A novel role for vaping in mitochondrial gene dysregulation and inflammation fundamental to disease development.

We constructed and analyzed the whole transcriptome in leukocytes of healthy adult vapers (with/without a history of smoking), 'exclusive' cigarette smokers, and controls (non-users of any tobacco products). Furthermore, we performed single-gene validation of expression data, and biochemical validation of vaping/smoking status by plasma cotinine measurement. Computational modeling, combining primary analysis (age- and sex-adjusted limmaVoom) and sensitivity analysis (cumulative e-liquid- and pack-year modeling), revealed that 'current' vaping, but not 'past' smoking, is significantly associated with gene dysregulation in vapers. Comparative analysis of the gene networks and canonical pathways dysregulated in vapers and smokers showed strikingly similar patterns in the two groups, although the extent of transcriptomic changes was more pronounced in smokers than vapers. Of significance is the preferential targeting of mitochondrial genes in both vapers and smokers, concurrent with impaired functional networks, which drive mitochondrial DNA-related disorders. Equally significant is the dysregulation of immune response genes in vapers and smokers, modulated by upstream cytokines, including members of the interleukin and interferon family, which play a crucial role in inflammation. Our findings accord with the growing evidence on the central role of mitochondria as signaling organelles involved in immunity and inflammatory response, which are fundamental to disease development.