Genetic Components Linked to HS Associated with Disease Risk

The variety of common hidradenitis suppurativa (HS) is located nearby SOX9 and KLF5 genes were associated with the risk of HS, according to a study published in JAMA Dermatology.

These genetic or near-genetic factors may be associated with the genetic risk of the disease and the development of clinical symptoms such as cysts, comedones, and inflammatory tunnels specific to HS, the authors noted. Novel insights into disease pathogenesis related to these genes may help predict disease progression and future new therapeutic approaches.

HS is a chronic itchy skin disease with a high morbidity reported to be highly heritable. However, the genetic understanding of HS is incomplete, and the limited genome-wide association studies (GWASs) performed on HS have not identified a significant risk factor.

First, the researchers’ goal was to identify genes associated with HS and to clarify the genes and genetic pathways.

“While the γ-secretase complex genetic variant has been implicated in less than 5% of patients. [with HS]most genetic risks are unknown. [GWASs] provide the opportunity to identify common genetic variants that contribute to HS susceptibility,” the researchers wrote.

Genetic research found 753 patients with HS from August 2018 to July 2021. GWAS was performed on 720 patients (following quality control) and controls from the Add Health study and then analyzed 2 large biobanks . Variants at 3 loci were tested for frequency (290). Data analysis was conducted from September 2021 to December 2022.

Main outcome measures identified loci, and associations of P < 1 × 10^-8 it is considered important.

A total of 753 patients were recruited, and 720 were finally included in the analysis. The mean (SD) age at onset of symptoms was 20.3 (10.57) years and at enrollment was 35.3 (13.52) years; 360 patients were black, and 575 were female. In a meta-analysis of the 4 studies, 2 HS-linked loci were identified and replicated, with the lead variant rs10512572 (P = 2.3 × 10^-11) and rs17090189 (P < 1 × 10^-8) near the SOX9 and KLF5 genes, respectively. Variants of these loci are located in regulatory elements identified in skin tissues.

Genes at 2 loci appear to have direct and/or complementary roles in epithelial differentiation.

Genetics SOX9 and KLF5 they have a role in skin and follicular inflammation but have not previously been linked to HS pathogenesis. In adult mice, inhibition SOX9 Exposure of adult mice resulted in the development of keratin pearls and loss of keratin 1 expression, leading to epidermal differentiation and loss of follicle stem cells. This difference with respect to the epidermis can explain the development of cysts, comedones, and epithelialized tunnels.

Mouse overdrive KLF5 leading to hyperkeratosis, follicular occlusion, and skin erosion, which are hallmarks of HS. Deletion of KLF5 Disruption of barrier function and association with atopic dermatitis, non-healing wounds, and IL-17-driven colitis in mice. This colitis is associated with changes in the gut microbiota and stimulation of the IL-22/STAT3/IL-17 pathway. Antibiotics and IL-17-neutralizing antibodies were released, similar to HS treatment responses.

Bowel contractions KLF5 Exposure is associated with higher disease severity in human colitis.

More research is needed with HS GWASs with better power to examine other diseases and to discover shared risk mechanisms.

“In this genetic association study, as in all GWAS, identifying differential associations near candidate genes with a significant role in disease biology does not reveal causal effects of these differences or genes on disease risk,” the researchers wrote.

Some limitations existed in this study. Controls from Health Supplements may contain HS, which will lead to negative discrimination. The sample size is insufficient for the ability of researchers to identify significant areas between groups of ancestors or to assess the general occurrence of other ancestries.

“Ultimately, understanding how the gene leads to tunnel formation and an excessive inflammatory response may lead to successful therapies targeting HS pathogenesis,” the researchers concluded.

Reference

Sun Q, Broadaway KA, Edmiston SN, et al. Genetic variants associated with hidradenitis suppurativa. JAMA Dermatol. Published online 26 July 2023. doi:10.1001/jamadermatol.2023.2217