Polymorphismes géniques de marqueurs sérotoninergiques et alcoolodépendance Alcohol dependence and polymorphisms of serotonin-related genes

Résumé

Même si les facteurs génétiques ont un rôle modéré et peu spécifique, leur impact est réel sur la manière dont on rencontre l’alcool, et donc sur le risque de développer une dépendance. Les études de génétique moléculaire ont rapidement dépassé les gènes impliqués dans le métabolisme de l’alcool pour se consacrer à des aspects plus neurocognitifs, tempéramentaux et psychocomportementaux de la dysconsommation d’alcool. Une piste importante, détaillée dans cet article, concerne la sérotonine et son implication dans la capacité de différer l’action et le passage à l’acte. Parmi les gènes potentiellement impliqués dans la transmission sérotoninergique, le transporteur de la sérotonine a fait l’objet du plus grand nombre d’analyses. L’un des allèles de ce gène semble ainsi avoir un rôle significatif dans le risque d’alcoolodépendance, même si le phénotype impliqué (c’est-à-dire ce qui est réellement transmis) reste encore mal défini.

Summary

Genetic factors have a non-specific but significant impact on the risk of alcohol-dependence. Molecular genetic analyses are now less devoted to the genes involved in the metabolism of ethanol, focusing on core concepts of addiction, such as arousal, pleasure, reward, craving, and impulsivity. Indeed, the neuro-cognitive functions, temperament traits and psycho-behavioral specificities of patients with alcohol abuse or dependence led to select new sets of candidate genes. One of them are related to serotonin transmission, as serotonin modulates dopaminergic pathways, and is also stimulated by many addictive susbstances. The genetic analyses of serotonin in alcohol-dependence are mainly focused on the serotonin transporter gene (5-HTT), as one polymorphism within the promoter has a functional impact. From the 16 case-control association studies yet performed, many are positive, and one family-based study showed a large excess of transmission of the short allele. We performed a meta-analysis of the case-control studies showing that the S allele could be a risk factor for a phenotype related to alcohol-dependence (OR=1.31), with still unknown boundaries. Other genes coding for serotonin receptors were analysed with mainly negative results, for example the 5-HT_2A, 5-HT_2C, 5-HT_5A and 5-HT₇ receptors. The 5-HT_1B could be more interesting as being located in a locus linked to alcohol preference in rodents, and associated with antisocial alcoholism in two human studies. Genetics may thus provide new insights about the different mechanisms which explain why some subjects are more at risk for the development of alcohol abuse or dependence. Genes involved in the transmission, reuptake and metabolism of serotonin constitute a set of candidate genes that could be involved in core aspects of alcoholism, such as the tendency to prefer immediate reward, despite negative consequences.