RESUMO
P-Glycoprotein (ABCB1-type P-gp), a membrane protein encoded by the multi drug resistant gene (MDR1), expressing on the blood brain barrier protects the brain from many drugs including dexamethasone. Psychiatric disorders, schizophrenia and depression, have known to have abnormal hypothalamus-pituitary-adrenal (HPA) activity, which is assessed by non-suppression of cortisol in dexamethasone suppression test. The poor response to dexamethasone in these patients' population suggested the impaired activity on dexamethasone penetration into the brain via P-gp, which was associated with MDR1 polymorphisms. We, therefore, examined five SNPs of the MDR1 gene, -1517 T>C (promoter), -41 A>G (intron -1), -129 T>C (exon 1b), 2677 G>A,T (exon 21) and 3435 C>T (exon 26), in Japanese patients with schizophrenia (n=121) and mood disorders (n=62), and compared with the control subjects (n=160). The frequency of MDR1 mutant alleles at -1517, -41 and -129 in patients with mood disorders was significantly lower (2.4, 5.6, 2.4%, respectively) than those of controls (7.8, 13.7, 7.8%, respectively) (p<0.05). The frequencies of MDR1 2677 G/A and A/A genotype in mood disorders was significantly higher (17.7, 6.5%, respectively) than controls (11.2, 0%, respectively) (p<0.05). The 2677A allele frequency in mood disorders (20.2%) was significant higher than controls (10.9%) (p<0.05). Haplotype of 129-2677-3435 (T-A-C) in mood disorders was significantly higher (14.4%) than controls (8.0%) (p<0.05). There was no significant difference in allele and genotype frequencies between the patients with schizophrenia and controls. These findings suggested that predispose to mood disorders, not schizophrenia, was associated with possible alteration of P-gp activities corresponding MDR1 polymorphism at least partly.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Depressão/genética , Transtornos do Humor/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Sequência de Bases , Estudos de Casos e Controles , Primers do DNA , Depressão/tratamento farmacológico , Dexametasona/uso terapêutico , Humanos , Íntrons , Japão , Transtornos do Humor/tratamento farmacológico , Regiões Promotoras Genéticas , Esquizofrenia/tratamento farmacológicoAssuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antipsicóticos/farmacocinética , Resistência a Medicamentos/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Alelos , Substituição de Aminoácidos , Antipsicóticos/uso terapêutico , Frequência do Gene , Humanos , Esquizofrenia/tratamento farmacológicoRESUMO
OBJECTIVE: Glutathione-S-transferases, NAD(P)H: quinone oxidoreductase1 (NQO1) and NRH: quinone oxidoreductase2 (NQO2) provide important cellular defences against the neurotoxicity induced by catecholamine-derived o-quinones and oxidative stress during redox cycling. In this study, we investigated the association between polymorphisms of the NQO2 gene and schizophrenia. METHODS: We analysed the promoter and coding regions of the NQO2 gene for 102 patients with schizophrenia and for 234 controls using single-strand conformational change polymorphism and PCR direct-sequencing analyses and the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was measured. RESULTS: We identified 12 variants including the insertion/deletion (I/D) polymorphism of the 29 base pair nucleotide sequence in the promoter region. The frequency of the D allele was significantly higher in the schizophrenic group than in the control group (P=0.0109). Especially, in patients with the episodic type as course specifiers, this value was highly significant (P=0.0016) and the significance remained after the Bonferroni correction. The 29 base pair nucleotide sequence contains four repeats of the putative core sequence of the Sp1-binding cis-element that is important in the activation of gene expression. Our preliminary data, although sample size was not enough, demonstrated that the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was higher in individuals homozygous (II) for the I allele than in those heterozygous (ID) or homozygous (DD) for the D allele. CONCLUSION: The present data suggest that individuals with the deletion of the 29 base pair sequence in the promoter region of the NQO2 gene may confer susceptibility to a certain form of schizophrenia.
Assuntos
Mutagênese Insercional/genética , Quinona Redutases/genética , Esquizofrenia/genética , Deleção de Sequência , Adulto , Sequência de Bases , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Esquizofrenia/classificação , Esquizofrenia/enzimologiaRESUMO
The human gamma-aminobutyric acid type B (GABA(B)) receptor gene is a candidate gene for schizophrenia due to its chromosomal location and neurobiologic roles. In the present study, association analyses of genetic polymorphisms of the GABA(B) receptor gene with schizophrenia were carried out in 102 unrelated schizophrenic patients and 100 healthy controls, using a polymerase chain reaction-based, single-strand conformational polymorphism analysis. Although the Ala20Val and Gly489Ser mutations were not found in our samples, we found a novel polymorphism of (AC)n dinucleotide repeats located approximately 1.6 kb upstream from the translational start site. No significant difference in allele frequencies was found between controls and patients with schizophrenia (P = 0.0587) using the Monte Carlo method. Significant differences were found between controls and patients with continuous-course schizophrenia (P = 0.0019), and between controls and patients with a positive family history of psychoses (P = 0.0015). These differences, however, were not significant after Bonferroni correction. These data did not support our hypothesis that polymorphisms of the GABA(B) receptor gene may confer vulnerability for schizophrenia.
