RESUMO
Methotrexate (MTX), a structural analog of folic acid, is widely employed in the treatment of different cancers and autoimmune diseases. Despite the successful results observed, the main disadvantage lies in interpatient variability in the pharmacokinetic and pharmacodynamic parameters. In particular, adverse events and toxicities induced by MTX are a matter of concern and can be the cause of dose reduction or treatment discontinuation. Among the different approaches to reduce MTX therapeutic limitations, pharmacogenomics contributes by considering the effect of inherited genetic differences on those parameters. This review provides an update on MTX pharmacogenomics. It reports the contribution of main gene polymorphisms involved in the influx, efflux, cellular effect, and elimination on MTX toxicity and efficacy, on all the diseases treated with this drug. From the analysis of the data presented in this review, we concluded that only gene polymorphisms MTHFR rs1801133, SLC19A1 rs1051266, and TYMS rs34743033 could influence clinical decision-making.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Imunossupressores/efeitos adversos , Metotrexato/efeitos adversos , Farmacogenética/métodos , Variantes Farmacogenômicos , Polimorfismo Genético , Medicina de Precisão/métodos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Tomada de Decisão Clínica , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Seleção de Pacientes , Testes Farmacogenômicos , Valor Preditivo dos Testes , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Medição de Risco , Timidilato Sintase/genética , Timidilato Sintase/metabolismoRESUMO
BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C-1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Linfoma não Hodgkin/genética , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Idoso , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteína Carregadora de Folato Reduzido/genética , Tetra-Hidrofolato Desidrogenase/genética , Timidilato Sintase/genética , Adulto JovemRESUMO
Folate deficiency during pregnancy has been related to low birth weight, preterm (PT) birth and other health risks in the offspring; however, it is unknown whether prematurity is related to low folate transport through the placenta due to altered expression of specific folate transporters. We determined placental expression (mRNA and protein concentrations by RT-qPCR and WB respectively) of specific folate transporters: RFC, PCFT/HCP1 and FOLR1 in chorionic (fetal) and basal (maternal) plates of placentas of PT pregnancies (PT, 32-36 weeks, n = 51). Term placentas were used as controls (T, 37-41 weeks, n = 47). Folates and vitamin B12 levels were measured by electrochemiluminescence in umbilical cord blood of newborns. FOLR1 mRNA expression was lower and protein concentration higher in PT placentas (both plates) relative to the control group (p <0.05). In addition, gestational age was positively correlated with mRNA expression (Rho = 0.7), and negatively with protein concentration (Rho = -0.7 for chorionic and -0.43 for basal plate). PCFT/HCP1 mRNA was lower in PT placentas, without changes in protein levels. RFC did not differ in PT placentas compared to controls. PT newborns presented higher cord blood folate level (p = 0.049) along with lower vitamin B12 concentration compared to controls (p = 0.037).In conclusion, placental FOLR1 mRNA was positively associated with gestational age. Conversely, FOLR1 protein concentrations along with folate/vitamin B12 ratio in cord blood were negatively associated with gestational age. Placental FOLR1 is likely the main placental folate transporter to the fetus in newborns.
Assuntos
Sangue Fetal/metabolismo , Transportadores de Ácido Fólico/metabolismo , Ácido Fólico/sangue , Placenta/metabolismo , Vitamina B 12/sangue , Adulto , Feminino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Transportadores de Ácido Fólico/genética , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Gravidez , Nascimento Prematuro/sangue , Nascimento Prematuro/genética , Nascimento Prematuro/metabolismo , Transportador de Folato Acoplado a Próton/genética , Transportador de Folato Acoplado a Próton/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Nascimento a Termo/sangue , Nascimento a Termo/genética , Nascimento a Termo/metabolismo , Adulto JovemRESUMO
BACKGROUND: Folate and vitamin B12 are essential nutrients, whose deficiencies are considerable public health problems worldwide, affecting all age groups. Low levels of these vitamins have been associated with high concentrations of homocysteine (Hcy) and can lead to health complications. Several genetic polymorphisms affect the metabolism of these vitamins. The aims of this study were to assess folate, vitamin B12 and homocysteine status in distinct Brazilian individuals after the initiation of folic acid fortification by Brazilian authorities and to investigate the effects of RFC1 A80G, GCPII C1561T and MTHFR C677T polymorphisms on folate, vitamin B12 and Hcy levels in these populations. METHODS: A total of 719 individuals including the elderly, children, as well as pregnant and lactating women were recruited from our health care center. Folate, vitamin B12 and Hcy levels were measured by conventional methods. Genotype analyses of RFC1 A80G, GCPII C1561T and MTHFR C677T polymorphisms were performed by PCR-RFLP. RESULTS: The overall prevalence of folate and vitamin B12 deficiencies were 0.3% and 4.9%, respectively. Folate deficiency was observed only in the elderly (0.4%) and pregnant women (0.3%), whereas vitamin B12 deficiency was observed mainly in pregnant women (7.9%) and the elderly (4.2%). Plasma Hcy concentrations were significantly higher in the elderly (33.6%). Pregnant women carrying the MTHFR 677TT genotype showed lower serum folate levels (p = 0.042) and higher Hcy levels (p = 0.003). RFC1 A80G and GCPII C1561T polymorphisms did not affect folate and Hcy levels in the study group. After a multivariate analysis, Hcy levels were predicted by variables such as folate, vitamin B12, gender, age and RFC1 A80G polymorphism, according to the groups studied. CONCLUSION: Our results suggest that folate deficiency is practically nonexistent in the post-folic acid fortification era in the subgroups evaluated. However, screening for vitamin B12 deficiency may be particularly relevant in our population, especially in the elderly.
Assuntos
Deficiência de Ácido Fólico/epidemiologia , Ácido Fólico/sangue , Homocisteína/sangue , Deficiência de Vitamina B 12/epidemiologia , Vitamina B 12/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Brasil/etnologia , Carboxipeptidases/genética , Criança , Pré-Escolar , Feminino , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/metabolismo , Humanos , Lactente , Lactação/sangue , Lactação/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Gravidez/sangue , Gravidez/metabolismo , Prevalência , Proteína Carregadora de Folato Reduzido/genética , Fatores de Risco , Fatores Sexuais , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/genética , Deficiência de Vitamina B 12/metabolismo , Adulto JovemRESUMO
Osteosarcoma is a primary malignant tumor in adolescents, associated with high mortality and morbidity. The high-dose methotrexate (MTX) chemotherapy used to treat this disease may induce primary or secondary drug resistance, resulting in a reduced effect of comprehensive treatment. In this study, the relationship between reduced folate carrier (RFC) gene expression and intracellular drug concentration in MTX-resistant osteosarcoma cells (Saos-2) was investigated. MTX-resistant human osteosarcoma cells (Saos-2/MTX2.2, Saos-2/MTX4.4) were prepared. The sensitivities of Saos-2 (primary cells), Saos-2/MTX2.2, and Saos-2/MTX4.4 cells to MTX, diamminedichloroplatinum (DDP), ifosfamide (IFO), epirubicine (EPI), adriamycin (ADM), theprubicin (THP), and paclitaxel (PTX) were detected by MTT. The median inhibitory concentration (IC50) and resistance index were measured. Semi-quantitative RT-PCR was used to evaluate the expression of RFC gene in cells. The intracellular (3)H-MTX concentration was determined. Results showed that IC50 of Saos-2/MTX2.2 and Saos-2/MTX4.4 was 4.87 and 12.73 times that of Saos-2, respectively. Both Saos-2/MTX2.2 and Saos-2/MTX4.4 had resistance to IFO, ADM, EPI, THP, and PTX, but not DDP. Compared to Saos-2/MTX2.2 and Saos-2/MTX4.4, the expression of RFC mRNA in Saos-2 was significantly higher. The intracellular (3)H-MTX concentration reached a peak at 50 min. After 70 min, the concentration was maintained at a plateau. During this phase, the (3)H-MTX concentration in Saos-2 cells was 2.15 times higher than the concentration in Saos-2/MTX4.4 cells. The reduced RFC mRNA expression in PTX-resistant osteosarcoma cells may be related to the decrease in intracellular (3)H-MTX concentration.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica/efeitos dos fármacos , Metotrexato/farmacologia , RNA Mensageiro/genética , Proteína Carregadora de Folato Reduzido/genética , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/análogos & derivados , Cisplatino/farmacologia , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Epirubicina/farmacologia , Humanos , Ifosfamida/farmacologia , Osteócitos/efeitos dos fármacos , Osteócitos/metabolismo , Osteócitos/patologia , Paclitaxel/farmacologia , RNA Mensageiro/metabolismo , Proteína Carregadora de Folato Reduzido/metabolismo , TrítioRESUMO
BACKGROUND: The reduced folate carrier (RFC1) is a major methotrexate transporter whose impaired function was recognized as a frequent mechanism of antifolate resistance. Recently, a G80A polymorphism has been described in the RFC1. This study evaluated the effect of the G80A polymorphism in the RFC1 gene on survival and risk of relapse of acute lymphoblastic leukemia. METHODS AND RESULTS: Seventy patients with acute lymphoblastic leukemia were genotyped by polymerase chain reaction restriction fragment length polymorphism method. An association between the polymorphism and risk of relapse was found (P < 0.05). Patients with the G/A genotype have 3.97 (95% confidence interval, 1.12-14.06) and carriers of the A/A genotype have 7.84 (95% confidence interval, 1.66-37.10) higher chance of a relapse. Other variables such as age and leukocyte count were associated (P < 0.05) with the risk of relapse of disease. Individuals with G/A or A/A genotypes had poorer survival (log-rank test, P = < 0.05). CONCLUSIONS: These data suggest a role of the polymorphism G80A in the risk of relapse and the mortality risk in patients with acute lymphoblastic leukemia from the State of Guerrero, Mexico.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Carregadora de Folato Reduzido/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Recidiva , 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
OBJECTIVE: To examine the associations between variants of genes involved in the uptake, retention, and metabolism of folate and depressive symptoms and to analyze whether such associations are direct or through mediation by folate or homocysteine. METHODS: We performed a cross-sectional analysis of data from 976 Puerto Rican adults, aged 45 to 75 years, residing in the greater Boston area, Massachusetts. Twelve single nucleotide polymorphisms (SNPs) in genes involved in folate uptake, retention, and metabolism were investigated. These include FOLH1 (folate hydrolase), FPGS (folate polyglutamate synthase), GGH (γ-glutamyl hydrolase), MTHFR (methylenetetrahydrofolate reductase), MTR (methionine synthase), PCFT (proton-coupled folate transporter), and RFC1 (reduced folate carrier 1). The Center for Epidemiologic Studies Depression Scale (CES-D) was used to measure depressive symptoms. RESULTS: The FOLH1 rs61886492 C>T (or 1561C>T) polymorphism was significantly associated with lower CES-D score (p = .0025) after adjusting for age, sex, population admixture, smoking, and educational attainment. Individuals with the TT and TC genotypes were 49% less likely (odds ratio = 0.51, 95% confidence interval = 0.29-0.89) to report mild depressive symptoms (CES-D score ≥16 and ≤26) and 64% less likely (odds ratio = 0.36, 95% confidence interval = 0.18-0.69) to report moderate to severe depressive symptoms (CES-D score >26), compared with those with the CC genotype. No significant mediation effects by plasma folate or homocysteine on the associations between this single nucleotide polymorphism and CES-D score were observed. CONCLUSIONS: The FOLH1 1561C>T polymorphism may be associated with the risk of depressive symptoms.
Assuntos
Depressão/genética , Ácido Fólico/genética , Glutamato Carboxipeptidase II/genética , Polimorfismo de Nucleotídeo Único/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Adulto , Idoso , Boston/epidemiologia , Estudos Transversais , Depressão/sangue , Depressão/epidemiologia , Feminino , Receptor 1 de Folato/genética , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/epidemiologia , Frequência do Gene , Genótipo , Homocisteína/sangue , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Transportador de Folato Acoplado a Próton/genética , Escalas de Graduação Psiquiátrica , Ácidos Pteroilpoliglutâmicos/genética , Porto Rico/etnologia , Fosfato de Piridoxal/sangue , Proteína Carregadora de Folato Reduzido/genética , Vitamina B 12/sangue , gama-Glutamil Hidrolase/genéticaRESUMO
This study aimed to investigate the role of maternal polymorphisms, as well as their risk genotypes combinations of MTR A2756G, MTRR A66G, CBS 844ins68, and RFC A80G, involved in folate/homocysteine metabolism, as possible risk factors for Down syndrome (DS) in Southern Brazil. A case-control study was conducted with 239~mothers of DS children and 197~control mothers. The investigation of polymorphisms was performed by PCR and PCR-RFLP. The distribution of genotypic variants was similar in both groups when they were analyzed separately. An investigation of combined risk genotypes showed that the risk of having a DS child for one, two or three risk genotypes was 6.23, 6.96 and 5.84 (95%CI 1.48-26.26; 1.69-28.66; 1.37-24.86), respectively. The combined MTRR 66G and MTHFR 677T alleles were significantly more common among mothers of children with DS than among control mothers (OR 1.55; IC 95% 1.03-2.35). The results show that individual polymorphisms studied in this work are not associated with DS; however, the effects of the combined risk genotypes among MTR, MTRR, CBS and RFC genes are considered maternal risk factors for DS offspring in our population.
Assuntos
Síndrome de Down/genética , Ácido Fólico/metabolismo , Polimorfismo Genético , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Adulto , Brasil , Estudos de Casos e Controles , Cistationina beta-Sintase/genética , Feminino , Ferredoxina-NADP Redutase/genética , Estudos de Associação Genética , Genótipo , Humanos , Idade Materna , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteína Carregadora de Folato Reduzido/genética , Fatores de RiscoRESUMO
BACKGROUND: Polymorphisms in genes that are involved in folic acid metabolism may be important maternal risk factors for the birth of a child with nonsyndromic cleft lip and/or palate (NSCL/P). The aim of this study was to determine the involvement of polymorphic variants in four genes (MTHFR, MTHFD1, MTR, and SLC19A1) that encode proteins related to folic acid metabolism in the women with susceptibility for having a child with NSCL/P. METHODS: DNA samples from 106 mothers of children with NSCL/P (case group) and from 184 mothers of healthy children (control group) were genotyped by polymerase chain reaction associated with restriction fragment length polymorphism (PCR-RFLP). RESULTS: One of 29 polymorphisms was associated with significantly increased maternal risk for NSCL/P. Mothers exhibiting the A variant allele (GA genotype) of the MTHFR rs2274976 polymorphism demonstrated a ~6 times increased risk for having a child with NSCL/P compared to G allele carriers (OR, 5.76; 95% CI, 3.32-9.99, p = 0.000001). Among mothers who did not use vitamins, the OR of NSCL/P was increased to 8.34 (95% CI, 3.75-18.55, p = 0.000001) in the presence of the GA genotype of the MTHFR rs2274976 polymorphism compared to those with the GG genotype. Gene-gene interaction analysis showed that the combination of MTHFR rs2274976, MTHFD1 rs2236225, and SLC19A1 rs1051266 was the best model for prediction of maternal risk for NSCL/P. CONCLUSION: The findings of the present study suggested that genetic variants of folic acid metabolic genes may modulate maternal susceptibility for having an offspring with NSCL/P.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adolescente , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Masculino , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Antígenos de Histocompatibilidade Menor , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Gravidez , Proteína Carregadora de Folato Reduzido/genética , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Polymorphisms in the genes of folate and methionine metabolism enzymes have been associated with some forms of cancer by affecting DNA synthesis, repair, and methylation. PROCEDURE: A case-control study of 72 retinoblastoma cases and 98 cancer-free children controls was performed to investigate whether the polymorphisms of the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), carrier of reduced folate 1 (RFC-1 A80G) and thymidylate synthase (TYMS 2R > 3R) altered the risk for retinoblastoma. RESULTS: MTR A2756G AG plus GG genotype frequencies were higher in patients than in controls (45% vs. 26%, P = 0.03). Individual carriers of the variant allele G had a 2.02 (95% CI: 1.05-3.92)-fold increased risk for retinoblastoma. In contrast, no association was observed with respect to MTHFR C677T and A1298C, RFC A80G, and TYMS polymorphisms. CONCLUSIONS: This study presents evidence for an association between the MTR A2756G polymorphism and retinoblastoma susceptibility in a Northeast population from Brazil.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Predisposição Genética para Doença , Neoplasias da Retina/genética , Retinoblastoma/genética , Brasil , Estudos de Casos e Controles , Criança , Pré-Escolar , Genótipo , Humanos , Lactente , Recém-Nascido , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Proteína Carregadora de Folato Reduzido/genética , Fatores de Risco , Timidilato Sintase/genéticaRESUMO
BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR), glutamate carboxypeptidase II (GCPII) and reduced folate carrier (RFC1) gene polymorphisms were associated with folate status. We investigated the effects of these polymorphisms on serum folate (SF) and folate-related metabolites in mothers and their neonates. METHODS: Cobalamin (Cbl), SF, total homocysteine (tHcy), methylmalonic acid (MMA), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured in 275 healthy women and their neonates. MTHFR C677T, GCPII C1561T and RFC1 A80G polymorphisms were determined by PCR-RFLP. RESULTS: Maternal tHcy was affected individually by MTHFR C677T and GCPII C1561T polymorphisms and by combined genotypes MTHFR 677TT/GCPII 1561CC and MTHFR 677TT/RFC1 80AG. The MTHFR and RFC1 polymorphisms were not associated with variations in vitamins or SAM, SAH and MMA in neonates. Neonatal tHcy was predicted directly by maternal tHcy and inversely by maternal SF, neonatal Cbl and neonatal RFC1 80G allele (AG+GG genotypes). Maternal MMA and SAM/SAH were predicted by creatinine and Cbl, respectively. Neonatal MMA was predicted by maternal MMA and GCPII 1561T allele (CT+TT genotypes) and by neonatal Cbl. CONCLUSIONS: Maternal tHcy was affected by MTHFR C677T, RFC1 A80G and GCPII C1561T polymorphisms. Maternal GCPII C1561T variant was associated with neonatal MMA. Neonatal RFC1 A80G polymorphism influenced tHcy in neonates.
Assuntos
Ácido Fólico/metabolismo , Glutamato Carboxipeptidase II/genética , Polimorfismo Genético/genética , Gravidez/metabolismo , Proteína Carregadora de Folato Reduzido/genética , Complexo Vitamínico B/metabolismo , Adulto , Brasil/epidemiologia , DNA/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Etnicidade , Feminino , Ácido Fólico/sangue , Homocisteína/sangue , Humanos , Recém-Nascido , Ácido Metilmalônico/sangue , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase Via Transcriptase Reversa , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Fatores Socioeconômicos , Vitamina B 12/sangue , Complexo Vitamínico B/sangue , Adulto JovemRESUMO
The aim of the present study was to investigate the effect of polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, A2756G in methionine synthase reductase (MTR) gene and A80G in reduced folate carrier 1 (RFC1) gene, and plasma homocysteine (Hcy), on the maternal risk for Down syndrome (DS). Seventy-two DS mothers and 194 mothers who had no children with DS were evaluated. The investigation of the MTHFR C677T, MTR A2756G and RFC1 A80G polymorphisms was performed by polymerase chain reaction and enzyme digestion and the MTHFR A1298C polymorphism by allele-specific polymerase chain reaction. Hcy quantification was carried out by liquid chromatography-tandem mass spectrometry. The median number of polymorphic alleles for the four loci tested was greater in DS mothers compared to the control group, and the presence of three or more polymorphic alleles increased the risk for having a child with DS 1.74 times. Elevated maternal risk for DS was also observed when plasma Hcy concentration was higher than 4.99 micromol/L. In conclusion, the presence of three or more polymorphic alleles for MTHFR C677T, MTHFR A1298C, MTR A2756G, and RFC1 A80G, and plasma Hcy concentrations higher than 4.99 micromol/L are maternal risk factors for DS.