RESUMO
OBJECTIVES: Transcobalamin II (TC) promotes the cellular uptake of cobalamin (Cbl) through receptor-mediated endocytosis of the TC-cbl complex in peripheral tissues. TC deficiency is a rare disorder that causes intracellular Cbl depletion. It presents in early infancy with a failure to thrive, diarrhea, anemia, agammaglobulinemia, and pancytopenia. Data from five TC-deficient patients including clinical, biochemical, and molecular findings, as well as long-term outcomes, were collected. CASE PRESENTATION: Mutation analysis revealed one unreported pathogenic variant in the TCN2 gene. One patient had exocrine pancreatic insufficiency. We conducted a retrospective analysis of C3 and C3/C2 from dried blood samples, as this is implemented for newborn screening (NBS). We detected a marked increase in the C3/C2 ratio in two samples. Treatment was based on parenteral Cbl. Three patients treated before six months of age had an initial favorable outcome, whereas the two treated later or inadequately had neurological impairment. CONCLUSIONS: This is the first report of Argentinean patients with TC deficiency that detected a new variant in TCN2. NBS may be a tool for the early detection of TC deficiency. This data emphasizes that TC deficiency is a severe disorder that requires early detection and long-term, aggressive therapy. Accurate diagnosis is imperative, because early detection and treatment can be life-saving.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Anemia Macrocítica , Deficiência de Vitamina B 12 , Recém-Nascido , Humanos , Vitamina B 12/uso terapêutico , Transcobalaminas/genética , Estudos Retrospectivos , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/tratamento farmacológico , Deficiência de Vitamina B 12/genética , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Diagnóstico PrecoceAssuntos
Carbono/metabolismo , Metilação de DNA , Síndrome de Down/etiologia , Síndrome de Down/genética , Betaína-Homocisteína S-Metiltransferase/genética , Ingestão de Alimentos/fisiologia , Epigênese Genética , Feminino , Ácido Fólico/administração & dosagem , Genótipo , Humanos , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Polimorfismo Genético , Gravidez , Transcobalaminas/genéticaRESUMO
Down syndrome (DS) is the most common chromosomal disorder, resulting from the failure of normal chromosome 21 segregation. Studies have suggested that impairments within the one-carbon metabolic pathway can be of relevance for the global genome instability observed in mothers of individuals with DS. Based on the association between global DNA hypomethylation, genome instability, and impairments within the one-carbon metabolic pathway, the present study aimed to identify possible predictors, within the one-carbon metabolism, of global DNA methylation, measured by methylation patterns of LINE-1 and Alu repetitive sequences, in mothers of individuals with DS and mothers of individuals without the syndrome. In addition, we investigated one-carbon genetic polymorphisms and metabolites as maternal predisposing factors for the occurrence of trisomy 21 in children. Eighty-three samples of mothers of children with DS with karyotypically confirmed free trisomy 21 (case group) and 84 of mothers who had at least one child without DS or any other aneuploidy were included in the study. Pyrosequencing assays were performed to access global methylation. The results showed that group affiliation (case or control), betaine-homocysteine methyltransferase (BHMT) G742A and transcobalamin 2 (TCN2) C776G polymorphisms, and folate concentration were identified as predictors of global Alu DNA methylation values. In addition, thymidylate synthase (TYMS) 28-bp repeats 2R/3R or 3R/3R genotypes are independent maternal predisposing factors for having a child with DS. This study adds evidence that supports the association of impairments in the one-carbon metabolism, global DNA methylation, and the possibility of having a child with DS.
Assuntos
Carbono/metabolismo , Metilação de DNA/genética , Síndrome de Down/genética , Síndrome de Down/metabolismo , Estudo de Associação Genômica Ampla , Instabilidade Genômica/genética , Relações Mãe-Filho , Mães , Adolescente , Adulto , Idoso , Elementos Alu/genética , Betaína-Homocisteína S-Metiltransferase/genética , Betaína-Homocisteína S-Metiltransferase/metabolismo , Feminino , Ácido Fólico/metabolismo , Predisposição Genética para Doença/genética , Humanos , Elementos Nucleotídeos Longos e Dispersos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Timidilato Sintase/genética , Transcobalaminas/genética , Transcobalaminas/metabolismo , Adulto JovemRESUMO
Gaucher disease (GD), one of the most common lysosomal disorders, is caused by deficiency of ß-glucocerebrosidase. Based on the presence and severity of neurological complications, GD is classified into types I, II (the most severe form), and III. Abnormalities in systemic markers of vitamin B12 (B12 ) metabolism have been reported in GD type I patients, suggesting a higher prevalence of B12 deficiency in these patients. A 2-month-old male with GD type II was admitted to the hospital presenting jaundice, hepatosplenomegaly, and ichthyosis. At admission, cholestasis and ascites, abnormal liver function enzymes, prolonged prothrombin time, and high levels of B12 were confirmed. Analysis of biomarkers of B12 status revealed elevated B12 and holo-transcobalamin (holo-TC) levels. The B12 profile found in our patient is the opposite to what is described for GD type I patients. Holo-TC may increase in inflammatory states or due to liver diseases. In GD, the accumulation of glucocerebroside may be a trigger that initiates a systemic inflammatory reaction, characterized by macrophage activation. We suggest higher levels of holo-TC could be associated with a more severe (neuronopathic) GD, and be a biomarker of GD type II.
Assuntos
Biomarcadores/sangue , Doença de Gaucher/sangue , Doença de Gaucher/diagnóstico , Transcobalaminas , Doença de Gaucher/genética , Glucosilceramidase/deficiência , Glucosilceramidase/genética , Humanos , Lactente , Masculino , Prognóstico , Avaliação de Sintomas , Transcobalaminas/metabolismo , Vitamina B 12/metabolismoRESUMO
Embora Salmonella Enteritidis (SE) seja capaz de metabolizar 1,2-propanodiol (1,2-Pd), utilizado como fonte de carbono e de energia ao longo de uma rota dependente de vitamina B12, a importância deste composto na infeção de Gallus gallus domesticus por SE permanece desconhecida. No presente estudo, foram construídos um mutante de SE sem os genes pduCDE, que codifica a propanodiol desidratase (Pdu), e outro contendo as deleções no pduCDE e também nos genes cobS e cbiA, responsáveis pela síntese de vitamina B12. Em seguida, avaliou-se a importância do metabolismo do 1,2-Pd em SE para colonização intestinal de infecção sistêmica de poedeiras comerciais. As estirpes mutantes de SE foram capazes de colonizar o intestino, de serem excretadas nas fezes e de invadir o baço e o fígado na mesma intensidade que a estirpe selvagem, o que sugere que os produtos dos genes pduC, pduD, pduE, cobS e cbiA não são essenciais durante infecção por Salmonella Enteritidis nessa espécie.(AU)
Assuntos
Animais , Salmonella enteritidis/patogenicidade , Salmonella enteritidis/ultraestrutura , Galinhas/microbiologia , Microbioma Gastrointestinal , TranscobalaminasRESUMO
Four biomarkers are commonly employed to diagnose B12 deficiency: vitamin B12 (B12), holotranscobalamin (HoloTC), methylmalonic acid (MMA), and homocysteine (Hcy). 4cB12, a combined index of the B12 status, has been suggested to improve the recognition of B12 deficiency. We aimed to evaluate the four different markers for detecting B12 deficiency, as determined by 4cB12. Within a large, mixed patient population, 11,833 samples had concurrent measurements of B12, HoloTC, MMA, and Hcy. 4cB12 was calculated according to the methods described by Fedosov. Diagnostic cutoffs as well as diagnostic accuracy for the detection of B12 deficiency were assessed with receiver operating characteristic (ROC) analysis. The median age was 56 years, and women accounted for 58.8% of the samples. Overall, the area under the curve (AUC) for the detection of subclinical B12 deficiency was highest for HoloTC (0.92), followed by MMA (0.91), B12 (0.9) and Hcy (0.78). The difference between HoloTC and B12 was driven by a significantly higher AUC for HoloTC (0.93) than for B12 (0.89), MMA (0.91), and Hcy in women 50 years and older (0.79; p < 0.05 for all). In the detection of subclinical B12 deficiency, there were no significant differences in the AUCs of HoloTC, B12, and MMA among men and women <50 years. In conclusion, in women < 50 years and in men, HoloTC, MMA, or Hcy do not appear superior to B12 for the detection of B12 deficiency. For women 50 years and older, HoloTC seems to be the preferred first-line marker for the detection of subclinical B12 deficiency.
Assuntos
Homocisteína/metabolismo , Ácido Metilmalônico/metabolismo , Transcobalaminas/metabolismo , Deficiência de Vitamina B 12/diagnóstico , Vitamina B 12/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Deficiência de Vitamina B 12/metabolismoRESUMO
BACKGROUND: Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B12) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. METHODS: Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. RESULTS: Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. CONCLUSIONS: Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell- and compartment-specific vitamin B12 metabolism in Gaucher disease.
Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Vitamina B 12/metabolismo , beta-Glucosidase/genética , Técnicas de Cultura de Células , Feminino , Fibroblastos/metabolismo , Doença de Gaucher/metabolismo , Doença de Gaucher/patologia , Homocisteína/metabolismo , Humanos , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Ácido Metilmalônico/metabolismo , Mutação , Fenótipo , Saposinas/genética , Transcobalaminas/metabolismoRESUMO
We examined whether polymorphisms in the methylenetetrahydrofolate dehydrogenase (MTHFD) and transcobalamin (TC) genes, which are involved in folate metabolism, affect maternal risk for Down syndrome. We investigated 76 Down syndrome mothers and 115 control mothers from Bengbu, China. Genomic DNA was isolated from the peripheral lymphocytes. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFD G1958A and TC C776G. The frequencies of the polymorphic alleles were 24.3 and 19.1% for MTHFD 1958A, 53.9 and 54.2% for TC 776G, in the case and control groups, respectively. No significant differences were found between two groups in relation to either the allele or the genotype frequency for both polymorphisms. However, when gene-gene interactions between these two polymorphisms together with previous studied C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were analyzed, the combined MTHFR 677CT/TT and MTHFD 1958AA/GA genotype was found to be significantly associated with the risk of having a Down syndrome child [odds ratio (OR) = 3.11; 95% confidence interval (95%CI) = 1.07-9.02]. In addition, the combined TC 776CG and MTHFR 677TT genotype increased the risk of having a child with Down syndrome 3.64-fold (OR = 3.64; 95%CI = 1.28-10.31). In conclusion, neither MTHFD G1958A nor TC C776G polymorphisms are an independent risk factor for Down syndrome. However, the combined MTHFD/MTHFR, TC/MTHFR genotypes play a role in the risk of bearing a Down syndrome child in the Chinese population.
Assuntos
Aminoidrolases/genética , Síndrome de Down/genética , Formiato-Tetra-Hidrofolato Ligase/genética , Estudos de Associação Genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Complexos Multienzimáticos/genética , Transcobalaminas/genética , Adulto , Povo Asiático/genética , Criança , China , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Feminino , Ácido Fólico/genética , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Studies have shown that the maternal risk for Down syndrome (DS) may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B
Assuntos
Síndrome de Down/etiologia , Ácido Fólico/sangue , Gravidez de Alto Risco/genética , Adulto , Betaína-Homocisteína S-Metiltransferase/genética , Vias Biossintéticas/genética , Estudos de Casos e Controles , Feminino , Ferredoxina-NADP Redutase/genética , Ácido Fólico/metabolismo , Estudos de Associação Genética , Haplótipos , Humanos , Modelos Logísticos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Ácido Metilmalônico/sangue , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Gravidez , Proteína Carregadora de Folato Reduzido/genética , Fatores de Risco , Transcobalaminas/genéticaRESUMO
Alterations in folate metabolism may contribute to the process of carcinogenesis by influencing DNA methylation and genomic stability. Polymorphisms in genes encoding enzymes involved in this pathway may alter enzyme activity and consequently interfere in concentrations of homocysteine and S-adenosylmethionine that are important for DNA synthesis and cellular methylation reactions. The objectives were to investigate MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms involved in folate metabolism on head and neck cancer risk and the association between these polymorphisms with risk factors. Polymorphisms were investigated in 762 individuals (272 patients and 490 controls) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Real Time-PCR. Chi-square and Multiple logistic regression were used for the statistical analysis. Multiple logistic regression showed that tobacco and male gender were predictors for the disease (P < 0.05). Hardy-Weinberg equilibrium showed that the genotypic distributions were in equilibrium for both groups in all polymorphisms studied. The BHMT 742GA or AA genotypes associated with tobacco consumption (P = 0.016) increase the risk for head and neck squamous cell carcinoma (HNSCC). The present study suggests that BHMT 742GA polymorphism associated to tobacco modulate HNSCC risk. However, further investigation of gene-gene interactions in folate metabolism and studies in different populations are needed to investigate polymorphisms and HNSCC risk.
Assuntos
Betaína-Homocisteína S-Metiltransferase/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Polimorfismo de Nucleotídeo Único/genética , Transcobalaminas/genética , Brasil/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/metabolismo , Metilação de DNA/genética , Feminino , Ácido Fólico/metabolismo , Instabilidade Genômica/genética , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Modelos Logísticos , Masculino , Antígenos de Histocompatibilidade Menor , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Fatores de RiscoRESUMO
A fissura de lábio e/ou palato (FL/P) é considerada a anomalia craniofacial mais comum entre os seres humanos. A etiologia da FL/P isolada é complexa e de origem multifatorial, compreendendo diversos fatores genéticos e ambientais. Dentre os fatores ambientais, sabe-se que os déficits nutricionais desempenham um papel fundamental na etiologia dessa anomalia...Os resultados sugerem que os polimorfismos dos genes TCN2 (rs1801198) e MTRR (rs 1801394) não estão associados com FL/P, porém este último gene deve ser melhor investigado em outras populações em função dos resultados limítrofes obtidos. O hábito de fumar durante a gestação foi considerado um forte fator de risco para FL/P.
Assuntos
Humanos , Distribuição de Qui-Quadrado , Fenda Labial , Fissura Palatina , Anormalidades Craniofaciais , Modelos Logísticos , Polimorfismo Genético , Gravidez , Fatores de Risco , Fumar , TranscobalaminasRESUMO
Human milk contains a multitude of bioactive proteins, with very diverse functions. Some of these proteins are involved in the synthesis and expression of milk, but the majority appears to have evolved to provide physiological activities in the breast-fed infant. These activities are exerted by a wide variety of mechanisms and have largely been unraveled by in vitro studies. To be active in the gastrointestinal tract, these proteins must be able to resist proteolytic degradation, at least for some time. We have evaluated the human milk proteins lactoferrin, haptocorrin, alpha(1)-antitrypsin, and transforming growth factor -beta in an in vitro digestion model, mimicking the conditions of the infant gastrointestinal milieu. These bioactive proteins are resistant against proteolysis and can remain intact or as larger fragments through passage of the gastrointestinal tract. In vitro digestibility assays can be helpful to assess which human milk proteins can resist proteolysis and to what extent.
Assuntos
Proteínas do Leite/metabolismo , Leite Humano/fisiologia , Animais , Digestão , Feminino , Trato Gastrointestinal/metabolismo , Humanos , Lactente , Lactoferrina/fisiologia , Leite Humano/química , Transcobalaminas/fisiologia , Fator de Crescimento Transformador beta/fisiologia , alfa 1-Antitripsina/fisiologiaRESUMO
BACKGROUND: Vitamin B12 is indispensable for proper brain functioning and cytosolic synthesis of S-adenosylmethionine. Whether its deficiency produces effects on viability and apoptosis of neurons remains unknown. There is a particular interest in investigating these effects in Parkinson disease where Levodopa treatment is known to increase the consumption of S-adenosylmethionine. To cause deprivation of vitamin B12, we have recently developed a cell model that produces decreased synthesis of S-adenosylmethionine by anchoring transcobalamin (TCII) to the reticulum through its fusion with Oleosin (OLEO). METHODOLOGY: Gene constructs including transcobalamin-oleosin (TCII-OLEO) and control constructs, green fluorescent protein-transcobalamin-oleosin (GFP-TCII-OLEO), oleosin-transcobalamin (OLEO-TCII), TCII and OLEO were used for expression in N1E-115 cells (mouse neuroblastoma) and in substantia nigra of adult rats, using a targeted transfection with a Neurotensin polyplex system. We studied the viability and the apoptosis in the transfected cells and targeted tissue. The turning behavior was evaluated in the rats transfected with the different plasmids. PRINCIPAL FINDINGS: The transfection of N1E-115 cells by the TCII-OLEO-expressing plasmid significantly affected cell viability and increased immunoreactivity of cleaved Caspase-3. No change in propidium iodide uptake (used as a necrosis marker) was observed. The transfected rats lost neurons immunoreactive to tyrosine hydroxylase. The expression of TCII-OLEO was observed in cells immunoreactive to tyrosine hydroxylase of the substantia nigra, with a superimposed expression of cleaved Caspase-3. These cellular and tissular effects were not observed with the control plasmids. Rats transfected with TCII-OLEO expressing plasmid presented with a significantly higher number of turns, compared with those transfected with the other plasmids. CONCLUSIONS/SIGNIFICANCE: In conclusion, the TCII-OLEO transfection was responsible for apoptosis in N1E-115 cells and rat substantia nigra and for Parkinson-like phenotype. This suggests evaluating whether vitamin B12 deficit could aggravate the PD in patients under Levodopa therapy by impairing S-adenosylmethionine synthesis in substantia nigra.
Assuntos
Apoptose , Doença de Parkinson/patologia , Proteínas de Plantas/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Substância Negra/metabolismo , Transcobalaminas/metabolismo , Vitamina B 12/metabolismo , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Metanfetamina/farmacologia , Camundongos , Necrose , Plasmídeos/genética , Transporte Proteico/efeitos dos fármacos , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/enzimologia , Transfecção , Transgenes/genéticaRESUMO
Recent evidence shows that almost 92% of the DS children are born from young mothers, suggesting that other risk factors than advanced maternal age must be involved. In this context, some studies demonstrated a possible link between DS and maternal polymorphisms in genes involved in folate metabolism. These polymorphisms, as well as low intake of folate could generate genomic instability, DNA hypomethylation and abnormal segregation, leading to trisomy 21. We compared the frequency of CBS 844ins68, MTR 2756A>G, RFC-1 80G> A and TC 776C>G polymorphisms among 114 case mothers and 110 matched controls, in order to observe whether these variants act as risk factors for DS. The genotype distributions revealed that there were not significant differences between both samples. However, when we proceed the multiplicative interaction analyses between the four polymorphisms described above together with the previously studied MTHFR 677C>T, MTHFR 1298A>C and MTRR 66A>G polymorphisms, our results show that the combined genotype TC 776CC / MTHFR 677TT and TC 776CC / MTR 2756AG were significantly higher in the control sample. Nevertheless, there was no significant association after Bonferroni correction. Our results suggest that maternal folate-related polymorphisms studied here have no influence on trisomy 21 susceptibility in subjects of Brazilian population.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Cistationina beta-Sintase/genética , Síndrome de Down/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo Genético , Transcobalaminas/genética , Adolescente , Adulto , Brasil/epidemiologia , Criança , DNA/genética , Síndrome de Down/epidemiologia , Síndrome de Down/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Mães , Fatores de RiscoRESUMO
CONTEXT AND OBJECTIVE: There is evidence that polymorphisms of genes involved in folate metabolism may be associated with higher risk that mothers may bear a Down's syndrome (DS) child. This study therefore had the objective of investigating the A80G polymorphism of the reduced folate carrier 1 (RFC1) gene and the C776G polymorphism of the transcobalamin 2 (TC2) gene as maternal risk factors for DS among Brazilian women. DESIGN AND SETTING: Analytical cross-sectional study with control group, at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS: Sixty-seven mothers of DS individuals with free trisomy 21, and 113 control mothers, were studied. Molecular analysis of the polymorphisms was performed by means of the polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP), followed by electrophoresis on 2 percent agarose gel. RESULTS: The frequencies of the polymorphic alleles were 0.51 and 0.52 for RFC1 80G, and 0.34 and 0.34 for TC2 776G, in the case and control groups, respectively. Thus, there were no differences between the groups in relation to either the allele or the genotype frequency, for both polymorphisms (P = 0.696 for RFC1 A80G; P = 0.166 for TC2 C776G; P = 0.268 for combined genotypes). CONCLUSION: There was no evidence of any association between the RFC1 A80G and TC2 C776G polymorphisms and the maternal risk of DS in the sample evaluated.
CONTEXTO E OBJETIVO: Considerando as evidências de que polimorfismos em genes envolvidos no metabolismo do folato podem estar associados ao risco materno elevado para a síndrome de Down (SD), o objetivo deste estudo foi investigar os polimorfismos A80G do gene carregador de folato reduzido 1 (RFC1) e C776G do gene transcobalamina 2 (TC2) como fatores de risco maternos para a SD em mulheres brasileiras. TIPO E ESTUDO LOCAL: Estudo transversal analítico com grupo controle, realizado na Faculdade de Medicina de São José do Rio Preto (Famerp). MÉTODOS: Foram avaliadas 67 mães de indivíduos com trissomia livre do 21 e 113 mães de indivíduos sem a síndrome. A análise molecular dos polimorfismos foi realizada pela técnica de reação em cadeia da polimerase/polimorfismo de comprimento fragmentos de restrição (PCR-RFLP), seguida por eletroforese em gel de agarose 2 por cento. RESULTADOS: As freqüências dos alelos polimórficos foram de 0,51 e 0,52 para RFC1 80G e 0,34 e 0,34 para TC2 776G nos grupos caso e controle, respectivamente. Assim, não houve diferença nas freqüências alélicas e genotípicas para ambos os polimorfismos entre os grupos (P = 0,696 para RFC1 A80G; P = 0,166 para TC2 C776G; p = 0,268 para genótipos combinados). CONCLUSÃO: Não há evidência de associação entre os polimorfismos RFC1 A80G e TC2 C776G e o risco materno para a SD na casuística avaliada.
Assuntos
Adulto , Feminino , Humanos , Síndrome de Down/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo Genético/genética , Transcobalaminas/genética , Alelos , Brasil , Estudos de Casos e Controles , Estudos Transversais , Genótipo , Mães , Fatores de RiscoRESUMO
CONTEXT AND OBJECTIVE: There is evidence that polymorphisms of genes involved in folate metabolism may be associated with higher risk that mothers may bear a Down's syndrome (DS) child. This study therefore had the objective of investigating the A80G polymorphism of the reduced folate carrier 1 (RFC1) gene and the C776G polymorphism of the transcobalamin 2 (TC2) gene as maternal risk factors for DS among Brazilian women. DESIGN AND SETTING: Analytical cross-sectional study with control group, at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS: Sixty-seven mothers of DS individuals with free trisomy 21, and 113 control mothers, were studied. Molecular analysis of the polymorphisms was performed by means of the polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP), followed by electrophoresis on 2% agarose gel. RESULTS: The frequencies of the polymorphic alleles were 0.51 and 0.52 for RFC1 80G, and 0.34 and 0.34 for TC2 776G, in the case and control groups, respectively. Thus, there were no differences between the groups in relation to either the allele or the genotype frequency, for both polymorphisms (P = 0.696 for RFC1 A80G; P = 0.166 for TC2 C776G; P = 0.268 for combined genotypes). CONCLUSION: There was no evidence of any association between the RFC1 A80G and TC2 C776G polymorphisms and the maternal risk of DS in the sample evaluated.
Assuntos
Síndrome de Down/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo Genético/genética , Transcobalaminas/genética , Adulto , Alelos , Brasil , Estudos de Casos e Controles , Estudos Transversais , Feminino , Genótipo , Humanos , Mães , Proteína Carregadora de Folato Reduzido , Fatores de RiscoRESUMO
One of the etiologies of hyperhomocysteinemia is decreased vitamin B(12). Genetic variation in the transcobalamin II gene, the transporter of vitamin B(12) to the cells, may produce altered homocysteine levels. We determined transcobalamin II C776G polymorphism, homocysteine, folate and vitamin B(12) levels and analyzed the interactive effect with the methylenetetrahydrofolate reductase C677T and A1298C and methionine synthase reductase A66G polymorphisms in 207 healthy Brazilian children. The prevalence of GG genotype of transcobalamin II C776G polymorphism in this Brazilian population, a highly miscigeneous population was 12.5% and the statistical analysis showed that this population is in Hardy-Weinberg equilibrium, it could be considered representative of the general population. We observed a significant increase in homocysteine in the 776GG vs. 776CC genotype, corroborating the influence of age as a determinant of homocysteine in relation to this polymorphism. When we analyzed vitamin B(12) and its relationship with the C776G polymorphism, we found no significant differences. Only 776CG/66AA or 776GG/66AG genotypes presented a significant increase in homocysteine when compared with other groups. In the multivariate analysis, transcobalamin II C776G (CC/CG vs. GG), methylenetetrahydrofolate reductase C677T (CC/CT vs. TT), folate, gender and age presented statistical significance in relation to the homocysteine. These can be considered independent risk factors for hyperhomocysteinemia in this children group. Our results, if confirmed in other populations, highlight the necessity for investigation of the transcobalamin II C776G polymorphism in the research for hyperhomocysteinemia risk factors.
Assuntos
Ácido Fólico/sangue , Homocisteína/sangue , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Transcobalaminas/genética , Vitamina B 12/sangue , Brasil , Criança , Pré-Escolar , Feminino , Ferredoxina-NADP Redutase/genética , Frequência do Gene , Genótipo , Humanos , Lactente , Modelos Lineares , Masculino , Análise Multivariada , Valores de Referência , Fatores de RiscoAssuntos
Polimorfismo de Nucleotídeo Único , Transcobalaminas/genética , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Homocisteína/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Risco , Trombose Venosa/epidemiologia , Trombose Venosa/etiologiaAssuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adulto , Pessoa de Meia-Idade , Idoso , Transcobalaminas/genética , Trombose Venosa/genética , Polimorfismo de Nucleotídeo Único , Brasil/epidemiologia , Análise Mutacional de DNA , Trombose Venosa/etiologia , Trombose Venosa/epidemiologia , Homocisteína/sangueRESUMO
INTRODUÇAO: A vitamina B12 é hidrossolúvel, não-sintetizada pelo organismo humano, presente em alimentos de origem animal. Sua deficiência é muito freqüente entre idosos, vegetarianos e indivíduos que adotam baixa dieta protéica ou apresentam problemas de absorção gastrintestinal. FISIOPATOLOGIA: A deficiência de vitamina B12 leva a transtornos hematológicos, neurológicos e cardiovasculares, principalmente, por interferir no metabolismo da homocisteína (Hcy) e nas reações de metilação do organismo. Muitas vezes a deficiência pode permanecer assintomática por longos períodos, desencadeando uma deficiência crônica que, se mantida, pode levar a manifestações neurológicas irreversíveis. METODOLOGIAS: Metodologias eficientes que permitam um diagnóstico precoce são imprescindíveis. Porém um método considerado padrão-ouro ainda não é consensual. A dosagem sérica de vitamina B12 sofre algumas restrições pelos problemas de sensibilidade e especificidade, podendo ocorrer sintomas de deficiência mesmo com vitamina B12 sérica dentro dos níveis normais ou, de outro modo, ocorrendo baixos níveis de vitamina B12 sérica sem, contudo, apresentar baixos níveis da fração de vitamina realmente disponível para as células e sem apresentar sintomatologia. Novas alternativas vêm surgindo, como a dosagem de transcobalamina II (Tc II), a única fração de vitamina B12 disponível para as células, ou a dosagem de ácido metilmalônico (MMA) e Hcy, metabólitos que aumentam quando ocorre diminuição de vitamina B12 intracelular. Estes testes apresentam algumas vantagens, mas também limitações importantes para uso rotineiro. CONCLUSAO: Em casos subclínicos, um diagnóstico correto e precoce representa ainda um desafio, e futuros estudos são necessários para definir um método padrão para diagnóstico laboratorial da deficiência de vitamina B12.