Directionally opposing effects of a shared immune genetic signature on atopic dermatitis and glioblastoma: integrative insights from single-cell and clustered Mendelian randomization analyses

BackgroundEpidemiological studies have consistently documented an inverse association between atopic dermatitis (AD) and glioblastoma (GBM), yet the immunogenetic mechanisms underlying this paradox remain elusive. We hypothesized that distinct immune subsets driven by shared genetic variants exhibiting antagonistic pleiotropy may explain this relationship. ObjectiveTo dissect the immunogenetic basis underlying the inverse association between AD and GBM by integrating single-cell transcriptomics and clustered Mendelian randomization, and to identify shared immune subsets and genetic variants exhibiting antagonistic pleiotropy that may explain this epidemiological paradox. MethodsWe integrated single-cell RNA sequencing (scRNA-seq) of publicly available datasets from AD skin (GSE153760) and GBM tumors (GSE256490) with genome-wide association study (GWAS) summary statistics. Disease-specific immune cell subsets were identified, and pathway enrichment was conducted on marker genes. Clustered Mendelian randomization (MR-Clust) was applied to detect heterogeneous causal effects, followed by drug target enrichment analysis using the DGIdb database. ResultsscRNA-seq revealed that Th2A cells were the predominant pathogenic subset in AD lesions, whereas S100A9+HLA-low suppressive monocytes were enriched in the GBM microenvironment. Both subsets shared enrichment in the NF-{kappa}B and Fc{varepsilon}RI signaling pathways, revealing a common immunological framework linking peripheral Type 2 inflammation to central nervous system immunosuppression. MR-Clust identified a distinct genetic cluster (Cluster 2) comprising 32 genes (e.g., IL4R, JAK1, SYK, FCER1G) significantly overexpressed in these cell types. This cluster exhibited antagonistic pleiotropy: it was directionally associated with reduced AD risk (OR = 0.930, 95% CI 0.846-1.023, p = 0.137) but a non-significant risk trend for GBM (OR = 1.447, 95% CI 0.737-2.841, p = 0.283). Drug target analysis indicated that Cluster 2 genes are primary targets of approved AD therapies, including dupilumab (IL4R) and JAK inhibitors (JAK1). ConclusionOur integrative analysis uncovers an immune-genetic axis linking Th2A cells in AD to suppressive monocytes in GBM, providing a mechanistic basis for their inverse comorbidity. These findings highlight a potential therapeutic paradox, underscoring the need for pharmacovigilance regarding long-term cancer risk in AD patients receiving targeted immunomodulators.