Proton Pump Inhibitor Target Genes and Asthma Susceptibility: A Mendelian Randomization Study with Identification of IL-2 as a Potential Mediator

Background Previous observational studies examining the relationship between proton pump inhibitors (PPIs) and asthma have been marked by considerable debate, and the underlying mechanism remained unknown. This study aims to elucidate the causal relationship between PPIs and asthma through the Mendelian randomization (MR). Methods: Instrumental variables that proxied target gene expression of PPI were obtained from the eQTLGen consortium and GTEx project. We obtained data on asthma separately from the Trans-National Asthma Genetic Consortium (TAGC), and FinnGen consortium. Drug target MR and summary-data-based Mendelian Randomization (SMR) approaches were employed to investigate the causal relationship between PPI target genes and asthma. We also performed two-sample MR analyses between inflammatory proteins and asthma, and mediation analysis was conducted to investigate the potential mediators between casual associations. A series of sensitivity and colocalization analyses were performed to detect the robustness of MR results. Results: The elevation of MAPT and DDAH1 levels is associated with an increased risk of asthma, while the elevation of AHR levels is also associated with a decreased risk of asthma. SMR analysis also provided evidence of an association between MAPT and asthma. We found a causal association between four inflammatory proteins and asthma. In addition, our mediation analysis suggests that Interleukin-2 (IL-2) may serve as a potential mediator of the causal associations of AHR and MAPT with asthma, with estimated mediation proportions of 26.5% and 28.7%, respectively. Conclusion: This study confirms causal links between PPI-related genes including AHR, DDAH1, MAPT and asthma. IL-2 may play a mediating role in the pathways linking AHR and MAPT to asthma.