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BACKGROUND: Hidradenitis suppurativa (HS) is a common, chronic, and debilitating inflammatory disease that most commonly affects intertriginous skin. Despite its high heritability, the genetic underpinnings of HS remain poorly understood.OBJECTIVE: To identify genetic signals associated with HS, determine genetic relationships with other diseases, and investigate potential molecular genetic mechanisms.METHODS: We performed a genome-wide association study meta-analysis of six studies, totaling 4,540 cases and over 1 million controls and identified genetic correlations with other common diseases. We integrated the HS data with expression quantitative trait loci from 10 trait-relevant tissues, epigenomic and transcriptomic data from human scalp, differential expression data from HS lesions versus adjacent skin, and mesenchymal Hi-C chromatin looping data. To identify functional noncoding variants, we performed transcriptional reporter assays for signals near KLF5 and SOX9.RESULTS: We identified eleven significant HS signals across seven loci: four corresponded to previously reported associations, four represented novel signals within known loci, and three were signals in newly implicated loci. We identified significant genetic correlation between HS and other inflammatory conditions, particularly inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes, and asthma. We prioritized candidate genes for the 11 signals. The risk allele at KLF5 exhibited 10-fold greater transcriptional activity than the non-risk allele, while risk alleles at SOX9 showed significantly reduced transcriptional activity.CONCLUSIONS: Our results provide insights into potential genetic mechanisms underlying HS and suggest potential therapeutic targets for this challenging condition.