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<p>Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder primarily affecting intertriginous regions, characterized by painful nodules, abscesses, and sinus tracts. Beyond its dermatologic manifestations, HS is associated with systemic inflammation and may increase the risk of cardiovascular diseases (CVDs) and metabolic disorders. Although genome-wide association studies (GWAS) have identified HS-related loci, the molecular mechanisms linking HS to systemic comorbidities remain unclear. This study investigates the shared genetic architecture between HS and 30 systemic traits (15 CVDs and 15 metabolic traits) using linkage disequilibrium score regression (LDSC), identifying significant genetic correlations with hypertension (r<sub>g</sub> = 0.24), body mass index (BMI, r<sub>g</sub> = 0.39), and triglycerides (r<sub>g</sub> = 0.18). Cross-trait meta-analyses revealed 83 pleiotropic SNPs. Gene-based analyses (MAGMA, SMR, GCTA-fastBAT) highlighted 243 genes enriched in immune and metabolic pathways. We further performed bidirectional and mediation Mendelian randomization analyses, confirming a potential bidirectional causal relationship between HS and hypertension, with BMI acting as a partial mediator. Drug prioritization based on pathway-pairing scores identified 37 candidate therapies. These findings suggest shared genetic and causal links between HS and systemic traits and offer directions for translational research, though experimental validation is warranted.</p>

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Decoding the shared genetic architecture of hidradenitis suppurativa with cardiovascular diseases and metabolic traits

  • 期刊论文

  • 发表日期：

    2025年12月9日

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  • Yuan Hu,
  • Ming-jie He,
  • Chun-shui Yu

摘要

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder primarily affecting intertriginous regions, characterized by painful nodules, abscesses, and sinus tracts. Beyond its dermatologic manifestations, HS is associated with systemic inflammation and may increase the risk of cardiovascular diseases (CVDs) and metabolic disorders. Although genome-wide association studies (GWAS) have identified HS-related loci, the molecular mechanisms linking HS to systemic comorbidities remain unclear. This study investigates the shared genetic architecture between HS and 30 systemic traits (15 CVDs and 15 metabolic traits) using linkage disequilibrium score regression (LDSC), identifying significant genetic correlations with hypertension (rg = 0.24), body mass index (BMI, rg = 0.39), and triglycerides (rg = 0.18). Cross-trait meta-analyses revealed 83 pleiotropic SNPs. Gene-based analyses (MAGMA, SMR, GCTA-fastBAT) highlighted 243 genes enriched in immune and metabolic pathways. We further performed bidirectional and mediation Mendelian randomization analyses, confirming a potential bidirectional causal relationship between HS and hypertension, with BMI acting as a partial mediator. Drug prioritization based on pathway-pairing scores identified 37 candidate therapies. These findings suggest shared genetic and causal links between HS and systemic traits and offer directions for translational research, though experimental validation is warranted.