RESUMO
To investigate the role of the corticotropin releasing hormone receptor 1 (CRHR1) in patterns of human alcohol drinking and its potential contribution to alcohol dependence, we analysed two independent samples: a sample of adolescents, which consisted of individuals from the 'Mannheim Study of Risk Children' (MARC), who had little previous exposure to alcohol, and a sample of alcohol-dependent adults, who met DSM-IV criteria of alcohol dependence. Following determination of allelic frequencies of 14 polymorphisms of the CRHR1 gene, two haplotype tagging (ht)SNPs discriminating between haplotypes with a frequency of > or =0.7% were identified. Both samples were genotyped and systematically examined for association with the htSNPs of CRHR1. In the adolescent sample, significant group differences between genotypes were observed in binge drinking, lifetime prevalence of alcohol intake and lifetime prevalence of drunkenness. The sample of adult alcohol-dependent patients showed association of CRHR1 with high amount of drinking. This is the first time that an association of CRHR1 with specific patterns of alcohol consumption has been reported. Our findings support results from animal models, suggesting an importance of CRHR1 in integrating gene-environment effects in alcohol use disorders.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Polimorfismo de Nucleotídeo Único , Receptores de Hormônio Liberador da Corticotropina/genética , Adolescente , Adulto , Fatores Etários , Feminino , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Masculino , Valores de Referência , Índice de Gravidade de DoençaRESUMO
Alcohol dependence is one of the most common addictive diseases and known to be in part genetically transmitted, based on an oligogenic background in which each gene involved contributes only little to the resulting phenotype. Besides influencing other signal transduction mechanisms, alcohol specifically inhibits the NMDA signaling cascade, which mediates the excitatory effects of glutamate in the brain. Target molecules, sensitive to ethanol, include the NMDA receptors as well as downstream molecules of the glutamatergic system, glutamate transporters, and associated regulatory proteins. Adaptive processes of the glutamatergic system during chronic alcohol consumption may play a major role for later development of reward symptoms. Candidate gene studies, including association studies and animal models, are powerful and sensitive for detecting oligogenic effects and thus important to alcoholism research.
