Dissecting the pathogenic effects of smoking in blood DNA methylation on allergic diseases.

Background: Allergic diseases, such as asthma and allergic rhinitis, present significant health challenges globally. Elucidating the genetic and epigenetic foundations is crucial for developing effective interventions. Methods: We performed two-sample Mendelian Randomization (MR) analyses to investigate the associations between smoking behaviors and various allergic diseases, leveraging data from the FinnGen database. Additionally, we examined the relationships of DNA methylation (CpG sites) with allergic diseases, employing mQTLs as epigenetic proxies. Furthermore, we conducted reverse MR analyses on CpG sites that exhibited cross-allergic disease effects. Results: In our genomic MR analysis, smoking behaviors such as smoking initiation and the number of cigarettes smoked per day were identified to be causally associated with an increased risk of asthma. Additionally, there was suggestive evidence linking smoking initiation to atopic contact dermatitis. Our epigenetic MR analysis found that methylation changes at 46 CpG sites, assessed via mQTLs, were significantly associated with asthma risk. Notably, cg17272563 (PRRT1), cg03689048 (BAT3), cg20069688 (STK19), and cg20513976 (LIME1) were identified with cross-allergic effects. Crucially, reverse MR analysis substantiated these associations. Conclusions: Our study has highlighted the associations between smoking behaviors and allergic diseases in the genetic and epigenetic landscape, notably asthma. We identified several DNA methylation-related CpG sites, such as cg03689048 (BAT3), cg17272563 (PRRT1), and cg20069688 (STK19), which demonstrate cross-allergic potential and reverse causal relationships.