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1.
Pol J Pathol ; 71(1): 69-74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32429658

RESUMO

Molecular next gene sequencing was used to evaluate mutations in 409 common mutated cancer-related genes in malignant mesothelioma of tunica vaginalis testis (MMTVT) of 81-year-old man. Multifocal papillary-solid areas contained necrosis among highly cellular fields with multiple mitoses. It was positive for WT1, CKAE1/AE3, calretinin, CK7 with negativity for CK5, PSA, TTF-1. Following mutations were revealed in PARP1 (NM_001618: c.2285TG, p.K135R), MTRR (NM_024010: c.147A>G, p.I49M) and two sorts of mutations in structure of KMT2C gene (NM_170606: c.2447_2448insA (c.2447dupA), p.Y816fs and NM_170606: c.1042G>A, p.D348N) for the first time in MMTVT.


Assuntos
Mesotelioma/genética , Neoplasias Testiculares/genética , Adenosina Trifosfatases/genética , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Ferredoxina-NADP Redutase/genética , Humanos , Masculino , Mutação , Fator de Transcrição PAX8/genética , Poli(ADP-Ribose) Polimerase-1/genética , Ubiquitina-Proteína Ligases/genética
2.
Wei Sheng Yan Jiu ; 49(1): 123-131, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32290927

RESUMO

OBJECTIVE: To analyze geographical distribution characteristics of folate metabolism related single nucleotide polymorphisms. METHODS: This work made a statistical analysis of MTHFR and MTRR gene polymorphism distribution about Chinese Han and minority childbearing age women in 16 provinces and 2 municipalities from 64 published Chinese literatures, depicted the regional distributive characteristics of the two gene polymorphisms, and analyzed the association with neural tube defects status for a long time in China. RESULTS: By summarizing and analyzing single nucleotide polymorphisms of MTHFR C677 T in Chinese Han and minority childbearing age women in 16 provinces and 2 municipalities, the results showed that MTHFR 677 TT and 677 T allele frequency increased steadily from south to north, MTHFR 1298 CC occupied a very small proportion. Through interaction analysis of A1298 C and C677 T, the result showed that two genes presented a linkage imbalance, and TT/AA frequency distribution presented a gradually decreasing trend from north to south, and there were no TT/AC, TT/CC, and CT/CC nationwide, it was found that MTRR 66 AA accounted from 34% to 58%, with the northern part slightly higher than the southern part. And MTRR 66 GG was between 5% and 17%. CONCLUSION: We could pay attention to gene polymorphism risk assessment to reduce neural tube defects for childbearing age women, in order to provide powerful human genetics data support for improving the birth population quality and national public health policy.


Assuntos
Ferredoxina-NADP Redutase/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Carbono , China , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Geografia , Humanos , Redes e Vias Metabólicas
3.
Genet Test Mol Biomarkers ; 24(3): 150-155, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32119787

RESUMO

Purpose: The methylene tetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, and the methionine synthase reductase (MTRR) A66G polymorphisms are the three most common folate metabolism-related loci in the Chinese population. They are associated with numerous birth defects or congenital diseases. To facilitate screening and genetic counseling, we established a method for the simultaneous detection of these three polymorphisms using the Luminex liquid suspension chip and multiple asymmetric polymerase chain reactions (PCRs). Materials and Methods: The three polymorphisms were amplified by multiplex PCR with biotinylated primers, followed by hybridization with six probe-linked magnetic microspheres. The mean fluorescent intensity value in each microsphere was detected by Luminex Magpix for polymorphism detection in 150 samples and confirmed by sequencing. Results: The consistency between the Luminex liquid suspension chip method and sequencing was 100%. Among the 150 randomized samples, the minor allele frequency (MAF) of MTHFR C677T was 0.41, which was the most common variant allele, followed by MTRR A66G (MAF = 0.24), and finally MTHFR A1298C (MAF = 0.19). Conclusion: The Luminex liquid suspension chip method can replace sequencing to analyze the MTHFR C677T, MTRR A1298C, and MTRR A66G loci simultaneously as a rapid, convenient, accurate, and stable method for large-scale testing.


Assuntos
Ferredoxina-NADP Redutase/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Reação em Cadeia da Polimerase/métodos , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Primers do DNA/genética , Feminino , Ferredoxina-NADP Redutase/análise , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/análise , Polimorfismo de Nucleotídeo Único/genética
4.
Clin Exp Hypertens ; 42(1): 52-60, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30786773

RESUMO

Background: Hypertension (HTN), dyslipidemia and hyperhomocysteinemia (HHcy) are risk factors for cardiovascular disease (CVD).Methods: Hypertensive Chinese subjects (n = 228) were enrolled. MTHFR C667T, MTHFR A1298C, MTR A2756G, and MTRR A66G genotypes were determined. Unconditional logistic regression was performed to determine the associations of serum Hcy status and genotypes with HTN and dyslipidemia.Results: The mean age of hypertensive adults was 65.53 ± 9.94 years, including 88 (38.6%) men and 140 (61.4%) women. Patients with MTHFR 667TT and MTRR GG carriers showed higher serum Hcy levels (P = 0.019 and 0.018, respectively), which is associated with higher serum triacylglycerols (TAG) and total cholesterol (TC) levels (P = 0.014 and 0.044, respectively) and a higher risk for hypertriglyceridemia (OR = 1.889, 95% CI: 1.105-3.229, P = 0.020). Compared with low Hcy and MTRR 66AA, those with high Hcy and 66AA or 66AG+GG showed higher odd\s of hypertriglyceridemia (MTRR 66AA+ high Hcy: OR: 2.692, 95% CI: 1.189-6.096, Pcombined = 0.018; MTRR 66AG/GG+ high Hcy: OR: 3.433, 95% CI: 1.517-7.772, Pcombined = 0.003, respectively). Patients with high Hcy and MTHFR 667CC, as well as those with low Hcy and 667CT+TT, showed lower odds of uncontrolled SBP (MTHFR 667CC+ high Hcy: OR: 0.338, 95% CI: 0.115-0.996, Pcombined = 0.049; MTHFR 667CT/TT+ low Hcy: OR: 0.421, 95% CI: 0.193-0.921, Pcombined = 0.030) compared to patients with low Hcy and MTHFR 667CC.Conclusions: Serum Hcy status and Hcy metabolism gene polymorphisms (MTHFR C667T and MTRR A66G) may have synergistic effects on the prevalence of HTN and dyslipidemia.


Assuntos
Ferredoxina-NADP Redutase/genética , Homocisteína/sangue , Hipertensão/genética , Hipertrigliceridemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Colesterol/sangue , Feminino , Ácido Fólico , Heterozigoto , Humanos , Hipertensão/sangue , Hipertrigliceridemia/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/sangue
5.
Medicine (Baltimore) ; 98(51): e18273, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860974

RESUMO

BACKGROUND: Methionine synthase reductase gene (MTRR A66G) polymorphism and methionine synthase gene (MTR A2756G) polymorphism have shown an association with idiopathic male infertility risk in several ethnic populations. However, their small sample sizes and inconsistent outcomes have prevented strong conclusions. We performed a meta-analysis with published studies to evaluate the associations of the 2 single nucleotide polymorphisms (SNPs) and idiopathic male infertility risk. METHODS: A thorough literature search was performed up to Jun 21, 2019 with Medline, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), China Biology Medical literature (CBM), China Science and Technology Journal Database (VIP), and Chinese literature (Wan Fang) databases. Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the strength of associations. RESULTS: Seventeen studies including 3269 cases and 3192 controls met the inclusion criteria. Our meta-analysis showed that the MTR A2756G mutation may contribute to genetic susceptibility to the risk of idiopathic male infertility in Non-Asians, but not to Asian population, whereas the MTRR A66G polymorphism may be unrelated to idiopathic male infertility in both Non-Asian and Asian populations. In the stratified analysis by infertility type, the MTR A2756G polymorphism was a risk factor for both non-obstructive azoospermia (NOA) and oligoasthenoteratozoospermia (OAT) patients. However, the MTRR A66G polymorphism is associated with risk for OAT in Asian, but not in Non-Asian population. CONCLUSION: This meta-analysis suggested that the MTR A2756G and MTRR A66G polymorphisms were risk factors for idiopathic male infertility. Studies with larger sample sizes and representative population-based cases and well-matched controls are needed to validate our results.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Ferredoxina-NADP Redutase/genética , Infertilidade Masculina/genética , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Fatores de Risco
6.
FEBS Open Bio ; 9(12): 2126-2136, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31665566

RESUMO

Ferredoxin-NADP+ reductase (FNR) in plants receives electrons from ferredoxin (Fd) at the end of the photosynthetic electron transfer chain and converts NADP+ to NADPH. The interaction between Fd and FNR in plants was previously shown to be attenuated by NADP(H). Here, we investigated the molecular mechanism of this phenomenon using maize FNR and Fd, as the three-dimensional structure of this complex is available. NADPH, NADP+ , and 2'5'-ADP differentially affected the interaction, as revealed through kinetic and physical binding analyses. Site-directed mutations of FNR which change the affinity for NADPH altered the affinity for Fd in the opposite direction to that for NADPH. We propose that the binding of NADP(H) causes a conformational change of FNR which is transferred to the Fd-binding region through different domains of FNR, resulting in allosteric changes in the affinity for Fd.


Assuntos
Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , NADP/metabolismo , Sequência de Aminoácidos/genética , Transporte de Elétrons/genética , Transporte de Elétrons/fisiologia , Ferredoxina-NADP Redutase/fisiologia , Ferredoxinas/metabolismo , Cinética , Modelos Moleculares , Oxirredução , Fotossíntese/genética , Conformação Proteica , Zea mays/genética , Zea mays/metabolismo
7.
Mol Omics ; 15(5): 340-347, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31429849

RESUMO

Adrenodoxin reductase, a widely conserved mitochondrial P450 protein, catalyses essential steps in steroid hormone biosynthesis and is highly expressed in the adrenal cortex. The yeast adrenodoxin reductase homolog, Arh1p, is involved in cytoplasmic and mitochondrial iron homeostasis and is required for activity of enzymes containing an Fe-S cluster. In this paper, we investigated the response of yeast to the loss of a single copy of ARH1, an oxidoreductase of the mitochondrial inner membrane, which is among the few mitochondrial proteins that is essential for viability in yeast. The phenotypic, transcriptional, proteomic, and metabolic landscape indicated that Saccharomyces cerevisiae successfully adapted to this loss, displaying an apparently dosage-insensitive cellular response. However, a considered investigation of transcriptional regulation in ARH1-impaired yeast highlighted that a significant hierarchical reorganisation occurred, involving the iron assimilation and tyrosine biosynthetic processes. The interconnected roles of the iron and tyrosine pathways, coupled with oxidative processes, are of interest beyond yeast since they are involved in dopaminergic neurodegeneration associated with Parkinson's disease. The identification of similar responses in yeast, albeit preliminary, suggests that this simple eukaryote could have potential as a model system for investigating the regulatory mechanisms leading to the initiation and progression of early disease responses in humans.


Assuntos
Ferredoxina-NADP Redutase/metabolismo , Haploinsuficiência , Proteínas de Membrana/metabolismo , Doença de Parkinson/metabolismo , Ploidias , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Biologia Computacional , Ferredoxina-NADP Redutase/genética , Regulação Enzimológica da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Humanos , Proteínas com Ferro-Enxofre/biossíntese , Proteínas de Membrana/genética , Mutação , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
8.
Med Sci Monit ; 25: 5801-5812, 2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31377750

RESUMO

BACKGROUND This study aimed to screen common and low-frequency variants of nonobstructive azoospermia (NOA)-associated genes, and to construct a database for NOA-associated single nucleotide variants (SNVs). MATERIAL AND METHODS Next-generation sequencing of 466 NOA-associated genes was performed in 34 patients with NOA (mean age, 29.06±4.49 years) and 40 sperm donors (mean age, 25.08±5.75 years) from the Han population of northeast China. The SNV database was constructed by summarizing NOA non-negatively-associated SNVs showing statistical differences between NOA cases and controls, and then selecting low-frequency variants using Baylor's pipeline, to identify statistically valid SNVs. RESULTS There were 65 SNVs identified that were significantly different between both groups (p<0.05). Five genetic variants showed positive correlations with NOA: MTRR c.537T>C (rs161870), odds ratios (OR), 3.686, 95% confidence interval (CI), 1.228-11.066; MTRR, c.1049A>G (rs162036), OR, 3.686, 95% CI, 1.228-11.066; PIWIL1, c.1580G>A (rs1106042), OR, 4.737, 95% CI, 1.314-17.072; TAF4B, c.1815T>C (rs1677016), OR, 3.599, 95% CI, 1.255-10.327; and SOX10 c.927T>C (rs139884), OR, 3.192, 95% CI, 1.220-8.353. Also, 52 NOA non-negatively associated SNVs and 39 SNVs were identified by Baylor's pipeline and selected for the SNV database. CONCLUSIONS Five genetic variants were shown to have positive correlations with NOA. The SNV database constructed contained NOA non-negatively associated SNVs and low-frequency variants. This study showed that this approach was an effective strategy to identify risk alleles of NOA.


Assuntos
Azoospermia/genética , Adulto , Alelos , Proteínas Argonauta/genética , Grupo com Ancestrais do Continente Asiático/genética , Azoospermia/metabolismo , China/epidemiologia , Grupos Étnicos/genética , Ferredoxina-NADP Redutase/genética , Frequência do Gene/genética , Predisposição Genética para Doença , Variação Genética/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Infertilidade Masculina/genética , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição SOXE/genética , Análise de Sequência de DNA/métodos , Espermatogênese/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética
9.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370354

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Epigênese Genética , Redes e Vias Metabólicas/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Idoso , Idoso de 80 Anos ou mais , DNA (Citosina-5-)-Metiltransferases/metabolismo , Feminino , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , Ácido Fólico/metabolismo , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Metionina/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Timidilato Sintase/genética , Timidilato Sintase/metabolismo
10.
Oncogene ; 38(35): 6256-6269, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332290

RESUMO

p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this study, we found that FDXR deficiency decreased mutant p53 expression along with altered iron metabolism in p53R270H/- MEFs and cancer cells carrying mutant p53. Consistently, we found that decreased expression of mutant p53 by FDXR deficiency inhibited mutant p53-R270H to induce carcinoma and high grade pleomorphic sarcoma in FDXR+/-; p53R270H/- mice as compared with p53R270H/- mice. Moreover, we found that like its effect on wild-type p53, loss of IRP2 increased mutant p53 expression. However, unlike its effect to suppress cell growth in cells carrying wild-type p53, loss of IRP2 promoted cell growth in cancer cells expressing mutant p53. Finally, we found that ectopic expression of IRP2 suppressed cell growth in a mutant p53-dependent manner. Together, our data indicate that mutant p53 gain-of-function can be suppressed by IRP2 and FDXR deficiency, both of which may be explored to target tumors carrying mutant p53.


Assuntos
Carcinogênese/genética , Proteína 2 Reguladora do Ferro/fisiologia , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/patologia , Células Cultivadas , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , Mutação com Ganho de Função/fisiologia , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Células HCT116 , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
11.
Georgian Med News ; (290): 124-127, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322528

RESUMO

Autism spectrum disorders (ASD) are considered an epidemic - only in the last 5 years the incidence of pathology has increased from 1: 166 to 1:68 children. The main role in the pathogenesis of ASD currently belongs to the violation of the epigenetic status in the form of gene polymorphisms. An example is the polymorphic variants of the genes of the folate-methionine cycle enzymes, which regulate the epigenetic status through a methylation process. The article presents a case of autism spectrum disorder against the background of impaired epigenetic status (metabolic dopamine neurotransmitters and the methylation cycle). Individually selected metabolic correction based on biochemical parameters allowed improving behavior, stimulating speech development, stopping long subfebrile and hypersalivation.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/reabilitação , Epigênese Genética/genética , Ferredoxina-NADP Redutase/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Transtorno Autístico , Criança , Metilação de DNA , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Receptores de Dopamina D2
12.
Pathobiology ; 86(4): 190-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238314

RESUMO

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


Assuntos
Ferredoxina-NADP Redutase/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único , Alelos , Pai , Feminino , Ácido Fólico/metabolismo , Genótipo , Homocisteína/metabolismo , Homocistinúria/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Mães , Espasticidade Muscular/genética , Defeitos do Tubo Neural/fisiopatologia , Polimorfismo de Fragmento de Restrição , Gravidez , Transtornos Psicóticos/genética , Tunísia
13.
Genes Genomics ; 41(8): 983-991, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209768

RESUMO

BACKGROUND: Hyperhomocysteinemia is a potential risk factor for the development of metabolic syndrome (MetS). Among genes involved in homocysteine metabolism, polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are known to be associated with MetS incidence. However, effects of polymorphisms of other folate metabolism-related genes on MetS susceptibility are not well known yet. OBJECTIVE: This study was to determine whether methionine synthase (MTR) 2756A > G, methionine synthase reductase (MTRR) 66A > G, and thymidylate synthase enhancer region (TSER) 2R/3R polymorphisms might be associated with risks of MetS development in the Korean population. METHODS: Genotype analysis of the three polymorphisms was performed for a total of 483 subjects including 236 MetS patients and 247 unrelated healthy controls using polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: The present study revealed that MTRR and TSER polymorphisms were associated with susceptibility to MetS. Several genotypes and allele combinations from the three polymorphisms were also related to the MetS prevalence. When polymorphism data were stratified according to the risk components of MetS, MTR polymorphism was significantly associated with an increased risk of MetS in subjects with systolic blood pressure < 132.7 mmHg (AOR 1.842, 95% CI 1.039-3.266, P = 0.037) and fasting blood glucose level < 106.3 mg/dL (AOR 1.772, 95% CI 1.069-2.937, P = 0.027). MTRR polymorphism was significantly associated with a decreased risk of MetS in subjects with triglyceride level < 216.3 mg/dL (AOR 0.616, 95% CI 0.399-0.951, P = 0.029). To the best of our knowledge, this is the first to provide reliable evidence about the association of other folate metabolism-related gene polymorphisms besides MTHFR with MetS susceptibility and its risk factors. CONCLUSION: Results of this study suggest that MTRR and TSER polymorphisms might be potential genetic markers for the risk of MetS development in Korean population.


Assuntos
Ferredoxina-NADP Redutase/genética , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Timidilato Sintase/genética , Adulto , Elementos Facilitadores Genéticos , Feminino , Ácido Fólico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade
14.
Asian Pac J Cancer Prev ; 20(5): 1445-1451, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31127906

RESUMO

Purpose: Some variations in the sequence of methionine synthase reductase (MTRR) gene can increase the risk of various cancers such as prostate cancer. The aim of this study was to investigate the association between prostate cancer and the MTRR A66G and C524T gene single nucleotide polymorphisms (SNPs) using an in silico analysis. Methods: In this case-control study, 218 Iranian men, including 108 men with prostate cancer and 110 prostate cancer-free men, were enrolled. The MTRR A66G and C524T genotyping was performed by PCR-RFLP. Some of the bioinformatics tools were employed for the evaluation of polymorphism on the molecular aspects of the MTRR. Results: With regard to the MTRR A66G polymorphism, the genotype AG (OR: 0.85, 95% CI: 0.47-1.54, p= 0.6014), genotype GG (OR: 0.89, 95% CI: 0.42-1.87, p= 0.7512), and allele G (OR: 0.92, 95% CI: 0.63-1.35, p= 0.6686) were not associated with prostate cancer risk. However, the data for C524T SNP showed that the genotype CT was associated with prostate cancer risk (OR: 1.92, 95% CI: 1.06-3.47, p= 0.0308). Further, carriers of the allele T (OR: 1.80, 95% CI: 1.04-3.13, p= 0.0358) were associated with high risk of prostate cancer. In addition, bioinformatics analysis revealed that C524T SNP could affect some molecular aspects of the protein structure, while having no effect on the mRNA structure. Conclusion: The MTRR C524T is a genetic risk factor for prostate cancer; however, the MTRR A66G is not suggested as a suitable biomarker for prostate cancer. To obtain more reliable results, further studies are recommended to use larger sample sizes and investigate the effects of environmental factors.


Assuntos
Ferredoxina-NADP Redutase/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Alelos , Estudos de Casos e Controles , Frequência do Gene/genética , Genótipo , Humanos , Irã (Geográfico) , Masculino , Fatores de Risco
15.
Oncol Rep ; 41(6): 3488-3498, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002356

RESUMO

Epigenetic analysis of the association between the methylation status of the promoter region of the MTRR (5­methyltetrahydrofolate­homocysteine methyltransferase reductase) gene and the risk of acute lymphoblastic leukemia (ALL) in children plays an important role in the early diagnosis, assessment of the malignant degree, treatment and evaluation of the risk of relapse and prognosis of the disease. In the present study, RT­qPCR was used to detect the mRNA levels of the MTRR and MTHFR (methylenetetrahydrofolate reductase) genes in the bone marrow of 20 ALL patients and 20 age­ and sex­matched controls with normal bone marrow. The methylation pattern of the MTRR promoter region in eligible DNA samples was quantitatively analyzed using MALDI­TOF MS. The results indicated that the mRNA expression level of MTRR in the bone marrow from children with ALL was lower than that in the control samples (P<0.05), but no significant difference was detected in the MTHFR gene between the two groups (P>0.05). According to the risk classification of ALL in children with high, medium and low risk, the low­risk group had a higher methylation rate of CpG_6 compared to the medium­risk group. However, the medium­risk group had a higher CpG_46.47 methylation rate compared to the low­risk group. The methylation rates of CpG_26 and CpG_46.47 in the high­risk group were higher than these rates in the low­risk group, while the CpG_42.23.44 methylation rate was lower in the high­risk group than in the low­risk group (P<0.05). The methylation rates at CpG_1, CpG_10, CpG_48 sites, score and the average methylation rate in the ALL­H (high) group (≥50x109/l) were lower than these in the ALL­NH (not high) group (<50x109/l) and the control group (P<0.05). We conclude that abnormal MTRR mRNA expression and the methylation of the MTRR promoter can be used to classify the risk of ALL in children.


Assuntos
Metilação de DNA/genética , Ferredoxina-NADP Redutase/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Adolescente , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas , Fatores de Risco
16.
Ital J Pediatr ; 45(1): 37, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30867013

RESUMO

BACKGROUND: Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring. METHODS: We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones. RESULTS: There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271-13.258; OR = 3.333, 95%CI: 1.068-10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070-3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023-3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361-11.308). CONCLUSION: Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.


Assuntos
Deficiência de Ácido Fólico/genética , Predisposição Genética para Doença/epidemiologia , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Carbono/metabolismo , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Feminino , Ferredoxina-NADP Redutase/genética , Deficiência de Ácido Fólico/diagnóstico , Deficiência de Ácido Fólico/epidemiologia , Marcadores Genéticos/genética , Genótipo , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Antígenos de Histocompatibilidade Menor/genética , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/fisiopatologia , Razão de Chances , Gravidez , Valores de Referência
17.
Medicine (Baltimore) ; 98(8): e14283, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813130

RESUMO

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


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Ferredoxina-NADP Redutase/genética , Predisposição Genética para Doença , Infertilidade Masculina/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , China , Humanos , Masculino , Fatores de Risco
18.
Am J Clin Nutr ; 109(3): 674-683, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30848279

RESUMO

BACKGROUND: The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms. OBJECTIVES: This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk. METHODS: We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings). RESULTS: The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk. CONCLUSIONS: The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Doenças Fetais/enzimologia , Fígado/metabolismo , Defeitos do Tubo Neural/enzimologia , Vitamina B 12/metabolismo , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Estudos de Casos e Controles , Feminino , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , Doenças Fetais/genética , Doenças Fetais/metabolismo , Ácido Fólico/análise , Ácido Fólico/metabolismo , Idade Gestacional , Humanos , Fígado/química , Fígado/embriologia , Fígado/enzimologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Gravidez , Vitamina B 12/análise
19.
Mol Genet Genomic Med ; 7(5): e633, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884202

RESUMO

BACKGROUND: Gastric cancer (GC), the second leading cause of cancer mortality behind lung cancer worldwide, is caused by both genetic and environmental factors. In this study, we evaluated the association between the genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthesis reductase (MTR), and methyltransferase reductase (MTRR) genes and ischemic stroke risk in Chinese population. METHODS: A case-control study was conducted including 681 patients with GC and 756 healthy controls. Chi-squared test/Fisher's exact test and genetic model were used to evaluate associations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression. RESULTS: In the allele model, using the chi-square test, we found that the rs1532268 in MTRR with a minor allele T was significantly associated with increased risk of GC (OR = 1.24, 95% CI, 1.00-1.53; p = 0.048). In the genetic model analysis, we identified that the single-nucleotide polymorphism of the rs1801133 in MTHFR could increase the GC risk in the recessive model (OR = 1.31, 95% CI, 1.01-1.70; p = 0.042) and log-additive model (OR = 1.19, 95% CI, 1.02-1.38; p = 0.025). In MTHFR, a strong linkage of rs2274976 and rs1801133 was detected. The haplotype "GC" in the MTHFR gene was found to prominently increase the risk of GC (OR = 1.26, 95% CI: 1.07-1.47; p = 0.005). Other haplotypes did not display the correlativity. CONCLUSION: This study suggested that MTR and MTHFR polymorphisms may contribute to increase the risk of GC.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Ferredoxina-NADP Redutase/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Mol Biotechnol ; 61(4): 261-273, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729436

RESUMO

The cholesterol hydroxylase/lyase (CHL) system, located in the mitochondria of the mammalian adrenal cortex cells, consists of cytochrome P450scc (CYP11A1), adrenodoxin (Adx), and adrenodoxin reductase (AdR) and performs the first stage of the steroidogenesis: AdR and Adx enable the electron transfer between NADPH and cytochrome P450scc, and P450scc catalyzes the conversion of cholesterol into pregnenolone. CHL system was reconstructed in Escherichia coli using the polycistronic plasmid pTrc99A/CHL. In E. coli cells, the recombinant proteins form the catalytically active system. CHL activity towards 22R-hydroxycholesterol was 4.0 ± 1.3 nmol pregnenolone/h per 1 mg homogenate protein. The alteration of the order of heterologous cDNAs in the expression cassette from AdR-Adx-P450scc to P450scc-Adx-AdR results in alteration of stoichiometric ratio P450scc/Adx/AdR from 1:1.45:4.2 to 1:1.67:0.98; the former ratio is more optimal for the functioning of the cytochrome P450scc. The application of modified cDNA of Adx (AdxS112W) does not increase the CHL activity; however, the introduction of the second copy of AdxS112W gene into the expression cassette increases both the expression level of АdxS112W and the CHL activity in comparison with P450scc/АdxS112W/AdR system. In vivo activity of the CHL system in bacteria is limited by the substrate uptake by bacterial cells: it varied in the range of 0.05-0.62 mg pregnenolone/l resting cell suspension per 1-day cultivation, depending on the type and concentration of permeabilizing agents in the medium. The obtained results contribute to the knowledge of CHL system functioning in living bacteria.


Assuntos
Adrenodoxina/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Escherichia coli/crescimento & desenvolvimento , Ferredoxina-NADP Redutase/genética , Adrenodoxina/metabolismo , Animais , Bovinos , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Escherichia coli/genética , Ferredoxina-NADP Redutase/metabolismo , Expressão Gênica , Engenharia Genética , Hidroxicolesteróis/metabolismo , Espectrometria de Massas , NADP/metabolismo , Pregnenolona/metabolismo , Proteínas Recombinantes/metabolismo
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