Multiomics Approach Identifies Novel Genetic Determinants and Therapeutic Targets for Asthma

Asthma constitutes a widespread chronic respiratory disease with multifactorial origins, in which definitive genetic components remain incompletely understood. This investigation synthesized transcriptomic data and Mendelian randomization (MR) to delineate causative genes contributing to asthma predisposition. Evaluation of the GSE43696 cohort disclosed 267 genes displaying expression alterations between healthy controls (n = 20) and asthmatic cases (n = 88). MR methods discerned seven causal genes, consisting of six protective determinants (GPRIN3, SHISA2, DUSP5, FCER1A, USP36, and LGALS2; OR < 1) and one risk-associated determinant (CXCL6; OR > 1). Independent validation with the GSE63142 series verified pronounced suppression of five genes in asthma specimens. Functional enrichment studies connected these genes to immune-related cascades, including IL-17/NF-κB signal transduction and Th17 cell differentiation, alongside metabolic activities. Single-cell transcriptomic assessment of 32,809 cells exposed compartmentalized expression profiles: FCER1A and LGALS2 predominated in dendritic cells, DUSP5 in goblet cells, SHISA2 in ionocytes, and USP36 in T cells. Immune cell infiltration evaluation demonstrated shifted distributions of mast cells, eosinophils, and monocytes, exhibiting substantial linkages with immune mediators such as CCR5 and CXCL10. Transcription factor exploration recognized cisbp__M0561 as the predominant regulatory element. Connectivity Map-based interrogation nominated KI-8751, verrucarin-A, and homoharringtonine as plausible therapeutic candidates. This consolidated multiomics framework elucidates previously uncharacterized pathological processes and prospective treatment avenues for asthma.