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Disease‐associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue‐specific activity of the cannabinoid‐1 receptor gene promoter; implications for cannabinoid pharmacogenetics

Cannabinoid receptor‐1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Toward addressing the hypothesis that genetic changes w...

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Detalles Bibliográficos
Autores principales: Hay, Elizabeth A., Cowie, Philip, McEwan, Andrew R., Ross, Ruth, Pertwee, Roger G., MacKenzie, Alasdair
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973010/
https://www.ncbi.nlm.nih.gov/pubmed/31608546
http://dx.doi.org/10.1002/humu.23931
Descripción
Sumario:Cannabinoid receptor‐1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Toward addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterized the effects of disease‐associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake, and anxiety‐like behavior. We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that human‐specific C‐allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T‐allele and demonstrated a differential response to CB1 agonism. We further demonstrate a role for the AP‐1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral t‐allele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell‐specific approaches used in our study represent an important step in gaining a mechanistic understanding of the roles of noncoding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics.