible articles published through September 15, 2013. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Publication bias and subgroup analyses were also performed. Eight articles, which consisted of 10,066 subjects (2,672 patients and 7,394 controls), were included in the meta-analysis. Homozygous MTHFR 1298C individuals were 1.29 times more likely to develop skin cancer (95% CI, 1.04-1.61) compared with A1298C allele (AA or AC) carriers. There was an increased risk for C allele homozygotes compared with the 1,298 AA+AC carriers (OR, 1.45; 95% CI, 1.08-1.96) when restricted to basal cell carcinomas (BCC). The 1298C homozygote carriers increased the odds of BCC by 1.47 times (95% CI, 1.07-2.01) compared with those who were 1298A homozygote carriers. ORs for all genetic models yielded a null association. The data obtained from this meta-analysis suggest that the MTHFR 1298C allele is associated with increased skin cancer risk, particularly BCC; however, no association was observed between the MTHFR C677T polymorphism and skin cancer. PMID:25306137

  16. A common variant in MTHFR influences response to chemoradiotherapy and recurrence of rectal cancer

    PubMed Central

    Nikas, Jason B; Lee, Janet T; Maring, Elizabeth D; Washechek-Aletto, Jill; Felmlee-Devine, Donna; Johnson, Ruth A; Smyrk, Thomas C; Tawadros, Patrick S; Boardman, Lisa A; Steer, Clifford J

    2015-01-01

    An important determinant of the pathogenesis and prognosis of various diseases is inherited genetic variation. Single-nucleotide polymorphisms (SNPs), variations at a single base position, have been identified in both protein-coding and noncoding DNA sequences, but the vast majority of millions of those variants are far from being functionally understood. Here we show that a common variant in the gene MTHFR [rs1801133 (C>T)] not only influences response to neoadjuvant chemoradiotherapy in patients with rectal cancer, but it also influences recurrence of the disease itself. More specifically, patients with the homozygous ancestral (wild type) genotype (C/C) were 2.91 times more likely (291% increased benefit) to respond to neoadjuvant chemoradiotherapy {95% CI: [1.23, 6.89]; P=0.0150} and 3.25 times more likely (325% increased benefit) not to experience recurrence of the disease {95% CI: [1.37, 7.72]; P=0.0079} than patients with either the heterozygous (C/T) or the homozygous mutation (T/T) genotype. These results identify MTHFR as an important genetic marker and open up new, pharmacogenomic strategies in the treatment and management of rectal cancer. PMID:26693073

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  19. MTHFR C677T and A1298C polymorphisms as predictors of radiotherapy response in head and neck squamous cell carcinoma.

    PubMed

    Anders, Q S; Stur, E; Agostini, L P; Garcia, F M; Reis, R S; Santos, J A; Mendes, S O; Maia, L L; Peterle, G T; Stange, V; Carvalho, M B; Tajara, E H; Santos, M; Silva-Conforti, A M A; Louro, I D

    2015-01-01

    The C677T and A1298C polymorphisms in methylene-tetrahydrofolate reductase (MTHFR), which regulates the release of active folate in the body, may have reduced activity. Given that folate participates in important intracellular pathways, such as nucleotide synthesis and biomolecule methylation, it seems plausible that patients with head and neck squamous cell carcinoma (HNSCC) may respond differently to radiotherapy treatments, based on genetic polymor-phisms. Therefore, this study sought to understand the role of these polymorphisms in HNSCC patient radiotherapy response. Genotypes were detected by PCR-RFLP after extraction of DNA from peripheral blood lymphocytes. Survival curves were analyzed by the Kaplan- Meier model, and significant differences were analyzed by the Wil-coxon test. Response to radiotherapy in patients with laryngeal SCC was significantly associated with the MTHFR C677T polymorphism (P = 0.030). Indeed, the presence of at least one T allele decreases the mortality rate up to 3-fold. Therefore, we propose that MTHFR C677T may represent a putative biomarker for radiotherapy prognosis in la-ryngeal SCC patients. PMID:26535623

  20. Nitrate reductase mutation alters potassium nutrition as well as nitric oxide-mediated control of guard cell ion channels in Arabidopsis.

    PubMed

    Chen, Zhong-Hua; Wang, Yizhou; Wang, Jian-Wen; Babla, Mohammad; Zhao, Chenchen; García-Mata, Carlos; Sani, Emanuela; Differ, Christopher; Mak, Michelle; Hills, Adrian; Amtmann, Anna; Blatt, Michael R

    2016-03-01

    Maintaining potassium (K(+) ) nutrition and a robust guard cell K(+) inward channel activity is considered critical for plants' adaptation to fluctuating and challenging growth environment. ABA induces stomatal closure through hydrogen peroxide and nitric oxide (NO) along with subsequent ion channel-mediated loss of K(+) and anions. However, the interactions of NO synthesis and signalling with K(+) nutrition and guard cell K(+) channel activities have not been fully explored in Arabidopsis. Physiological and molecular techniques were employed to dissect the interaction of nitrogen and potassium nutrition in regulating stomatal opening, CO2 assimilation and ion channel activity. These data, gene expression and ABA signalling transduction were compared in wild-type Columbia-0 (Col-0) and the nitrate reductase mutant nia1nia2. Growth and K(+) nutrition were impaired along with stomatal behaviour, membrane transport, and expression of genes associated with ABA signalling in the nia1nia2 mutant. ABA-inhibited K(+) in current and ABA-enhanced slow anion current were absent in nia1nia2. Exogenous NO restored regulation of these channels for complete stomatal closure in nia1nia2. While NO is an important signalling component in ABA-induced stomatal closure in Arabidopsis, our findings demonstrate a more complex interaction associating potassium nutrition and nitrogen metabolism in the nia1nia2 mutant that affects stomatal function. PMID:26508536

  1. Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension

    PubMed Central

    CAI, WEIJUAN; YIN, LIANG; YANG, FANG; ZHANG, LEI; CHENG, JIANG

    2014-01-01

    The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (?2=6.658, ?2=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID:25279160

  2. Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension.

    PubMed

    Cai, Weijuan; Yin, Liang; Yang, Fang; Zhang, Lei; Cheng, Jiang

    2014-11-01

    The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (?(2)=6.658, ?(2)=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID:25279160

  3. Association between the MTHFR C677T polymorphism and gastric cancer susceptibility: A meta-analysis of 5,757 cases and 8,501 controls

    PubMed Central

    CHEN, LONG; LU, NING; ZHANG, BAI-HONG; WENG, LI; LU, JUN

    2015-01-01

    Current data regarding the association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of developing gastric cancer are insufficient to draw definite conclusions. Therefore, the present meta-analysis was conducted to achieve a more precise estimation of the association. MEDLINE, EMBASE and Wanfang database searches resulted in the identification of 28 eligible studies describing 5,757 cases and 8,501 controls. The strength of the association between the MTHFR C677T polymorphism and gastric cancer risk were evaluated using crude odds ratios (ORs), with 95% confidence intervals (CIs). The pooled ORs were determined using homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (TT+CT vs. CC) and recessive (TT vs. CC+CT) models. When all studies were pooled into the meta-analysis, significant associations were identified between the MTHFR C677T polymorphism and the risk of gastric cancer (homozygous model: OR, 1.39; 95% CI, 1.201.62; heterozygous model: OR, 1.18; 95% CI, 1.051.32; dominant model: OR, 1.23; 95% CI, 1.101.38; recessive model: OR, 1.26; 95% CI, 1.121.42). Stratification of the data by ethnicity identified a statistically significantly elevated risk of gastric cancer in Asian MTHFR C677T polymorphism populations (homozygous model: OR, 1.64; 95% CI, 1.431.90; heterozygous model: OR, 1.30; 95% CI, 1.161.45; dominant model: OR, 1.39; 95% CI, 1.251.54; recessive model: OR, 1.41; 95% CI, 1.251.51), but not in Caucasian populations (homozygous model: OR, 1.15; 95% CI, 0.891.48; heterozygous model: OR, 1.03; 95% CI, 0.841.25; dominant model: OR, 1.05; 95% CI, 0.861.28; recessive model: OR, 1.09; 95% CI, 0.911.31). Following adjustment for heterogeneity, the current meta-analysis demonstrated that the MTHFR C677T polymorphism was not associated with the risk of gastric cancer in Caucasian individuals. Furthermore, no evidence of publication bias was observed. Thus, the current meta-analysis indicates that the MTHFR C677T allele may be a low-penetrant risk factor for the development of gastric cancer in Asian populations. PMID:26622644

  4. The Bipolar Association Case-Control Study (BACCS) and meta-analysis: No association with the 5,10-Methylenetetrahydrofolate reductase gene and bipolar disorder.

    PubMed

    Cohen-Woods, Sarah; Craig, Ian; Gaysina, Darya; Gray, Joanna; Gunasinghe, Cerisse; Craddock, Nick; Elkin, Amanda; Jones, Lisa; Kennedy, James; King, Nicole; Korszun, Ania; Knight, Jo; Owen, Michael; Parikh, Sagar; Strauss, John; Sterne, Abram; Tozzi, Federica; Perry, Julia; Muglia, Pierandrea; Vincent, John; McGuffin, Peter; Farmer, Anne

    2010-10-01

    Bipolar disorder (BD) is a complex genetic disease for which the underlying pathophysiology has yet to be fully explained. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in folate-mediated one-carbon metabolism and folate deficiency can be associated with psychiatric symptoms. A single base variant in MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme and has recently been implicated in BD. We conducted an association study of this polymorphism in 897 patients with bipolar I or bipolar II disorder, and 1,687 healthy control subjects. We found no evidence for genotypic or allelic association in this sample. We also performed a meta-analysis of our own, and all published data, and report no evidence for association. Our findings suggest that the MTHFR C677T polymorphism is not involved in the genetic etiology of clinically significant BD. PMID:20552676

  5. Association of Blood Lead Levels with Methylenetetrahydrofolate Reductase Polymorphisms among Chinese Pregnant Women in Wuhan City

    PubMed Central

    Shen, Wei; Zhang, Bin; Liu, Shuyun; Wu, Hongling; Gu, Xue; Qin, Lingzhi; Tian, Ping; Zeng, Yun; Ye, Linxiang; Ni, Zemin; Wang, Qi

    2015-01-01

    Background Pregnancy is an important stimulus of bone lead release. Elevated blood lead levels (BLLs) may cause adverse pregnancy outcomes for mothers and harmful lead effects on fetuses. However, the reports about maternal BLL changes during pregnancy are conflicting to some extent. This article is to explore the variations in BLLs among pregnant women. The relationships of BLLs with methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms, which are associated with bone resorption, were also studied. A total of 973 women, including 234, 249, and 248 women in their first, second, and third trimesters, respectively, and 242 non-pregnant women, were recruited at the Wuhan Women and Children Medical Health Center. Methods BLLs were determined using a graphite furnace atomic absorption spectrometer. Single-nucleotide polymorphisms of MTHFR were identified with the TaqMan probe method. Results The geometric mean (geometric standard deviation) of BLLs was 16.2 (1.78) ?g/L for all participants. All the studied MTHFR alleles were in Hardy-Weinberg equilibrium. Multiple-linear regression analysis revealed the following results. Among the pregnant women, those that carried MTHFR 677CC (i.e. wild-genotype homozygote) and 1298CC (i.e. mutant-genotype homozygote) exhibited higher BLLs than those that carried 677CT/TT (standardized ? = 0.074, P = 0.042) and 1298AC/AA (standardized ? = 0.077, P = 0.035) when other covariates (e.g., age, no. of children, education and income, etc.) were adjusted. The BLLs of pregnant women consistently decreased during the pregnancy and these levels positively correlated with BMI (standard ? = 0.0860.096, P<0.05). Conclusions The 1298CC mutant-type homozygote in the MTHFR gene is a risk factor for high BLLs among low-level environmental lead-exposed Chinese pregnant women, whose BLLs consistently decreased during gestation. PMID:25723397

  6. Methylenetetrahydrofolate reductase polymorphisms/haplotypes and risk of gastric cancer: a case-control analysis in China.

    PubMed

    Shen, Hongbing; Newmann, Ana S; Hu, Zhibin; Zhang, Zhengdong; Xu, Yaochu; Wang, Liwei; Hu, Xu; Guo, Jiangtao; Wang, Xinru; Wei, Qingyi

    2005-02-01

    Studies have suggested that low dietary folate intake is associated with an increased risk of gastric cancer. Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and influences DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. We hypothesized that three MTHFR common variants (i.e. C677T, A1298C and G1793A) and their haplotypes are associated with the risk of gastric cancer. To test this hypothesis, we genotyped these polymorphisms in a population-based case-control study of 320 incident gastric adenocarcinoma cases and 313 cancer-free controls in a Chinese population. Consistent with our previous observations, the 677TT genotype was associated with a significantly increased risk for gastric cancer (adjusted OR =1.79, 95% CI =1.02-3.15) compared with the 677CC genotype; the association was more evident for gastric cardia adenocarcinoma (adjusted OR =2.60, 95% CI =1.30-5.21). When we used the haplotype analyses and assumed MTHFR 677T, 1298C and 1793A as risk alleles, individuals with 6 variant alleles had a significantly (4.64-fold) increased risk for gastric cardia adenocarcinoma (OR =4.64, 95% CI =1.34-16.01) compared with those having 0-2 variants. These findings suggest that the MTHFR common variants and their haplotypes may play a role in the etiology of gastric cancer, particularly gastric cardia adenocarcinoma. Future studies using large sample sizes and incorporating detailed data on dietary folate intake and related serological measurements are warranted to confirm our findings. PMID:15643524

  7. Heterotrimeric NADH-Oxidizing Methylenetetrahydrofolate Reductase from the Acetogenic Bacterium Acetobacterium woodii

    PubMed Central

    Bertsch, Johannes; ppinger, Christian; Hess, Verena; Langer, Julian D.

    2015-01-01

    ABSTRACT The methylenetetrahydrofolate reductase (MTHFR) of acetogenic bacteria catalyzes the reduction of methylene-THF, which is highly exergonic with NADH as the reductant. Therefore, the enzyme was suggested to be involved in energy conservation by reducing ferredoxin via electron bifurcation, followed by Na+ translocation by the Rnf complex. The enzyme was purified from Acetobacterium woodii and shown to have an unprecedented subunit composition containing the three subunits RnfC2, MetF, and MetV. The stable complex contained 2 flavin mononucleotides (FMN), 23.5 1.2 Fe and 24.5 1.5 S, which fits well to the predicted six [4Fe4S] clusters in MetV and RnfC2. The enzyme catalyzed NADH:methylviologen and NADH:ferricyanide oxidoreductase activity but also methylene-tetrahydrofolate (THF) reduction with NADH as the reductant. The NADH:methylene-THF reductase activity was high (248 U/mg) and not stimulated by ferredoxin. Furthermore, reduction of ferredoxin, alone or in the presence of methylene-THF and NADH, was never observed. MetF or MetVF was not able to catalyze the methylene-THF-dependent oxidation of NADH, but MetVF could reduce methylene-THF using methyl viologen as the electron donor. The purified MTHFR complex did not catalyze the reverse reaction, the endergonic oxidation of methyl-THF with NAD+ as the acceptor, and this reaction could not be driven by reduced ferredoxin. However, addition of protein fractions made the oxidation of methyl-THF to methylene-THF coupled to NAD+ reduction possible. Our data demonstrate that the MTHFR of A. woodii catalyzes methylene-THF reduction according to the following reaction: NADH + methylene-THF ? methyl-THF + NAD+. The differences in the subunit compositions of MTHFRs of bacteria are discussed in the light of their different functions. IMPORTANCE Energy conservation in the acetogenic bacterium Acetobacterium woodii involves ferredoxin reduction followed by a chemiosmotic mechanism involving Na+-translocating ferredoxin oxidation and a Na+-dependent F1Fo ATP synthase. All redox enzymes of the pathway have been characterized except the methylenetetrahydrofolate reductase (MTHFR). Here we report the purification of the MTHFR of A. woodii, which has an unprecedented heterotrimeric structure. The enzyme reduces methylene-THF with NADH. Ferredoxin did not stimulate the reaction; neither was it oxidized or reduced with NADH. Since the last enzyme with a potential role in energy metabolism of A. woodii has now been characterized, we can propose a quantitative bioenergetic scheme for acetogenesis from H2 plus CO2 in the model acetogen A. woodii. PMID:25733614

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

    PubMed

    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

  9. 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

  10. Methylenetetrahydrofolate reductase genotype association with the risk of follicular lymphoma.

    PubMed

    Ismail, Said I; Ababneh, Nida A; Khader, Yousef; Abu-Khader, Ahmad A; Awidi, Abdullah

    2009-12-01

    The metabolism of folate is essential in DNA synthesis, and polymorphisms of genes involved in such metabolism have been implicated in many types of cancer. Among these, the methylene tetrahydrofolate reductase gene (MTHFR) encodes an enzyme that converts folate to a methyl donor used for DNA methylation. We studied the association between the different genotypes of the two most common MTHFR polymorphisms, C677T and A1298C, and the risk of follicular lymphoma (FL). For this purpose, 55 previously diagnosed FL patients and 170 normal control subjects were examined using polymerase chain reaction followed by restriction fragment length polymorphism. The frequency of the A1298C CC homozygous mutant genotype was significantly higher in patients with FL than in control subjects (OR = 3.51, 95% CI = 1.39-8.86, P = 0.008). No such association was found for the heterozygous A1298C AC genotype (OR = 1.08, 95% CI = 0.55-2.12, P = 0.83). On the other hand, no significant association was found for either the C677T CT heterozygous genotype (OR = 0.79, 95% CI = 0.42-1.51, P = 0.49) or the C677T TT homozygous mutant genotype (OR = 0.55, 95% CI = 0.12-2.65, P = 0.46). The present findings add to the very few reports suggesting a link between the A1298C CC homozygous MTHFR genotype and a higher risk of developing FL, and the first such in a Jordanian population. PMID:19963111

  11. Characterization of aldose reductase and aldehyde reductase from rat testis.

    PubMed

    Kawasaki, N; Tanimoto, T; Tanaka, A

    1989-06-13

    Aldose reductase (alditol:NAD(P)+ 1-oxidoreductase, EC 1.1.1.21) and aldehyde reductase (alcohol:NADP+ oxidoreductase, EC 1.1.1.2) were purified to a homogeneity from rat testis. The molecular weights of aldose reductase and aldehyde reductase were estimated to be 38,000 and 41,000 by SDS-polyacrylamide gel electrophoresis, and the pI values of these enzymes were found to be 5.3 and 6.1 by chromatofocusing, respectively. Aldose reductase had activity for aldo-sugars such as xylose, glucose and galactose, whereas aldehyde reductase was virtually inactive for these aldo-sugars. The Km values of aldose reductase for aldo-sugars were relatively high. When a correction was made for the fraction of aldo-sugar present as the aldehyde form, which is the real substrate of the enzyme, the Km values were much lower. Aldose reductase utilized both NADPH and NADH as coenzyme, whereas aldehyde reductase utilized only NADPH. Aldose reductase was activated significantly by sulfate ion, while aldehyde reductase was little affected. Both enzymes were inhibited strongly by the known aldose reductase inhibitors. However, aldehyde reductase was in general less susceptible to these inhibitors when compared to aldose reductase. Both aldose reductase and aldehyde reductase treated with pyridoxal 5-phosphate have lost the susceptibility to aldose reductase inhibitor, suggesting that in these two enzymes aldose reductase inhibitor interacts with a lysine residue. PMID:2500152

  12. The association between MTHFR 677C>T genotype and folate status and genomic and gene-specific DNA methylation in the colon of individuals without colorectal neoplasia1234

    PubMed Central

    Hanks, Joanna; Ayed, Iyeman; Kukreja, Neil; Rogers, Chris; Harris, Jessica; Gheorghiu, Alina; Liu, Chee Ling; Emery, Peter

    2013-01-01

    Background: Decreased genomic and increased gene-specific DNA methylation predispose to colorectal cancer. Dietary folate intake and the methylenetetrahydrofolate reductase polymorphism (MTHFR 677C>T) may influence risk by modifying DNA methylation. Objective: We investigated the associations between MTHFR 677C>T genotype, folate status, and DNA methylation in the colon. Design: We conducted a cross-sectional study of 336 men and women (age 19–92 y) in the United Kingdom without colorectal neoplasia. We obtained blood samples for measurement of serum and red blood cell folate, plasma homocysteine, and MTHFR 677C>T genotype and colonic tissue biopsies for measurement of colonic tissue folate and DNA methylation (genomic- and gene-specific, estrogen receptor 1, ESR1; myoblast determination protein 1, MYOD1; insulin-like growth factor II, IGF2; tumor suppressor candidate 33, N33; adenomatous polyposis coli, APC; mut-L homolog 1, MLH1; and O6-methylguanine-DNA methyltransferase, MGMT) by liquid chromatography/electrospray ionization mass spectrometry and pyrosequencing, respectively. Results: Of the 336 subjects recruited, 185 (55%) carried the CC, 119 (35%) the CT, and 32 (10%) the TT alleles. No significant differences in systemic markers of folate status and colonic tissue folate between genotypes were found. The MTHFR TT genotype was not associated with genomic or gene-specific DNA methylation. Biomarkers of folate status were not associated with genomic DNA methylation. Relations between biomarkers of folate status and gene-specific methylation were inconsistent. However, low serum folate was associated with high MGMT methylation (P = 0.001). Conclusion: MTHFR 677C>T genotype and folate status were generally not associated with DNA methylation in the colon of a folate-replete population without neoplasia. This trial was registered at clinicaltrials.gov as ISRCTN43577261. PMID:24108782

  13. The role of the methylenetetrahydrofolate reductase 677 and 1298 polymorphisms in Cretan children with acute lymphoblastic leukemia.

    PubMed

    Karathanasis, Nikolaos V; Stiakaki, Eftichia; Goulielmos, George N; Kalmanti, Maria

    2011-01-01

    Acute lymphoblastic leukemia (ALL) is the most common form of malignancy in children. Recently, many studies have examined factors influencing both the susceptibility to ALL and the metabolism of widely used chemotherapeutic agents. These factors include, among others, single-nucleotide polymorphisms in various genes, such as the gene encoding for methylenetetrahydrofolate reductase (MTHFR), which has been proven polymorphic at the nucleotide positions 677 and 1298. Thirty-five children with ALL and 48 healthy adults of Cretan origin were genotyped for the presence of the MTHFR 677 and 1298 single-nucleotide polymorphisms. The possible correlation of the polymorphisms with the risk for ALL and the presence of methotrexate-induced toxicities were examined. No significant association between the MTHFR genotypes and the susceptibility to ALL was observed. A borderline statistically significant relationship was detected after methotrexate administration, between the C677T genotype (polymorphisms) and leukopenia (p?=?0.050) and between the A1298C polymorphism and normal aspartate transaminase and alanine transaminase values (p?=?0.065 and p?=?0.053, respectively), which was strengthened for aspartate transaminase, after grouping the A1298A and A1298C genotypes together (p?=?0.039). In our population the MTHFR C677T and A1298C polymorphisms are related with hematologic toxicity and hepatotoxicity, respectively, and could be suggested as prognostic factors for these adverse events. PMID:21117954

  14. Association of single nucleotide polymorphisms in MTHFR and ABCG2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer.

    PubMed

    Zhao, Jing; Li, Wenhua; Zhu, Dan; Yu, Qihe; Zhang, Zhe; Sun, Menghong; Cai, Sanjun; Zhang, Wen

    2014-01-01

    Either oxaliplatin- or irinotecan-containing regimen could receive a good effectiveness in patients with metastatic colorectal cancer as the first-line chemotherapy, but not all patients would benefit from the treatment they have received. This study was to investigate the role of single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family G member 2 (ABCG2) in selecting the most appropriate treatment for individual patients. Ninety-two metastatic colorectal cancer patients treated with first-line 5-fluoropyrimidine (5-FU), leucovorin, and oxaliplatin (FOLFOX), capecitabine, and oxaliplatin (XELOX) and sixty-two patients receiving 5-FU, leucovorin, and irinotecan (FOLFIRI) were reviewed. The SNPs of MTHFR and ABCG2 were detected using gene sequencing method after DNA PCR amplification, which was extracted from peripheral blood karyocytes. Clinical characteristics and gene polymorphisms were evaluated in univariate and multivariate analysis as predictive factors for response rate (RR) and progression-free survival (PFS). In patients bearing 2-4 genotypes of MTHFR 677C/C, MTHFR 1298 A/C or C/C, ABCG2 34G/G, and ABCG2 421C/A or A/A, those who received oxaliplatin-based chemotherapy achieved a higher RR (41.7 vs. 18.8 %, P = 0.027) and longer median PFS (mPFS) than irinotecan-based therapy [8.9 vs. 7.1 m, FOLFIRI: hazard ratio (HR) = 1.722, 95 % confidence interval (CI) 1.026-2.892, P = 0.040, compared with FOLFOX/XELOX]; on the contrary, patients carrying 0 or 1 above genotype exhibited better outcomes after receiving FOLFIRI chemotherapy (mPFS: 9.3 vs. 6.4 m, FOLFIRI: HR = 0.422, 95 % CI 0.205-0.870, P = 0.019, compared with FOLFOX/XELOX). Combination of SNPs with MTHFR and ABCG2 may play a role in helping clinicians to select first-line chemotherapy for patients with metastatic colorectal cancer. PMID:24338217

  15. Cardiovascular Events Are Not Associated with MTHFR Polymorphisms, But Are Associated with Methotrexate Use and Traditional Risk Factors in US Veterans with Rheumatoid Arthritis

    PubMed Central

    Davis, Lisa A.; Cannon, Grant W.; Pointer, Lauren F.; Haverhals, Leah M.; Wolff, Roger K.; Mikuls, Ted R.; Reimold, Andreas M.; Kerr, Gail S.; Richards, J. Steuart; Johnson, Dannette S.; Valuck, Robert; Prochazka, Allan; Caplan, Liron

    2014-01-01

    Objective C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event. Results Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26%). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95% CI 1.033.90), prior MI (HR 1.70, 95% CI 1.062.71), hyperlipidemia (HR 1.57, 95% CI 1.012.43), and increased modified Charlson-Deyo index (HR 1.23, 95% CI 1.131.34). MTX use (HR 0.66, 95% CI 0.440.99) and increasing education (HR 0.87, 95% CI 0.800.95) were associated with a lower risk for CV events. Conclusion Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective. (First Release April 1 2013; J Rheumatol 2013;40:80917; doi:10.3899/ jrheum.121012) PMID:23547211

  16. 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.

  17. 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 future researches in related fields. PMID:23472119

  18. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders.

    PubMed

    Sener, Elif Funda; 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

  19. 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

  20. Methylenetetrahydrofolate Reductase Activity Is Involved in the Plasma Membrane Redox System Required for Pigment Biosynthesis in Filamentous Fungi ?

    PubMed Central

    Frandsen, Rasmus J. N.; Albertsen, Klaus Selk; Stougaard, Peter; Srensen, Jens L.; Nielsen, Kristian F.; Olsson, Stefan; Giese, Henriette

    2010-01-01

    Methylenetetrahydrofolate reductases (MTHFRs) play a key role in biosynthesis of methionine and S-adenosyl-l-methionine (SAM) via the recharging methionine biosynthetic pathway. Analysis of 32 complete fungal genomes showed that fungi were unique among eukaryotes by having two MTHFRs, MET12 and MET13. The MET12 type contained an additional conserved sequence motif compared to the sequences of MET13 and MTHFRs from other eukaryotes and bacteria. Targeted gene replacement of either of the two MTHFR encoding genes in Fusarium graminearum showed that they were essential for survival but could be rescued by exogenous methionine. The F. graminearum strain with a mutation of MET12 (Fg?MET12) displayed a delay in the production of the mycelium pigment aurofusarin and instead accumulated nor-rubrofusarin and rubrofusarin. High methionine concentrations or prolonged incubation eventually led to production of aurofusarin in the MET12 mutant. This suggested that the chemotype was caused by a lack of SAM units for the methylation of nor-rubrofusarin to yield rubrofusarin, thereby imposing a rate-limiting step in aurofusarin biosynthesis. The Fg?MET13 mutant, however, remained aurofusarin deficient at all tested methionine concentrations and instead accumulated nor-rubrofusarin and rubrofusarin. Analysis of MET13 mutants in F. graminearum and Aspergillus nidulans showed that both lacked extracellular reduction potential and were unable to complete mycelium pigment biosynthesis. These results are the first to show that MET13, in addition to its function in methionine biosynthesis, is required for the generation of the extracellular reduction potential necessary for pigment production in filamentous fungi. PMID:20543064

  1. 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 >15?mol/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. PMID:25839940

  2. Quinone Reductase 2 Is a Catechol Quinone Reductase

    SciTech Connect

    Fu, Yue; Buryanovskyy, Leonid; Zhang, Zhongtao

    2008-09-05

    The functions of quinone reductase 2 have eluded researchers for decades even though a genetic polymorphism is associated with various neurological disorders. Employing enzymatic studies using adrenochrome as a substrate, we show that quinone reductase 2 is specific for the reduction of adrenochrome, whereas quinone reductase 1 shows no activity. We also solved the crystal structure of quinone reductase 2 in complexes with dopamine and adrenochrome, two compounds that are structurally related to catecholamine quinones. Detailed structural analyses delineate the mechanism of quinone reductase 2 specificity toward catechol quinones in comparison with quinone reductase 1; a side-chain rotational difference between quinone reductase 1 and quinone reductase 2 of a single residue, phenylalanine 106, determines the specificity of enzymatic activities. These results infer functional differences between two homologous enzymes and indicate that quinone reductase 2 could play important roles in the regulation of catecholamine oxidation processes that may be involved in the etiology of Parkinson disease.

  3. [C677T polymorphism of the methylentetrahydrofolate reductase gene in mothers of children affected with neural tube defects].

    PubMed

    Morales de Machn, Alisandra; Mndez, Karile; Sols, Ernesto; Borjas de Borjas, Lisbeth; Bracho, Ana; Hernndez, Mara Luisa; Negrn, Aimara; Delgado, Wilmer; Snchez, Yanira

    2015-09-01

    Neural tube defects (NTD) are the most common congenital anomalies of the central nervous system, with a multifactorial pattern of inheritance, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene 677C>T polymorphism has been implicated as a risk factor for NTD. The main objective of this research was to investigate the association of the 677C>T polymorphism of the MTHFR gene as a genetic risk factor for NTD. Molecular analysis was performed in DNA samples from 52 mothers with antecedent of NTD offspring and from 119 healthy control mothers. Using the Polymerase Chain Reaction, a 198 bases pairs fragment was digested with the restriction enzyme Hinfi. 677T MTHFR allele frequencies for the problem and the control groups were 51.92% and 34.45%, respectively, and 677C MTHFR allele frequencies were 48.08% and 65.55%, respectively. There were significant differences in allele (p: 0.002) and genotype (p: 0.007) frequencies between these two groups. The odds ratio (OR) to the TT genotype vs. the CC genotype was estimated as OR: 4.9 [95% CI: 1,347-6.416] p: 0.002; CT+TT vs. CC: OR: 2.9 [95% CI: 1.347-6.416] p: 0.005; TT vs. CT+CC: OR: 2.675 [95% CI: 1,111-6.441] p: 0.024. The data presented in this study support the relationship between MTHFR 677C>T polymorphism and risk in mothers with antecedent of NTD offspring. PMID:26710543

  4. Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies

    PubMed Central

    Rai, Vandana; Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakesh

    2014-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis. Aim A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome. Methods PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment. Results Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR?=?1.26, 95% CI?=?1.091.46, p?=?0.001; for TT vs. CC, OR?=?1.49, 95% CI?=?1.131.97, p?=?0.008; for CT vs. CC, OR?=?1.29, 95% CI?=?1.101.51, p?=?0.001; for TT+CT vs. CC, OR?=?1.35, 95% CI?=?1.131.60, p?=?0.0008; for TT vs. CT+CC, OR?=?0.76, 95% CI?=?0.600.94, p?=?0.01). Conclusion The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy. PMID:25265565

  5. Methylenetetrahydrofolate Reductase A1298C Polymorphism and Breast Cancer Risk: A Meta-analysis of 33 Studies.

    PubMed

    Rai, V

    2014-11-01

    Methylenetetrahydrofolate reductase (MTHFR) enzyme is essential for DNA synthesis and DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and different types of cancers. Several studies have investigated the association between the MTHFR A1298C polymorphism and breast cancer (BC) risk, but the results were inconclusive. To assess the risk associated with MTHFR A1298C polymorphism, a comprehensive meta-analysis was performed. PubMed, Google Scholar, Elsevier and Springer Link databases were searched for case-control studies relating the association between MTHFR A1298C polymorphism and BC risk and estimated summary odds ratios (ORs) with confidence intervals (CIs) for assessment. Up to January 2014, 33 case-control studies involving 15,919 BC patients and 19,700 controls were included in the present meta-analysis. The results showed that the A1298C polymorphism was not associated with BC risk in all the five genetic models (C vs. A allele (allele contrast): OR = 0.99, 95% confidence interval (CI): 0.93-1.05; AC versus AA (heterozygote/codominant): OR = 0.97, 95% CI: 0.89-1.04; CC versus AA (homozygote): OR = 0.99, 95% CI: 0.91-1.06; CC + AC versus AA (dominant model): OR = 0.97, 95% CI: 0.90-1.05; and CC versus AC + AA (recessive model): OR = 0.99, 95% CI: 0.91-1.07). The present meta-analysis did not support any association between the MTHFR A1298C polymorphism and BC risk. PMID:25506474

  6. Methylenetetrahydrofolate Reductase A1298C Polymorphism and Breast Cancer Risk: A Meta-analysis of 33 Studies

    PubMed Central

    Rai, V

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) enzyme is essential for DNA synthesis and DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and different types of cancers. Several studies have investigated the association between the MTHFR A1298C polymorphism and breast cancer (BC) risk, but the results were inconclusive. To assess the risk associated with MTHFR A1298C polymorphism, a comprehensive meta-analysis was performed. PubMed, Google Scholar, Elsevier and Springer Link databases were searched for case-control studies relating the association between MTHFR A1298C polymorphism and BC risk and estimated summary odds ratios (ORs) with confidence intervals (CIs) for assessment. Up to January 2014, 33 case-control studies involving 15,919 BC patients and 19,700 controls were included in the present meta-analysis. The results showed that the A1298C polymorphism was not associated with BC risk in all the five genetic models (C vs. A allele (allele contrast): OR = 0.99, 95% confidence interval (CI): 0.931.05; AC versus AA (heterozygote/codominant): OR = 0.97, 95% CI: 0.891.04; CC versus AA (homozygote): OR = 0.99, 95% CI: 0.911.06; CC + AC versus AA (dominant model): OR = 0.97, 95% CI: 0.901.05; and CC versus AC + AA (recessive model): OR = 0.99, 95% CI: 0.911.07). The present meta-analysis did not support any association between the MTHFR A1298C polymorphism and BC risk. PMID:25506474

  7. Methylenetetrahydrofolate reductase gene C677T, A1298C polymorphisms and pre-eclampsia risk: a meta-analysis.

    PubMed

    Li, Xing; Luo, Ya L; Zhang, Qiong H; Mao, Chen; Wang, Xi W; Liu, Shan; Chen, Qing

    2014-08-01

    To determine whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with pre-eclampsia susceptibility. Literature searches of the Pubmed, Embase, BIOSIS Previews and Web of Science were conducted to identify all eligible articles up to January 18th, 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) of five genetic models were calculated by fixed-effects or random-effects model. Publication bias, subgroup analysis, meta-regression and sensitivity analysis were also performed. A number of 49 studies including 51 samples consisted of 18,009 subjects (6,238 patients and 11,771 controls) were finally included. MTHFR C677T allele (TT or CT) carriers were 1.12 times more likely to develop pre-eclampsia (95% CI 1.04-1.21) compared with 677CC homozygous individuals. Similar results were obtained under other genetic models. Restricted to severe pre-eclampsia, there was an increased risk for 677TT homozygotes compared with 677CC homozygotes (OR 1.43; 95% CI 1.12-1.83). Subgroup analysis revealed a significant positive association between the C677T polymorphism (TT or CT) and pre-eclampsia in Asians (OR 1.41; 95% CI 1.11-1.79) and white population (OR 1.14; 95% CI 1.03-1.25). Meta-regression showed that study population, blinded genotyping, matching of cases and controls were not substantial sources of heterogeneity. For the MTHFR A1298C, ORs for all genetic models yielded a null association. This meta-analysis suggests that the MTHFR 677T allele might be associated with increased pre-eclampsia risk in Asian and white ethnicity and the subgroup of severe pre-eclampsia, while no association is observed between the MTHFR A1298C polymorphism and pre-eclampsia. PMID:24898880

  8. 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 C36) 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

  9. The protective effect of methylenetetrahydrofolate reductase C677T polymorphism against prostate cancer risk: Evidence from 23 case-control studies.

    PubMed

    Guo, Shanqi; Jiang, Xingkang; Chen, Xiaobo; Chen, Liang; Li, Xiaojiang; Jia, Yingjie

    2015-07-01

    Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were considered to have some influence on both folate metabolism and cancer risk. Previous studies on the relation between MTHFR C677T polymorphism and prostate cancer (PCa) risk remained controversial. To derive a more precise estimation of the relationship, we carried out an update comprehensive meta-analysis to assess the associations of the MTHFR C677T polymorphism with the susceptibility of PCa. Twenty-three trials with a total of 24,024 participants on the MTHFR C677T polymorphism that met inclusion criteria were analyzed in the current study. Overall, no statistical relationship was found with any MTHFR C677T genetic model associated with susceptibility to PCa (TT versus CC, OR=0.83, 95% CI 0.68-1.02, P=0.07; CT versus CC, OR=0.95, 95% CI 0.85-1.07, P=0.43; Dominant, OR=0.93, 95% CI 0.83-1.03, P=0.17; Recessive, OR=0.84, 95% CI 0.70-1.02, P=0.09.). Nevertheless, subgroup analysis found a reduced PCa risk associated with polymorphism in Asian population (TT versus CC, CT versus CC, dominant and recessive model). Moreover, the protective effect of polymorphism against PCa risk was also shown upon hospital-based studies (TT versus CC, and recessive model). When benign prostate hyperplasia was chosen as controls, both TT versus CC and recessive model showed significant difference. In addition, the protective effect of homozygote TT against high aggressive PCa was proved to have significant difference. Taken together, the existing evidence indicates the homozygote TT of MTHFR C677T should be viewed as a protective factor against PCa risk for clinical practice with the consideration of different gene background, study design as well as specific controls. PMID:25841988

  10. Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer.

    PubMed

    Boccia, Stefania; Boffetta, Paolo; Brennan, Paul; Ricciardi, Gualtiero; Gianfagna, Francesco; Matsuo, Keitaro; van Duijn, Cornelia M; Hung, Rayjean J

    2009-01-01

    Authors report the results of four meta-analyses of studies that examined the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and head and neck cancer (nine studies, 2076 cases and 4834 controls for C677T; four studies, 1439 cases and 3941 controls for A1298C), and lung cancer (ten studies, 5274 cases and 7435 controls for C677T; seven studies, 5098 cases and 6243 controls for A1298C). The summary odds ratio (OR) of head and neck cancer was 0.92 (95% CI: 0.76-1.11) for MTHFR 677 TT and 0.68 (95% CI: 0.37-1.26) for MTHFR 1298 CC. The OR of lung cancer was 1.22 [95% confidence interval (CI): 0.95-1.55] for MTHFR 677 TT and 1.07 (95% CI: 0.83-1.38) for MTHFR 1298 CC. Results from the meta-analysis of three studies on C677T stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR = 1.37, 95% CI: 0.92-2.06 for head and neck and OR = 1.28, 95% CI: 0.97-1.68 for lung) versus high folate intake (OR = 0.85, 95% CI: 0.63-1.16 for head and neck, and OR = 0.94, 95% CI: 0.79-1.12 for lung). Despite the lack of formal statistical significance, these findings are consistent with the hypothesis that folate play a role in lung and head/neck carcinogenesis, and show the need to incorporate data on folate intake when interpreting results of MTHFR polymorphisms in relation to cancer risk. PMID:18789576

  11. MTHFR gene polymorphism in acute lymphoblastic leukemia among North Indian children: a case-control study and meta-analysis updated from 2011.

    PubMed

    Roy Moulik, Nirmalya; Parveen, Farah; Kumar, Archana; Awasthi, Shally; Agrawal, Suraksha

    2014-07-01

    Studies on the association of methylenetetrahydrofolate reductase (MTHFR) genotype in childhood acute lymphoblastic leukemia (ALL) have yielded conflicting results. The present study examines this association in north Indian children with ALL and includes an updated meta-analysis. MTHFR (677 and 1298) genotype of children with ALL and healthy adult controls were done by the PCR-restriction fragment length polymorphism (PCR-RFLP) method and were compared using various models of inheritance. A total of 150 patients and 300 controls were included. The 677T allele was found protective (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.04-0.94), whereas 1298C allele led to an increase in risk (OR 4.44, 95% CI 2.19-8.99) of childhood ALL. Meta-analysis included 31 and 27 studies examining the association of 677 and 1298 genotypes, respectively. The 677 C -> T polymorphism was protective (OR 0.90, 95% CI 0.82-0.99). Protection was more pronounced in folate-sufficient populations as compared with those not covered by folate fortification guidelines. The 1298A->C polymorphism was associated with a marginal increase in risk (OR 1.19, 95% CI 1.01-1.40). PMID:24919644

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

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

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

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

    PubMed

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

    2016-02-14

    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. PMID:26804455

  14. Methylenetetrahydrofolate reductase C677T polymorphism is associated with increased risk of coronary artery disease in young South African Indians.

    PubMed

    Ramkaran, Prithiksha; Phulukdaree, Alisa; Khan, Sajidah; Moodley, Devapregasan; Chuturgoon, Anil A

    2015-10-15

    Methylenetetrahydrofolate reductase (MTHFR) reduces 5',10'-methylenetetrahydrofolate to 5'-methyltetrahydrofolate, and is involved in remethylation of homocysteine to methionine, two important reactions involved in folate metabolism and methylation pathways. The common MTHFR C677T single nucleotide polymorphism (SNP) (rs1801133) has been associated with raised levels of homocysteine, a well known risk factor for coronary artery disease (CAD). CAD is a major cause of mortality worldwide. The age of onset of this chronic disorder is on the decline, particularly in the Indian population. Indians in South Africa (SA) have a higher prevalence of premature CAD compared to Black South Africans. The MTHFR C677T SNP has not been investigated in the SA Indian population. The present study therefore investigated the MTHFR C677T SNP in young SA Indian males with CAD compared to young Indian and Black male controls. A total of 290 subjects were recruited into this study which included 106 CAD patients (diagnosed on angiography, mean age 37.5, range 24-45 years), 100 Indian male controls (mean age 37.5, range 28-45 years), and 84 Black male controls (mean age 36.4, range 25-45). Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) was used to genotype CAD patients and healthy controls. Data for clinical markers were obtained from pathology reports. There was a significant association between the 677 MTHFR variant (T) allele and CAD patients compared to the healthy Indian controls (p=0.0353, OR=2.105 95% CI 1.077-4.114). Indian controls presented with a higher frequency of the variant allele compared to Black controls (7% vs. 2% respectively, p=0.0515 OR=3.086 95% CI 0.9958-9.564). The MTHFR C677T SNP did not influence levels of total cholesterol, LDL, HDL, triglycerides, fasting glucose, fasting insulin, HbA1c or hsCRP. The higher frequency of the MTHFR 677 variant allele in South African Indians may be a contributing factor to the higher risk profile for the development of premature CAD in Indians. PMID:26095803

  15. Association of 677 C>T (rs1801133) and 1298 A>C (rs1801131) Polymorphisms in the MTHFR Gene and Breast Cancer Susceptibility: A Meta-Analysis Based on 57 Individual Studies

    PubMed Central

    Li, Kai; Li, Wusheng; Dong, Xi

    2014-01-01

    Objective The 677 C>T and 1298 A>C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene have been widely reported and considered to have a significant effect on breast cancer risk, but the results are inconsistent. A meta-analysis based on 57 eligible studies was carried out to clarify the role of MTHFR gene polymorphisms in breast cancer. Methods and Results Eligible articles were identified by searching databases including PubMed, Web of Science, EMBASE, CNKI and CBM for the period up to August 2012. Finally, a total of 57 studies were included in this meta-analysis. Crude ORs with 95% CIs were used to assess the association between the MTHFR polymorphisms and breast cancer risk. The pooled ORs were performed with additive model, dominant model and recessive model, respectively. Subgroup analysis was also performed by ethnicity. The statistical heterogeneity across studies was examined with ?2-based Q-test. A meta-analysis was performed using the Stata 12.0 software. Overall, the 677 C allele was significantly associated with breast cancer risk (OR?=?0.942, 95%CI?=?0.898 to 0.988) when compared with the 677 T allele in the additive model, and the same results were also revealed under other genetic models. Simultaneously, the 1298 A allele was not associated with the breast cancer susceptibility when compared with the 1298 C allele (OR?=?0.993, 95%CI?=?0.978 to 1.009). Furthermore, analyses under the dominant, recessive and the allele contrast model yielded similar results. Conclusions The results of this meta-analysis suggest that 677 C>T polymorphism in the MTHFR gene may contribute to breast cancer development. However, the 1298 A>C polymorphism is not significantly associated with increased risks of breast cancer. PMID:24945727

  16. The relationship between methylenetetrahydrofolate reductase c.677TT genotype and oligozoospermia in infertile male patients living in the Trakya region of Turkey.

    PubMed

    Gurkan, H; Tozk?r, H; Gnc, E; Ulusal, S; Yazar, M

    2015-11-01

    Methylenetetrahydrofolate reductase (MTHFR), the key enzyme of the folate metabolic pathway, has been reported to be five times more active in the testicles compared to other organs in adult mice. The aim of this study was to investigate the relationship between MTHFR c.677C>T and c.1298A>C polymorphisms and infertility in nonobstructive azoospermic and oligozoospermic male patients living in the Trakya region of Turkey. The study population included 75 nonobstructive azoospermic and 62 oligozoospermic, nonconsanguineous patients who were referred to the Department of Medical Genetics of Trakya University between 01.03.2012 and 01.06.2013 due to infertility and who had been diagnosed based on clinical examinations and spermiograms. All of the patients had a normal karyotype without a Y chromosome microdeletion. Melting curve analysis with labelled probes and primers that were designed by the manufacturers and the real-time polymerase chain reaction method were used. The MTHFR c.677TT genotype frequency in the oligozoospermic infertile male patient group was greater than that of the fertile control group [odds ratio (OR) = 2.675 (95% CI: 0.979-7.305), (P < 0.048)]. The MTHFR c.677TT genotype may be a genetic risk factor for oligozoospermic infertile male patients who live in the Trakya region of Turkey. PMID:25428700

  17. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and susceptibility to acute lymphoblastic leukemia in a cohort of Egyptian children.

    PubMed

    Mosaad, Youssef M; Abousamra, Nashwa K; Elashery, Rasha; Fawzy, Iman M; Eldein, Omar A Sharaf; Sherief, Doaa M; El Azab, Hend M M

    2015-01-01

    This case-control study was planned to investigate the possible role of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as a risk factor for the development of acute lymphoblastic leukemia (ALL) in a cohort of Egyptian children. Typing of MTHFR C677T and A1298C polymorphisms was done using restriction fragment length polymorphism (RFLP) for 100 children with ALL and 100 age- and sex-matched healthy controls. No significant differences were found between patients with ALL and controls for the frequency of MTHFR C677T and A1298C alleles, genotypes, combined genotypes or haplotypes. The C677T and A1298C genotype frequency was different from that in Korean and Chinese populations (p < 0.5) and was similar to that in British, French-Canadian and German-Caucasian populations (p > 0.5). Our findings suggest that MTHFR C677T and A1298C polymorphisms are unlikely to affect the development of childhood ALL in an Egyptian population from Delta. PMID:25629981

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

    PubMed

    Ozen, Filiz; Sen, Metin; Ozdemir, Ozturk

    2014-01-01

    Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and the incidence is also increasing in Turkey. Our present aim was to investigate any association between germ-line methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey. A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study. Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reverse- hybridization principle and real-time PCR methods. Results were compared in Pearson Chi-square and multiple logistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allele frequency 4.2-fold increased in CRC when compared with the control group.The second SNP MTHFR 1298CC (homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group. The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>C genotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a larger sample size. PMID:25292054

  19. Relationship of MTHFR gene 677C ? T polymorphism, homocysteine, and estimated glomerular filtration rate levels with the risk of new-onset diabetes.

    PubMed

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

    2015-02-01

    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 677 C ? 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 677 CC 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 677 C ? T polymorphism was more strongly associated with the risk of NOD among females with higher body mass index (BMI, ? 23 vs <23 kg/m(2), 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 ?mol/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 m(2)) 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 677 TT 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

  20. Lack of association between MTHFR Ala222Val and Glu429Ala polymorphisms and bladder cancer risk: A meta-analysis of case-control studies

    PubMed Central

    SHI, RONG; ZHAO, ZHEN; ZHOU, HUI; ZHOU, JUEYU; TAN, WANLONG

    2014-01-01

    Bladder cancer is a commom malignancy in the urinary tract that is influenced by genetic and environmental factors. The role of functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene with bladder cancer risk remains to be determined. This meta-analysis was performed to derive a more precise estimation of MTHFR Ala222Val and Glu429Ala polymorphisms and bladder cancer risk. Data were collected with the last report up to September 2013. A total of 3,463 cases and 3,927 controls for Ala222Val, and 3,177 cases and 3,502 controls for Glu429Ala were analyzed. The pooled odds ratios (ORs) and 95% confidence interval (CI) were estimated for the association with bladder cancer risk. Overall, no significant associations of Ala222Val and Glu429Ala polymorphisms with bladder cancer risk were found (for Ala222Val: Val/Val vs. Ala/Ala: OR, 1.02; 95% CI: 0.80–1.29; Val/Ala vs. Ala/Ala: OR, 1.02; 95% CI: 0.92–1.12; dominant model: OR, 1.01; 95% CI: 0.87–1.17; recessive model: OR, 1.00; 95% CI: 0.87–1.15; and for Glu429Ala: Ala/Ala vs. Glu/Glu: OR, 1.11; 95% CI: 0.78–1.58; Ala/Glu vs. Glu/Glu: OR, 1.16; 95% CI: 0.95–1.40; dominant model: OR, 1.15; 95% CI: 0.94–1.41; recessive model: OR, 0.96; 95% CI: 0.79–1.15). In stratified analyses by ethnicity, significant associations were observed for Glu429Ala polymorphism in individuals of Middle Eastern descent (Ala/Glu vs. Glu/Glu: OR, 2.11; 95% CI: 1.26–3.53; dominant model: OR, 2.16; 95% CI: 1.16–4.01; recessive model: OR, 1.82; 95% CI: 1.11–3.01). This meta-analysis demonstrated that overall there was no association of MTHFR Ala222Val and Glu429Ala polymorphisms with bladder cancer risk. However, in the stratified analysis by ethnicity the MTHFR Glu429Ala polymorphism was significantly associated with increased bladder cancer risk in individuals of Middle Eastern descent. PMID:24748982

  1. Association between Maternal MTHFR Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in Offspring, A Meta-Analysis Based on 15 Case-Control Studies

    PubMed Central

    Pan, Xinjuan; Wang, Ping; Yin, Xinjuan; Liu, Xiaozhuan; Li, Di; Li, Xing; Wang, Yongchao; Li, Hongle; Yu, Zengli

    2015-01-01

    Background The methylenetetrahydrofolate reductase (MTHFR) is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, conflicting results have been obtained when evaluating the association between maternal MTHFR C677T and A1298C polymorphisms and the risk of NSCL/P. In light of this gap, a meta-analysis of all eligible case-control studies was conducted in the present study. Materials and Methods A total of 15 case-control studies were ultimately identified after a comprehensive literature search and Hardy-Weinberg equilibrium (HWE) examination. Cochranes Q test and index of heterogeneity (I2) indicated no obvious heterogeneity among studies. Results Fixed or random-effects models were used to calculate the pooled odds ratios (ORs). The results showed that the TT genotype in mothers increased the likelihood of having NSCL/P offspring 1.25 times (95% CI: 1.047-1.494) more than the CC homozygotes. Meanwhile, maternal TT genotype increased the risk of producing NSCL/P offspring in recessive model (OR=1.325, 95% CI: 1.124-1.562). However, the CT heterozygote and the CT+TT dominant models had no association with NSCL/P offspring compared with the CC wild-type homozygote model. Subgroup analyses based on ethnicity indicated that maternal TT genotype increased the likelihood of having NSCL/P offspring in Whites (OR=1.308, 95% CI: 1.059-1.617) and Asians (OR=1.726, 95% CI: 1.090-2.733) in recessive model. Also, subgroup analyses based on source of control showed that mothers with the 677TT genotype had a significantly increased susceptibility of having NSCL/P children in hospital based population (HB) when compared with CC homozygotes (OR=1.248, 95% CI: 1.024-1.520) and un- der the recessive model (OR=1.324, 95% CI: 1.104-1.588). Furthermore, maternal A1298C polymorphism had no significant association with producing NSCL/P offspring (dominant model OR=0.952, 95% CI: 0.816-1.111, recessive model OR=0.766, 95% CI: 0.567-1.036). Conclusion MTHFR C677T polymorphism is associated with the risk of generating NSCL/P offspring, and being a 677TT homozygote is a risk factor. MTHFR A1298C polymorphism was not associated with generating NSCL/P offspring. However, further work should be performed to confirm these findings. PMID:25780529

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Lpez-Corts, Andrs; Echeverra, Carolina; Oa-Cisneros, Fabin; Snchez, Mara Eugenia; Herrera, Camilo; Cabrera-Andrade, Alejandro; Rosales, Felipe; Ortiz, Malena; Paz-Y-Mio, Csar

    2015-08-01

    Breast cancer (BC) is the leading cause of cancer-related death among women in 2014. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and MTR reductase (MTRR) are enzymes that play an important role in folate metabolism. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G, and MTRR A66G, alter plasmatic folate and homocysteine concentrations, causing problems during the repairment, synthesis, and methylation of the genetic material. Therefore, it is essential to know how BC risk is associated with histopathological and immunohistochemical characteristics, genotype polymorphisms, and gene expression in a high altitude Ecuadorian mestizo population. DNA was extracted from 195 healthy and 114 affected women. Genotypes were determined by restriction enzymes and genomic sequencing. mRNA was extracted from 26 glandular breast tissue samples, both from cancerous tissue and healthy tissue adjacent to the tumor. Relative gene expression was determined with the comparative Livak method (2(-??CT)). We found significant association between the rs1801133 (A222V) genotypes and an increased risk of BC development: C/T (odds ratio [OR]?=?1.8; 95 % confidence interval [CI]?=?1.1-3.2; P?=?0.039), T/T (OR?=?2.9; 95 % CI?=?1.2-7.2; P?=?0.025), and C/T?+?T/T (OR?=?1.9; 95 % CI?=?1.1-3.3; P?=?0.019). Regarding relative gene expression, we found significant mRNA subexpression between the combined genotypes C/T?+?T/T (rs1801133) and triple negative breast cancer (TNBC) (P?=?0.034). In brief, the MTHFR gene and its protein could act as potential predictive biomarkers of BC, especially TNBC among the high altitude Ecuadorian mestizo population. PMID:25801246

  4. Are MTHFR C677T and MTRR A66G Polymorphisms Associated with Overweight/Obesity Risk? From a Case-Control to a Meta-Analysis of 30,327 Subjects

    PubMed Central

    Fan, Shu-Jun; Yang, Bo-Yi; Zhi, Xue-Yuan; He, Miao; Wang, Da; Wang, Yan-Xun; Wang, Yi-Nuo; Wei, Jian; Zheng, Quan-Mei; Sun, Gui-Fan

    2015-01-01

    Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in a Chinese Han population and then performed a meta-analysis by combining previous studies (5431 cases and 24,896 controls). In our case-control study, the MTHFR C677T polymorphism was not significantly associated with being overweight/obesity when examining homozygous codominant, heterozygous codominant, dominant, recessive and allelic genetic models. The following meta-analysis confirmed our case-control results. Heterogeneity was minimal in the overall analysis, and sensitivity analyses and publication bias tests indicated that the meta-analytic results were reliable. Similarly, both the case-control study and meta-analysis found no significant association between the MTRR A66G polymorphism and being overweight/obesity. However, sensitivity analyses showed that the associations between the MTRR A66G polymorphism and being overweight/obesity became significant in the dominant, heterozygous codominant and allelic models after excluding our case-control study. The results from our case-control study and meta-analysis suggest that both of the two polymorphisms are not associated with being overweight/obesity. Further large-scale population-based studies, especially for the MTRR A66G polymorphism, are still needed to confirm or refute our findings. PMID:26016497

  5. C677T polymorphism of the MTHFR gene and variant hemoglobins: a study in newborns from Salvador, Bahia, Brazil.

    PubMed

    Couto, Fbio David; Adorno, Elisngela Vitria; Menezes, Joelma Figueiredo; Moura Neto, Jos Pereira; Rgo, Marco Antnio Vasconcelos; Reis, Mitermayer Galvo dos; Gonalves, Marilda Souza

    2004-01-01

    The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) is associated with an increase in total homocysteine serum levels (tHcy), described as a risk factor for cardiovascular disease. Eight hundred forty-three neonates from two different maternity hospitals, one public and another private, in Salvador, Bahia, Brazil were screened for this polymorphism by PCR and RFLP. The T-allele frequency in the total sample was 0.23, and the prevalence rates of heterozygous and homozygous carriers were 36.2% and 5.3%, respectively. The T-allele frequency differed and the T/T genotype was more prevalent at the private maternity hospital. The hemoglobin (Hb) profile was investigated by HPLC in 763 newborns. The frequency of variant Hb was higher at the public than at the private maternity hospital. The association of the C677T polymorphism and the Hb profile was investigated in 683 newborns, showing a relatively high frequency of variant Hbs and the T allele. These data could provide an important basis for further studies focusing on potential risks of vaso-occlusive events in these individuals. PMID:15073633

  6. Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with male infertility: a meta-analysis.

    PubMed

    Shen, Ouxi; Liu, Renping; Wu, Wei; Yu, Lugang; Wang, Xinru

    2012-01-01

    Published data on the association between the methylenetetrahydrofolate reductase (MTHFR) gene A1298C (rs1801131) polymorphism and male infertility risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of seven case-control studies including 1633 cases and 1735 controls were selected to evaluate the possible association. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the additive model, dominant model, recessive model, and allele-frequency genetic model. In the overall analysis, the frequency of the C1298 allele (C vs. A) was significantly associated with susceptibility to male infertility (OR = 1.12, 95% CI = 1.00-1.26). A subgroup analysis of the subjects showed that MTHFR 1298C was associated with significant increased risk of azoospermia in homozygote comparison (CC vs. AA) and recessive mode (CC vs. AA/AC) (OR = 1.66 for CC vs. AA genotype; OR = 1.67 for CC vs. AA/AC genotype). However, no statistically significant increased risk of oligoasthenoteratozoospermia was found in any of the genetic models. In conclusion, this meta-analysis supports that the MTHFR A1298C polymorphism is capable of causing male infertility susceptibility, especially azoospermia. PMID:22175540

  7. Association of the APOE, MTHFR and ACE Genes Polymorphisms and Stroke in Zambian Patients

    PubMed Central

    Atadzhanov, Masharip; Mwaba, Mwila H.; Mukomena, Patrice N.; Lakhi, Shabir; Rayaprolu, Sruti; Ross, Owen A.; Meschia, James F.

    2013-01-01

    The aim of the present study was to investigate the association of APOE, MTHFR and ACE polymorphisms with stroke in the Zambian population. We analyzed 41 stroke patients and 116 control subjects all of Zambian origin for associations between the genotype of the APOE, MTHFR and ACE polymorphisms and stroke. The APOE ?2?4 genotype showed increased risk for hemorrhagic stroke (P<0.05) and also a high risk for ischemic stroke (P=0.05). There was complete absence of the APOE ?2?2 and the MTHFR TT genotypes in the Zambian population. The difference between cases and controls was not significant for the other genetic variants when analyzed for relationship between stroke, stroke subtype and genotype. We show that genetic variation at the APOE locus affects susceptibility to stroke. No detectable association were observed for the MTHFR and ACE genotypes and stroke in the Zambian population. PMID:24416484

  8. A common haplotype for the 677T thermolabile variant of the 5,10-methylenetetrahydrofolate reductase gene in thrombophilic patients and controls.

    PubMed

    Linnebank, M; Homberger, A; Nowak-Gttl, U; Koch, H G

    2002-12-01

    The common polymorphic transition 677C>T in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene causes a thermolabile enzyme variant. This variant is associated with moderate hyperhomocysteinemia, a risk factor for vascular disease and thrombophilia. Up to now, it remained unclear if the thermolabile MTHFR variant either directly predisposes to vascular disease, or if 677T is only a genetic marker for another causative genetic alteration in cis. Aim of this study was to characterize the genetic background of 677T-alleles by haplotype analysis. We analyzed 25 individuals of German descent homozygous for 677T: nine young patients, who had suffered from thromboembolic events, and 16 healthy controls. The results of this study demonstrate that the 677T alleles are associated with a common haplotype most likely due to a founder effect and that the 677T haplotype was the same in the healthy and the thrombophilic German subjects. PMID:12442281

  9. Association between the methylenetetrahydrofolate reductase c.677C>T polymorphism and bone mineral density: an updated meta-analysis.

    PubMed

    Li, Hong-Zhuo; Wang, Wei; Liu, Yi-Ling; He, Xiao-Feng

    2016-02-01

    Many studies have reported an association between the methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism and reduced bone mineral density (BMD), but results have been inconsistent. We, therefore, performed a meta-analysis to further explore this association. Twenty-one studies, comprising 33,045 subjects, analyzed the association of MTHFR c.677C>T with femoral neck BMD. Significant association with reduced BMD was observed in Caucasians (recessive model: WMD = -0.004 g/cm(2), 95 % CI -0.008 to -0.006), post-menopausal women (recessive model: WMD = -0.005 g/cm(2), 95 % CI -0.007 to -0.003), men (dominant model: WMD = -0.004 g/cm(2), 95 % CI -0.005 to -0.004; recessive model: WMD = -0.004 g/cm(2), 95 % CI -0.005 to -0.004; TT vs. CC: WMD = -0.006 g/cm(2), 95 % CI -0.006 to -0.006; CT vs. CC: WMD = -0.003 g/cm(2), 95 % CI -0.003 to -0.003), and cohort studies (recessive model: WMD = -0.003 g/cm(2), 95 % CI -0.006 to -0.001). Twenty-two studies, which included 32,271 subjects, analyzed the MTHFR c.677C>T association with lumbar spine BMD. Significant association with reduced BMD was observed in Caucasians, women, post-menopausal women, men, and cohort studies. Seven studies, comprising 6806 subjects, analyzed the MTHFR c.677C>T association with total hip BMD, but no significant association was observed in any population. Nine studies involving 5591 subjects analyzed the association with total body BMD. Significant association with reduced BMD was observed in overall and women subgroup analyses. In summary, this meta-analysis indicates that the MTHFR c.677C>T polymorphism is associated with reduced BMD in lumbar spine and femoral neck in Caucasians, post-menopausal women, and men, and with total body BMD in women. In addition, our results suggest that new studies examining the association between MTHFR c.677C>T polymorphism and BMD of lumbar spine and femoral neck in Asians is warranted, because I (2) > 75.0 % was observed. PMID:26231982

  10. Association of a Methylene Tetrahydrofolate Reductase C677T Polymorphism with Several Blood Chemical Levels in a Chinese Population

    PubMed Central

    Wen, Can; Lv, Jiao-Feng; Wang, Ling; Zhu, Wei-Feng

    2015-01-01

    Background: The methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with hypertension in certain populations. This study investigated the relationship between the MTHFR polymorphism and hypertension and correlated blood lipid indexes, including homocysteine (HCY), lipoprotein (a) [Lp (a)], high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A I (Apo AI), Apo B, glucose (GLU), total cholesterol (TC), and triglyceride (TG), in a Chinese population. Materials and Methods: A total of 174 patients with hypertension and 634 healthy control individuals from Jiangxi Province were recruited between June 2012 and September 2012 for genotyping of the MTHFR C677T polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Biochemical parameters were also assessed in these subjects and statistically compared to the MTHFR C677T polymorphism and the risk for hypertension. Results: HCY and Lp (a) levels were significantly higher in subjects with a MTHFR 677TT genotype than in those with a CC/CT genotype, independent of hypertension. The frequency of the TT genotype and the T allele in hypertension patients was significantly higher than in the healthy controls. Furthermore, in the male hypertension patient group, the average levels of HCY, HDL, Apo AI, and TC were significantly different from those in female hypertension patients (pHCY=0.001, pHDL=0.004, pApo AI<0.001, pTC=0.012). In the male control group, the average levels of HCY, HDL, Apo AI, GLU, and TC were significantly different from those of female controls (pHCY<0.001, pHDL<0.001, pApo AI<0.001, pGLU=0.001, and pTC=0.004). Conclusion: Our data demonstrate that the MTHFR C677T polymorphism is positively correlated with an increased risk of hypertension through an increase in HCY levels. The blood lipid correlative index was different between male and female hypertension patients and controls. PMID:25489783

  11. Effect of MTHFR Gene Polymorphism Impact on Atherosclerosis via Genome-Wide Methylation

    PubMed Central

    Lin, Xuefeng; Zhang, Wei; Lu, Qun; Lei, Xinjun; Wang, Tingzhong; Han, Xuanmao; Ma, Aiqun

    2016-01-01

    Background Atherosclerosis seriously threats human health. Homocysteine is an independent risk factor closely related to DNA methylation. MTHFR C667T loci polymorphism is closely associated with homocysteine level. This study aimed to investigate the relationship among MTHFR C667T loci polymorphism, genome-wide methylation, and atherosclerosis. Material/Methods Blood sample was collected from 105 patients with coronary atherosclerosis and 105 healthy controls. Pyrosequencing methylation was used to detect LINE-1 methylation level. Polymerase chain reaction-restriction enzyme fragment length polymorphism (PCR-RFLP) was used to test MTHFR. Results LINE-1 methylation level in the patient group was significantly lower than in the controls (t=5.007, P<0.001). MTHFR C667T genotype distribution presented marked differences in the 2 groups. TT genotype carriers had significantly increased risk of atherosclerosis (OR=3.56, P=0.009). Three different genotypes of MTHFR C667T loci showed different LINE-1 methylation level between the 2 groups (P<0.01). LINE-1 methylation level in TT and CT genotype carriers was obviously lower than in CC genotype carriers (P<0.05). Conclusions MTHFR C667T loci polymorphism may affect atherosclerosis by regulating genome methylation level. PMID:26828698

  12. Effect of MTHFR Gene Polymorphism Impact on Atherosclerosis via Genome-Wide Methylation.

    PubMed

    Lin, Xuefeng; Zhang, Wei; Lu, Qun; Lei, Xinjun; Wang, Tingzhong; Han, Xuanmao; Ma, Aiqun

    2016-01-01

    BACKGROUND Atherosclerosis seriously threats human health. Homocysteine is an independent risk factor closely related to DNA methylation. MTHFR C667T loci polymorphism is closely associated with homocysteine level. This study aimed to investigate the relationship among MTHFR C667T loci polymorphism, genome-wide methylation, and atherosclerosis. MATERIAL AND METHODS Blood sample was collected from 105 patients with coronary atherosclerosis and 105 healthy controls. Pyrosequencing methylation was used to detect LINE-1 methylation level. Polymerase chain reaction-restriction enzyme fragment length polymorphism (PCR-RFLP) was used to test MTHFR. RESULTS LINE-1 methylation level in the patient group was significantly lower than in the controls (t=5.007, P<0.001). MTHFR C667T genotype distribution presented marked differences in the 2 groups. TT genotype carriers had significantly increased risk of atherosclerosis (OR=3.56, P=0.009). Three different genotypes of MTHFR C667T loci showed different LINE-1 methylation level between the 2 groups (P<0.01). LINE-1 methylation level in TT and CT genotype carriers was obviously lower than in CC genotype carriers (P<0.05). CONCLUSIONS MTHFR C667T loci polymorphism may affect atherosclerosis by regulating genome methylation level. PMID:26828698

  13. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia.

    PubMed

    Eissa, Deena Samir; Ahmed, Tamer Mohamed

    2013-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. Two polymorphisms, C677T and A1298C, were described leading to reduced enzyme activity. Methotrexate (MTX) is an antifolate agent of consolidation and maintenance therapy of acute lymphoblastic leukaemia (ALL). Despite its clinical success, MTX can be associated with serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. There is evidence that MTX toxicity can be affected by polymorphisms in genes encoding for drug-metabolizing enzymes such as MTHFR. Therefore, we aimed to investigate the influence of MTHFR C677T and A1298C polymorphisms on the frequency of MTX-related toxicity, disease outcome and patients' survival. MTHFR polymorphisms were assessed in 50 adult patients with de novo ALL using real-time PCR. Patients were followed-up for the development of haematologic and/or nonhaematologic toxicity and assessment of clinical outcome. Frequency of C677T polymorphisms was 42% for TT, 24% for CT and 34% for CC; A1298C polymorphisms were 28, 6 and 66% for CC, AC and AA, respectively. MTX therapy was significantly associated with neutropaenia, hepatic and gastrointestinal toxicities, unfavourable response at day 14 of induction therapy, increased relapse and mortality rates and shorter survival in patients with 677 TT genotype than in those with CC and CT, whereas 1298 CC genotype patients had lower frequency of neutropaenia, hepatic toxicity and relapse than in those with AA and AC. Our study suggests MTHFR polymorphism as an attractive predictor of MTX-related toxicity in adult ALL, considering it a potential prognostic factor influencing disease outcome. PMID:23183238

  14. Association of the methylenetetrahydrofolate reductase gene C677T polymorphism with the risk of male infertility: a meta-analysis.

    PubMed

    Zhu, Xudong; Liu, Zhiguo; Zhang, Maochen; Gong, Ruihong; Xu, Yajun; Wang, Baoming

    2016-03-01

    Several molecular epidemiological studies have been conducted to examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility susceptibility, but the results remain inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of 26 case-control studies including 5659 infertility cases and 5528 controls were selected to evaluate the possible association. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association of C677T polymorphism with male infertility in the additive model, dominant model, recessive model and allele-frequency genetic model. In the overall analysis, the frequency of the 677T allele was significantly associated with male infertility susceptibility (OR = 2.32, 95%CI = 2.04-2.65 for TT vs. CC genotype; OR = 1.09, 95%CI = 1.00-1.19 for CT vs. CC genotype; OR = 1.19, 95%CI = 1.10-1.29 for CT/TT vs. CC genotype; OR = 1.54, 95%CI = 1.36-1.74 for TT vs. CC/TT genotype; OR = 1.22, 95%CI = 1.15-1.30 for T vs. C allele). A subgroup analysis of the subjects showed that significantly strong association between MTHFR C677T polymorphism and male infertility was present only in Asians, but not in Caucasians. Additionally, MTHFR C677T was associated with a significant increase in the risk of azoospermia in all genetic models. Meanwhile, no significantly increased risks of oligoasthenotertozoospermia (OAT) were found in most of the genetic models. In conclusion, this meta-analysis is in favor that the MTHFR C677T polymorphism is capable of causing male infertility susceptibility, especially in Asians and the subgroup of azoospermia. PMID:26584688

  15. Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with colorectal cancer risk: A meta-analysis.

    PubMed

    Zhao, Mengmeng; Li, Xuelian; Xing, Chengzhong; Zhou, Baosen

    2013-09-01

    Colorectal cancer (CRC) is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. This meta-analysis was conducted to determine the effect of methylenetetrahydrofolate reductase (MTHFR) mutants on the risk of CRC. A literature search was conducted on PubMed, Medline and the China National Knowledge Infrastructure (CNKI) databases. Eligible studies were collected based on rigorous criteria of inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the fixed- or random-effects model. After all the studies were pooled, the OR of CRC for individuals carrying the MTHFR 677TT genotype, compared to the CC genotype, was 0.89 (95% CI: 0.82-0.97). When analyzed by ethnicity, Asians with the MTHFR 1298CC genotype exhibited a decreased risk of CRC (OR=0.69; 95% CI: 0.54-0.89). In a mixed population, a significantly reduced risk of CRC was observed among carriers of the 677TT (OR=0.86; 95% CI: 0.76-0.96) and the 1298CC (OR=0.82; 95% CI: 0.69-0.98) genotypes, compared to the wild-type homozygous genotype. In the subgroup of colon cancer, the OR of 677TT vs. CC+CT was 0.83 (95% CI: 0.72-0.96) and the OR of 1298CC vs. AA+AC was 0.81 (95% CI: 0.69-0.96). In the rectal cancer subgroup, the OR of 677TT vs. CC+CT was 0.86 (95% CI: 0.77-0.97). Therefore, this meta-analysis suggested that the MTHFR 677T and 1298C alleles were associated with a low risk of CRC. PMID:24649029

  16. Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease.

    PubMed

    Ghazouani, Lakhdar; Abboud, Nesrine; Mtiraoui, Nabil; Zammiti, Walid; Addad, Faouzi; Amin, Haitham; Almawi, Wassim Y; Mahjoub, Touhami

    2009-02-01

    Elevation in homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene variants, C677T and A1298C, have been linked with atherothrombosis. However their exact contribution to coronary artery disease (CAD) remains controversial. Moreover, data from Tunisian patients are scarse. We examined the association of MTHFR C677T and A1298C, and changes in plasma homocysteine in 352 Tunisian patients with angiographically-demonstrated CAD, and 390 age and gender-matched healthy subjects. Significantly higher frequency of 677T allele and homozygous 677T/T genotype were seen in patients vs. control subjects; the distribution of A1298C alleles and genotypes being comparable in the two groups. Specific MTHFR haplotypes comprising 677C/1298A (P < 0.001) and 677T/1298A (P < 0.001) were negatively and positively associated with CAD, respectively. Plasma homocysteine concentration was significantly higher in 677T/T genotype with respect to 677C/C and 677C/T genotypes in patients and controls, but homocysteine levels were generally comparable between both groups. Univariate analysis identified 677T/1298A (P = 0.033) haplotype to be positively associated with CAD, which remained significant by multivariate analysis after adjusting for a number of covariates (P = 0.038). MTHFR C677T, but not A1298C SNPs, is associated with CAD and with elevated homocysteine levels in a Tunisian population. The negative and positive association of the 1298A allele with CAD being indicative of a neutral (absent) effect of the A1298C SNP on disease pathogenesis. PMID:18204887

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

    PubMed Central

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

    2010-01-01

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

  18. Methylenetetrahydrofolate reductase polymorphisms at 3'-untranslated region are associated with susceptibility to preterm birth

    PubMed Central

    Zhu, Qin; Dai, Jianrong; Wang, Benjing; Liu, Minjuan; Wang, Yun; Tao, Jianying; Li, Hong

    2015-01-01

    Background Etiology and mechanism of preterm birth (PTB) is complicated. Genetic susceptibility is one of the key factors involved in the pathogenic mechanism underlying PTB. Methods A subset of single nucleotide polymorphisms (SNPs) selected by bioinformatics approach from 3'-untranslated region (3'-UTR) of methylenetetrahydrofolate reductase (MTHFR) gene were subjected to SNaPshot analysis in a case-control study. Three SNPs (rs45451599, rs1537515, rs1537516) were simultaneously tested in one tube, among 1,135 DNA samples including 480 PTBs and 655 term controls. Results Two perfectly correlated (r2=1) SNPs, rs1537515 and rs1537516, were found significantly associated with PTB susceptibility [P=0.012; OR: 0.65; 95% confidence interval (CI), 0.47-0.91]. The frequencies of the minor alleles were lower in PTB cases than in controls, which the frequencies were 0.066 in PTB cases and 0.095 in controls. G and T allele frequencies of rs1537515 were the same with rs1537516 (P=0.011; OR: 0.666; 95% CI, 0.49-0.91). Rs45451599 was not found associated with PTB (P=0.52; OR: 0.76; 95% CI, 0.33-1.74). The 18-25 nucleotides in length of microRNAs (miRNAs) which can regulate gene expressions are involved in binding partial complementary sequences within 3'-UTR. The two loci are at 3'-UTR of MTHFR mRNA. Rs1537516 is a potential target of miR-1304-3p, while rs1537515 is miR-1224-3p and miR-3150-5p. Conclusions In conclusion, rs1537515 and rs1537516 within the 3'-UTR of the MTHFR gene may be associated with susceptibility to PTB. PMID:26835361

  19. Genetic Association between Methylenetetrahydrofolate Reductase Gene Polymorphism and Risk of Osteonecrosis of the Femoral Head

    PubMed Central

    Chai, Wei; Zhang, Zhendong; Ni, Ming; Geng, Peiliang; Lian, Zijian; Zhang, Guoqiang; Shi, Lewis L.; Chen, Jiying

    2015-01-01

    Background. Methylenetetrahydrofolate reductase (MTHFR) SNP rs1801133 has been frequently investigated in recent years. Relevant candidate gene association studies with this SNP and osteonecrosis of the femoral head (ONFH) reported conflicting results. Meta-analysis provides a method to combine these data and to determine the association in a larger sample size. Method. We conducted a systematic search to identify possible studies. Four pooled ORs (odds ratios, T versus C, TT versus CC, TT/CT versus CC, and TT versus CT/CC), along with 95% confidence interval (CI), were calculated to evaluate the association between SNP rs1801133 and ONFH susceptibility. Both fixed effects model and random effects model were used. Findings. We eventually included twelve studies in this analysis, with results showing no overall association between ONFH susceptibility and SNP rs1801133 (T versus C: OR = 1.15, 95% CI = 0.971.38; TT versus CC: OR = 1.15, 95% CI = 0.911.46; TT/CT versus CC: OR = 1.09, 95% CI = 0.951.25; and TT versus CT/CC: OR = 1.16, 95% CI = 0.931.45). When stratified based on ethnicity, the results were still not significant. Conclusion. Our findings are generally supportive of no association between MTHFR SNP rs1801133 and the etiology of ONFH. PMID:25688352

  20. Prevalence of methylenetetrahydrofolate reductase 677 C-T polymorphism among mothers of Down syndrome children

    PubMed Central

    Kaur, Anupam; Kaur, Amandeep

    2013-01-01

    INTRODUCTION: The relationship between chromosomal non-disjunction leading to aneuploidy and folate metabolism has drawn attention in the recent years. In this study, we examined the polymorphism in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR), namely, 677 C-T in women having Down syndrome (DS) children. MATERIALS AND METHODS: The prevalence of these variant genotypes (MTHFR 677 C-T polymorphism) in women having DS children (case mothers) (n = 110) was compared with controls (n = 111) from Punjab. Genotyping was done using the polymerase chain reaction method followed by restriction fragment length polymorphism. RESULTS: In the present study, 1.8% of case mothers had TT genotype while none of the control mothers showed this genotype. T allele frequency among cases was 0.13 and 0.11 in controls. The Chi-square value showed a non-significant difference between cases and controls. CONCLUSION: No association has been observed between 677 C-T polymorphism and risk of non-disjunction in case mothers. Detection of polymorphisms in more genes of folate pathway is required to find out the exact cause of non-disjunction. PMID:24497705

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-11-15

    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

  3. Properties of Ribonucleoside Diphosphate Reductase in Nucleotide-Permeable Cells

    PubMed Central

    Warner, Huber R.

    1973-01-01

    Ribonucleoside diphosphate (RDP) reductase activity can be readily assayed in ether-treated Escherichia coli cells. The rate of cytidine 5?-diphosphate (CDP) reduction observed in ether-treated cells by using saturating substrate concentrations is about 25% of the rate of de novo deoxyribonucleotide synthesis required to account for in vivo deoxyribonucleic acid synthesis. Optimal activity is observed in the presence of magnesium ions and a positive effector. Adenosine 5?-triphosphate (ATP), deoxy ATP (dATP), and deoxythimidine triphosphate serve as positive effectors, and dATP also serves as a negative effector. These effects on the activity in ether-treated cells resemble those observed in vitro with highly purified enzyme. When the RDP reductase activity in these cells is assayed by using high specific activity 3H-CDP as substrate, even at nonsaturating substrate concentrations, the sensitivity of the assay is sufficient to make it useful for the assay of the low levels of reductase activity in cells not derepressed by thymine starvation or in cells containing mutationally altered RDP reductase. This assay is much easier to perform than the usual in vitro assay, since thioredoxin, thioredoxin reductase, and enzyme subunits B1 or B2 need not be first purified and added to the reaction mixtures. PMID:4146181

  4. MTHFR C677T genotype as a risk factor for epilepsy including post-traumatic epilepsy in a representative military cohort.

    PubMed

    Scher, Ann I; Wu, Holly; Tsao, Jack W; Blom, Henk J; Feit, Preethy; Nevin, Remington L; Schwab, Karen A

    2011-09-01

    The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition-and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07-2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted. PMID:21787169

  5. Nitrate Reductase and Soluble Cytochrome c Reductase(s) in Higher Plants 1

    PubMed Central

    Wallace, William; Johnson, Christopher B.

    1978-01-01

    The 4S cytochrome c (Cyt c) reductase activity of several plant species was markedly stimulated by cyanide and ferrocyanide but those of the 8S nitrate reductase component and other particulate components of the maize (Zea mays L.) scutellum by comparison, were increased only slightly. The effect of cyanide and ferrocyanide was not due to elimination of cytochrome oxidase interference but resulted from the stimulation of NADH-dependent reduction of Cyt c. A 4S Cyt c reductase component which could be isolated by ammonium sulfate fractionation and diethyl-aminoethyl-cellulose chromatography was found to be stimulated markedly by cyanide and ferrocyanide. The remaining 4S Cyt c reductase, which was insensitive to cyanide and ferrocyanide, was also fractionated with ammonium sulfate into two components. One of these, like the 8S Cyt c reductase, was sensitive to a protease from the maize roots which is relatively specific for nitrate reductase. This 4S Cyt c reductase species could be a subunit of nitrate reductase. PMID:16660377

  6. Acceleration of an aldo-keto reductase by minimal loop engineering

    PubMed Central

    Krump, C.; Vogl, M.; Brecker, L.; Nidetzky, B.; Kratzer, R.

    2014-01-01

    Aldo-keto reductases tighten coenzyme binding by forming a hydrogen bond across the pyrophosphate group of NAD(P)(H). Mutation of the hydrogen bonding anchor Lys24 in Candida tenuis xylose reductase prevents fastening of the safety belt around NAD(H). The loosened NAD(H) binding leads to increased turnover numbers (kcat) for reductions of bulky-bulky ketones at constant substrate and coenzyme affinities (i.e. Km Ketone, Km NADH). PMID:24951537

  7. The association between first trimester micronutrient intake, MTHFR genotypes, and global DNA methylation in pregnant women

    PubMed Central

    La Merrill, Michele; Torres-Snchez, Luisa; Ruiz-Ramos, Rubn; Lpez-Carrillo, Lizbeth; Cebrin, Mariano E; Chen, Jia

    2012-01-01

    Objective Our aim was to evaluate possible associations between consumption of micronutrients involved in one-carbon metabolism, MTHFR genotypes, and global DNA methylation in pregnant women. Methods A semi-quantitative dietary questionnaire was administered to 195 women during their first trimester in Morelos, Mexico. Two functional polymorphisms of the key folate-metabolizing gene, i.e. MTHFR 677 C>T and 1298 A>C, as well as global DNA methylation were assessed in peripheral blood drawn during the interview. Results Independent of maternal age and caloric intake, vitamin B6 deficiency was associated with 1.8 fold increased risk of hypomethylation in women carrying the MTHFR 677 T allele. Conclusions There exists a subpopulation that is more susceptible to B vitamin deficiencies. PMID:21443409

  8. Nitrate and periplasmic nitrate reductases

    PubMed Central

    Sparacino-Watkins, Courtney; Stolz, John F.; Basu, Partha

    2014-01-01

    The nitrate anion is a simple, abundant and relatively stable species, yet plays a significant role in global cycling of nitrogen, global climate change, and human health. Although it has been known for quite some time that nitrate is an important species environmentally, recent studies have identified potential medical applications. In this respect the nitrate anion remains an enigmatic species that promises to offer exciting science in years to come. Many bacteria readily reduce nitrate to nitrite via nitrate reductases. Classified into three distinct types – periplasmic nitrate reductase (Nap), respiratory nitrate reductase (Nar) and assimilatory nitrate reductase (Nas), they are defined by their cellular location, operon organization and active site structure. Of these, Nap proteins are the focus of this review. Despite similarities in the catalytic and spectroscopic properties Nap from different Proteobacteria are phylogenetically distinct. This review has two major sections: in the first section, nitrate in the nitrogen cycle and human health, taxonomy of nitrate reductases, assimilatory and dissimilatory nitrate reduction, cellular locations of nitrate reductases, structural and redox chemistry are discussed. The second section focuses on the features of periplasmic nitrate reductase where the catalytic subunit of the Nap and its kinetic properties, auxiliary Nap proteins, operon structure and phylogenetic relationships are discussed. PMID:24141308

  9. Association Between MTHFR Genetic Variants and Multiple Sclerosis in a Southern Iranian Population.

    PubMed

    Naghibalhossaini, Fakhraddin; Ehyakonandeh, Hesam; Nikseresht, Alireza; Kamali, Eskandar

    2015-01-01

    Multiple sclerosis (MS) is a demyelinating neuro- inflammatory autoimmune disease of the central nervous system. Genetic predisposition has long been suspected in the etiology of this disease. The association between MTHFR polymorphisms and MS has been ivestigated in different ethnic groups. We investigated the association between MTHFR C677T and A1298C missense variants and MS in 180 patients and 231 age- and gender-matched healthy controls in a Southern Iranian population. The mutagenically separated PCR (MS-PCR) and PCR-RFLP methods were used to genotype MTHFR at position 677 and 1298, respectively. Compared with controls, we observed a strong association between two MTHFR variants and the risk of developing MS. Subjects carrying 677T allele (CT and TT genotypes) had increased susceptibility to MS as compared to those carrying CC genotype (odds ratio (OR) for CT= 2.9, 95% confidence interval (95% CI)= 1.88-4.49; OR for TT= 6.23, 95% CI= 3.08-12.59). The variant 1298AC genotype also increased the risk for MS among our study population (OR= 2.14, 95% CI= 1.37-3.34). Combined genotype analysis for two MTHFR SNPs revealed that compared to the wild type genotypes (677CC/1298AA), 3 genotypes including TT/AC, CT/AC, and TT/AA were significantly at increased risk for MS development (OR= 13.9, 5.3, and 4.9, respectively). Our results suggest a possible gene dose- dependent association between MTHFR mutrant alleles and the risk of MS development. PMID:26261797

  10. Association Between MTHFR Genetic Variants and Multiple Sclerosis in a Southern Iranian Population

    PubMed Central

    Naghibalhossaini, Fakhraddin; Ehyakonandeh, Hesam; Nikseresht, Alireza; Kamali, Eskandar

    2015-01-01

    Multiple sclerosis (MS) is a demyelinating neuro- inflammatory autoimmune disease of the central nervous system. Genetic predisposition has long been suspected in the etiology of this disease. The association between MTHFR polymorphisms and MS has been ivestigated in different ethnic groups. We investigated the association between MTHFR C677T and A1298C missense variants and MS in 180 patients and 231 age- and gender-matched healthy controls in a Southern Iranian population. The mutagenically separated PCR (MS-PCR) and PCR-RFLP methods were used to genotype MTHFR at position 677 and 1298, respectively. Compared with controls, we observed a strong association between two MTHFR variants and the risk of developing MS. Subjects carrying 677T allele (CT and TT genotypes) had increased susceptibility to MS as compared to those carrying CC genotype (odds ratio (OR) for CT= 2.9, 95% confidence interval (95% CI)= 1.88-4.49; OR for TT= 6.23, 95% CI= 3.08-12.59). The variant 1298AC genotype also increased the risk for MS among our study population (OR= 2.14, 95% CI= 1.37-3.34). Combined genotype analysis for two MTHFR SNPs revealed that compared to the wild type genotypes (677CC/1298AA), 3 genotypes including TT/AC, CT/AC, and TT/AA were significantly at increased risk for MS development (OR= 13.9, 5.3, and 4.9, respectively). Our results suggest a possible gene dose- dependent association between MTHFR mutrant alleles and the risk of MS development. PMID:26261797

  11. Association of a miR-34b binding site single nucleotide polymorphism in the 3'-untranslated region of the methylenetetrahydrofolate reductase gene with susceptibility to male infertility.

    PubMed

    Zhang, W; Lin, W-Q; Cao, H-F; Li, C-Y; Li, F

    2015-01-01

    This study aims to explore the possible associations between a genetic variation in the miR-34b binding site in the 3'-untranslated region (UTR) of the methylenetetrahydrofolate reductase (MTHFR) gene (rs55763075) with male infertility in a Chinese population. Genotype distributions of the rs55763075 single nucleotide polymorphism were investigated by polymerase chain reaction and direct sequencing in a Chinese cohort that included 464 infertile men with idiopathic azoospermia or oligospermia and 458 controls with normal fertility. Overall, no significant differences in the distributions of the genotypes of the MTHFR rs55763075 polymorphism were detected between the infertility and control groups. A statistically significant increased risk of male infertility was found for carriers of the rs55763075 AA genotype when compared with homozygous carriers of the rs55763075 GG genotype in the azoospermia subgroup (OR = 1.721; 95% CI = 1.055-2.807; P = 0.031). Furthermore, we found that rs55763075 was associated with folate and homocysteine levels in patients with idiopathic azoospermia. Our results indicated that the MTHFR 3'-UTR rs55763075 polymorphism might modify the susceptibility to male infertility with idiopathic azoospermia. PMID:26505368

  12. Ribonucleotide reductases: essential enzymes for bacterial life.

    PubMed

    Torrents, Eduard

    2014-01-01

    Ribonucleotide reductase (RNR) is a key enzyme that mediates the synthesis of deoxyribonucleotides, the DNA precursors, for DNA synthesis in every living cell. This enzyme converts ribonucleotides to deoxyribonucleotides, the building blocks for DNA replication, and repair. Clearly, RNR enzymes have contributed to the appearance of genetic material that exists today, being essential for the evolution of all organisms on Earth. The strict control of RNR activity and dNTP pool sizes is important, as pool imbalances increase mutation rates, replication anomalies, and genome instability. Thus, RNR activity should be finely regulated allosterically and at the transcriptional level. In this review we examine the distribution, the evolution, and the genetic regulation of bacterial RNRs. Moreover, this enzyme can be considered an ideal target for anti-proliferative compounds designed to inhibit cell replication in eukaryotic cells (cancer cells), parasites, viruses, and bacteria. PMID:24809024

  13. Ribonucleotide reductases: essential enzymes for bacterial life

    PubMed Central

    Torrents, Eduard

    2014-01-01

    Ribonucleotide reductase (RNR) is a key enzyme that mediates the synthesis of deoxyribonucleotides, the DNA precursors, for DNA synthesis in every living cell. This enzyme converts ribonucleotides to deoxyribonucleotides, the building blocks for DNA replication, and repair. Clearly, RNR enzymes have contributed to the appearance of genetic material that exists today, being essential for the evolution of all organisms on Earth. The strict control of RNR activity and dNTP pool sizes is important, as pool imbalances increase mutation rates, replication anomalies, and genome instability. Thus, RNR activity should be finely regulated allosterically and at the transcriptional level. In this review we examine the distribution, the evolution, and the genetic regulation of bacterial RNRs. Moreover, this enzyme can be considered an ideal target for anti-proliferative compounds designed to inhibit cell replication in eukaryotic cells (cancer cells), parasites, viruses, and bacteria. PMID:24809024

  14. The role of methylenetetrahydrofolate reductase C677T polymorphism on the peripheral blood natural killer cell proportion in women with unexplained recurrent miscarriages

    PubMed Central

    Park, Chan Woo; Han, Ae Ra; Kwak-Kim, Joanne; Park, So Yeon; Han, Jung Yeol; Koong, Mi Kyoung; Song, In Ok

    2011-01-01

    Objective To examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and hyperhomocysteinemia in women with unexplained recurrent miscarriages (RM) and to investigate the association between MTHFR genotype variants and alloimmune activation, proportion of peripheral blood natural killer (pbNK) cells. Methods A total of 39 patients with a history of two or more unexplained miscarriages were recruited to this study. The controls were women who had a live birth without a history of RM (n=50). The proportion of pbNK cells was measured by flow cytometry. Plasma homocysteine levels and the incidence of the MTHFR variant of the RM and control groups were compared. The proportion of pbNK cells was compared to the MTHFR variants in the RM group. Results No differences were found between the two groups' mean plasma homocysteine levels (7.61.5 mol/L vs. 7.12.1 mol/L) or incidence of the MTHFR genotype variant (CC, 35% vs. 33%; CT, 40% vs. 53%; and TT, 25% vs. 14%). In the RM group, individuals with the TT variant (7.71.1 mol/L) had higher homocysteine levels than those with the CC and CT variants (7.41.9 mol/L and 7.41.2 mol/L) and those with the CT variant (19.28.1%) had a higher proportion of CD3-/CD56+ pbNK cells than those with the CC and TT variants (17.76.6% and 17.97. 0%), but the results of both comparisons were statistically insignificant. Conclusion These preliminary results show no difference in plasma homocysteine levels between the RM and control groups or among MTHFR genotype variants in the RM group, which may suggest that the plasma homocysteine level is difficult to use as a predictive marker of RM in the Korean population. A study of a larger number of patients is needed. PMID:22384438

  15. NADPH-dependent reductases in dog thyroid: comparison of a third enzyme "glyceraldehyde reductase" to dog thyroid aldehyde reductase.

    PubMed

    Schaffhauser, M A; Sato, S; Kador, P F

    1996-03-01

    The increased incidence of thyroiditis reported to occur in diabetes has also been observed in long-term galactose-fed dogs where it is reduced by the administration of aldose reductase inhibitors. Since this suggests that thyroidal changes are linked to the abnormal accumulation of sugar alcohols (polyols), present studies were conducted to confirm the presence of aldose and aldehyde reductases in dog thyroid through isolation and characterization. Aldose and aldehyde reductases were isolated from dog thyroid by a series of chromatographic steps which included gel filtration on Sephadex G-100, affinity chromatography on Matrex Gel Orange A and chromatofocusing on Mono P. A third, labile NADPH-reductase was partially purified by gel filtration on Sephadex G-100, affinity chromatography on Matrex Green A and hydroxylapatite chromatography on BIO-GEL HT. The kinetic properties of aldose and aldehyde reductases and their susceptibility to inhibition by aldose reductase inhibitors are similar to those of dog kidney aldose and aldehyde reductases. However, the levels of aldose reductase present in thyroid are extremely low compared to the levels of aldehyde reductase. A third NADPH-dependent reductase, tentatively identified as glyceraldehyde reductase, is also present in dog thyroid. This novel enzyme utilizes NADPH to reduce DL-glyceraldehyde and is clearly distinct from the other aldo-keto reductases in molecular weight, substrate specificity, inhibition by aldose reductase inhibitors and immunological properties. In summary aldose reductase, aldehyde reductase and a third novel glyceraldehyde reductase, all of which can utilize glyceraldehyde as substrate, have been identified and characterized in dog thyroid. Only aldose and aldehyde reductases, which can catalyze the production of polyols and were inhibited by aldose reductase inhibitors, appear to be linked to thyroiditis. PMID:8920636

  16. Methylenetetrahydrofolate reductase variants associated with hypertension and cardiovascular disease interact with dietary polyunsaturated fatty acids to modulate plasma homocysteine in puerto rican adults.

    PubMed

    Huang, Tao; Tucker, Katherine L; Lee, Yu-Chi; Crott, Jimmy W; Parnell, Laurence D; Shen, Jian; Smith, Caren E; Ordovas, Jose M; Li, Duo; Lai, Chao-Qiang

    2011-04-01

    Although methylenetetrahydrofolate reductase (MTHFR) genetic variants are associated with plasma homocysteine (Hcy) and cardiovascular disease (CVD), little is known whether dietary fatty acid intake modulates these associations. The goal was to examine the interaction of MTHFR variants with dietary fatty acids influencing plasma Hcy in 995 Boston Puerto Rican adults. We found that plasma Hcy concentration was negatively correlated with (n-3) PUFA intake (r = -0.117; P = 0.022), and the ratio of (n-3):(n-6) PUFA in the diet (r = -0.122; P = 0.009). Further, 2 functional MTHFR variants, 1298A>C and 677C>T, which are not in linkage disequilibrium in this population, were significantly associated with hypertension (OR = 1.72, P = 0.024, and OR = 1.60, P = 0.002, respectively). In addition, the 1298A>C variant was significantly associated with CVD (OR = 3.32; P = 0.030). Importantly, this variant exhibited significant interactions with intakes of total and (n-6) PUFA and the (n-3):(n-6) PUFA ratio of the diet. The plasma Hcy concentration of carriers of risk allele 1298C was greater than that of noncarriers only when participants had consumed a high-PUFA diet (>7.8% energy) but was not greater when they had low intake of PUFA (?7.8% energy). In addition, participants with combined genotypes of both SNP (677 TT with 1298 AC or CC) who consumed high levels of (n-3) PUFA (>0.66% energy) had lower plasma Hcy compared with those who had the same genotype and consumed low levels of (n-3) PUFA (?0.66% energy). Our study suggests that dietary PUFA intake modulates the effect of 2 MTHFR variants on plasma Hcy in Boston Puerto Rican adults. PMID:21270364

  17. S-Nitrosoglutathione Reductase

    PubMed Central

    Que, Loretta G.; Yang, Zhonghui; Stamler, Jonathan S.; Lugogo, Njira L.; Kraft, Monica

    2009-01-01

    Rationale: Nitric oxide bioactivity, mediated through the formation of S-nitrosothiols (SNOs), has a significant effect on bronchomotor tone. S-Nitrosoglutathione is an endogenous bronchodilator that is decreased in children with asthmatic respiratory failure and in adults with asthma undergoing segmental airway challenge. Recently we showed that S-nitrosoglutathione reductase (GSNOR) regulates endogenous SNOs. Mice with genetic deletion of GSNOR are protected from airway hyperresponsivity in an allergic asthma model. Objectives: We hypothesized that GSNOR is increased in human asthma and correlates with lung SNO content and airway reactivity. Methods: We recruited 36 subjects with mild asthma with FEV1 88.5 2.3% predicted and 34 healthy control subjects with FEV1 100.7 2.5% predicted. Bronchoalveolar lavage (BAL) was performed in all subjects. Cell counts, differentials, GSNOR activity, and SNO levels were determined in BAL. Measurements and Main Results: SNO content was decreased in asthmatic BAL compared with control BAL and correlated inversely with GSNOR expression in BAL cell lysates. Furthermore, GSNOR activity measured from BAL samples was significantly increased in subjects with asthma compared with control subjects and correlated inversely with the provocative concentration of methacholine causing a 20% decrease in FEV1. Conclusions: These findings suggest that GSNOR is an important regulator of airway SNO content and airways hyperresponsiveness in human asthma. PMID:19395503

  18. Development and Characterization of Reference Materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 Genetic Testing

    PubMed Central

    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.

    2009-01-01

    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. PMID:19767587

  19. Characterization of mitochondrial thioredoxin reductase from C. elegans

    SciTech Connect

    Lacey, Brian M.; Hondal, Robert J. . E-mail: Robert.Hondal@uvm.edu

    2006-08-04

    Thioredoxin reductase catalyzes the NADPH-dependent reduction of the catalytic disulfide bond of thioredoxin. In mammals and other higher eukaryotes, thioredoxin reductases contain the rare amino acid selenocysteine at the active site. The mitochondrial enzyme from Caenorhabditis elegans, however, contains a cysteine residue in place of selenocysteine. The mitochondrial C. elegans thioredoxin reductase was cloned from an expressed sequence tag and then produced in Escherichia coli as an intein-fusion protein. The purified recombinant enzyme has a k {sub cat} of 610 min{sup -1} and a K {sub m} of 610 {mu}M using E. coli thioredoxin as substrate. The reported k {sub cat} is 25% of the k {sub cat} of the mammalian enzyme and is 43-fold higher than a cysteine mutant of mammalian thioredoxin reductase. The enzyme would reduce selenocysteine, but not hydrogen peroxide or insulin. The flanking glycine residues of the GCCG motif were mutated to serine. The mutants improved substrate binding, but decreased the catalytic rate.

  20. 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; 8169% (p?=?0.007). Conclusion: This study indicates that a patients 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

  1. Association between MTHFR A1298C polymorphism and hepatocellular carcinoma risk

    PubMed Central

    Zhang, Haiyan; Li, Guang; Zhang, Zhen

    2015-01-01

    Background: Hepatocarcinogenesis is a complex process that is influenced by many factors. Several studies have investigated the relationship between MTHFR A1298C polymorphism and hepatocellular carcinoma (HCC) risk, but the results are inconsistent. Therefore, we performed a meta-analysis covering a large sample size to address this controversy. Methods: Eligible studies were searched using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) databases. A total of 7 studies from 6 publications with 2035 cases and 3096 controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) was calculated by the fixed or random effects to evaluate the correlation between MTHFR A1298C polymorphism and HCC risk. The Q statistic and I2 statistic were used to assess the statistical heterogeneity among studies. Publication bias was evaluated by Eggers linear regression test and Beggs funnel plot. Results: In present study, the results showed that MTHFR A1298C polymorphism was not significantly associated with risk of HCC based on CC + AC vs. AA genetic model (OR=1.01, 95% CI=0.90-1.13). Similarly, in the subgroup analysis by ethnicity, no significant HCC risk was found in Asian population (OR=1.02, 95% CI=0.91-1.14). In the subgroup analysis based on source of control, we found that MTHFR A1298C polymorphism showed no effects on the occurrence of HCC in the population-based (PB) and hospital-based (HB) group (OR=0.97, 95% CI=0.83-1.15; OR=1.04, 95% CI=0.89-1.21). Conclusion: This meta-analysis suggested that MTHFR A1298C polymorphism may not be a risk factor for HCC. PMID:26309569

  2. Isolated menthone reductase and nucleic acid molecules encoding same

    DOEpatents

    Croteau, Rodney B; Davis, Edward M; Ringer, Kerry L

    2013-04-23

    The present invention provides isolated menthone reductase proteins, isolated nucleic acid molecules encoding menthone reductase proteins, methods for expressing and isolating menthone reductase proteins, and transgenic plants expressing elevated levels of menthone reductase protein.

  3. MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction.

    PubMed

    Mansoori, Nasim; Tripathi, Manjari; Luthra, Kalpana; Alam, Rizwan; Lakshmy, Ramakrishnan; Sharma, Subhadra; Arulselvi, Subramanyam; Parveen, Shama; Mukhopadhyay, Asok K

    2012-05-01

    Genetic risk factors play an important role in the pathogenesis of Alzheimer disease (AD) and vascular dementia (VaD). In this case-control study, we examined C677T and A1298C (rs1801133 and rs1801131) polymorphism in the methylenetetrahydrofolate reductase (MTHFR) genes and their correlation with plasma levels of homocysteine (Hcy) in AD and VaD cases and evaluated the gene-gene interaction (epistasis) with IL-6-174 G/C (rs1800795). CC genotype was associated with elevated levels of plasma homocysteine (p = 0.004) as compared with genotype AA of rs1801131. In AD, we observed a significant (p = 0.04) association with C alleles of rs1801131. Regression analysis revealed that the presence of both rs1801133 T and rs1800795 C alleles increased the odds of developing AD by 2.5 and VaD by 3.7-fold. While rs1800795 (CC or GC) genotypes alone increased the odds of developing VaD by 2.2-fold, the presence of CC genotype of rs1801131 nullified this effect. The findings support the hypothesis that multiple genes are involved to alter the odds of developing AD and VaD. PMID:22015309

  4. Polymorphic Variants of Cytochrome P450 2B6 (CYP2B6.4–CYP2B6.9) Exhibit Altered Rates of Metabolism for Bupropion and Efavirenz: A Charge-Reversal Mutation in the K139E Variant (CYP2B6.8) Impairs Formation of a Functional Cytochrome P450-Reductase Complex

    PubMed Central

    Zhang, Haoming; Sridar, Chitra; Kenaan, Cesar; Amunugama, Hemali; Ballou, David P.

    2011-01-01

    In this study, metabolism of bupropion, efavirenz, and 7-ethoxy-4-trifluoromethylcoumarin (7-EFC) by CYP2B6 wild type (CYP2B6.1) and six polymorphic variants (CYP2B6.4 to CYP2B6.9) was investigated in a reconstituted system to gain a better understanding of the effects of the mutations on the catalytic properties of these naturally occurring variants. All six variants were successfully overexpressed in Escherichia coli, including CYP2B6.8 (the K139E variant), which previously could not be overexpressed in mammalian COS-1 cells (J Pharmacol Exp Ther 311:34–43, 2004). The steady-state turnover rates for the hydroxylation of bupropion and efavirenz and the O-deethylation of 7-EFC showed that these mutations significantly alter the catalytic activities of CYP2B6. It was found that CYP2B6.6 exhibits 4- and 27-fold increases in the Km values for the hydroxylation of bupropion and efavirenz, respectively, and CYP2B6.8 completely loses its ability to metabolize any of the substrates under normal turnover conditions. However, compared with CYP2B6.1, CYP2B6.8 retains 77% of its 7-EFC O-deethylase activity in the presence of tert-butyl hydroperoxide as an alternative oxidant, indicating that the heme and the active site are catalytically competent. Presteady-state measurements of the rate of electron transfer from NADPH-dependent cytochrome P450 reductase (CPR) to CYP2B6.8 using stopped-flow spectrophotometry revealed that CYP2B6.8 is incapable of accepting electrons from CPR. These observations provide conclusive evidence suggesting that the charge-reversal mutation in the K139E variant prevents CYP2B6.8 from forming a functional complex with CPR. Results from this work provide further insights to better understand the genotype–phenotype correlation regarding CYP2B6 polymorphisms and drug metabolism. PMID:21659470

  5. 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 (?2=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

  6. Engineering towards nitroreductase functionality in ene-reductase scaffolds.

    PubMed

    Park, Jonathan T; Gómez Ramos, Lizzette M; Bommarius, Andreas S

    2015-03-23

    Nitroreductases (NRs) and ene-reductases (ERs) both utilize flavin mononucleotide cofactors but catalyze distinct reactions. NRs reduce nitroaromatics, whereas ERs reduce unsaturated C=C double bonds, and these functionalities are known to somewhat overlap. Recent studies on the ER xenobiotic reductase A (XenA) from Pseudomonas putida demonstrated the possibility of increasing NR activity with active site modifications. Structural comparison between NRs and ERs led us to hypothesize that active site cavity size plays an important role in determining enzyme functionality. Residues of ER KYE1 from Kluyveromyces lactis were selected to increase the binding pocket size, compensate for hydrogen bonding pattern changes, and eliminate ER activity. Single variants were screened, and promising mutations were combined. Variant F296A/Y275A showed a 100-fold improvement in NR specific activity over wild-type, and variant H191A/F296A/Y375A exhibited complete conversion to a NR. PMID:25703443

  7. Methylenetetrahydrofolate Reductase Gene Polymorphism and Risk of Type 2 Diabetes Mellitus

    PubMed Central

    Yang, Na-Na; Li, Le-Qun

    2013-01-01

    Objective This review aimed to comprehensively assess the literature examining a possible link between the rs1801133 polymorphism (677C?T) in the gene encoding the methylenetetrahydrofolate reductase (MTHFR) gene and risk of type 2 diabetes mellitus (DM). Research Design and Methods Several research databases were systematically searched for studies examining the genotype at the rs1801133 polymorphism in healthy control individuals and individuals with type 2 DM. Genotype frequency data were examined across all studies and across subsets of studies according to ethnicity and presence of serious DM-related complications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results A total of 4855 individuals with type 2 DM and 5242 healthy controls from 15 countries comprising Asian, Caucasian and African ethnicities were found to satisfy the inclusion criteria and included in the review. Genotype at the rs1801133 polymorphism was not consistently associated with either increased or reduced risk of type 2 DM; the OR across all studies was 0.91 (95%CI 0.82 to 1.00) for the C- vs. T-allele, 0.88 (0.75 to 1.03) for CC vs. CT+TT, 0.82 (0.71 to 0.95) for CC vs. TT, and 1.15 (1.03 to 1.29) for TT vs. CC+CT. Similar results were found when the meta-analysis was repeated separately for each ethnic subgroup, and for subgroups with or without serious DM-related complications. Conclusions There does not appear to be compelling evidence of an association between the genotype at the rs1801133 polymorphism of the MTHFR gene and risk of type 2 DM. PMID:24023947

  8. DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences

    PubMed Central

    Burghardt, Kyle J; Pilsner, J Richard; Bly, Michael J; Ellingrod, Vicki L

    2012-01-01

    Aim In schizophrenia, metabolic syndrome incidence is double that of the general population, with women having a higher incidence. Pharmacogenetically regulated folic acid may be related to this risk. DNA methylation and metabolic syndrome within this group has not been previously studied. Methods Metabolic syndrome was evaluated with fasting laboratory measurements, and dietary and lifestyle assessments. Methylation analysis used a peripheral sample for the LINE-1 assay. DNA was also genotyped for MTHFR 677C/T. Results This analysis included 133 subjects. We found a significant relationship between LINE-1 methylation, and an interaction between MTHFR and gender, controlling for serum folate (p = 0.008). Females with the 677TT genotype had the lowest methylation (56%) compared with the other groups (75%). Conclusion TT genotype females had the lowest methylation, which may explain metabolic syndrome gender differences in schizophrenia. Folate supplementation may be a suggested intervention within schizophrenia; however, additional work is required. PMID:22690662

  9. Associations of MTHFR Gene Polymorphisms with Hypertension and Hypertension in Pregnancy: A Meta-Analysis from 114 Studies with 15411 Cases and 21970 Controls

    PubMed Central

    Yang, Boyi; Fan, Shujun; Zhi, Xueyuan; Li, Yongfang; Liu, Yuyan; Wang, Da; He, Miao; Hou, Yongyong; Zheng, Quanmei; Sun, Guifan

    2014-01-01

    Background Several epidemiological studies have investigated the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with hypertension (H) or hypertension in pregnancy (HIP). However, the results were controversial. We therefore performed a comprehensive meta-analysis to provide empirical evidences on the associations. Methodologies The English and Chinese databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, cumulative meta-analysis and assessment of publication bias were performed in our study. Principal Findings A total of 114 studies with 15411 cases and 21970 controls were included, 111 studies with 15094 cases and 21633 controls for the C677T polymorphism and 21 with 2533 cases and 2976 controls for the A1298C polymorphism. Overall, the C677T polymorphism was significantly associated with H and HIP (H & HIP: OR = 1.26, 95% CI = 1.17–1.34; H: OR = 1.36, 95% CI = 1.20–1.53; HIP: OR = 1.21, 95% CI = 1.08–1.32). Stratified analysis by ethnicity revealed a significant association among East Asians and Caucasians, but not among Latinos, Black Africans, and Indians and Sri Lankans. In the stratified analyses according to source of controls, genotyping method, sample size and study quality, significant associations were observed in all the subgroups, with the exception of population based subgroup in H studies and large sample size and “others” genotyping method subgroups in HIP studies. For the A1298C polymorphism, no significant association was observed either in overall or subgroup analysis under all genetic models. Conclusions This meta-analysis suggests that the MTHFR C677T rather than A1298C polymorphism may be associated with H & HIP, especially among East Asians and Caucasians. PMID:24505291

  10. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility.

    PubMed

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-12-01

    There are several evidences supporting the role of 5-10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03-1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02-1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06-1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01-1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03-1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06-1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99-1.14; p = 0.05). PMID:26629412

  11. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility

    PubMed Central

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-01-01

    There are several evidences supporting the role of 510 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR=1.08, 95% CI=1.031.13, p=<0.001; TT+CT vs. CC: OR=1.06, 95% CI=1.021.09, p=<0.001; TT vs. CC: OR=1.17, 95% CI=1.061.28, p=0.001; CT vs. CC OR=1.05, 95% CI=1.011.08, p=0.005; TT vs. CT+CC: OR=1.12, 95% CI=1.031.22, p=0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR=1.26; 95% CI: 1.061.51; p=0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR=1.08; 95% CI: 0.991.14; p=0.05). PMID:26629412

  12. Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

    PubMed Central

    2010-01-01

    Background The association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and serum lipid profiles is still controversial in diverse ethnics. Bai Ku Yao is an isolated subgroup of the Yao minority in China. The aim of the present study was to eveluate the association of MTHFR C677T polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 780 subjects of Bai Ku Yao and 686 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the MTHFR C677T was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05-0.001). The frequency of C and T alleles was 77.4% and 22.6% in Bai Ku Yao, and 60.9% and 39.1% in Han (P < 0.001); respectively. The frequency of CC, CT and TT genotypes was 58.7%, 37.3% and 4.0% in Bai Ku Yao, and 32.6%, 56.4% and 11.0% in Han (P < 0.001); respectively. The levels of TC and LDL-C in both ethnic groups were significant differences among the three genotypes (P < 0.05-0.01). The T allele carriers had higher serum TC and LDL-C levels than the T allele noncarriers. The levels of ApoB in Han were significant differences among the three genotypes (P < 0.05). The T allele carriers had higher serum ApoB levels as compared with the T allele noncarriers. The levels of TC, TG and LDL-C in Bai Ku Yao were correlated with genotypes (P < 0.05-0.001), whereas the levels of LDL-C in Han were associated with genotypes (P < 0.001). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, cigarette smoking, and blood pressure in the both ethnic groups. Conclusions The differences in serum TC, TG, LDL-C and ApoB levels between the two ethnic groups might partly result from different genotypic and allelic frequencies of the MTHFR C677T or different MTHFR gene-enviromental interactions. PMID:20977771

  13. Human kidney aldose and aldehyde reductases.

    PubMed

    Sato, S; Kador, P F

    1993-01-01

    Mounting experimental evidence links increased aldose reductase activity with diabetes-related kidney functional changes. To investigate the interrelationship of NADPH-dependent reductases in the human kidney, both aldose reductase and aldehyde reductase were purified from human kidney by a series of chromatographic procedures, including gel filtration on Sephadex G-100, affinity chromatography on Matrex Gel Orange A, and chromatofocusing on Mono P. Each purified enzyme appeared as a single band on polyacrylamide gel after electrophoresis or isoelectric focusing. Aldose reductase has a pI of 5.7 and apparent molecular weight of 37 kDa, calculated from SDS-polyacrylamide gel electrophoresis, while aldehyde reductase has a pI of 5.2 and molecular weight of 39 kDa. Similar molecular weights were also obtained by gel filtration, indicating that both aldose and aldehyde reductases are present as monomers in the human kidney. Aldehyde reductase is primarily localized in the cortex, while the medulla contains aldose reductase. Both enzymes displayed properties consistent with the general characteristics of aldose and aldehyde reductases obtained from either rat or dog kidney. Purified aldose reductase utilizes aldose sugars such as D-xylose, D-glucose, and D-galactose as substrates while aldehyde reductase preferentially reduces D-glucuronate and oxidizes L-gulonate to D-glucuronate. Despite the lower apparent affinity of aldehyde reductase for aldose sugars (approximately 20- to 100-fold less) both enzymes reduced D-xylose, D-glucose, and D-galactose to their respective sugar alcohols in in vitro incubation studies where the generated sugar alcohols were identified by gas chromatography. Both enzymes were also inhibited by aldose reductase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8343612

  14. MTHFR C677T polymorphism interaction with heavy alcohol consumption increases head and neck carcinoma risk

    PubMed Central

    Zhuo, Xianlu; Song, Jue; Li, Dairong; Wu, Yongzhong; Zhou, Qi

    2015-01-01

    MTHFR C677T polymorphism has been indicated to be a risk factor for cancers, but its association with head and neck cancer (HNC) risk remains inconclusive. In the present study, we aimed to get a more precise estimation by performing a quantitative meta-analysis. Published papers up to Jun 2014 was searched and screened. Necessary information was rigorously extracted for data pooling and analyzing, and then, subgroup analyses on ethnicity, source of controls, sample size, tumor type, smoking and drinking status were also carried out. As a result, twenty-three case-control studies including 14298 subjects were included. The overall data failed to reveal a significant association between MTHFR C677T polymorphism and HNC risk (homozygote comparison model: OR?=?1.16; 95%CI?=?0.93-1.45; dominant model: OR?=?1.05; 95%CI?=?0.90-1.21; recessive model: OR?=?1.14; 95%CI?=?0.93-1.38). However, in the subgroup analysis about drinking status, increase risk was shown in the heavy drinking subgroup (TT vs CC: OR?=?3.11; 95%CI?=?1.52-3.02). In conclusion, the results of the present study suggest that Homozygous TT alleles of MTHFR C677T polymorphism might be a risk factor for HNC among individuals who have a heavy drinking history. Further studies are needed to get a more definitive conclusion. PMID:26035704

  15. Role of plasma homocysteine levels and MTHFR polymorphisms on IQ scores in children and young adults with epilepsy treated with antiepileptic drugs.

    PubMed

    Di Rosa, Gabriella; Lenzo, Patrizia; Parisi, Eleonora; Neri, Milena; Guerrera, Silvia; Nicotera, Antonio; Alibrandi, Angela; German, Eva; Caccamo, Daniela; Span, Maria; Tortorella, Gaetano

    2013-12-01

    Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. High plasma total Hcy (tHcy) has been quite frequently reported in patients with epilepsy treated with antiepileptic drugs (AEDs) mainly related to plasma folate reduction induced by AEDs themselves. The role of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene (MTHFR) on the increase of plasma tHcy in patients with epilepsy taking AEDs is still controversial. Cognitive impairment may be associated with epilepsy either as the result of the epileptic syndrome per se or as a side effect induced by the AEDs. High plasma tHcy levels were associated with lower cognitive performances in patients affected by Alzheimer's disease and mild cognitive impairment and in healthy elderly. We searched for a correlation between plasma tHcy levels with the intelligence quotient (IQ) scores in a population of children and young adults with epilepsy treated with old and/or newer AEDs. The study group encompassed 179 patients (92 M, 51.5%) followed at our Unit of Child Neuropsychiatry and aged between 4 and 25years (mean+SD: 14.034.25). The inclusion criteria included the following: 1) diagnosis of epilepsy of "unknown cause" (cryptogenic) according to the ILAE classification, 2) age older than 3years, 3) stabilized antiepileptic treatment for at least 6months, and 4) clinical records of cognitive tests, plasma tHcy value, and results of MTHFR polymorphisms. Patients' mean tHcy value was 9.713.13?M/L (tHcy<9?M/L as our laboratory cutoff in nonepileptic controls). The mean TIQ score was 85.22 (SD24.12); the mean VIQ score was 86.32 (SD20.86); and the mean PIQ score was 86.94 (SD21.51). C677T and A1298C MTHFR polymorphisms were detected in 74/92 (80%) examined patients and distributed into the following: CT (22.3%), TT (14.9%), CC (10.3%) for C677T, AC (16%), CC (1.1%), and AA (30.3%) for A1298C. Plasma tHcy levels were not significantly related to the IQ scores (TIQ, VIQ, or PIQ). Two significant findings came out. First, patients on AED polytherapy showed significantly lower TIQ, VIQ, and PIQ scores compared with the ones with AED monotherapy (p=0.032; p=0.008; p=0.005, respectively). However, this significant difference was not observed with the plasma tHcy levels compared with AED treatment. Second, patients with the 677TT genotype showed significantly higher tHcy levels versus those with the wt ones (p=0.049). In the latter group of patients, although the mean TIQ score was lower compared with the mean TIQ score in those with the wt ones, the difference only approached statistical significance (p=0.056). To our knowledge, this is the first study investigating the relationship between tHcy levels and cognitive scores in children with epilepsy treated with AEDs. Analysis of wider samples, selective neuropsychological tests, and prospective recruitment of patients might be encouraged. PMID:24183735

  16. Evaluation of Factor V G1691A, prothrombin G20210A, Factor XIII V34L, MTHFR A1298C, MTHFR C677T and PAI-1 4G/5G genotype frequencies of patients subjected to cardiovascular disease (CVD) panel in south-east region of Turkey.

    PubMed

    Oztuzcu, Serdar; Ergun, Sercan; Ula?l?, Mustafa; Nacarkahya, Glper; I?ci, Yusuf Ziya; I?ci, Mehri; Bayraktar, Recep; Tamer, Ali; akmak, Ecir Ali; Arslan, Ahmet

    2014-06-01

    Cardiovascular disease (CVD) risk factors, such as arterial hypertension, obesity, dyslipidemia or diabetes mellitus, as well as CVDs, including myocardial infarction, coronary artery disease or stroke, are the most prevalent diseases and account for the major causes of death worldwide. In the present study, 4,709 unrelated patients subjected to CVD panel in south-east part of Turkey between the years 2010 and 2013 were enrolled and DNA was isolated from the blood samples of these patients. Mutation analyses were conducted using the real-time polymerase chain reaction method to screen six common mutations (Factor V G1691A, PT G20210A, Factor XIII V34L, MTHFR A1298C and C677T and PAI-1 -675 4G/5G) found in CVD panel. The prevalence of these mutations were 0.57, 0.25, 2.61, 13.78, 9.34 and 24.27 % in homozygous form, respectively. Similarly, the mutation percent of them in heterozygous form were 7.43, 3.44, 24.91, 44.94, 41.09 and 45.66%, respectively. No mutation was detected in 92 (1.95%) patients in total. Because of the fact that this is the first study to screen six common mutations in CVD panel in south-east region of Turkey, it has a considerable value on the diagnosis and treatment of these diseases. Upon the results of the present and previous studied a careful examination for these genetic variants should be carried out in thrombophilia screening programs, particularly in Turkish population. PMID:24532105

  17. A novel point mutation in a 3{prime} splice site of the NADH-cytochrome b{sub 5} reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia

    SciTech Connect

    Shirabe, Komie; Takeshita, Masazumi; Landi, M.T.

    1995-08-01

    Hereditary methemoglobinemia with generalized deficiency of NADH-cytochrome b{sub 5} reductase (b{sub 5}R) (type II) is a rare disease characterized by severe developmental abnormalities, which often lead to premature death. Although the molecular relationship between the symptoms of this condition and the enzyme deficit are not understood, it is thought that an important cause is the loss of the lipid metabolizing activities of the endoplasmic reticulum-located reductase. However, the functions of the form located on outer mitochondrial membranes have not been considered previously. In this study, we have analyzed the gene of an Italian patient and identified a novel G{r_arrow}T transversion at the splice-acceptor site of the 9th exon, which results in the complete absence of immunologically detectable b{sub 5}R in blood cells and skin fibroblasts. In cultured fibroblasts of the patient, NADH-dependent cytochrome c reductase, ferricyanide reductase, and semidehydroascorbate reductase activities were severely reduced. The latter activity is known to be due to b{sub 5}R located on outer mitochondrial membranes. Thus, our results demonstrate that the reductase in its two membrane locations, endoplasmic reticulum and outer mitochondrial membranes, is the product of the same gene and suggest that a defect in ascorbate regeneration may contribute to the phenotype of hereditary methemoglobinemia of generalized type. 37 refs., 5 figs., 2 tabs.

  18. Status of Vitamins B-12 and B-6 but Not of Folate, Homocysteine, and the Methylenetetrahydrofolate Reductase C677T Polymorphism Are Associated with Impaired Cognition and Depression in Adults123

    PubMed Central

    Moorthy, Denish; Peter, Inga; Scott, Tammy M.; Parnell, Laurence D.; Lai, Chao-Qiang; Crott, Jimmy W.; Ordovás, José M.; Selhub, Jacob; Griffith, John; Rosenberg, Irwin H.; Tucker, Katherine L.; Troen, Aron M.

    2012-01-01

    The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene differs in frequency in various ethnic groups that have differing prevalence of age-related cognitive impairments. We used a series of neuro-psychological tests to examine the association of the MTHFR C677T polymorphism with cognition and depression and also to assess whether genotype modifies the association of folate and homocysteine with these outcomes. This study analyzed pooled cross-sectional data from 2 ethnically diverse cohorts of community-living adults: the Boston Puerto Rican Health Study (n = 939) and the Nutrition, Aging, and Memory in Elders study (n = 1017). Individuals in both cohorts underwent anthropometric and laboratory measurements and dietary and health assessments using validated questionnaires between the years 2003 and 2007. Cognitive outcomes included measures of global cognition [Mini-Mental Status Exam (MMSE)], depression (Center for Epidemiological Studies Depression Scale), and 3 factor scores for the domains of attention, executive function, and memory that were derived from a detailed set of neuropsychological tests. Low plasma vitamin B-12 concentrations were associated with poorer MMSE scores and higher depression scores, and low vitamin B-6 concentrations were associated with lower MMSE and worse attention and executive function in the multivariate analysis. In contrast, MTHFR genotype, folate, and homocysteine were not associated with cognition or depression in either ethnicity-pooled or stratified analysis. The current study did not find evidence of an association between the MTHFR C677T TT genotype and impaired cognition or depression in a population with adequate folate status and a high prevalence of cognitive impairment and depression. PMID:22739363

  19. Inheritance of nitrite reductase and regulation of nitrate reductase, nitrite reductase, and glutamine synthetase isozymes.

    PubMed Central

    Heath-Pagliuso, S; Huffaker, R C; Allard, R W

    1984-01-01

    Banding patterns of nitrate reductase (NR), nitrite reductase (NiR), and glutamine synthetase (GS) from leaves of diploid barley (Hordeum vulgare), tetraploid wheat (Triticum durum), hexaploid wheat (Triticum aestivum), and tetraploid wild oats (Avena barbata) were compared following starch gel electrophoresis. Two NR isozymes, which appeared to be under different regulatory control, were observed in each of the three species. The activity of the more slowly migrating nitrate reductase isozyme (NR1) was induced by NO3- in green seedlings and cycloheximide inhibited induction. However, the activity of the faster NR isozyme (NR2) was unaffected by addition of KNO3, and it was not affected by treatments of cycloheximide or chloramphenicol. Only a single isozyme of nitrite reductase was detected in surveys of three tetraploid and 18 hexaploid wheat, and 48 barley accessions; however, three isozymes associated with different ecotypes were detected in the wild oats. Inheritance patterns showed that two of the wild oat isozymes were governed by a single Mendelian locus with two codominant alleles; however, no variation was detected for the third isozyme. Treatment of excised barely and wild oat seedlings with cycloheximide and chloramphenicol showed that induction of NiR activity was greatly inhibited by cycloheximide, but only slightly by chloramphenicol. Only a single GS isozyme was detected in extracts of green leaves of wheat, barley, and wild oat seedlings. No electrophoretic variation was observed within or among any of these three species. Thus, this enzyme appears to be the most structurally conserved of the three enzymes. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:11541965

  20. Fatty acyl-CoA reductase

    SciTech Connect

    Reiser, Steven E.; Somerville, Chris R.

    1998-12-01

    The present invention relates to bacterial enzymes, in particular to an acyl-CoA reductase and a gene encoding an acyl-CoA reductase, the amino acid and nucleic acid sequences corresponding to the reductase polypeptide and gene, respectively, and to methods of obtaining such enzymes, amino acid sequences and nucleic acid sequences. The invention also relates to the use of such sequences to provide transgenic host cells capable of producing fatty alcohols and fatty aldehydes.

  1. Multiloculated hydrocephalus of intrauterine-onset: a case report of an unexpected MTHFR A1298C positive test result.

    PubMed

    Cizmeci, M N; Akelma, A Z; Kosehan, D; Kutukoglu, I; Sonmez, F M

    2013-01-01

    Loculated hydrocephalus is a condition in which discrete fluid-filled compartments form in association with the ventricular system of the brain. Multiloculated hydrocephalus is a subgroup of this entity involving more than one segment of the ventricular system. Abnormal descent of the cerebellar components can cause multiloculated hydrocephalus due to various pathogenesis. However, studies report no more than 10% of correlation between cerebellar herniation and hydrocephalus. We report an infant with MTHFR A1298C homozygosity, who had hydrocephalus of intrauterine-onset. Alterations in the folate metabolism might lead to congenital hydrocephalus and there is growing data on the prothrombotic effects of MTHFR polymorphisms. To the best of our knowledge, there has been no reported case of MTHFR A1298C homozygosity and intrauterine-onset multiloculated hydrocephalus as a co-existence in the literature. PMID:24341140

  2. TPMT and MTHFR Genotype is not Associated With Altered Risk of Thioguanine-Related Sinusoidal Obstruction Syndrome in Pediatric Acute Lymphoblastic Leukemia: A Report from the Childrens Oncology Group

    PubMed Central

    Wray, Lisa; Vujkovic, Marijana; McWilliams, Thomas; Cannon, Shannon; Devidas, Meenakshi; Stork, Linda; Aplenc, Richard

    2014-01-01

    Sinusoidal obstruction syndrome is a complication of therapy for pediatric ALL and may be modified by thiopurine methyltransferase activity as well as by MTHFR genotype. We assessed TPMT * 3A, * 3B, * 3C, and MTHFR C677T and A1298C germline genetic polymorphisms among 351 patients enrolled in the thioguanine treatment arm of CCG-1952 clinical trial. TPMT and MTHFR C677T genotypes were not associated with SOS risk. The combination of MTHFR and TPMT variant genotypes was not associated with SOS risk. These suggest that germline genetic variation in TPMT and MTHFR do not significantly alter SOS risk in patients exposed to thioguanine. PMID:24737678

  3. MTHFR C677T Gene Polymorphism and Head and Neck Cancer Risk: A Meta-Analysis Based on 23 Publications

    PubMed Central

    Niu, Yu-Ming; Deng, Mo-Hong; Chen, Wen; Zeng, Xian-Tao; Luo, Jie

    2015-01-01

    Objective. Conflicting results on the association between MTHFR polymorphism and head and neck cancer (HNC) risk were reported. We therefore performed a meta-analysis to derive a more precise relationship between MTHFR C677T polymorphism and HNC risk. Methods. Three online databases of PubMed, Embase, and CNKI were researched on the associations between MTHFR C677T polymorphism and HNC risk. Twenty-three published case-control studies involving 4,955 cases and 8,805 controls were collected. Odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the relationship between MTHFR C677T polymorphism and HNC risk. Sensitivity analysis, cumulative analyses, and publication bias were conducted to validate the strength of the results. Results. Overall, no significant association between MTHFR C677T polymorphism and HNC risk was found in this meta-analysis (T versus C: OR = 1.04, 95% CI = 0.921.18; TT versus CC: OR = 1.15, 95% CI = 0.901.46; CT versus CC: OR = 1.00, 95% CI = 0.851.17; CT + TT versus CC: OR = 1.01, 95% CI = 0.871.18; TT versus CC + CT: OR = 1.11, 95% CI = 0.981.26). In the subgroup analysis by HWE, ethnicity, study design, cancer location, and negative significant associations were detected in almost all genetic models, except for few significant risks that were found in thyroid cancer. Conclusion. This meta-analysis demonstrates that MTHFR C677T polymorphism may not be a risk factor for the developing of HNC. PMID:25802478

  4. Polymorphisms of MTHFR C677T and A1298C association with oral carcinoma risk: a meta-analysis.

    PubMed

    Zhuo, Xianlu; Ling, Junjun; Zhou, Yan; Zhao, Houyu; Song, Yufeng; Tan, Yinghui

    2012-07-01

    Investigations regarding association of MTHFR polymorphisms with oral carcinoma risk have yielded inconclusive results. Thus, meta-analyses were performed. Results showed that no associations of C677T polymorphisms with oral carcinoma were observed for the overall data. In subgroup analyses by drinking status, homozygous TT alleles exhibited elevated oral cancer susceptibility in heavy drinkers. For A1298C polymorphism, CC alleles presented a possible preventive role for oral cancer. Collectively, results suggest that MTHFR 677TT polymorphism might be a low-penetrant risk factor for oral carcinoma only in heavy drinkers. Conversely, 1298CC alleles might play a preventive role for oral cancer. PMID:22536935

  5. Creatine kinase MM TaqI and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms influence exercise-induced C-reactive protein levels.

    PubMed

    Miranda-Vilela, Ana Luisa; Akimoto, Arthur K; Lordelo, Graciana S; Pereira, Luiz C S; Grisolia, Cesar K; Klautau-Guimarães, Maria de Nazaré

    2012-03-01

    Physical training induces beneficial adaptations, but exhausting exercise increases reactive oxygen species, which can cause muscular injuries with consequent inflammatory processes, implying jeopardized performance and possibly overtraining. Acute strenuous exercise almost certainly exceeds the benefits of physical activity; it can compromise performance and may contribute to increased future risk of cardiovascular disease (CVD) in athletes. Polymorphisms in the muscle-type creatine kinase (CK-MM) gene may influence performance and adaptation to training, while many potentially significant genetic variants are reported as risk factors for CVD. Therefore, we investigated the influence of polymorphisms in CK-MM TaqI and NcoI, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and C-reactive protein (CRP G1059C) genes on exercise-induced damage and inflammation markers. Blood samples were taken immediately after a race (of at least 4 km) that took place outdoors on flat tracks, and were submitted to genotyping and biochemical evaluation of aspartate aminotransferase (AST), CK, CRP and high-sensitivity CRP (hs-CRP). CK-MM TaqI polymorphism significantly influenced results of AST, CK and hs-CRP, and an association between MTHFR C677T and A1298C with CRP level was found, although these levels did not exceed reference values. The results indicate that these polymorphisms can indirectly influence performance, contribute to higher susceptibility to exercise-induced inflammation or protection against it, and perhaps affect future risks of CVD in athletes. PMID:21706313

  6. Creatine kinase MM TaqI and methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms influence exercise-induced C-reactive protein levels.

    PubMed

    Miranda-Vilela, Ana Luisa; Akimoto, Arthur K; Lordelo, Graciana S; Pereira, Luiz C S; Grisolia, Cesar K; Klautau-Guimarães, Maria de Nazaré

    2012-01-01

    Physical training induces beneficial adaptations, but exhausting exercise increases reactive oxygen species, which can cause muscular injuries with consequent inflammatory processes, implying jeopardized performance and possibly overtraining. Acute strenuous exercise almost certainly exceeds the benefits of physical activity; it can compromise performance and may contribute to increased future risk of cardiovascular disease (CVD) in athletes. Polymorphisms in the muscle-type creatine kinase (CK-MM) gene may influence performance and adaptation to training, while many potentially significant genetic variants are reported as risk factors for CVD. Therefore, we investigated the influence of polymorphisms in CK-MM TaqI and NcoI, methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and C-reactive protein (CRP G1059C) genes on exercise-induced damage and inflammation markers. Blood samples were taken immediately after a race (of at least 4 km) that took place outdoors on flat tracks, and were submitted to genotyping and biochemical evaluation of aspartate aminotransferase (AST), CK, CRP and high-sensitivity CRP (hs-CRP). CK-MM TaqI polymorphism significantly influenced results of AST, CK and hs-CRP, and an association between MTHFR C677T and A1298C with CRP level was found, although these levels did not exceed reference values. Results indicate that these polymorphisms can indirectly influence performance, contribute to higher susceptibility to exercise-induced inflammation or protection against it, and perhaps affect future risks of CVD in athletes. PMID:21516340

  7. Cerebral venous and sinus thrombosis and thrombophilic mutations in Western Iran: association with factor V Leiden.

    PubMed

    Rahimi, Zohreh; Mozafari, Hadi; Bigvand, Amir Hossein Amiri; Doulabi, Reza Mohammad; Vaisi-Raygani, Asad; Afshari, Dariush; Razazian, Nazanin; Rezaei, Mansour

    2010-08-01

    The present study aimed at investigating the prevalence of factor V Leiden G1691A, prothrombin G20210A, and MTHFR C677T in cerebral venous and sinus thrombosis (CVST) patients and their possible association with CVST in Western Iran. A total of 24 CVST patients with the mean age of 37.1 +/- 11.7 years and 100 sex- and age-matched healthy individuals from Kermanshah Province of Iran with ethnic background of Kurd were studied for factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T by PCR-RFLP method using Mnl I, Hind III, and Hinf I restriction enzymes, respectively. Prevalence of factor V Leiden was 16.7% in patients and 2% in control group. A significant association was found between factor V Leiden mutation and CVST with odds ratio (OR) of 9.8 (95% confidence intervals [CI] 1.68-57.2, P = .01). No prothrombin G20210A was found among patients. In patients, MTHFR C677T tended to be higher (58.3%) compared to control (44%), OR of 1.8 (95% CI 0.73-4.5, P = .2). Our study for the first time has determined the prevalence of inherited thrombophilia in a homogenous ethnic group of CVST patients and suggests that factor V Leiden, and not the prothrombin gene mutation is a risk factor for CVST in Western Iran. PMID:19703820

  8. Association of the rs1801133 variant in the MTHFR gene and sporadic Parkinson's disease.

    PubMed

    García, S; Coral-Vázquez, Rm; Gallegos-Arreola, M P; Montes-Almanza, L A; Canto, P; García-Martínez, F A; Chavira-Hernández, G; Palma-Flores, C; Dávila-Maldonado, L; Cuevas-García, C F; López Hernández, L B

    2015-01-01

    The MTHFR gene has been reported as a susceptibility locus for sporadic Parkinson's disease (sPD). The functional variant rs1801133 has been linked to hyperhomocysteinemia and dopaminergic cell death. Among different populations, Mexican-Mestizos (most present-day Mexicans) have the highest frequency of this variant. Therefore, we sought to determine a possible association of rs1801133 with SPD. In total, 356 individuals were included: 140 patients with PD, diagnosed according to the Queen Square Brain Bank criteria, and 216 neurologically healthy controls. Genotyping was performed using TaqMan probes for rs1801133 and real-time PCR. Logistic regression analysis with adjustment for smoking and gender was used to test for an association between genotype and SPD. The CC genotype was associated with SPD; exp() = 2.06; 95% CI: 1.101-3.873, p = 0.024. No association with age at onset, cognitive impairment or gender was found in our study group. Our data suggest an important role of MTHFR gene variants in SPD. PMID:25909872

  9. Association between MTHFR 677C/T and 1298A/C gene polymorphisms and breast cancer risk.

    PubMed

    Zhang, X F; Liu, T; Li, Y; Li, S

    2015-01-01

    We performed a case-control study to investigate the association between single nucleotide polymorphisms in the MTHFR gene (677C/T and 1298A/C) and risk of breast cancer. This case-control study included 216 breast cancer cases and 216 controls. The MTHFR 677C/T and 1298A/C gene polymorphisms were assessed by polymerase chain reaction restriction fragment length polymorphism. We observed an increased likelihood of breast cancer patients having a higher age at menarche and first live birth, and a greater family history of breast cancer, especially among first-degree relatives. In addition, individuals with the TT genotype of MTHFR 677C/T were associated with increased risk of breast cancer by logistic regression analysis; the adjusted odds ratio (95%CI) was 3.05 (1.17-8.87). In conclusion, the results of our study indicated that the MTHFR C677T gene polymorphism could play a role in the development of breast cancer. PMID:26662439

  10. Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia.

    PubMed

    Salazar, J; Alts, A; del Ro, E; Estella, J; Rives, S; Tasso, M; Navajas, A; Molina, J; Villa, M; Vivanco, J L; Torrent, M; Baiget, M; Badell, I

    2012-10-01

    Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5?g?m? had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3?g?m? (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL. PMID:21747412

  11. The Frequency of Some Thrombophilic Mutations in Eastern Turkey

    PubMed Central

    Ozturk, Nurinnisa; Bakan, Ebubekir; Gul, Mehmet Ali; Bakan, Nuri; Sebin, Engin; Kiziltunc, Ahmet

    2016-01-01

    Objective: Factor V / Factor II / Methylenetetrahydrofolate reductase, gene polymorphisms are closely associated with thrombophilia. Regional frequencies of these mutations may show a characteristic state. The aim of our study was to evaluate the frequency of commonly seen Factor V / Factor II / Methylenetetrahydrofolate reductase gene polymorphisms in Eastern Turkey. Materials and Methods: In 433 patients sent to the laboratory with the suspicion of thrombophilia, using whole blood samples, an automated Nucleic Acid Test was used for mutation determinations in Verigene System. The kit module was designed to detect the Factor V G1691A / Factor II G20210A / Methylenetetrahydrofolate reductase gene C677T single nucleotide polymorphisms. Results: In 433 patients, 8.7% for Factor V G1691A polymorphisms were heterozygous genotype, 3.9% for Factor II G20210A polymorphisms were heterozygous genotype, and 43.9% for methylenetetrahydrofolate reductase 677C>T polymorphisms were heterozygous genotype and 3.0% homozygous mutation genotype. Conclusion: Detection of these commonly seen Factor V / Factor II / Methylenetetrahydrofolate reductase single nucleotide polymorphisms can help to identify patients in high risk group and to evaluate the interaction of genetic and acquired risk factors. Our findings suggest that commonly seen thrombophilic allele mutation frequency in our region is the same as the data reported in the literature.

  12. The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with Down syndrome.

    PubMed

    Martnez-Fras, M L

    2008-06-01

    Studies on the structure of the methylenetetrahydrofolate reductase (MTHFR) gene and the mechanisms by which folate may reduce homocysteine levels in bacteria and in humans have provided a rationale to understand the conflicting epidemiological observations between the studies on the 677C-T and 1298A-C MTHFR polymorphic variants, and the risk of having an infant with Down syndrome (DS). However, three of the combined genotypes (CTCC, TTAC, and TTCC) are very infrequent in the human population. In fact, these three rare genotypes were only observed in two of the eight epidemiological studies that analyzed these genotype combinations and the risk of DS. In a study of the Indian population these three genotypes were identified in mothers of DS children but not in control mothers demonstrating a statistically significant increase in the risk of giving birth to DS infants. Conversely, the CTCC and TTAC genotypes were only observed in control mothers and not in mothers of DS infants in the Spanish study, while the TTCC genotype was not observed in any Spanish mother analyzed. These results were not related to the frequency of the T allele, since this was lower in the Indian population (21.4% among case mothers and 12.4% in control mothers) than in the Spanish population (33.9%). At present, several important biological aspects on the Hcy cycle are known, including: (a) the biochemical structure and function of the MTHFR enzyme, (b) the biological basis for the effect of the different 677C-T and 1298A-C MTHFR genotype combinations on Hcy levels, (c) that folate is not synthesized by the organism that obtained it from the diet, (d) that TT homozygotes will be at particular risk when their folate status is low because the mutant enzyme requires much higher levels of folate than the physiological one to stabilize the binding of flavin-adenosine-dinucleotide (FAD), (e) that the release of flavin is prevented by increasing the levels of folate, and (f) that the cystathionine-beta-synthase gene is located on chromosome 21. Together, these facts suggest that destabilization of the Hcy cycle in function of the levels of S-adenosylmethionine (SAM), may be modified by some embryonic and maternal genotypes, as well as by maternal nutritional status and life style. This may also influence the probability that some embryos survive to birth, but in different way for those with and without trisomy 21, as is discussed in this article. PMID:18446861

  13. Phenotypic classification of male pseudohermaphroditism due to steroid 5{alpha}-reductase 2 deficiency

    SciTech Connect

    Sinnecker, G.H.G; Hiort, O.; Kruse, K.; Dibbelt, L.

    1996-05-03

    Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5{alpha}-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5{alpha}-reductase 2 deficiency (SRD). T/DHT-ratios were highly increased in the classical syndrome, but variable in the less severe affected patients. Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5{alpha}-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5{alpha}-reductase 2 deficiency. 22 refs., 2 figs., 2 tabs.

  14. Neuroprotective role for carbonyl reductase?

    PubMed

    Maser, Edmund

    2006-02-24

    Oxidative stress is increasingly implicated in neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, and Creutzfeld-Jakob diseases or amyotrophic lateral sclerosis. Reactive oxygen species seem to play a significant role in neuronal cell death in that they generate reactive aldehydes from membrane lipid peroxidation. Several neuronal diseases are associated with increased accumulation of abnormal protein adducts of reactive aldehydes, which mediate oxidative stress-linked pathological events, including cellular growth inhibition and apoptosis induction. Combining findings on neurodegeneration and oxidative stress in Drosophila with studies on the metabolic characteristics of the human enzyme carbonyl reductase (CR), it is clear now that CR has a potential physiological role for neuroprotection in humans. Several lines of evidence suggest that CR represents a significant pathway for the detoxification of reactive aldehydes derived from lipid peroxidation and that CR in humans is essential for neuronal cell survival and to confer protection against oxidative stress-induced brain degeneration. PMID:16406002

  15. Tetrathionate reductase of Salmonella thyphimurium: a molybdenum containing enzyme

    SciTech Connect

    Hinojosa-Leon, M.; Dubourdieu, M.; Sanchez-Crispin, J.A.; Chippaux, M.

    1986-04-29

    Use of radioactive molybdenum demonstrates that the tetrathionate reductase of Salmonella typhimurium is a molydenum containing enzyme. It is proposed that this enzyme shares with other molybdo-proteins, such as nitrate reductase, a common molybdenum containing cofactor the defect of which leads to the loss of the tetrathionate reductase and nitrate reductase activities.

  16. MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection.

    PubMed

    Neves Filho, Eduardo Henrique Cunha; Alves, Markenia Kelia Santos; Lima, Valeska Portela; Rabenhorst, Silvia Helena Barem

    2010-12-01

    MTHFR C677T and Helicobacter pylori infection are believed to play critical roles in the DNA methylation process, an epigenetic feature frequently found in gastric cancer. The aim of this study was to verify the associations between the MTHFR C677T polymorphism and the methylation status of three gastric cancer-related genes. The influence of H. pylori strains was also assessed. DNA extracted from 71 gastric tumor samples was available for MTHFR C677T genotyping by PCR-RFLP, promoter methylation identification by MS-PCR and H. pylori detection and posterior subtyping (cagA and vacA genes) by PCR. In the distal tumors, a positive correlation was found between the methylation of CDKN2A and the allele T carriers (r=0.357; p=0.009). Considering the eldest patients (age ?60 years old), this correlation was even higher (r=0,417; p=0.014). H. pylori infection by highly pathogenic strains (cagA+/vacAs1m1) was also found correlated to promoter methylation of CDKN2A and the allele T carriers in distal tumors (r=0.484; p=0.026). No significant correlation was verified between MTHFR C677T genotype and promoter methylation status when we analyzed the general sample. DNA methylation in CDKN2A associated to the MTHFR 677T carrier is suggested to be a distal tumor characteristic, especially in those 60 years old or older, and it seems to depend on the infection by H. pylori cagA/vacAs1m1 strains. PMID:20957490

  17. Association between the MTHFR A1298C polymorphism and risk of cancer: evidence from 265 case-control studies.

    PubMed

    Zhu, Xin-Li; Liu, Zhi-Zhong; Yan, Sen-Xiang; Wang, Wei; Chang, Rui-Xia; Zhang, Chun-Yan; Guo, Yan

    2016-02-01

    Many molecular, epidemiological studies have been performed to explore the association between MTHFR A1298C polymorphism and cancer risk. However, the results were inconsistent or even contradictory. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR A1298C (81,040 cases and 114,975 controls from 265 studies) polymorphism. Overall, significant association was observed between MTHFR A1298C polymorphism and cancer risk when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, significantly increased cervical cancer (dominant model: OR 1.46, 95 % CI 1.13-1.90; AC vs. AA: OR 1.48, 95 % CI 1.13-1.92) and lymphoma (dominant model: OR 1.22, 95 % CI 1.04-1.44; recessive model: OR 1.66, 95 % CI 1.15-2.39; CC vs. AA: OR 1.75, 95 % CI 1.21-2.53) risk were observed in Asians, and significantly decreased colorectal cancer risk was found in Asians (recessive model: OR 0.75, 95 % CI 0.59-0.96; CC vs. AA: OR 0.77, 95 % CI 0.60-1.00). In summary, this meta-analysis suggests that MTHFR A1298C polymorphism is associated with increased cervical cancer and lymphoma risk in Asians, and MTHFR A1298C polymorphism is associated with decreased colorectal cancer risk in Asians. Moreover, this meta-analysis also points out the importance of new studies, such as oral cancer and chronic myeloid leukemia, because they had high heterogeneity in this meta-analysis (I (2) > 75 %). PMID:26156333

  18. Imine Reductases: A Comparison of Glutamate Dehydrogenase to Ketimine Reductases in the Brain

    PubMed Central

    Jamie, Joanne F.; Cooper, Arthur J. L.

    2013-01-01

    A key intermediate in the glutamate dehydrogenase (GDH)-catalyzed reaction is an imine. Mechanistically, therefore, GDH exhibits similarities to the ketimine reductases. In the current review, we briefly discuss (a) the metabolic importance of the GDH reaction in liver and brain, (b) the mechanistic similarities between GDH and the ketimine reductases, (c) the metabolic importance of the brain ketimine reductases, and (d) the neurochemical consequences of defective ketimine reductases. Our review contains many historical references to the early work on amino acid metabolism. This work tends to be overlooked nowadays, but is crucial for a contemporary understanding of the central importance of ketimines in nitrogen and intermediary metabolism. The ketimine reductases are important enzymes linking nitrogen flow among several key amino acids, yet have been little studied. The cerebral importance of the ketimine reductases is an area of biomedical research that deserves far more attention. PMID:23314864

  19. Evaluation of C677T polymorphism of the methylenetetra hydrofolate reductase gene and its association with levels of serum homocysteine, folate, and vitamin B12 as maternal risk factors for Down syndrome

    PubMed Central

    Mohanty, Pankaj K.; Kapoor, Seema; Dubey, Anand P.; Pandey, Sanjeev; Shah, Renuka; Nayak, Hemant K.; Polipalli, Sunil K.

    2012-01-01

    AIMS AND OBJECTIVE: Evaluation of C677T polymorphisms of the methylenetetra hydrofolate reductase (MTHFR) gene and its association with level of serum homocysteine, folate, and vitamin B12 as possible maternal risk factors for Down syndrome. DESIGN: This was a casecontrol study. MATERIAL AND METHODS Fifty-two mothers (mean age 27.6 years) with babies having free trisomy 21 of North Indian ethnicity and 52 control nonlactating mothers (mean age 24.9 years) of same ethnicity attending services of genetic lab for bloodletting for other causes were enrolled after informed written consent. Fasting blood was collected and was used for determination of plasma homocysteine, vitamin B12, and folate (serum and RBC), and for PCR amplification of the MTHFR gene. RESULTS: The prevalence of MTHFR C677T polymorphism in north Indian mothers of babies with trisomy 21 Down syndrome was 15.38% compared to 5.88 % in controls. The difference between two groups was not statistically significant (P = 0.124). Low serum folate was demonstrated in 34.62% of cases vs. 11.54% in controls, which was significant (P = 0.005). Low RBC folate was found in 30.7% of cases versus 11.53% in controls, which was not significant (P = 0.059), when analyzed independently. But on multiple regression analysis the difference was statistically significant. Low serum vitamin B12 was found in 42.31% of cases versus 34.62% in controls, which was not significant (P = 0.118). The mean serum homocysteine in cases was 10.35 0.68 while controls were 9.02 0.535. CONCLUSION: Serum levels of folate were low in cases. The RBC folate levels were comparable in both groups. However the combined serum folate and RBC folate were low in cases compared to control groups. Homocysteine levels in our study were higher in Down syndrome mothers compared to controls; however high-serum level of Homocysteine had no association with MTHFR polymorphism. No association of serum vitamin B12 with MTHFR polymorphism in occurrence of Down syndrome births was found. Peri- or preconceptional folate supplementation may therefore lead to a decline in DS births, if supported by larger studies. PMID:23716934

  20. Correlation of methylenetetrahydrofolate reductase polymorphisms with homocysteine metabolism in healthy Lebanese adults.

    PubMed

    Mahfouz, Rami A; Cortas, Najwa K; Charafeddine, Khalil M; Abdul Khalik, Rabab N; Sarieddine, Doja S; Kadi, Raneem H; Daher, Rose T

    2012-08-10

    Hyperhomocysteinemia is associated with several vascular and teratogenic conditions. Determinants of total homocysteine concentrations include genetic and nutritional factors. This study assesses the relation between homocysteine concentrations and MTHFR gene polymorphisms at two common alleles (C677T (rs1801133) and A1298C (rs1801131)) as well as other predictors of homocysteine (folate, vitamin B(12), body mass index (BMI), age, and gender) in a group of healthy Lebanese: 109 males and 124 females aged 17-55years. We used serum for the determination of homocysteine, folate and vitamin B(12) levels and blood drawn in EDTA tubes for molecular analysis of MTHFR polymorphisms. Hyperhomocysteinemia was present in 59/233 (25.3%) of the subjects, with male/female ratio of 1.95. Multivariable regression analysis showed that homocysteine levels were negatively related to folate and vitamin B(12) and positively related to male gender and C677T homozygosity; but not A1298C polymorphism, BMI or age. The prevalence of wild, heterozygous, and homozygous C677T genotypes was 45.0%, 43.3% and 11.6%, respectively; with a carrier frequency of 54.9% and allelic frequency of 33.3%. The A1298C genotypic prevalence was 39.5%, 30.9%, and 29.6% respectively; with a carrier frequency of 60.5% and allelic frequency of 45.1%. C677T/A1289C compound heterozygosity was present in 47/233 (20.2%) of volunteers. In this first pilot study, gender, folate, vitamin B(12) and C677T mutational status could explain around 32% of homocysteine variations. Future larger studies are recommended to investigate other predictors of homocysteine variation and combine them with markers explored in this and other studies, in order to evaluate their impact on vascular and/or congenital diseases. PMID:22652272

  1. Evolution Alters the Enzymatic Reaction Coordinate of Dihydrofolate Reductase

    PubMed Central

    2015-01-01

    How evolution has affected enzyme function is a topic of great interest in the field of biophysical chemistry. Evolutionary changes from Escherichia coli dihydrofolate reductase (ecDHFR) to human dihydrofolate reductase (hsDHFR) have resulted in increased catalytic efficiency and an altered dynamic landscape in the human enzyme. Here, we show that a subpicosecond protein motion is dynamically coupled to hydride transfer catalyzed by hsDHFR but not ecDHFR. This motion propagates through residues that correspond to mutational events along the evolutionary path from ecDHFR to hsDHFR. We observe an increase in the variability of the transition states, reactive conformations, and times of barrier crossing in the human system. In the hsDHFR active site, we detect structural changes that have enabled the coupling of fast protein dynamics to the reaction coordinate. These results indicate a shift in the DHFR family to a form of catalysis that incorporates rapid protein dynamics and a concomitant shift to a more flexible path through reactive phase space. PMID:25369552

  2. Human Neuroglobin Functions as a Redox-regulated Nitrite Reductase*

    PubMed Central

    Tiso, Mauro; Tejero, Jess; Basu, Swati; Azarov, Ivan; Wang, Xunde; Simplaceanu, Virgil; Frizzell, Sheila; Jayaraman, Thottala; Geary, Lisa; Shapiro, Calli; Ho, Chien; Shiva, Sruti; Kim-Shapiro, Daniel B.; Gladwin, Mark T.

    2011-01-01

    Neuroglobin is a highly conserved hemoprotein of uncertain physiological function that evolved from a common ancestor to hemoglobin and myoglobin. It possesses a six-coordinate heme geometry with proximal and distal histidines directly bound to the heme iron, although coordination of the sixth ligand is reversible. We show that deoxygenated human neuroglobin reacts with nitrite to form nitric oxide (NO). This reaction is regulated by redox-sensitive surface thiols, cysteine 55 and 46, which regulate the fraction of the five-coordinated heme, nitrite binding, and NO formation. Replacement of the distal histidine by leucine or glutamine leads to a stable five-coordinated geometry; these neuroglobin mutants reduce nitrite to NO ?2000 times faster than the wild type, whereas mutation of either Cys-55 or Cys-46 to alanine stabilizes the six-coordinate structure and slows the reaction. Using lentivirus expression systems, we show that the nitrite reductase activity of neuroglobin inhibits cellular respiration via NO binding to cytochrome c oxidase and confirm that the six-to-five-coordinate status of neuroglobin regulates intracellular hypoxic NO-signaling pathways. These studies suggest that neuroglobin may function as a physiological oxidative stress sensor and a post-translationally redox-regulated nitrite reductase that generates NO under six-to-five-coordinate heme pocket control. We hypothesize that the six-coordinate heme globin superfamily may subserve a function as primordial hypoxic and redox-regulated NO-signaling proteins. PMID:21296891

  3. Purification and properties of aldose reductase and aldehyde reductase from EHS tumor cells.

    PubMed

    Tanimoto, T; Sato, S; Kador, P F

    1990-02-01

    Engelbreth-Holm-Swarm (EHS) tumor cells were utilized as a model for investigating the production of basement membrane components. These cells contain two immunologically distinct NADPH-dependent reductases, aldose reductase (EC 1.1.1.21) and aldehyde reductase (EC 1.1.1.2), which were purified to apparent homogeneity by a combination of procedures which included ammonium sulfate fractionation, Sephadex G-75 gel filtration, Matrex Gel Orange A affinity chromatography, and chromatofocusing on Pharmacia Mono P. The molecular weights of aldose and aldehyde reductases were estimated to be 38K and 40K, respectively, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Substrate specificity studies showed that both enzymes were capable of reducing a variety of aldehydes to their respective alcohols; however, only aldehyde reductase oxidized L-gulonic acid. Surprisingly, both enzymes showed similar reactivities with D-glucose and D-galactose, suggesting that both aldose and aldehyde reductases may contribute to sorbitol production in the EHS tumor cell. The activities of both enzymes were increased by the presence of sulfate ion, but chloride ion decreased the activity of aldose reductase. Both aldose and aldehyde reductases were inhibited by a series of structurally diverse aldose reductase inhibitors. PMID:2106320

  4. Genetics Home Reference: Sepiapterin reductase deficiency

    MedlinePLUS

    ... episodes called oculogyric crises. These episodes involve abnormal rotation of the eyeballs; extreme irritability and agitation; and ... least 30 cases have been described in the scientific literature. What genes are related to sepiapterin reductase ...

  5. Assimilatory nitrate reductase from Acinetobacter calcoaceticus.

    PubMed

    Villalobo, A; Roldn, J M; Rivas, J; CrdenasJ

    1977-03-01

    A soluble nitrate reductase from the bacterium Acinetobacter calcoaceticus grown on nitrate has been characterized. The reduction of nitrate to nitrite is mediated by an enzyme of 96000 molecular weight that can use as electron donors either viologen dyes chemically reduced with dithionite or enzymatically reduced with NAD(P)H, through specific diaphorases which utilize viologens as electron acceptors. Nitrate reductase activity is molybdenumdependent as shown by tungstate antagonistic experiments and is sensitive to--SH reagents and metal chelators such as KCN. The enzyme synthesis is repressed by ammonia. Moreover, nitrate reductase activity undergoes a quick inactivation either by dithionite and temperature or by dithionite in the presence of small amounts of nitrate. Cyanate prevents this inactivating process and can restore the activity once the inactivation had occurred, thus suggesting that an interconversion mechanism may participate in the regulation of Acinetobacter nitrate reductase. PMID:849099

  6. Genetics Home Reference: 5-alpha reductase deficiency

    MedlinePLUS

    ... for a chemical reaction that converts the hormone testosterone to DHT. DHT is essential for the normal ... steroid 5-alpha reductase 2 from effectively converting testosterone to DHT in the developing reproductive tissues. These ...

  7. Structure of a bacterial homologue of vitamin K epoxide reductase.

    PubMed

    Li, Weikai; Schulman, Sol; Dutton, Rachel J; Boyd, Dana; Beckwith, Jon; Rapoport, Tom A

    2010-01-28

    Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain gamma-carboxylation of many blood coagulation factors. Here, we report the 3.6 A crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins to reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anticoagulant. PMID:20110994

  8. Structure of a bacterial homologue of vitamin K epoxide reductase

    SciTech Connect

    Li, Weikai; Schulman, Sol; Dutton, Rachel J.; Boyd, Dana; Beckwith, Jon; Rapoport, Tom A.

    2010-03-19

    Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain {gamma}-carboxylation of many blood coagulation factors. Here, we report the 3.6 {angstrom} crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins to reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anticoagulant.

  9. Sequential backbone resonance assignments of the E. coli dihydrofolate reductase Gly67Val mutant: folate complex.

    PubMed

    Puthenpurackal Narayanan, Sunilkumar; Maeno, Akihiro; Wada, Yuji; Tate, Shin-Ichi; Akasaka, Kazuyuki

    2016-04-01

    Occasionally, a mutation in an exposed loop region causes a significant change in protein function and/or stability. A single mutation Gly67Val of E. coli dihydrofolate reductase (DHFR) in the exposed CD loop is such an example. We have carried out the chemical shift assignments for H(N), N(H), C(α) and C(β) atoms of the Gly67Val mutant of E. coli DHFR complexed with folate at pH 7.0, 35 °C, and then evaluated the H(N), N(H), C(α) and C(β) chemical shift changes caused by the mutation. The result indicates that, while the overall secondary structure remains the same, the single mutation Gly67Val causes site-specific conformational changes of the polypeptide backbone restricted around the adenosine-binding subdomain (residues 38-88) and not in the distant catalytic domain. PMID:26482924

  10. Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment☆

    PubMed Central

    Rajagopalan, Priya; Jahanshad, Neda; Stein, Jason L.; Hua, Xue; Madsen, Sarah K.; Kohannim, Omid; Hibar, Derrek P.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Bis, Joshua C.; Kuller, Lewis H.; Riverol, Mario; Becker, James T.; Lopez, Oscar L.; Thompson, Paul M.

    2012-01-01

    A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75 ± 7.1 years) scanned with brain MRI and genotyped as part of Alzheimer's Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76 ± 5.5 years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR ‘T’ alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2–8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5–1.5% per T allele at 1 year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5–12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI. PMID:24179750

  11. The KC Channel in the cbb3-Type Respiratory Oxygen Reductase from Rhodobacter capsulatus Is Required for Both Chemical and Pumped Protons

    PubMed Central

    Y?ld?z, Glgez Gke; Gennis, Robert B.; Daldal, Fevzi

    2014-01-01

    The heme-copper superfamily of proton-pumping respiratory oxygen reductases are classified into three families (A, B, and C families) based on structural and phylogenetic analyses. Most studies have focused on the A family, which includes the eukaryotic mitochondrial cytochrome c oxidase as well as many bacterial homologues. Members of the C family, also called the cbb3-type oxygen reductases, are found only in prokaryotes and are of particular interest because of their presence in a number of human pathogens. All of the heme-copper oxygen reductases require proton-conducting channels to convey chemical protons to the active site for water formation and to convey pumped protons across the membrane. Previous work indicated that there is only one proton-conducting input channel (the KC channel) present in the cbb3-type oxygen reductases, which, if correct, must be utilized by both chemical protons and pumped protons. In this work, the effects of mutations in the KC channel of the cbb3-type oxygen reductase from Rhodobacter capsulatus were investigated by expressing the mutants in a strain lacking other respiratory oxygen reductases. Proton pumping was evaluated by using intact cells, and catalytic oxygen reductase activity was measured in isolated membranes. Two mutations, N346M and Y374F, severely reduced catalytic activity, presumably by blocking the chemical protons required at the active site. One mutation, T272A, resulted in a substantially lower proton-pumping stoichiometry but did not inhibit oxygen reductase activity. These are the first experimental data in support of the postulate that pumped protons are taken up from the bacterial cytoplasm through the KC channel. PMID:24563037

  12. Characterization of thyroidal glutathione reductase

    SciTech Connect

    Raasch, R.J.

    1989-01-01

    Glutathione levels were determined in bovine and rat thyroid tissue by enzymatic conjugation with 1-chloro-2,4-dinitrobenzene using glutathione S-transferase. Bovine thyroid tissue contained 1.31 {+-} 0.04 mM reduced glutathione (GSH) and 0.14 {+-} 0.02 mM oxidized glutathione (GSSG). In the rat, the concentration of GSH was 2.50 {+-} 0.05 mM while GSSG was 0.21 {+-} 0.03 mM. Glutathione reductase (GR) was purified from bovine thyroid to electrophoretic homogeneity by ion exchange, affinity and molecular exclusion chromatography. A molecular weight range of 102-109 kDa and subunit size of 55 kDa were determined for GR. Thyroidal GR was shown to be a favoprotein with one FAD per subunit. The Michaelis constants of bovine thyroidal GR were determined to be 21.8 {mu}M for NADPH and 58.8 {mu}M for GSSG. The effect of thyroid stimulating hormone (TSH) and thyroxine (T{sub 4}) on in vivo levels of GR and glucose 6-phosphate dehydrogenase were determined in rat thyroid homogenates. Both enzymes were stimulated by TSH treatment and markedly reduced following T{sub 4} treatment. Lysosomal hydrolysis of ({sup 125}I)-labeled and unlabeled thyroglobulin was examined using size exclusion HPLC.

  13. Thioredoxin Reductase and its Inhibitors

    PubMed Central

    Saccoccia, Fulvio; Angelucci, Francesco; Boumis, Giovanna; Carotti, Daniela; Desiato, Gianni; Miele, Adriana E; Bellelli, Andrea

    2014-01-01

    Thioredoxin plays a crucial role in a wide number of physiological processes, which span from reduction of nucleotides to deoxyriboucleotides to the detoxification from xenobiotics, oxidants and radicals. The redox function of Thioredoxin is critically dependent on the enzyme Thioredoxin NADPH Reductase (TrxR). In view of its indirect involvement in the above mentioned physio/pathological processes, inhibition of TrxR is an important clinical goal. As a general rule, the affinities and mechanisms of binding of TrxR inhibitors to the target enzyme are known with scarce precision and conflicting results abound in the literature. A relevant analysis of published results as well as the experimental procedures is therefore needed, also in view of the critical interest of TrxR inhibitors. We review the inhibitors of TrxR and related flavoreductases and the classical treatment of reversible, competitive, non competitive and uncompetitive inhibition with respect to TrxR, and in some cases we are able to reconcile contradictory results generated by oversimplified data analysis. PMID:24875642

  14. Characterization and reconstitute of a [Fe4S4] adenosine 5'-phosphosulfate reductase from Acidithiobacillus ferrooxidans.

    PubMed

    Zheng, Chunli; Zhang, Yanfei; Liu, Yuandong; Wu, Anna; Xia, Lexian; Zeng, Jia; Liu, Jianshe; Qiu, Guanzhou

    2009-06-01

    Adenosine 5'-phosphosulfate (APS) reductase is a key enzyme involved in the pathways of sulfate reduction and sulfide oxidation in the biological sulfur cycle. In this study, the gene of APS reductase from Acidithiobacillus ferrooxidans was cloned and expressed in Escherichia coli, the soluble protein was purified by one-step affinity chromatography to apparent homogeneity. The molecular mass of the recombinant APS reductase was determined to be 28 kDa using SDS-PAGE. According to optical and EPR spectra results of the recombinant protein confirmed that the iron-sulfur cluster inserted into the active site of the protein. Site-directed mutation for the enzyme revealed that Cys110, Cys111, Cys193, and Cys196 were in ligation with the iron-sulfur cluster. The [Fe4S4] cluster could be assembled in vitro, and exhibited electron transport and redox catalysis properties. As we know so far, this is the first report of expression in E. coli of APS reductase from A. ferrooxidans. PMID:19225840

  15. CATALYTIC ADVANTAGES PROVIDED BY SELENOCYSTEINE IN METHIONINE-S-SULFOXIDE REDUCTASES

    PubMed Central

    Kim, Hwa-Young; Fomenko, Dmitri E.; Yoon, Yeo-Eun; Gladyshev, Vadim N.

    2008-01-01

    Methionine sulfoxide reductases are key enzymes that repair oxidatively damaged proteins. Two distinct stereospecific enzyme families are responsible for this function: MsrA (methionine-S-sulfoxide reductase) and MsrB (methionine-R-sulfoxide reductase). In the present study, we identified multiple selenoprotein MsrA sequences in organisms from bacteria to animals. We characterized the selenocysteine (Sec)-containing Chlamydomonas MsrA and found that this protein exhibited 1050-fold higher activity than either its cysteine (Cys) mutant form or the natural mouse Cys-containing MsrA, making this selenoenzyme the most efficient MsrA known. We also generated a selenoprotein form of mouse MsrA and found that the presence of Sec increased the activity of this enzyme when a resolving Cys was mutated in the protein. These data suggest that the presence of Sec improves the reduction of methionine sulfoxide by MsrAs. However, the oxidized selenoprotein could not always be efficiently reduced to regenerate the active enzyme. Overall, this study demonstrates that sporadically evolved Sec-containing forms of methionine sulfoxide reductases reflect catalytic advantages provided by Sec in these and likely other thiol-dependent oxidoreductases. PMID:17105189

  16. A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

    PubMed Central

    Zeidner, Joshua F.; Karp, Judith E.; Blackford, Amanda L.; Smith, B. Douglas; Gojo, Ivana; Gore, Steven D.; Levis, Mark J.; Carraway, Hetty E.; Greer, Jacqueline M.; Ivy, S. Percy; Pratz, Keith W.; McDevitt, Michael A.

    2014-01-01

    Myeloproliferative neoplasms are a varied group of disorders that can have prolonged chronic phases, but eventually accelerate and can transform into a secondary acute myeloid leukemia that is ultimately fatal. Triapine is a novel inhibitor of the M2 subunit of ribonucleotide reductase. Sequential inhibition of ribonucleotide reductase with triapine and an M1 ribonucleotide reductase inhibitor (fludarabine) was noted to be safe, and led to a 29% complete plus partial response rate in myeloproliferative neoplasms. This article reports the findings of a phase II trial of triapine (105 mg/m2/day) followed by fludarabine (30 mg/m2/day) daily for 5 consecutive days in 37 patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. The overall response rate was 49% (18/37), with a complete remission rate of 24% (9/37). Overall response rates and complete remissions were seen in all disease subsets, including secondary acute myeloid leukemia, in which the overall response rate and complete remission rate were 48% and 33%, respectively. All patients with known JAK2 V617F mutations (6/6) responded. The median overall survival of the entire cohort was 6.9 months, with a median overall survival of both overall responders and complete responders of 10.6 months. These data further demonstrate the promise of sequential inhibition of ribonucleotide reductase in patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. This study was registered with clinicaltrials.gov (NCT00381550). PMID:24362550

  17. Structural and mechanistic insights on nitrate reductases.

    PubMed

    Coelho, Catarina; Romo, Maria Joo

    2015-12-01

    Nitrate reductases (NR) belong to the DMSO reductase family of Mo-containing enzymes and perform key roles in the metabolism of the nitrogen cycle, reducing nitrate to nitrite. Due to variable cell location, structure and function, they have been divided into periplasmic (Nap), cytoplasmic, and membrane-bound (Nar) nitrate reductases. The first crystal structure obtained for a NR was that of the monomeric NapA from Desulfovibrio desulfuricans in 1999. Since then several new crystal structures were solved providing novel insights that led to the revision of the commonly accepted reaction mechanism for periplasmic nitrate reductases. The two crystal structures available for the NarGHI protein are from the same organism (Escherichia coli) and the combination with electrochemical and spectroscopic studies also lead to the proposal of a reaction mechanism for this group of enzymes. Here we present an overview on the current advances in structural and functional aspects of bacterial nitrate reductases, focusing on the mechanistic implications drawn from the crystallographic data. PMID:26362109

  18. Atomic Structure of Salutaridine Reductase from the Opium Poppy (Papaver somniferum)

    SciTech Connect

    Higashi, Yasuhiro; Kutchan, Toni M.; Smith, Thomas J.

    2011-11-18

    The opium poppy (Papaver somniferum L.) is one of the oldest known medicinal plants. In the biosynthetic pathway for morphine and codeine, salutaridine is reduced to salutaridinol by salutaridine reductase (SalR; EC 1.1.1.248) using NADPH as coenzyme. Here, we report the atomic structure of SalR to a resolution of {approx}1.9 {angstrom} in the presence of NADPH. The core structure is highly homologous to other members of the short chain dehydrogenase/reductase family. The major difference is that the nicotinamide moiety and the substrate-binding pocket are covered by a loop (residues 265-279), on top of which lies a large 'flap'-like domain (residues 105-140). This configuration appears to be a combination of the two common structural themes found in other members of the short chain dehydrogenase/reductase family. Previous modeling studies suggested that substrate inhibition is due to mutually exclusive productive and nonproductive modes of substrate binding in the active site. This model was tested via site-directed mutagenesis, and a number of these mutations abrogated substrate inhibition. However, the atomic structure of SalR shows that these mutated residues are instead distributed over a wide area of the enzyme, and many are not in the active site. To explain how residues distal to the active site might affect catalysis, a model is presented whereby SalR may undergo significant conformational changes during catalytic turnover.

  19. 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

  20. The NosX and NirX proteins of Paracoccus denitrificans are functional homologues: their role in maturation of nitrous oxide reductase.

    PubMed

    Saunders, N F; Hornberg, J J; Reijnders, W N; Westerhoff, H V; de Vries, S; van Spanning, R J

    2000-09-01

    The nos (nitrous oxide reductase) operon of Paracoccus denitrificans contains a nosX gene homologous to those found in the nos operons of other denitrifiers. NosX is also homologous to NirX, which is so far unique to P. denitrificans. Single mutations of these genes did not result in any apparent phenotype, but a double nosX nirX mutant was unable to reduce nitrous oxide. Promoter-lacZ assays and immunoblotting against nitrous oxide reductase showed that the defect was not due to failure of expression of nosZ, the structural gene for nitrous oxide reductase. Electron paramagnetic resonance spectroscopy showed that nitrous oxide reductase in cells of the double mutant lacked the Cu(A) center. A twin-arginine motif in both NosX and NirX suggests that the NosX proteins are exported to the periplasm via the TAT translocon. PMID:10960107

  1. Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate.

    PubMed

    Pezzetti, F; Martinelli, M; Scapoli, L; Carinci, F; Palmieri, A; Marchesini, J; Carinci, P; Caramelli, E; Rullo, R; Gombos, F; Tognon, M

    2004-07-01

    The pathogenesis of cleft lip with or without cleft palate (CL/P) is complex; its onset could be due to the interaction of various genetic and environmental factors. Recently MTHFR functional polymorphisms were found to increase the risk of this common malformation; however, this finding is still debated. We investigated 110 sporadic CL/P patients, their parents and 289 unrelated controls for c.665C>T (commonly known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala) polymorphism in the MTHFR gene. Transmission disequilibrium test (TDT) showed no distortion in allele transmission. Nevertheless, association studies revealed significant differences in allele frequencies between mothers of CL/P patients and controls. This work supports the hypothesis that a lower MTHFR enzyme activity in pregnant women, mostly related to the c.665C>T variant form, is responsible for a higher risk of having CL/P affected offspring. PMID:15221800

  2. 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

  3. Nitric oxide reductase from Pseudomonas stutzeri. Primary structure and gene organization of a novel bacterial cytochrome bc complex.

    PubMed

    Zumft, W G; Braun, C; Cuypers, H

    1994-01-15

    Nitric oxide (NO) reductase is an integral membrane component of the anaerobic respiratory chain of Pseudomonas stutzeri that transforms nitrate to dinitrogen (denitrification). The enzyme catalyzes the reduction of NO to nitrous oxide. The structural genes for the NO reductase complex, norC and norB, were sequenced and their organization established by primer extension and Northern blot analysis. The norCB genes encoding the cytochrome c and cytochrome b subunits of the enzyme are contiguous and transcribed as a single 2.0-kb transcript. The promoter region has a canonical recognition motif for the transcriptional activator protein Fnr, centered at -40.5 nucleotides from the initiation site of transcription. No similarity of the derived gene products to known cytochromes of b- or c-type was found in a data bank search. Post-translational processing of the two subunits was limited to the removal of the terminal methionine to leave an N-terminal serine in either subunit. The mature cytochrome c subunit (16508Da, 145 residues) is predicted to be a bitopic protein with a single membrane anchor. The mature cytochrome b subunit (53006Da, 473 residues) is a putatively polytopic, strongly hydrophobic membrane-bound protein with 12 potential transmembrane segments. Several histidine and proline residues were identified with potentially structural and/or functional importance. Mutational inactivation of NO reductase by deletion of norB or the norCB genes affected strongly the in vivo activity of respiratory nitrite reductase (cytochrome cd1), but to a much lesser extent the expression level of this enzyme. In turn, mutational inactivation of the structural gene for cytochrome cd1, nirS, or loss of in vivo nitrite reduction by mutation of the nirT gene, encoding a presumed tetraheme cytochrome, lowered the expression level of NO reductase to 5-20%, but hardly its catalytic activity. The cellular concentration of NO reductase increased again on restoration of nitrite reduction in the nirS::Tn5 mutant MK202 by complementation with nirS or with the heterologous nirK gene, encoding the Cu-containing nitrite reductase from Pseudomonas aureofaciens. Thus, NO may be required as an inducer for its own reductase. Our results show that the nitrite-reducing system and the NO-reducing system are not operating independently from each other but are interlaced by activity modulation and regulation of enzyme synthesis. PMID:7508388

  4. Respiratory arsenate reductase as a bidirectional enzyme

    USGS Publications Warehouse

    Richey, C.; Chovanec, P.; Hoeft, S.E.; Oremland, R.S.; Basu, P.; Stolz, J.F.

    2009-01-01

    The haloalkaliphilic bacterium Alkalilimnicola ehrlichii is capable of anaerobic chemolithoautotrophic growth by coupling the oxidation of arsenite (As(III)) to the reduction of nitrate and carbon dioxide. Analysis of its complete genome indicates that it lacks a conventional arsenite oxidase (Aox), but instead possesses two operons that each encode a putative respiratory arsenate reductase (Arr). Here we show that one homolog is expressed under chemolithoautotrophic conditions and exhibits both arsenite oxidase and arsenate reductase activity. We also demonstrate that Arr from two arsenate respiring bacteria, Alkaliphilus oremlandii and Shewanella sp. strain ANA-3, is also biochemically reversible. Thus Arr can function as a reductase or oxidase. Its physiological role in a specific organism, however, may depend on the electron potentials of the molybdenum center and [Fe–S] clusters, additional subunits, or constitution of the electron transfer chain. This versatility further underscores the ubiquity and antiquity of microbial arsenic metabolism.

  5. Phylogenomics of Mycobacterium Nitrate Reductase Operon.

    PubMed

    Huang, Qinqin; Abdalla, Abualgasim Elgaili; Xie, Jianping

    2015-07-01

    NarGHJI operon encodes a nitrate reductase that can reduce nitrate to nitrite. This process enhances bacterial survival by nitrate respiration under anaerobic conditions. NarGHJI operon exists in many bacteria, especially saprophytic bacteria living in soil which play a key role in the nitrogen cycle. Most actinomycetes, including Mycobacterium tuberculosis, possess NarGHJI operons. M. tuberculosis is a facultative intracellular pathogen that expands in macrophages and has the ability to persist in a non-replicative form in granuloma lifelong. Nitrogen and nitrogen compounds play crucial roles in the struggle between M. tuberculosis and host. M. tuberculosis can use nitrate as a final electron acceptor under anaerobic conditions to enhance its survival. In this article, we reviewed the mechanisms regulating nitrate reductase expression and affecting its activity. Potential genes involved in regulating the nitrate reductase expression in M. tubercul