Dynamic CD4+ T Cell Genetics Identifies Candidate Therapeutic Targets for Allergic Rhinitis: Mendelian Randomization with Exploratory Single-Cell Contextualization

Abstract

Background: Allergic rhinitis is common and clinically heterogeneous, but the genes whose genetically regulated immune-state expression influences susceptibility remain incompletely resolved. Methods: We integrated dynamic CD4+ T cell eQTL data (46 activation-state profiles) with allergic rhinitis GWAS summary statistics, applying transcriptome-wide Mendelian randomization (MR), colocalization, SMR/HEIDI, metabolite screening, paired single-cell RNA-seq and TCR analysis, and computational follow-up. Colocalization support was prespecified as conditional ratio PP.H4/(PP.H3 + PP.H4) > 0.7; HEIDI at p > 0.05. Results: After MHC-region exclusion, 50,654 gene-profile pairs were tested and 129 MR-significant genes were identified. Colocalization supported 418 pairs (111 genes); 70 genes passed both SMR and HEIDI; and cross-database comparison yielded a nine-gene overlap set. In GSE200107, baseline good-versus-poor responder differences were larger than treatment-induced transcriptional change; patient-level reanalysis found no pair surviving multiple-testing correction (n = 4 vs. 3); these findings are hypothesis-generating. Paired TCR analysis suggested greater clonotype renewal in good responders (descriptive). Structure-guided screening prioritized unvalidated binder candidates for SLC25A46 and TLR1 (TLR1 TIR docking −5.86 kcal/mol; MD RMSD 0.20 nm). Conclusions: An exploratory metabolite screen yielded nominally significant indirect-effect signals, but the candidate metabolite did not colocalize with the disease locus. This framework prioritizes candidate therapeutic targets for allergic rhinitis.

The authors' abstract, as published at the source. Biomedicines, 2026 · DOI ↗