Leveraging Genomic Databases to Identify Missense Variants and Therapeutic Targets for Atopic Dermatitis

บทคัดย่อ

Objective  Atopic dermatitis (AD) is a complex inflammatory skin disorder with a strong genetic component. Identifying missense variants with functional relevance is essential for understanding disease mechanisms and informing therapeutic development. This study identified functionally relevant SNPs for AD using integrated genomic and bioinformatics analyses.

Methods  We screened 180 AD-associated SNPs from the GWAS Catalog
and filtered missense variants with genome-wide significance. Functional impact was assessed using PolyPhen-2 and Sorting Intolerant From Tolerant (SIFT). Population allele frequencies were extracted from the 1000 Genomes Project, tissue expression profiles from the GTEx Portal, and drug–gene interactions from DGIdb.

Results Two prioritized missense variants were identified: rs2228145 in IL6R, a common benign variant that modulates IL-6 signaling, and rs183884396 in TESPA1, a rare variant predicted to be damaging and
enriched in European populations. TESPA1 showed minimal expression in healthy skin but substantial expression in immune-relevant tissues, suggesting an indirect immunoregulatory role in AD. IL6R demonstrated broad immune-tissue expression and multiple interactions with approved anti-inflammatory drugs, underscoring its therapeutic relevance.

Conclusion By integrating genomic, functional, and pharmacological data, this study highlighted TESPA1 as a biologically plausible yet understudied immunoregulatory gene and IL6R as a clinically actionable target in AD. These computational findings are hypothesis-generating and warrant experimental validation to elucidate variant-specific mechanisms. Importantly, the identification of IL6R-targeting drugs and the ancestry-specific
nature of TESPA1 variation provides a foundation for future precision- medicine approaches in AD.