IL-1 Signaling Enrichment in Inflammatory Skin Disease Loci with Higher-risk Allele Frequencies in African Ancestry

Inflammatory skin diseases (ISDs) exhibit varying prevalence across different ancestry background and geographical regions. Genetic research for complex ISDs has predominantly centered on European Ancestry (EurA) populations and genetic effects on immune cell responses but generally failed to consider contributions from other cell types in skin. Here, we utilized 273 genetic signals from seven different ISDs: acne, alopecia areata (AA), atopic dermatitis (AD), psoriasis, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and vitiligo, to demonstrate enriched IL1 signaling in keratinocytes, particularly in signals with higher risk allele frequencies in the African ancestry. Using a combination of ATAC-seq, Bru-seq, and promoter capture Hi-C, we revealed potential regulatory mechanisms of the acne locus on chromosome 2q13. We further demonstrated differential responses in keratinocytes upon IL1β stimulation, including the pro-inflammatory mediators CCL5, IL36G, and CXCL8. Taken together, our findings highlight IL1 signaling in epidermal keratinocytes as a contributor to ancestry-related differences in ISDs.