Predicting thrombotic cardiovascular outcomes induced by waterpipe-associated chemicals using comparative toxicogenomic database: Genes, phenotypes, and pathways.

Hookah, or waterpipe, is a tobacco smoking device that has gained popularity in the United States. A growing body of evidence demonstrates that waterpipe smoke (WPS) is associated with various adverse effects on human health, including infectious diseases, cancer, and cardiovascular diseases (CVDs), particularly thrombotic events. However, the molecular mechanisms through which WPS contributes to disease development remain unclear. In this study, we utilized an analytical approach based on the Comparative Toxicogenomics Database (CTD) to integrate chemical, gene, phenotype, and disease data to predict potential molecular mechanisms underlying the effects of WPS, based on its chemical and toxicant profile. Our analysis revealed that CVDs were among the top disease categories with regard to the number of curated interactions with WPS chemicals. We identified 5674 genes common between those modulated by WPS chemicals and traditional tobacco smoking. The CVDs with the most curated interactions with WPS chemicals were hypertension, atherosclerosis, and myocardial infarction, whereas "particulate matter", "heavy metals", and "nicotine" showed the highest number of curated interactions with CVDs. Our analysis predicted that the potential mechanisms underlying WPS-induced thrombotic diseases involve common phenotypes, such as inflammation, apoptosis, and cell proliferation, which are shared across all thrombotic diseases and the three aforementioned chemicals. In terms of enriched signaling pathways, we identified several, including chemokine and MAPK signaling, with particulate matter exhibiting the most statistically significant association with all 12 significant signaling pathways related to WPS chemicals. Collectively, our predictive comprehensive analysis provides evidence that WPS negatively impacts health and offers insights into the potential mechanisms through which it exerts these effects. This information should guide further research to explore and better understand the WPS and other tobacco product-related health consequences.