DNA methylation abnormalities and altered whole transcriptome profiles after switching from combustible tobacco smoking to heated tobacco products.

Background:The use of heated tobacco products (HTPs) has increased exponentially in Japan since 2016; however, their effects on health remain a major concern. Methods:Tsuruoka Metabolome Cohort Study participants (n = 11,002) were grouped based on their smoking habits as never smokers (NS), past smokers (PS), combustible tobacco smokers (CS), and HTP users for <2 years. Peripheral blood mononuclear cells were collected from 52 participants per group matched to HTP users using propensity scores, and DNA and RNA were purified from the samples. DNA methylation (DNAm) analysis of the 17 smoking-associated DNAm biomarker genes (such as AHRR, F2RL3, LRRN3 and GPR15), as well as whole transcriptome analysis were performed. Results:Ten of the 17 genes were significantly hypomethylated in CS and HTP users compared to NS, among which AHRR, F2RL3 and RARA showed intermediate characteristics between CS and NS; nonetheless, AHRR expression was significantly higher in CS than in the other three groups. Conversely, LRRN3 and GPR15 were more hypomethylated in HTP users than in NS, and GPR15 expression was markedly upregulated in all the groups when compared to that in NS. Conclusions:HTP users (switched from CS <2 years) display abnormal DNAm and transcriptome profiles, albeit to a lesser extent than the CS. However, since the molecular genetic effects of long-term HTP use are still unknown, long-term molecular epidemiological studies are needed. Impact:This study provides new insights into the molecular genetic effects on DNAm and transcriptome profiles in HTP users that switched from CS.