Proteome-wide Mendelian randomization identifies therapeutic targets for asthma

Objectives: Asthma is a prevalent chronic inflammatory disease that involves a complex interaction between various cells of the innate and adaptive immune systems and epithelial cells. Anti-inflammatory therapeutic approaches have proven superior in controlling asthma and reducing exacerbation rates and are receiving increasing attention. The treatment of asthma is a potentially actionable target pending further validation. This study presented integrative evidence that supports both previously reported and emerging causal proteins, as well as potential drug targets, for asthma. Methods: Mendelian randomization (MR) analysis, colocalization (COLOC) analysis, phenome-wide association (PWAS) analysis, transcriptome analysis, single-cell data analysis, protein–protein interaction medication targets analysis. Results: Nephronectin (NPNT) and neuronal growth regulator 1 (NEGR1) were found to be statistically significantly associated with a noticeable protective effect against asthma, tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) showed a suggestive statistical association with a protective effect against asthma in MR analyses. COLOC indicated that NPNT and NEGR1 have greater potential as drug targets. Compared with normal tissues, NPNT exhibited a higher expression level in Type II pneumocytes; NEGR1 was upregulated in smooth muscle cells, regulatory T cells, plasmacytoid dendritic cells, helper T cells; TNFAIP3 expression was decreased in Cluster of differentiation 4 (CD4)-positive alpha-beta T cells, lung ciliated cell 1, smooth muscle cells, whereas it was elevated in CD8-positive alpha-beta T cell 1, helper T cells, and myelocytes in asthma lung tissues. The interaction between Integrin alpha-8 (ITGA8) and NPNT, as well as the interaction between melanocortin-4 receptor and NEGR1, might serve as potential therapeutic targets. Conclusion: NPNT and NEGR1 could be promising targets for current asthma medications. NEGR1 was first identified in MR of asthma, and we further performed across-omics validation to verify the roles of NPNT, NEGR1, and TNFAIP3.