Identification of allergic rhinitis-related genes and mediating immune cells based on cis-eQTL: A Mendelian randomization study

In this study, we aimed to identify genes causally associated with allergic rhinitis (AR) by extracting cis-expression quantitative trait loci (cis-eQTL) as instrumental variables using the Mendelian randomization (MR) method, and further explore the role mechanisms of gene-related immune cells in AR. All genome-wide association study (GWAS) and eQTL data were from public databases. Genes causally associated with AR were screened by the summary-data-based Mendelian randomization (SMR) method to obtain Gene set 1. Predicted AR-related genes from 5 databases were combined and intersected with Gene set 1 to get Gene set 2. Genes in Gene set 2 with H4 posterior probability > .75 were selected through colocalization analysis to obtain Gene set 3. Then, 2-step 2-sample MR analysis was used to identify potential mediating immune cells. Gene set 1 had 29 genes. Gene set 2 contained 10 genes after intersection. Gene set 3 included TNFRSF18, HCP5, and CD44. MR mediation analysis showed TNFRSF18 could be a significant exposure, and CD3 on CD39+ activated Treg and CD4+ Treg could be mediators. TNFRSF18 negatively regulated AR and positively regulated the 2 immune cells, while immune cells negatively regulated AR. TNFRSF18, HCP5, and CD44 are significantly causally associated with the development of AR and may serve as drug targets. Among them, TNFRSF18 is more strongly supported. It may inhibit AR progression by upregulating CD3 on CD39+ activated Treg and CD4+ Treg, highlighting the role of these immune cells in the gene-mediated protection against AR.