In summary, we identified a group of SNPs, upstream from the IL15 gene, that were associated with both smoking status and quantity of cigarette consumption. Interestingly, a key SNP, rs17354547, which is highly conserved across multiple species, was replicated in an independent AA cohort for association with multiple ND phenotypes. Moreover, all of the nine SNPs were replicated in silico in a FHS cohort for association with smoking status. Remarkably, the association of the SNPs with smoking behavior-related phenotypes in both our GWAS and the two replication samples appeared to be male-specific. Higher prevalence of smoking in males than in females in the US (3) attaches additional importance to our findings. Some of the SNPs, located at potential TF binding sites, may regulate IL15 gene expression and consequently, could have an important regulatory effect on the immune system. The above findings, together with previous data from studies of drug addiction, compel us to propose a novel mechanism for smoking addiction modulated by the immune system, where the IL15 pathway may play a key role. The confirmation and elaboration of this hypothetical mechanism needs further detailed functional studies directed at IL15.
