2414-P: Skin Inflammation as a Mediator of Metabolic Dysfunction: The Role of EDARV370A Genetic Variation

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Introduction and Objective: Chronic inflammation contributes to obesity and type 2 diabetes, yet little is known about subclinical skin inflammation in metabolic disease. Prior work from our group revealed that carriers of the alanine variant of the EDAR gene (EDARV370A) have higher HbA1c. Because EDAR regulates skin development and NF-κB signaling, we hypothesized that variation in this gene influences skin inflammatory pathways. This study examined whether the EDAR alanine variant is associated with inflammatory signatures in skin and related mechanisms of metabolic dysfunction. Methods: Skin punch biopsies (3 mm) were obtained from volunteers homozygous for EDAR valine (n=5) or carrying at least one EDAR alanine allele (n=4). Samples were dissociated and analyzed by single-cell RNA sequencing. Cell type annotation, immune subclustering, and pseudo-bulk differential expression analyses were performed. Histological staining was conducted on a subset of biopsies. Previously published blood transcriptomes were reanalyzed by genotype. Results: EDAR alanine carriers had increased vascular cells (874 vs. 138; ~6.3-fold), fibroblasts (677 vs. 259; ~2.6-fold), and T cells (289 vs. 82; ~3.5-fold) compared with valine homozygotes. These changes were accompanied by increased expression of endothelial (PECAM1, VWF), fibroblast (COL1A1, COL1A2, COL6A1/2), and T-cell (CD3E, CD3D, CD4, CD8A) markers. Pseudo-bulk analyses revealed enrichment of immune, cytokine, and tissue remodeling pathways. Histological analysis demonstrated a significant increase in papillary density (~15 vs. ~6 papillae per 20X field) in EDAR alanine carriers compared to valine homozygotes. Blood transcriptomics showed concordant inflammatory signatures in alanine carriers. Conclusion: The EDAR alanine variant is associated with immune and fibrotic remodeling in skin and concordant blood transcriptomic changes, supporting skin-associated inflammation as a contributor to insulin resistance and metabolic dysregulation. Disclosure D.K. Coletta: None. S. Palumbo: None. N. Fatima: None. E.N. Schuette: None. K. McCabe: None. O.D. Parra: None. M. Luo: None. L.J. Mandarino: None.

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