It was not until very recently that intergenic transcription has been recognized as an active and common cellular process. Evidence has shown that a significant portion of the transcriptome arises from outside annotated genes (31,32). As an important function, intergenic transcription can regulate expression at nearby genes (33,34). In particular, intergenic transcription was found to be an important mechanism underlying expression of cytokine genes, such as GM-CSF, IL3, IL4, IL5, IL 10, and IL13 (35-38). Given their location at potential TF binding sites, those SNPs identified in our GWAS that are upstream from the cytokine gene IL15, might potentially regulate IL15 gene expression through intergenic transcription. Importantly, the SNP, rs17354547, replicated in both the AA and FHS cohorts, as well as the TF binding site that can be potentially modulated by this SNP, are highly conserved across multiple species (Figure 2), further supporting the functional importance of this SNP in transcription regulation. Overall, our findings suggest that the observed association of the SNPs upstream of the IL15 gene with smoking status and multiple ND phenotypes may be mediated through regulation of IL15 gene expression, and that this appears to represent a novel mechanism underlying smoking behavior.
