Genomic structural equation modeling dissects Th2‐mediated and Th2‐independent genetic pathways of the atopic march

Introduction

Atopic dermatitis (AD) and childhood‐onset asthma (COA) share genetic susceptibility, but the contribution captured by type 2 (Th2) inflammatory traits and the residual sharing are incompletely resolved. The atopic march is one clinical trajectory rather than a universal sequence.

Methods

We used genomic structural equation modeling (Genomic SEM) to examine genetic covariance among AD, COA, blood eosinophil count, and IgE‐related protein abundance. A latent Th2 factor defined two model‐based components, termed Th2‐mediated and Th2‐independent. Component GWAS, MAGMA/FOCUS, single‐cell scoring, spatial mapping, Mendelian randomization (MR), and protein‐QTL SMR informed candidate prioritization. Functional follow‐up compared HSPA1A and HSPA1B knockdown, combined knockdown, and pharmacological IKK inhibition.

Results

Component‐based analyses prioritized 121 Th2‐mediated and 204 Th2‐independent genes, including 71 shared genes. Alternative genetic‐covariance structures provided a transparent comparison of AD‐to‐COA representations. MR estimates were evaluated across complementary sensitivity estimators, and HSPA1A/HSPA1B SMR associations were interpreted together with their HEIDI heterogeneity results. Lesional‐skin spatial contrasts attenuated after adjustment for an epidermal marker‐expression score. HSPA1B knockdown increased inflammatory outputs, with larger changes after combined HSPA1A/HSPA1B knockdown, while BMS‐345541 attenuated these changes.

Conclusion

The Th2‐based genetic decomposition provides a candidate map for allergic‐disease biology, including HSPA1B‐associated epithelial stress responses. The framework prioritizes testable biology across inherited susceptibility and epithelial stress responses, with longitudinal mediation, complete independence from type 2 biology, and skin‐to‐airway propagation reserved for direct clinical and mechanistic testing.

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