IL-1 signaling enrichment in inflammatory skin disease loci with higher-risk allele frequencies in African ancestry

Abstract

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.

Keywords: Ancestry Difference; Genetic; Inflammatory Skin Disease; Multi-Omics.

Figure 1. Study overview.

We collected GWAS loci from seven ISDs and computed the BCI variants for each locus. We utilized multi-omic data to ne-map the potential causal variants and reveal the regulatory mechanism: Bru-seq was used to detect eRNAs in keratinocytes; skin eQTL data from GTEx to reveal association between genotypes and expression profiles; ENCODE ChIP-seq data to identify TF binding sites; ATAC-seq assessed chromatin accessibility in keratinocytes; pc-HiC seq revealed physical interactions within the 3D chromosomal structure of keratinocytes; and single-cell sequencing displayed gene expression in keratinocytes. This figure is created with BioRender.com.

Figure 2. GWAS signals for ISD.

(a) GWAS loci count for each ISD; (b) BCI variant count for each ISD; (c) risk allele effect sizes (beta) of the BCI variant demonstrate variability across different ISDs; (d) the proportion of ISD loci that overlap with ATAC peaks, compared with other GWAS traits (red); (e) the proportion of ISD loci that overlap with the Bru-seq signal, compared with other GWAS traits; (f) the proportion of ISD loci that overlap with the eQTL signal, compared with other GWAS traits. (binomial test, p-value<0.05 marked as *)

Figure 3. IL-1 signaling among ISD signals with higher RAFs in AfrA

(a) the proportions of BCI variants (top) or loci (bottom) for ISDs having higher RAF in AfrA/EurA; (b) enrichment analysis result for eQTL targeted genes of the ISDs signals with RAFs higher in AfrA (b) or EurA (c); (d) Module score computed using eQTL targeted genes exhibit elevated expressions in keratinocytes (in addition to myeloid) comparing against other cell types ; (e) Up-regulation of IL1A and IL1R2 in lesional skin compared to non-lesional skin in psoriasis scRNA.

Figure 4. Multi-omic information to ne-map 2q14.1.

(a) regional association plot of acne locus 2:113609886_C_T (2q14.1), with the red line marks the BCI variant chr2:113627234_T; (b) we performed promoter capture Hi-C in keratinocytes to reveal interactions between region encompassing BCI variant chr2:113627234_T and the promoter regions of IL1A and IL1B, complementing the eQTL results; (c) ATAC peaks reveals that the variant is located within an open chromatin region in cultured human primary keratinocytes, indicative of a zone of active gene regulation; (d) Bru-seq reads was detected covering this region, suggesting transcribed active enhancer element; (e) ChIP-seq from keratinocytes have identified multiple transcription factors peaks that bind to this variant, FOXA1 as illustrated; (f) from PheWas, we discovered a significant association between the variant chr2:113627234:T and pericarditis(effect size 0.21, p-value of 8.1′10⁻⁷) or acute pericarditis(effect size 0.46, p-value of 8.3′10⁻⁶) from circulatory system. This figure is created with BioRender.com.

Figure 5. IL1 stimulation shows elevated effect in AfrA keratinocytes

(a) the difference of fold change of IL1-stimulation between Black donors (self-reported) and White donors (self-reported) keratinocytes (y-axis) versus the average IL1-stimulation fold change (all genes with FC>1.5 and p-value<0.05 are being shown); (b) the individual sample fold changes for CCL5, CXCL8, and IL36Gin Black donors and White donors.