Abstract
INTRODUCTION: Atopic dermatitis (AD) is a long-standing inflammatory dermatosis marked by intense itching and immune imbalance. Despite recent advances in targeted biologic therapies, limitations in efficacy and cost highlight the urgent need for novel therapeutic targets. METHODS: We employed Mendelian randomization (MR) by combining genome-wide association studies (GWAS), expression quantitative trait loci (eQTL), and protein QTL (pQTL) datasets to identify causal druggable genes associated with AD. To enhance the validity of causal inference, we further utilized colocalization and summary-data-based MR (SMR) techniques. We validated the expression of five prioritized genes using reverse transcription quantitative PCR (RT-qPCR), performed on RNA extracted from the peripheral blood of AD patients and healthy controls. RESULTS: The MR approach revealed 32 candidate genes with potential druggable properties linked to AD, with 12 showing strong colocalization signals (posterior probability of hypothesis 4 (PP.H4) > 0.8). The pQTL analysis indicated that increased plasma NMB levels were associated with a heightened risk of AD (OR = 1.18, p = 3.29 × 10^-8), a conclusion further corroborated by SMR analysis. RT-qPCR confirmed significantly elevated expression of NMB, IL2RA, IL1RL1, and PRKCQ in the peripheral blood samples of AD patients. Additionally, MR studies demonstrated that NMB was associated with bullous pemphigoid and urticaria. CONCLUSION: Integrative MR and PCR validation across Icelandic, Finnish and Chinese samples nominates NMB as a candidate AD target. These preliminary, multi-ancestry signals now require replication in large, population-matched cohorts before any therapeutic translation.