Alternative CHRNB4 3′-UTRs Mediate the Allelic Effects of SNP rs1948 on Gene Expression

Common genetic factors strongly contribute to both nicotine, the main addictive component of tobacco, and alcohol use. Several lines of evidence suggest nicotinic acetylcholine receptors as common sites of action for nicotine and alcohol. Specifically, rs1948, a single-nucleotide polymorphism (SNP) located in the CHRNB4 3′-untranslated region (UTR), has been associated to early age of initiation for both alcohol and tobacco use. To determine the allelic effects of rs1948 on gene expression, two rs1948-containing sequences of different lengths corresponding to the CHRNB4 3′-UTR were cloned into pGL3-promoter luciferase reporter vectors. Data obtained showed that the allelic effects of SNP rs1948 on luciferase expression are mediated by the length and species of transcripts generated. In addition, it was found that miR-3157 increased the overall luciferase expression while miR-138, a microRNA known to play a role in neuroadaptation to drug abuse, decreased luciferase expression when compared to basal conditions. These findings demonstrate the importance of SNP rs1948 on the regulation of CHRNB4 expression and provide the first evidence of CHRNB4 down-regulation by miR-138.