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Here, we examine a risk variant in the\n                    <jats:italic>aquaporin 3<\/jats:italic>\n                    (\n                    <jats:italic>AQP3<\/jats:italic>\n                    ) promoter and propose a mechanistic link between genotype to altered autophagy, skin barrier integrity, and wound healing in AD. A GWAS involving 1261\u2009AD cases and 4062 controls of Chinese ancestry from the Singapore\u2013Malaysia cohort was performed. Linkage disequilibrium (LD) analysis and cis\u2010eQTL datasets were used to assess regulatory associations. Functional effects of promoter variants were validated using in\u00a0vitro luciferase assays and ex\u00a0vivo transcriptomic profiling. In\u00a0vitro experiments in HaCaT keratinocytes investigated the effect of siRNA\u2010mediated\n                    <jats:italic>AQP3<\/jats:italic>\n                    knockdown on autophagy, skin barrier integrity, and wound closure. A discovery GWAS identified significant association between AD and SNP rs12555686 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.67\u2009\u00d7\u200910\n                    <jats:sup>\u221211<\/jats:sup>\n                    , OR\u2009=\u20091.89), located in the promoter of\n                    <jats:italic>AQP3<\/jats:italic>\n                    . Two additional SNPs in strong LD (rs2231225, rs3758279) formed a major haplotype associated with reduced\n                    <jats:italic>AQP3<\/jats:italic>\n                    expression. Reduced\n                    <jats:italic>AQP3<\/jats:italic>\n                    expression was associated with decreased autophagy markers (\n                    <jats:italic>Beclin1<\/jats:italic>\n                    ,\n                    <jats:italic>ATG5<\/jats:italic>\n                    ,\n                    <jats:italic>ATG12<\/jats:italic>\n                    ,\n                    <jats:italic>GABARAPL2, LAMP2, ATG4C<\/jats:italic>\n                    ), increased senescence markers (\n                    <jats:italic>p21<\/jats:italic>\n                    ,\n                    <jats:italic>GADD45A<\/jats:italic>\n                    ,\n                    <jats:italic>SERPINE1<\/jats:italic>\n                    ), and elevated inflammatory cytokines (\n                    <jats:italic>IL8<\/jats:italic>\n                    ,\n                    <jats:italic>IL1B<\/jats:italic>\n                    ,\n                    <jats:italic>TNF<\/jats:italic>\n                    ). Lastly,\n                    <jats:italic>AQP3<\/jats:italic>\n                    knockdown in HaCaT keratinocytes reduced steady\u2010state LC3B\u2010II\/LC3B\u2010I ratio, reduced occludin expression, and delayed wound healing in\u00a0vitro. Promoter variants in\n                    <jats:italic>AQP3<\/jats:italic>\n                    link genetic susceptibility to gene signatures consistent with altered autophagy, cellular senescence, and inflammation in AD. These findings highlight\n                    <jats:italic>AQP3<\/jats:italic>\n                    as a potential modulator of both epithelial and immune\u2010related mechanisms in AD pathogenesis.\n                  <\/jats:p>","DOI":"10.1111\/exd.70358","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:05:52Z","timestamp":1789520752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>Aquaporin 3<\/i>\n                    Promoter Polymorphisms Reduce Gene Expression and Associate Altered Autophagy\u2010Related Gene Signatures With Atopic Dermatitis Susceptibility"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7116-8172","authenticated-orcid":false,"given":"Yi Ying Eliza","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science National University of Singapore  Singapore 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