Mediators of the association between allergic diseases and bronchiectasis: A bi-directional univariable and multivariable Mendelian randomization study and mediation analysis

Background
Emerging research indicates that bronchiectasis often coexists with a range of allergic illnesses. The pathogenesis of both conditions is highly complex, involving a variety of interconnected factors, such as immune responses, metabolic pathways, and gut microbiota. However, the precise causal relationship between bronchiectasis and allergy-related conditions remains poorly understood.
Materials and methods
We obtained published GWAS datasets for 5 allergic disorders (allergic asthma, allergic rhinitis, atopic conjunctivitis, atopic dermatitis, and chronic rhinosinusitis) and bronchiectasis, along with data on 731 immune cells, 91 inflammatory proteins, 1400 plasma metabolites, and 473 gut microbiotas. Using bi-directional two-sample Mendelian Randomization (TSMR), we explored causal relationships between allergic diseases and bronchiectasis and validated these findings in a replication cohort. We also applied Linkage Disequilibrium Score Regression (LDSC) to assess genetic correlations between the conditions. Additionally, the mediating effects of immune cells, inflammatory proteins, metabolites, and gut microbiota on the relationship between allergic disorders and bronchiectasis were assessed through two-step TSMR and multivariate MR analysis.
Results
Our study revealed that allergic asthma, allergic rhinitis, atopic conjunctivitis, and atopic dermatitis all increased the risk of developing bronchiectasis, with no causal relationship identified in the reverse direction. Additionally, positive genetic associations were observed between allergic asthma, allergic rhinitis, atopic dermatitis, and bronchiectasis, respectively. We identified a total of forty immune cells, 5 inflammatory proteins, ninety plasma metabolites, and nineteen gut microbiota species as causal factors contributing to bronchiectasis onset. In mediation analysis, we found that the metabolic ratio of Retinol (Vitamin A) to oleoyl-linoleoyl-glycerol (18:1 to 18:2) was a risk factor for allergic asthma developing bronchiectasis, while the level of CD14 on CD33dim HLA-DR + CD11b + cells was a risk factor for allergic rhinitis. Two specific metabolic ratios—the Aspartate to N-acetylglucosamine to N-acetylgalactosamine ratio and the Methionine to phosphate ratio—served as, respectively, risk and protective factors for atopic dermatitis-developing bronchiectasis.
Conclusion
Our findings suggest that allergic asthma, allergic rhinitis, atopic conjunctivitis, and atopic dermatitis increase the risk of developing bronchiectasis, with no evidence of a reverse causal relationship. Specifically, 3 metabolic ratios were identified as mediators between allergic diseases and bronchiectasis. Further studies are needed to clarify the underlying mechanisms.