Genetic Variants Associated With Hidradenitis Suppurativa

Abstract

Importance: Hidradenitis suppurativa (HS) is a common and severely morbid chronic inflammatory skin disease that is reported to be highly heritable. However, the genetic understanding of HS is insufficient, and limited genome-wide association studies (GWASs) have been performed for HS, which have not identified significant risk loci.

Objective: To identify genetic variants associated with HS and to shed light on the underlying genes and genetic mechanisms.

Design, setting, and participants: This genetic association study recruited 753 patients with HS in the HS Program for Research and Care Excellence (HS ProCARE) at the University of North Carolina Department of Dermatology from August 2018 to July 2021. A GWAS was performed for 720 patients (after quality control) with controls from the Add Health study and then meta-analyzed with 2 large biobanks, UK Biobank (247 cases) and FinnGen (673 cases). Variants at 3 loci were tested for replication in the BioVU biobank (290 cases). Data analysis was performed from September 2021 to December 2022.

Main outcomes and measures: Main outcome measures are loci identified, with association of P < 1 × 10-8 considered significant.

Results: A total of 753 patients were recruited, with 720 included in the analysis. Mean (SD) age at symptom onset was 20.3 (10.57) years and at enrollment was 35.3 (13.52) years; 360 (50.0%) patients were Black, and 575 (79.7%) were female. In a meta-analysis of the 4 studies, 2 HS-associated loci were identified and replicated, with lead variants rs10512572 (P = 2.3 × 10-11) and rs17090189 (P = 2.1 × 10-8) near the SOX9 and KLF5 genes, respectively. Variants at these loci are located in enhancer regulatory elements detected in skin tissue.

Conclusions and relevance: In this genetic association study, common variants associated with HS located near the SOX9 and KLF5 genes were associated with risk of HS. These or other nearby genes may be associated with genetic risk of disease and the development of clinical features, such as cysts, comedones, and inflammatory tunnels, that are unique to HS. New insights into disease pathogenesis related to these genes may help predict disease progression and novel treatment approaches in the future.

Figure 1.. Genetic Variants Associated With HS in a Meta-Analysis of GWAS Results From HS ProCARE, UKB, and FinnGen

Each dot corresponds to 1 variant; the x-axis indicates genomic position, and the y-axis shows the −log₁₀(P value) of variant association with hidradenitis suppurativa (HS). Dots above the orange and blue lines show variants that reached significant (P < 5 × 10⁻⁸) and suggestive (P < 1 × 10⁻⁶) thresholds, respectively, for genome-wide association studies (GWASs). HS ProCARE indicates HS Program for Research and Care Excellence; UKB, UK Biobank.

Figure 2.. HS Association Plots for 2 Loci With European LD

Variants associated with hidradenitis suppurativa (HS) in the 3-way meta-analysis located at the chromosome (chr) 17 locus (A) and the chr13 locus (B). Each point corresponds to 1 variant; the x-axis indicates genomic position, and the y-axis shows the −log₁₀(P value) of variant association with HS, and the size of each point indicates relative sample size analyzed for that variant. Variants are colored according to their linkage disequilibrium (LD) r² with the most significant variant in each region, which is shown as a purple diamond. The LD r² values are based on TOPMed European-ancestry individuals. Lines point to variants located in skin enhancers (see Figure 3). The nearest protein-coding genes are not located within the 400-kilobase regions shown.

Figure 3.. Candidate Genes and Regulatory Variants at 2 Hidradenitis Suppurativa Loci

Variants at the chromosome (chr) 17 locus (A) are located in an intergenic region more than 600 kb from SOX9. Among candidate variants, rs17226067, rs17825774, and rs17825799 (blue rectangle) are located in a regulatory region conserved across vertebrate species and characterized by DNase I hypersensitivity (accessible chromatin) and epigenomic marks of enhancers in NHEK epidermal keratinocytes (ENCODE consortium). Variants at the chr13 locus (B) are located in an intergenic region between KLF5 and KLF12, and candidate variant rs61957178 (blue rectangle) is located in a regulatory region characterized by epigenomic marks of enhancers in NHEK epidermal keratinocytes.