RESUMEN
Objectives Antioxidant response plays a key role in bronchopulmonary dysplasia (BPD) pathogenesis. The glutathione-S-tranferases pi 1 (GSTP1) and cytochrome P450 (CYP) detoxification enzymes protect cells from oxidative damage. The aim of the study was to investigate whether the A313G GSTP1 and G516T CYP2B6 inactivating polymorphisms could be associated with BPD susceptibility. Study Design To test this hypothesis, we conducted a case-control study enrolled 138 premature neonates ≤32 weeks of gestational age; of the 138, 46 developed BPD and 92 did not develop BPD. Genomic deoxyribonucleic acid was extracted from neonates' peripheral blood and was used as template for GSTP1 and CYP2B6 genotyping using the real-time polymerase chain reaction method. Results Our report provides evidence for a possible pathogenetic role of the G516T CYP2B6 polymorphism in BPD susceptibility. Although no differences in the frequencies of the GSTP1 variant genotypes were noticed between premature neonates who developed BPD and neonates who did not develop BPD, a significantly higher frequency of the GSTP1 polymorphism was observed in extremely low birth weight infants. Despite the small sample size, it is very interesting the fact that all neonates ≤1,000 g carrying the homozygous mutant GSTP1 genotype developed BPD. Conclusion Our results underscore the significance of both CYP2B6 and GSTP1 polymorphisms in modulating the risk of BPD.
Asunto(s)
Displasia Broncopulmonar/genética , Citocromo P-450 CYP2B6/genética , Gutatión-S-Transferasa pi/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Edad Gestacional , Grecia , Humanos , Recién Nacido , Recien Nacido Prematuro , Recién Nacido de muy Bajo Peso , Masculino , Estrés Oxidativo/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphism of genes encoding detoxification enzymes, such as NQO1 and GSTP1 could influence susceptibility to MS. The monoclonal antibody natalizumab is an effective treatment in MS. Natalizumab's efficacy in MS patients with regard to NQO1 and GSTP1 genetic polymorphisms is investigated. 130 patients with definite MS according to the Mc Donald's criteria treated monthly with natalizumab were included in the study. MS patients were classified with regard to their clinical subtype, gender and clinical outcome after Natalizumab administration. GSTP1 and NQO1 genotyping was performed using Real-Time PCR and PCR-RFLP assays. Among our cohort of MS patients, 88.5% responded and 11.5% manifested clinical deterioration after natalizumab treatment. Statistical analysis revealed a significantly increased frequency of double NQO1 and GSTP1 mutant polymorphisms in non responders compared to the responders. Therefore, patients who carry the wild type genotype or only one polymorphism for either NQO1 or GSTP1 gene have possibly a better clinical outcome after the natalizumab therapy. Our findings indicate that antioxidant efficiency might reflect a better clinical outcome after natalizumab administration. Hence, oxidative stress reduction might be another mechanism through which natalizumab exerts its protective effect.
Asunto(s)
Predisposición Genética a la Enfermedad , Gutatión-S-Transferasa pi/genética , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Natalizumab/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Adulto , Estudios de Cohortes , Demografía , Evaluación de la Discapacidad , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Germline polymorphisms of detoxification genes could influence susceptibility to Multiple Sclerosis (MS). Glutathione-S-transferases (GSTs) and NAD(P)H: quinone oxidoreductase 1 (NQO1) are detoxifying enzymes involved in biotransformation of metabolites preventing cells from oxidative damage. In order to evaluate the possible contribution of the A313G GSTP1 inactivating polymorphism, alone and in combination with the C609T NQO1 genetic variant in MS susceptibility, we performed a case-control study consisting of 254 MS patients and 370 healthy donors. Genotypes were investigated using a new Real-Time PCR and PCR-RFLP assays. The GSTP1 polymorphism was evaluated in relation to patients' characteristics (clinical subtypes, age and gender) and the NQO1 gene status. GSTP1 genotype distribution was similar between cases and controls. Higher frequency of GSTP1 heterozygotes was observed in patients with relapsing remitting disease (RRMS) (p = 0.019), especially in those presenting a benign form (EDSS ≤ 2 after 10-15 years from the disease onset). Interestingly, genotype distribution analysis of combined GSTP1 and NQO1 polymorphisms revealed significantly higher frequency of GSTP1 heterozygous (A/G) and NQO1 variant genotypes (C/T and T/T) in patients as compared to the controls (p = 0.031). The increased incidence of combined GSTP1 and NQO1 variant genotypes in MS patients may suggest that defective function of detoxification enzymes might be an important determinant of susceptibility and clinical manifestation of the disease. Moreover, the results suggest a possible role for the GSTP1 heterozygous background in the development of RRMS.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Gutatión-S-Transferasa pi/genética , Esclerosis Múltiple/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Evaluación de la Discapacidad , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Metilación de ADN , Gutatión-S-Transferasa pi/genética , Leucemia Mieloide/genética , Regiones Promotoras Genéticas/genética , Enfermedad Aguda , Aberraciones Cromosómicas , Deleción Cromosómica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Mutación de Línea Germinal , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
The NQO1 C(609)T germline polymorphism resulting in a lowering of enzyme activity may confer susceptibility to MDS. To assess this association, we performed a case-control study including 330 Greek patients with de novo MDS and 416 healthy donors, using a Real-Time PCR genotyping method. Focusing on cytogenetic aberrations most commonly found in MDS, we retrospectively genotyped 566 MDS/AML patients carrying -5/del(5q), -7/del(7q), +8, del(20q) and -Y. The case-control analysis revealed no differences in NQO1 genotype distribution. Interestingly, a 6-fold increased frequency of the homozygous variant genotype was observed among patients with isolated trisomy 8 (p<0.0001), suggesting that null NQO1 activity may influence the occurrence of +8 in MDS/AML.
Asunto(s)
Mutación de Línea Germinal/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Polimorfismo Genético/genética , Trisomía/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Aberraciones Cromosómicas , Cromosomas Humanos Par 8/genética , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
Models for the pathogenesis of myelodysplastic syndrome (MDS) imply the role of individual genetic variations in genes involved in detoxification mechanisms. GSTP1 enzyme plays a key role in the biotransformation of a variety of carcinogens. The corresponding gene is subject to a single nucleotide polymorphism (A(313)G) leading to abolished enzyme activity. In order to evaluate whether the GSTP1 polymorphism influences MDS susceptibility, we conducted a case-control study comprising 310 de novo patients and 370 healthy controls using a real-time polymerase chain reaction (PCR) genotyping method. The GSTP1 gene status was also evaluated in relation to patients' characteristics and chromosomal abnormalities. A significantly higher incidence of the GSTP1 variant genotypes was observed in patients with MDS compared to controls (p < 0.0001). The results revealed increased frequencies of heterozygotes in patients younger than 60 years old and of homozygotes G/G in older patients (p = 0.007). Our results provide evidence for a pathogenetic role of the GSTP1 polymorphism in MDS risk, probably in an age-dependent manner.
Asunto(s)
Predisposición Genética a la Enfermedad , Gutatión-S-Transferasa pi/genética , Síndromes Mielodisplásicos/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Estudios de Casos y Controles , Aberraciones Cromosómicas , Femenino , Frecuencia de los Genes , Genotipo , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphisms of genes encoding detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), could influence susceptibility to MS. To test this hypothesis we performed a case-control study in which we compared the distribution of NQO1 genotypes between 231 MS patients and 380 controls, using both PCR-RFLP and real-time PCR assays. Correlations with MS clinical subtype classification and gender were also evaluated. A significantly higher frequency of the homozygous (T/T) and heterozygous (C/T) NQO1 C(609)T variant genotypes was observed among MS patients compared to controls (P=0.01), with MS patients showing a 1.5-fold increased risk of carrying at least one variant T allele (P=0.009). Interestingly, patients belonging to the primary progressive subgroup exhibited a significantly higher incidence of the heterozygous C/T variant genotype, compared to the other forms of MS (P=0.019). There was no correlation of the NQO1 polymorphism with gender. These results provide the first evidence for a pathogenetic role for the NQO1 C(609)T polymorphism in MS susceptibility and suggest a possible role for the NQO1 genetic background in the development of primary progressive MS.