Proton pump inhibitor target genes and asthma susceptibility: a Mendelian randomization study with identification of IL-2 as a potential mediator

Objective
Previous observational studies on the relationship between proton pump inhibitors (PPIs) and asthma have yielded controversial results, with the underlying mechanisms remaining unclear. This study aimed to elucidate the causal relationship between PPIs and asthma using Mendelian randomization (MR) approaches.

Methods
Instrumental variables proxying the expression of PPI target genes were derived from the eQTLGen Consortium and GTEx project. Asthma summary statistics were obtained from the Trans-National Asthma Genetic Consortium (TAGC) and FinnGen consortium. Drug-target MR and summary-data-based MR (SMR) analyses were employed to assess the causal associations between PPI target genes and asthma. Two-sample MR was further conducted to evaluate the causal effects of inflammatory proteins on asthma, followed by mediation analysis to explore potential mediators. A series of sensitivity analyses and colocalization analyses were performed to test the robustness of our findings.

Results
Genetically proxied elevation of MAPT and DDAH1 levels was associated with an increased risk of asthma, while elevated AHR levels were linked to a decreased risk. The SMR analysis further supported the association between MAPT and asthma. We also identified causal associations between four inflammatory proteins and asthma. Mediation analysis suggested that interleukin-2 (IL-2) may serve as a potential mediator in the pathways from AHR and MAPT to asthma, with estimated mediation proportions of 26.5% and 28.7%, respectively.

Conclusion
This study provides genetic evidence supporting causal links between PPI-related genes (AHR, DDAH1, MAPT) and asthma. IL-2 may play a mediating role in the pathways connecting AHR and MAPT to asthma, offering novel insights into the potential mechanisms underlying the PPI–asthma relationship.