Résumé
Objective: Cocaine use disorders (CUDs) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, who had concomitant cocaine and crack dependence, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs; adjusted p-value [adjP] < 10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that the EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1, and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns may contribute to a better understanding of the biological mechanisms involved in CUD.
Sujets)
Humains , Mâle , Adulte , Jeune adulte , Crack , Méthylation de l'ADN , Troubles liés à la cocaïne/génétique , Troubles liés à la cocaïne/sang , Étude d'association pangénomique/méthodes , Études cas-témoins , Modèles linéaires , Histone-lysine N-methyltransferase/génétique , Statistique non paramétrique , Mitogen-Activated Protein Kinase 1/génétique , MAP Kinase Kinase 1/génétique , Mitogen-Activated Protein Kinase 3/génétique , Réseaux de régulation génique , Séquençage nucléotidique à haut débit , Antigènes d'histocompatibilité/génétique , Histone deacetylases/génétiqueRésumé
O presente artigo procura revisae as mais recentes contribuiçöes da genética molecular para o estudo da dependência de cocaína. Säo descritos os circuitos anátomos-fisiológicos envolvidos na produçäo de comportamento de dependência para, atravées de modelos experimentais pré-clínicos (ou seja, realizados em animais de laboratório), apresentar-se as evidências iniciais de que possa haver populaçöes geneticamente vulneráveis ao desenvolvimento de dependência de cocaína. Igualmente säo expostas as estratégias metodológicas mais promissoras neste campo de trabalho, com especial ênfase para a estratégia conhecida por QTL (Quantitative Trait Locus), que busca reconhecer heranças poligênicas. Por fim, o artigo esboça o modo pelo qual a engenharia genética poderá colaborar no futuro para o desenvolvimento de alternativas de prevençäo e tratamento do problema