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1.
Eur J Pediatr ; 180(10): 3181-3190, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33913025

RESUMEN

Although it is generally recognized that genetic and environmental factors are associated with the risk of congenital heart disease (CHD), the mechanism remains largely uncertain. This study aimed to investigate the association of maternal folate use, the time when folate use was started, and polymorphisms of the reduced folate carrier (RFC1) gene with the risk of CHD in offspring of Chinese descent, which can help provide new insight into the etiology of folate-related birth defects. A case-control study of 683 mothers of CHD patients and 740 mothers of healthy children was performed. The present study showed that mothers who did not use folate were at a significantly increased risk of CHD (OR=2.04; 95% CI: 1.42-2.93). When compared with those who started using folate prior to conception, mothers who started using folate from the first trimester of pregnancy (OR=1.90; 95% CI: 1.43-2.54) or from the second trimester of pregnancy (OR=8.92; 95% CI: 4.20-18.97) had a significantly higher risk of CHD. Maternal RFC1 gene polymorphisms at rs2236484 (AG vs AA: OR=1.79 [95% CI: 1.33-2.39]; GG vs AA: OR=1.64 [95% CI: 1.15-2.35]) and rs2330183 (CT vs CC: OR=1.54 [95% CI: 1.14-2.09]) were also significantly associated with CHD risk. Additionally, the risk of CHD was significantly decreased among mothers who had variant genotypes but used folate when compared with those who had variant genotypes and did not use folate.Conclusion: In those of Chinese descent, maternal folate use and the time when use started are significantly associated with the risk of CHD in offspring. Furthermore, maternal folate supplementation may help to offset some of the risks of CHD in offspring due to maternal RFC1 genetic variants. What is Known: • Folate use could help prevent CHD, but the relationship between the time when folate use is started and CHD has not received sufficient attention. • Studies have assessed the associations of folate metabolism-related genes with CHD, but genes involved in cellular transportation of folate, such as the RFC1 gene, have not garnered enough attention. What is New: • In those of Chinese descents, the time when folate use is started is significantly associated with the risk of CHD in offspring. • Maternal RFC1 polymorphisms were significantly associated with the risk of CHD. • Folate supplementation may help to offset some risks of CHD due to RFC1 genetic variants.


Asunto(s)
Ácido Fólico , Cardiopatías Congénitas , Proteína Portadora de Folato Reducido/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Humanos , Madres , Polimorfismo Genético , Factores de Riesgo
2.
J Trace Elem Med Biol ; 62: 126568, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32521439

RESUMEN

The aim of this study was to determine how folate and iron deficiency, and the subsequent supplementation of rats' diet with these nutrients, affects Slc19a1and Tfr2 gene expression and the metabolism of folate and iron. After 28 days of iron-folate deficiency 150 female rats were randomized into five experimental groups receiving a diet deficient in folic acid (FA), an iron-supplemented diet (DFE), an iron-deficient diet supplemented with FA (DFOL), a diet supplemented with iron and FA (FEFOL), and a diet deficient in iron and FA (D); there was also a control group (C). Samples were collected on days 2, 10, and 21 of the experiment. After two days of supplementation, Tfr2 mRNA level were 78 % lower in the DFE group than in the C group (p < 0.05); after 10 days, TfR2 levels in the FEFOL group were 82 % lower than in the C and the DFE group (p < 0.01). However, we did not find any differences at the protein level at any time-point. Hepcidin concentrations were higher in the DFE and the DFEFOL groups than in the D group after 21 days of supplementation (p < 0.01). Transcript and protein abundance of Slc19a1 gene did not differ between the groups at any time-point. Iron metabolism was affected by iron and folate deficiency and subsequent supplementation with these micronutrients, but TFR2 protein was not involved in the regulatory mechanism. Hepcidin expression can be are upregulated after 21 days of supplementation with 150 mg of iron/ kg of diet.


Asunto(s)
Deficiencia de Ácido Fólico/metabolismo , Deficiencias de Hierro , Hígado/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Receptores de Transferrina/metabolismo , Proteína Portadora de Folato Reducido/metabolismo , Animales , Transporte Biológico , Suplementos Dietéticos , Modelos Animales de Enfermedad , Femenino , Ácido Fólico/metabolismo , Ácido Fólico/farmacología , Deficiencia de Ácido Fólico/dietoterapia , Regulación de la Expresión Génica/efectos de los fármacos , Hepcidinas/metabolismo , Hierro/metabolismo , Hierro/farmacología , Hígado/efectos de los fármacos , Proteínas de Transporte de Membrana/genética , Antígenos de Histocompatibilidad Menor/genética , Ratas Wistar , Receptores de Transferrina/genética , Proteína Portadora de Folato Reducido/genética
3.
Nature ; 559(7715): 632-636, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29995852

RESUMEN

The chemotherapeutic drug methotrexate inhibits the enzyme dihydrofolate reductase1, which generates tetrahydrofolate, an essential cofactor in nucleotide synthesis2. Depletion of tetrahydrofolate causes cell death by suppressing DNA and RNA production3. Although methotrexate is widely used as an anticancer agent and is the subject of over a thousand ongoing clinical trials4, its high toxicity often leads to the premature termination of its use, which reduces its potential efficacy5. To identify genes that modulate the response of cancer cells to methotrexate, we performed a CRISPR-Cas9-based screen6,7. This screen yielded FTCD, which encodes an enzyme-formimidoyltransferase cyclodeaminase-that is required for the catabolism of the amino acid histidine8, a process that has not previously been linked to methotrexate sensitivity. In cultured cancer cells, depletion of several genes in the histidine degradation pathway markedly decreased sensitivity to methotrexate. Mechanistically, histidine catabolism drains the cellular pool of tetrahydrofolate, which is particularly detrimental to methotrexate-treated cells. Moreover, expression of the rate-limiting enzyme in histidine catabolism is associated with methotrexate sensitivity in cancer cell lines and with survival rate in patients. In vivo dietary supplementation of histidine increased flux through the histidine degradation pathway and enhanced the sensitivity of leukaemia xenografts to methotrexate. The histidine degradation pathway markedly influences the sensitivity of cancer cells to methotrexate and may be exploited to improve methotrexate efficacy through a simple dietary intervention.


Asunto(s)
Histidina/metabolismo , Metotrexato/farmacología , Metotrexato/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Amoníaco-Liasas/deficiencia , Amoníaco-Liasas/genética , Amoníaco-Liasas/metabolismo , Animales , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Femenino , Antagonistas del Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/uso terapéutico , Glutamato Formimidoiltransferasa/deficiencia , Glutamato Formimidoiltransferasa/genética , Glutamato Formimidoiltransferasa/metabolismo , Histidina/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Enzimas Multifuncionales , Nucleótidos/biosíntesis , Proteína Portadora de Folato Reducido/genética , Proteína Portadora de Folato Reducido/metabolismo , Tetrahidrofolato Deshidrogenasa/metabolismo , Tetrahidrofolatos/deficiencia , Tetrahidrofolatos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Epilepsy Res ; 142: 64-72, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29571151

RESUMEN

Folate is involved in metabolic processes and it has been implicated in both aggravation and amelioration of seizures. The aim of the current work was to study the effect of chronic temporal lobe epilepsy (TLE) on the plasma and brain concentrations of folate and on its uptake carriers in the brain - the reduced folate carrier (RFC), folate receptor α (FRα) and proton coupled folate transporter (PCFT). We utilized the rat lithium pilocarpine model for TLE. Approximately two months following status epilepticus, rats with spontaneous recurrent seizures (SRS) were sacrificed for brain and plasma folate concentration analyses and folate uptake carrier expression studies. RT-PCR and western blot analyses were utilized for quantification of folate carriers' mRNAs and proteins, respectively. The distribution of folate carriers in the brain was studied using immunohistochemistry. In the SRS rats we found lower plasma concentrations (10 ±â€¯0.9 in control vs. 6.6 ±â€¯1.6 ng/ml in SRS, P < 0.05), but preserved cortical and increased hippocampal levels of folate (0.5 ±â€¯0.1 in control vs. 0.9 ±â€¯0.2 ng/mg in SRS, P = 0.055). Hippocampus - to - plasma ratio of folate concentration was 3-fold higher in the SRS group, compared with the controls (0.13 ±â€¯0.03 vs. 0.04 ±â€¯0.02, respectively; P < 0.01). mRNA and protein levels of the folate uptake carriers did not differ between SRS rats and controls. However, immunofluorescent staining quantification revealed that the emission intensity of both RFC and FRα was elevated 8-fold and 4-fold, respectively, in hippocampal CA1 neurons of SRS rats, compared to controls (P < 0.01). PCFT was unquantifiable. If corroborated by complementary research in humans, the findings of this study may be utilized clinically for supplemental therapy planning, in imaging the epileptic focus, and for drug delivery into the epileptic brain. Further studies are required for better elucidating the clinical and mechanistic significance of altered folate balances in the epileptic brain.


Asunto(s)
Encéfalo/metabolismo , Ácido Fólico/metabolismo , Homeostasis/fisiología , Estado Epiléptico/metabolismo , Animales , Antígeno CD11b/metabolismo , Convulsivantes/toxicidad , Modelos Animales de Enfermedad , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Ácido Fólico/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/metabolismo , Homeostasis/efectos de los fármacos , Litio/toxicidad , Masculino , Fosfopiruvato Hidratasa/metabolismo , Pilocarpina/toxicidad , Transportador de Folato Acoplado a Protón/genética , Transportador de Folato Acoplado a Protón/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Proteína Portadora de Folato Reducido/genética , Proteína Portadora de Folato Reducido/metabolismo , Estadísticas no Paramétricas , Estado Epiléptico/inducido químicamente , Estado Epiléptico/patología
5.
J Pediatr Hematol Oncol ; 39(5): e270-e274, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28267080

RESUMEN

Accumulating evidence indicates that polymorphisms in folate pathway genes play a role in response to methotrexate (MTX) treatment in various diseases. This study explored the influence of these genetic polymorphisms on treatment outcome in pediatric osteosarcoma. Blood and tissue samples from 48 osteosarcoma patients were obtained, and the following polymorphisms were analyzed; SLC19A1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, and ATIC 347C>G. We evaluated associations between these candidate gene polymorphisms and treatment outcome, including histologic response and event-free and overall survival, of patients treated with high-dose MTX. Patients with ATIC 347C>G exhibited a good histologic response to chemotherapy (odds ratio, 0.13; 95% confidence interval, 0.017-0.978; P=0.048). However, none of these single nucleotide polymorphisms we examined affected event-free survival or overall survival rates of the patients. Even though the role of single nucleotide polymorphisms of ATIC in chemotherapy-induced tumor necrosis has not been investigated yet, the ATIC 347C>G polymorphism may influence the levels of adenosine after MTX treatment, which may affect the histologic response of osteosarcoma. This relationship warrants validation in a larger, prospective cohort study.


Asunto(s)
Transferasas de Hidroximetilo y Formilo/genética , Complejos Multienzimáticos/genética , Nucleótido Desaminasas/genética , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Polimorfismo de Nucleótido Simple , Adenosina/sangre , Adolescente , Antineoplásicos/uso terapéutico , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Metotrexato/uso terapéutico , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Osteosarcoma/mortalidad , Proteína Portadora de Folato Reducido/genética , Tasa de Supervivencia , Tetrahidrofolato Deshidrogenasa/genética
6.
Int J Biochem Cell Biol ; 79: 222-230, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27592453

RESUMEN

Folate deficiency contributes to impaired adult hippocampal neurogenesis, yet the mechanisms remain unclear. Here we use HT-22 hippocampal neuron cells as model to investigate the effect of folate deprivation (FD) on cell proliferation and apoptosis, and to elucidate the underlying mechanism. FD caused cell cycle arrest at G0/G1 phase and increased the rate of apoptosis, which was associated with disrupted expression of folate transport and methyl transfer genes. FOLR1 and SLC46A1 were (P<0.01) down-regulated, while SLC19A1 was up-regulated (P<0.01) in FD group. FD cells exhibited significantly (P<0.05) higher protein content of BHMT, MAT2b and DNMT3a, as well as increased SAM/SAH concentrations and global DNA hypermethylation. The expression of the total and all the 3 classes of IGF-1 mRNA variants was significantly (P<0.01) down-regulated and IGF-1 concentration was decreased (P<0.05) in the culture media. IGF-1 signaling pathway was also compromised with diminished activation (P<0.05) of STAT3, AKT and mTOR. CpG hypermethylation was detected in the promoter regions of IGF-1 and FOLR1 genes, while higher SLC19A1 mRNA corresponded to hypomethylation of its promoter. IGF-1 supplementation in FD media significantly abolished FD-induced decrease in cell viability. However, IGF-1 had limited effect in rescuing the cell phenotype when added 24h after FD. Taken together, down-regulation of IGF-1 expression and signaling is involved in FD-induced cell cycle arrest and apoptosis in HT-22 hippocampal neuron cells, which is associated with an abnormal activation of methyl transfer pathway and hypermethylation of IGF-1 gene promoter.


Asunto(s)
Apoptosis , Deficiencia de Ácido Fólico/patología , Puntos de Control de la Fase G1 del Ciclo Celular , Hipocampo/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neuronas/patología , Fase de Descanso del Ciclo Celular , Animales , Transporte Biológico , Línea Celular , Proliferación Celular , Supervivencia Celular , Islas de CpG/genética , Metilación de ADN , Regulación hacia Abajo , Epigénesis Genética , Receptor 1 de Folato/genética , Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/genética , Deficiencia de Ácido Fólico/metabolismo , Transportadores de Ácido Fólico/genética , Ratones , Regiones Promotoras Genéticas/genética , Proteína Portadora de Folato Reducido/genética , Transducción de Señal
7.
Mol Nutr Food Res ; 60(6): 1501-13, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26990146

RESUMEN

SCOPE: The present study was designed to identify the molecular mechanism of folate modulation and aging on aberrant liver folate transporter system. METHODS AND RESULTS: An in vivo rat model was used, in which weanling, young and adult rats were given folate deficient diet for 3 and 5 months and after 3 months of folate deficiency, one group received physiological folate repletion (2 mg/kg diet) and another group received over supplemented folate diet (8 mg/kg diet) for another 2 months. In adult group, 3 and 5 months of folate deficiency decreased serum and tissue folate levels with decreased uptake of folate, further associated with decreased expression levels of reduced folate carrier (RFC) and increased expression levels of folate exporter (ABCG2) at both mRNA and protein levels, which in turn regulated by promoter hypermethylation of RFC and promoter hypomethylation of ABCG2 gene. CONCLUSION: Promoter hypermethylation of RFC and promoter hypomethylation of ABCG2 may be attributed to the down regulation of RFC and up regulation of ABCG2 at mRNA and protein levels in conditions of 3 and 5 months of folate deficiency in the adult group.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Envejecimiento/genética , Epigénesis Genética , Hígado/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Proteína Portadora de Folato Reducido/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Metilación de ADN , Dieta , Suplementos Dietéticos , Ácido Fólico/administración & dosificación , Ácido Fólico/sangre , Deficiencia de Ácido Fólico/sangre , Deficiencia de Ácido Fólico/tratamiento farmacológico , Proteínas de Transporte de Membrana/genética , Antígenos de Histocompatibilidad Menor/genética , Regiones Promotoras Genéticas , Ratas , Proteína Portadora de Folato Reducido/genética
8.
Mol Med ; 21: 597-604, 2015 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-26193446

RESUMEN

Colorectal cancer is commonly treated with 5-fluorouracil and 5-formyltetrahydrofolate (leucovorin). Metabolic action of leucovorin requires several enzymatic steps that are dependent on expression of corresponding coding genes. To identify folate pathway genes with possible impact on leucovorin metabolism, a retrospective study was performed on 193 patients with stage III colorectal cancer. Relative expression of 22 genes putatively involved in leucovorin transport, polyglutamation and metabolism was determined in tumor and mucosa samples using quantitative real-time polymerase chain reaction. After surgery, patients received adjuvant 5-fluorouracil-based bolus chemotherapy with leucovorin during six months, and were followed for 3 to 5 years. Cox regression analysis showed that high tumoral expression of the genes SLC46A1/PCFT (proton-coupled folate transporter) and SLC19A1/RFC-1 (reduced folate carrier 1) correlated significantly (p < 0.001 and p < 0.01, respectively) with a decreased risk of recurrent disease, measured as disease-free survival (DFS). These two genes are involved in the transport of folates into the cells and each functions optimally at a different pH. We conclude that SLC46A1/PCFT and SLC19A1/RFC-1 are associated with DFS of patients with colorectal cancer and hypothesize that poor response to 5-fluorouracil plus leucovorin therapy in some patients may be linked to low expression of these genes. Such patients might need a more intensified therapeutic approach than those with high gene expression. Future prospective studies will determine if the expression of any of these genes can be used to predict response to leucovorin.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Ácido Fólico/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Transportador de Folato Acoplado a Protón/biosíntesis , Proteína Portadora de Folato Reducido/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Ácido Fólico/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Transportador de Folato Acoplado a Protón/genética , Proteína Portadora de Folato Reducido/genética , Transducción de Señal/efectos de los fármacos
9.
PLoS One ; 9(12): e114903, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25506935

RESUMEN

An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidate genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. The study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest.


Asunto(s)
Mutación , Proteína Portadora de Folato Reducido/genética , Disrafia Espinal/genética , Niño , Femenino , Ácido Fólico/metabolismo , Genómica/métodos , Humanos , Modelos Moleculares , Embarazo , Conformación Proteica , Proteína Portadora de Folato Reducido/química , Proteína Portadora de Folato Reducido/metabolismo , Programas Informáticos , Disrafia Espinal/metabolismo
10.
Cancer ; 120(21): 3329-3337, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25041994

RESUMEN

BACKGROUND: Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU. METHODS: The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304). RESULTS: There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06). CONCLUSIONS: Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.


Asunto(s)
Fluorouracilo/administración & dosificación , Predisposición Genética a la Enfermedad , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Neoplasias del Recto/genética , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Ácido Fólico , Estudios de Asociación Genética , Glicina Hidroximetiltransferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Polimorfismo de Nucleótido Simple , Neoplasias del Recto/patología , Proteína Portadora de Folato Reducido/genética , Timidilato Sintasa/genética
11.
Pharmacogenomics ; 15(6): 807-20, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24350725

RESUMEN

AIM: The aim of our study was to characterize the association of clinicopathological variables and the SLC19A1/RFC-1 G80A polymorphism in methotrexate (MTX)-related toxicity in Portuguese patients with rheumatoid arthritis. PATIENTS & METHODS: The study included 233 consecutively recruited patients with rheumatoid arthritis under MTX treatment. The SLC19A1 G80A polymorphism was evaluated by PCR-RFLP. RESULTS: Statistical analysis revealed that SLC19A1 80G carriers had increased risk of gastrointestinal toxicity (odds ratio [OR]: 2.61, p = 0.019) and that regular folic acid supplementation was associated with both overall and gastrointestinal toxicity protection (OR: 0.15, p < 0.001 and OR: 0.19, p < 0.001, respectively). Multivariate analysis confirmed the association of SLC19A1 80G and regular folic acid supplementation to gastrointestinal toxicity (OR: 5.53 and 0.13, respectively). Moreover, a multivariate Cox regression model demonstrated a higher risk of earlier gastrointestinal toxicity in SLC19A1 80G carriers (hazard ratio: 3.63, p = 0.002). CONCLUSION: SLC19A1 G80A genotyping may be a useful tool for clinicians to identify patients at higher risk for developing gastrointestinal toxicity related to MTX treatment.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Biomarcadores/metabolismo , Tracto Gastrointestinal/efectos de los fármacos , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Proteína Portadora de Folato Reducido/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Femenino , Ácido Fólico/administración & dosificación , Tracto Gastrointestinal/metabolismo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Portugal , Estudios Retrospectivos
12.
Schizophr Bull ; 39(2): 330-8, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22021659

RESUMEN

Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients.


Asunto(s)
Ácido Fólico/metabolismo , Esquizofrenia/genética , Psicología del Esquizofrénico , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Adulto , Catecol O-Metiltransferasa/genética , Estudios de Cohortes , Femenino , Ferredoxina-NADP Reductasa/genética , Ácido Fólico/sangre , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Glutamato Carboxipeptidasa II/genética , Humanos , Modelos Lineales , Masculino , Redes y Vías Metabólicas/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación Missense , Polimorfismo de Nucleótido Simple , Proteína Portadora de Folato Reducido/genética , Esquizofrenia/metabolismo , Índice de Severidad de la Enfermedad
13.
PLoS One ; 7(11): e47201, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23144806

RESUMEN

Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.


Asunto(s)
Receptor 1 de Folato/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína Portadora de Folato Reducido/genética , Adulto , Anciano , Anciano de 80 o más Años , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia sin Enfermedad , Femenino , Receptor 1 de Folato/metabolismo , Humanos , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/terapia , Ovario/metabolismo , Ovario/patología , Regiones Promotoras Genéticas , ARN Mensajero/genética , Proteína Portadora de Folato Reducido/metabolismo , Regulación hacia Arriba , Adulto Joven
14.
Cancer Chemother Pharmacol ; 69(3): 691-6, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21984221

RESUMEN

PURPOSE: In the last years, the influence of different genes involved in metabolism of chemotherapeutic agents has been studied. Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL) and Burkitt's lymphomas (BL). This study aims to evaluate the role of MTHFR C677T and A1298C polymorphisms and G80A reduced folate carrier gene (RFC1) in a cohort of adult patients with lymphoproliferative malignancies submitted to high-dose MTX followed by leucovorin rescue. METHODS: We performed the analysis of these polymorphisms on genomic DNA with RFLP-PCR. RESULTS: Patients carrying MTHFR A1298C variant showed decreased hepatic and hematological toxicity (P = 0.03). Overall survival (OS) and progression-free survival (PFS) between homozygous wild-type and variant patients for the RFC1 G(80)A were significantly different (P = 0.035 and P = 0.02, respectively). A significant correlation between hematological toxicity and age (P = 0.003) was observed. There was no significant influence of MTHFR C677T genotype on toxicity, OS and PFS. CONCLUSIONS: Leucovorin rescue given after high-dose MTX probably accounts for the lack of influence of C677T polymorphism. To better define a role of RFC1 polymorphism on patients outcome, it would be worthwhile to perform a study on intracellular MTX level and RFC1 substrate binding affinities in different genotypes.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético , Proteína Portadora de Folato Reducido/genética , Adolescente , Adulto , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Estudios de Cohortes , Supervivencia sin Enfermedad , Neoplasias Hematológicas/enzimología , Neoplasias Hematológicas/metabolismo , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/farmacocinética , Leucovorina/uso terapéutico , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Metotrexato/farmacocinética , Metotrexato/uso terapéutico , Persona de Mediana Edad , Adulto Joven
15.
Eur J Clin Pharmacol ; 67(10): 993-1006, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21509569

RESUMEN

PURPOSE: The objectives of this study were (1) to develop a population pharmacokinetic model of high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukaemia (ALL) and malignant lymphoma (ML) in order to investigate the influence of common polymorphisms in SLC19A1, MTHFR and ABCB1 on plasma levels of MTX and (2) to estimate MTX exposure in individual patients to study the association of genetic variability in the folate metabolic pathway with MTX toxicity. METHODS: The study population comprised 64 children with ALL/ML (age 1.6-16.8 years) who had received a total of 252 MTX courses (2-4 per patient). Common putative functional polymorphisms in the SLC19A1, MTHFR, MS, MTRR, TS and ABCB1 genes were analysed by PCR-based genotyping. Nonlinear mixed effects modelling was used for the pharmacokinetic analysis. RESULTS: The population typical value of clearance was 7.43 L/h (inter-individual variability 43.9%), central compartment volume was 16.7 L (46.6%), peripheral compartment volume was 2.6 L (63.3%) and distribution clearance was 0.0952 L/h (66.6%). MTX clearance decreased to 73.8% in patients with the MTHFR 677TT genotype. Patients homozygous for the variant MTHFR 1298A > C [odds ratio (OR) 0.14, 95% confidence interval (CI) 0.037-0.54] and SLC19A1 80A > G (OR 0.15, 95% CI 0.039-0.60) were at decreased risk for leucopenia. The TS 2R > 3R polymorphism was associated with a lower incidence of thrombocytopenia (OR 0.15, 95% CI 0.039-0.61) and mucositis (OR 0.016, 95% CI 0.0012-0.20). In contrast, the MTHFR 677TT polymorphism was associated with an increased incidence of mucositis (OR 23, 95% CI 2.1-240). CONCLUSIONS: A population pharmacokinetic model developed in this study implies only a limited influence of genetic factors on the systemic disposition of MTX. Clearance is moderately reduced in patients with the MTHFR 677TT genotype. Genetic polymorphisms in the folate metabolic pathway and SLC19A1 were associated with HD-MTX toxicity.


Asunto(s)
Ácido Fólico/genética , Ácido Fólico/metabolismo , Linfoma/genética , Linfoma/metabolismo , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Preescolar , Femenino , Genotipo , Humanos , Linfoma/tratamiento farmacológico , Masculino , Redes y Vías Metabólicas , Metotrexato/efectos adversos , Metotrexato/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mucositis/genética , Dinámicas no Lineales , Oportunidad Relativa , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteína Portadora de Folato Reducido/genética , Estudios Retrospectivos , Trombocitopenia/genética
16.
Birth Defects Res A Clin Mol Teratol ; 91(1): 50-60, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21254359

RESUMEN

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs), C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. Here, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP, and were there detectable interactions between these genes and environmental exposures? METHODS: Fourteen folate metabolism-related genes were interrogated using 89 SNPs in multiplex and simplex non-Hispanic white and Hispanic NSCLP families. RESULTS: Evidence for a risk association between NSCLP and SNPs in NOS3 and TYMS was detected in the non-Hispanic white group, whereas associations with MTR, BHMT2, MTHFS, and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected. CONCLUSIONS: These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with gender of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated.


Asunto(s)
Labio Leporino/complicaciones , Fisura del Paladar/complicaciones , Ácido Fólico/metabolismo , Genes/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Betaína-Homocisteína S-Metiltransferasa/genética , Ligasas de Carbono-Nitrógeno/genética , Labio Leporino/etnología , Labio Leporino/genética , Fisura del Paladar/etnología , Fisura del Paladar/genética , Hispánicos o Latinos/genética , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Óxido Nítrico Sintasa de Tipo III/genética , Proteína Portadora de Folato Reducido/genética , Timidilato Sintasa/genética , Población Blanca/genética
17.
Birth Defects Res A Clin Mol Teratol ; 88(8): 689-94, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20683905

RESUMEN

BACKGROUND: Meningomyelocele (MM) results from lack of closure of the neural tube during embryologic development. Periconceptional folic acid supplementation is a modifier of MM risk in humans, leading toan interest in the folate transport genes as potential candidates for association to MM. METHODS: This study used the SNPlex Genotyping (ABI, Foster City, CA) platform to genotype 20 single polymorphic variants across the folate receptor genes (FOLR1, FOLR2, FOLR3) and the folate carrier gene (SLC19A1) to assess their association to MM. The study population included 329 trio and 281 duo families. Only cases with MM were included. Genetic association was assessed using the transmission disequilibrium test in PLINK. RESULTS: A variant in the FOLR2 gene (rs13908), three linked variants in the FOLR3 gene (rs7925545, rs7926875, rs7926987), and two variants in the SLC19A1 gene (rs1888530 and rs3788200) were statistically significant for association to MM in our population. CONCLUSION: This study involved the analyses of selected single nucleotide polymorphisms across the folate receptor genes and the folate carrier gene in a large population sample. It provided evidence that the rare alleles of specific single nucleotide polymorphisms within these genes appear to be statistically significant for association to MM in the patient population that was tested.


Asunto(s)
Proteínas Portadoras/genética , Receptor 1 de Folato/genética , Receptor 2 de Folato/genética , Meningomielocele/genética , Proteína Portadora de Folato Reducido/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Ligamiento Genético , Hispánicos o Latinos/genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto Joven
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