RESUMEN
Several lines of evidence suggest that anxiety disorders have a strong genetic component, but so far only few susceptibility genes have been identified. There is preclinical and clinical evidence for a dysregulation of the central gamma-aminobutyric acid (GABA)-ergic tone in the pathophysiology of anxiety disorders. Diazepam binding inhibitor (DBI) has been suggested to play a pivotal role in anxiety disorders through direct and indirect, i.e. via synthesis of neuroactive steroids, modulation of GABA(A) receptor function. These findings suggest that the DBI gene can be postulated as a candidate for a genetic association study in this disorder. Thus, single nucleotide polymorphisms (SNPs) of the DBI gene were investigated for putative disease associations in a German sample of anxiety disorder patients suffering from panic attacks and matched controls. We were able to detect a significant association between a non-synonymous coding variant of DBI with anxiety disorders with panic attacks. The rare allele of this polymorphism was more frequent in controls than in patients (OR=0.43; 95% CI: 0.19-0.95). In conclusion, these results suggest a central role of DBI genetic variants in the susceptibility for the development of anxiety disorders that are characterized by the occurrence of panic attacks.
Asunto(s)
Trastornos de Ansiedad/genética , Inhibidor de la Unión a Diazepam , Trastorno de Pánico/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Agorafobia/diagnóstico , Agorafobia/genética , Agorafobia/psicología , Alelos , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/psicología , Estudios de Casos y Controles , Comorbilidad , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética , Alemania , Humanos , Masculino , Trastorno de Pánico/diagnóstico , Trastorno de Pánico/psicologíaRESUMEN
As a key regulator of the neuroendocrine stress axis and as a neuromodulator in the brain, the neuropeptide corticotropin-releasing hormone (CRH) plays an important role in various diseases of the central nervous system. Its cognate receptor CRH receptor type 1 (CRHR1) is a potential novel target for the therapeutic intervention in major depressive disorder. Therefore, a more precise understanding of involved intracellular signaling mechanisms is essential. The objective of this project was to identify specific target genes of CRHR1-mediated signaling pathways in the corticotrope cell line AtT-20 and in the neuronal cell line HN9 using microarray technology and qRT-PCR, respectively. In addition, we assessed the capacity of validated target genes to directly impact on CRHR1-dependent signaling using reporter assays. Thereby, we identified a set of CRHR1 downstream targets with diverging and cell type-specific roles which strengthen the role of CRH and CRHR1 as dynamic modulators of a variety of signal transduction mechanisms and cellular processes.