RESUMO
AIMS: In this study we explored possible epistasis between CYP2D6 (*3, *4, *5, *6 and *1xN), CYP3A5 (*3), CYP1A2 (*1C and *1F) and ABCB1 (G2677T) in schizophrenia and related disorders. MATERIALS & METHODS: A total of 344 patients diagnosed with schizophrenia and related disorders, and 484 healthy controls participated in the present study. We analyzed gene-gene interactions by multifactor dimensionality reduction. RESULTS: A four-way model including ABCB1 G2677T, CYP3A5*3, CYP1A2*1F and CYP2D6*4 variants had the best overall performances (accuracy: 0.573) and a crossvalidation consistency of 10/10 (permutation testing p < 0.004). CONCLUSION: Our results suggest a significant involvement of CYPs and transporters in brain metabolism and homeostasis, and provide evidence of gene-gene interactions among xenobiotic metabolizing and transporter genes in the context of schizophrenia.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Epistasia Genética , Esquizofrenia/enzimologia , Xenobióticos/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Transporte Biológico/genética , Encéfalo/enzimologia , Estudos de Casos e Controles , Interpretação Estatística de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/enzimologia , Transtornos Psicóticos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esquizofrenia/genética , Esquizofrenia Paranoide/enzimologia , Esquizofrenia Paranoide/genética , Xenobióticos/farmacocinéticaRESUMO
In a previous linkage disequilibrium mapping study, in the 3' end of ARVCF, we identified one intronic SNP rs165849 and one haplotype block associated with schizophrenia and related disorders. The aim of the present study was to explore whether functional genetic variants in the exonic regions of ARVCF included in this haplotype block are responsible for the association observed. To achieve this objective (1) the nine exons included in this haplotype block were resequenced in a group of 242 patients with schizophrenia and related disorders (Case 1). The SNPs identified were genotyped in a hospital-based control group of 373 subjects (Control 1) and an association study was performed. (2) The SNPs showing significant association in this analysis were genotyped in a new group of 102 patients with schizophrenia and related disorders (Case 2) and in a new group of 111 healthy subjects (Control 2). Three dbSNPs (rs35219372, rs5993890, and rs165815) were identified when the nine exons of ARVCF were resequenced. rs165815 was associated with schizophrenia and related disorders (homozygote CC OR = 3.39, permutated P value = 0.02). When the groups of cases (1 and 2) and controls (1 and 2) were merged, the analysis confirmed the association observed (homozygote CC OR = 3.25 permutated P value = 0.02). Given the role of ARVCF proposed in the neurodevelopmental hypothesis, our results further support the view that chromosome 22 contains a susceptibility gene, possibly ARVCF. The functional variant rs165815, which affects a critical region of ARVCF, is a considerable source of the genetic variability associated with the risk of developing schizophrenia.
Assuntos
Proteínas do Domínio Armadillo/genética , Moléculas de Adesão Celular/genética , Predisposição Genética para Doença , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Sequência de Bases , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genes Dominantes/genética , Genes Recessivos/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Dados de Sequência Molecular , Análise de Sequência de DNARESUMO
We investigated the relationship between several functional polymorphisms in genes coding for dopamine metabolism and transport enzymes (MAO-A VNTR; MAO-A 941T>G; DAT VNTR; DAT -67A/T; CYP2D6*3; CYP2D6*4; CYP2D6*5; CYP2D6*6) and the frequency of schizophrenia. Participants in the study were 242 subjects diagnosed with schizophrenia and related disorders and 290 hospital-based controls. Genomic DNA was isolated from whole blood and genotyped by several methods. However, there was no association between schizophrenia and the alleles, genotypes or diplotypes that were studied or their interactions. Polymorphisms in genes coding for dopamine metabolism and transport enzymes did not predispose to or protect from schizophrenia and related disorders.
Assuntos
Citocromo P-450 CYP2D6/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Monoaminoxidase/metabolismo , Polimorfismo Genético , Esquizofrenia/metabolismo , Adulto , Alelos , Citocromo P-450 CYP2D6/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Monoaminoxidase/genética , Esquizofrenia/epidemiologiaRESUMO
The purpose of this study was to investigate the relationship between functional polymorphisms in genes coding for dopamine metabolism and transport enzymes and the incidence of acute antipsychotic (AP)-induced extrapyramidal symptoms (EPS). We did not find evidence of the involvement of these polymorphisms in the predisposition towards or protection from EPS.
Assuntos
Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Monoaminoxidase/genética , Polimorfismo Genético/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Transtornos Mentais/tratamento farmacológico , Repetições Minissatélites/genética , Análise Multivariada , Estudos RetrospectivosRESUMO
We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3' downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3' region of the ARVCF gene.
