Broadaway K Alaine, Sun Quan, Edmiston Sharon N, Currin Kevin W, Vadlamudi Swarooparani, Miller-Fleming Tyne W, Shi Yue, Fajgenbaum Kristen, Melendez-Gonzalez Maria, Bui Helen, Blum Franklin R, Westerkam Linnea, Shams Rayad, Mallela Teja, Levitt Brandt, Lin Lan, Hao Honglin, Memili Aylin, Straub Peter, Zhou Wei, Harris Kathleen Mullan, Martin Alicia, Cox Nancy J, Liu Zhi, Thomas Nancy E, Li Yun, Mohlke Karen L, Sayed Christopher J
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
Br J Dermatol. 2025 Jul 12. doi: 10.1093/bjd/ljaf277.
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.
To identify genetic signals associated with HS, determine genetic relationships with other diseases, and investigate potential molecular genetic mechanisms.
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.
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.
Our results provide insights into potential genetic mechanisms underlying HS and suggest potential therapeutic targets for this challenging condition.
化脓性汗腺炎（HS）是一种常见的慢性致残性炎症性疾病，最常累及皮肤褶皱部位。尽管其遗传度较高，但HS的遗传基础仍知之甚少。
识别与HS相关的遗传信号，确定与其他疾病的遗传关系，并研究潜在的分子遗传机制。
我们对六项研究进行了全基因组关联研究荟萃分析，共纳入4540例病例和超过100万例对照，并确定了与其他常见疾病的遗传相关性。我们将HS数据与来自10个相关组织的表达数量性状位点、人类头皮的表观基因组和转录组数据、HS病变与相邻皮肤的差异表达数据以及间充质Hi-C染色质环化数据进行整合。为了识别功能性非编码变异，我们对KLF5和SOX9附近的信号进行了转录报告分析。
我们在七个位点识别出11个显著的HS信号：四个与先前报道的关联相对应，四个代表已知位点内的新信号，三个是新涉及位点的信号。我们确定了HS与其他炎症性疾病之间存在显著的遗传相关性，尤其是炎症性肠病、类风湿性关节炎、2型糖尿病和哮喘。我们对这11个信号的候选基因进行了优先级排序。KLF5处的风险等位基因表现出比非风险等位基因高10倍的转录活性，而SOX9处的风险等位基因显示转录活性显著降低。
我们的结果为HS潜在的遗传机制提供了见解，并为这种具有挑战性的疾病提出了潜在的治疗靶点。
