Aquaporin 3 Promoter Polymorphisms Reduce Gene Expression and Associate Altered Autophagy-Related Gene Signatures With Atopic Dermatitis Susceptibility.

Genome-wide association studies (GWAS) have uncovered multiple loci associated with atopic dermatitis (AD), although mechanistic understanding remains limited. Here, we examine a risk variant in the aquaporin 3 (AQP3) promoter and propose a mechanistic link between genotype to altered autophagy, skin barrier integrity, and wound healing in AD. A GWAS involving 1261 AD cases and 4062 controls of Chinese ancestry from the Singapore-Malaysia cohort was performed. Linkage disequilibrium (LD) analysis and cis-eQTL datasets were used to assess regulatory associations. Functional effects of promoter variants were validated using in vitro luciferase assays and ex vivo transcriptomic profiling. In vitro experiments in HaCaT keratinocytes investigated the effect of siRNA-mediated AQP3 knockdown on autophagy, skin barrier integrity, and wound closure. A discovery GWAS identified significant association between AD and SNP rs12555686 (p = 1.67 × 10-11, OR = 1.89), located in the promoter of AQP3. Two additional SNPs in strong LD (rs2231225, rs3758279) formed a major haplotype associated with reduced AQP3 expression. Reduced AQP3 expression was associated with decreased autophagy markers (Beclin1, ATG5, ATG12, GABARAPL2, LAMP2, ATG4C), increased senescence markers (p21, GADD45A, SERPINE1), and elevated inflammatory cytokines (IL8, IL1B, TNF). Lastly, AQP3 knockdown in HaCaT keratinocytes reduced steady-state LC3B-II/LC3B-I ratio, reduced occludin expression, and delayed wound healing in vitro. Promoter variants in AQP3 link genetic susceptibility to gene signatures consistent with altered autophagy, cellular senescence, and inflammation in AD. These findings highlight AQP3 as a potential modulator of both epithelial and immune-related mechanisms in AD pathogenesis.