Identifying therapeutic targets for allergic asthma through atopic dermatitis-associated genetic mechanisms

Allergic asthma (AA) is a chronic inflammatory disease with limited effective treatments, often co-occurring with atopic dermatitis (AD). Epidemiologic studies have shown a strong association between AD and AA, but their causal relationship remains unclear.

This study aimed to identify novel therapeutic targets and candidate drugs for AA.

We performed Mendelian (MR) analysis to evaluate the causal relationship between AD and AA. To identify potential therapeutic targets, we integrated drug-target MR, colocalization, functional enrichment, protein-protein interaction, and gene expression analyses. Drug candidates were prioritized using the Drug-Gene Interaction Database (DGIdb; dgidb.org) and the Comparative Toxicogenomics Database (CTD; ctdbase.org).

MR analysis confirmed that AD significantly increases the risk of AA (odds ratio = 1.64, P < .001). Integrating drug-target MR and colocalization analysis, we identified Janus kinase 2 (JAK2) as a potential causal gene (posterior probability [PP.H4] = 0.95), supported by functional enrichment, protein-protein interaction, and gene expression analyses. Drug screening via DGIdb and CTD prioritized hydroxyurea as the top candidate (composite score = 0.85), although its efficacy in AA remains to be validated.

We provide the first genomic evidence for a causal link between AD and AA. These findings highlight JAK2 as a potential therapeutic target and hydroxyurea as a candidate for clinical validation, paving the way for future research into shared immunogenetic mechanisms in allergic diseases.