Genomic and proteomic insights into hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with substantial heritability and clinical heterogeneity. Large-scale genetic studies often lack deep clinical or immunological phenotyping and typically rely on unmatched biobank controls. Our study overcomes this limitation by using carefully matched healthy comparators and integrating genomic, proteomic and pQTL analyses to dissect the molecular underpinnings of HS.

OBJECTIVES: To identify genetic variants associated with HS susceptibility using a genome-wide association study (GWAS) in a Greek cohort and to determine whether these variants influence systemic inflammation by integrating blood proteomic profiling and protein quantitative trait locus (pQTL) mapping.

METHODS: A case-control study involving 314 HS patients and 81 age-, sex- and comorbidity-matched healthy comparators of European (Greek) ancestry. Genomic DNA was analysed using GWAS, and inflammatory protein levels were assessed in a subset of participants using the Olink proteomics platform. GWAS meta-analysis was performed with the FinnGen biobank. Publicly available pQTL datasets were used to evaluate genetic regulation of differentially expressed proteins.

RESULTS: While the Greek GWAS alone revealed suggestive genetic loci, meta-analysis with FinnGen identified 60 genome-wide significant loci, including novel variants near HLA-DRA. Proteomic profiling uncovered 51 differentially expressed proteins (DEPs), with only four upregulated in HS patients. Severity-correlated proteins included IL-6, IL-17A and FGF21. Integration with pQTL data showed enrichment of HS-associated SNPs among pQTLs regulating DEPs, supporting the genetic basis for systemic inflammation in HS.

CONCLUSIONS: Our findings support a dual model of HS pathogenesis involving genetically driven epithelial dysfunction and systemic inflammation. The identification of HLA-DRA-associated variants raises the possibility that HS may share features with autoimmune diseases, while the proteomic profile dominated by innate cytokines suggests that an autoinflammatory component is also involved.

© 2026 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

PMID: 41793208