HS Genetics Point Toward the Hair Growth Cycle

Medscape

13-06-2025

A missense variant in WNT10A detected by a recent genome-wide association study (GWAS) in hidradenitis suppurativa (HS) suggested that drug-development efforts should target hair follicle biology, said the authors of a recent letter responding to the study. Increasing providers' and patients' knowledge about the genetic underpinnings of HS also could help reduce stigma around the disease, an expert told Medscape Dermatology .
The GWAS meta-analysis, published online on December 5, 2024, in the Journal of the American Academy of Dermatology ( JAAD ), included 4814 HS cases and 1.2 million control patients. RNA sequencing and other tools enabled authors led by Rune Kjærsgaard Andersen, MD, PhD, of the Department of Dermatology, Zealand University Hospital in Roskilde, Denmark, to identify eight independent HS-associated variants, including four previously unreported variants that all mapped to signaling pathways crucial in epidermal keratinization. Ultimately, the authors highlighted rs121908120-A, a missense variant in the WNT10A pathway, as protective against HS.
Noteworthy Discovery
The discovery of rs121908120-A is notable, wrote authors led by Olivia D. Perez, MD, of the Department of Dermatology, New York University School of Medicine in New York City, because of its clinical implications derived from previously reported disease associations at the WNT10A locus.
A 2023 British Journal of Dermatology publication showed that the rs121908120-A variant is elevated in patients with hair miniaturization disorders. Because the clinical effects of WNT10A deficiency on hair have been validated in a mouse model, added Perez and colleagues, 'a shortened hair follicle growth phase could be protective of HS, which has clinical implications for HS trials.' Their letter was published in the JAAD Notes and Comments section on May 5, 2025.
In the absence of functional genomic studies elucidating the mechanism(s) of the WNT10A pathway in HS, Perez and coauthors used data from a study published in Immunity in 2024 to investigate where this gene is expressed in lesional skin. Single-cell RNA sequencing showed that WNT10A is expressed in keratinocytes, including hair follicle infundibulum, proliferative cells, basal cells, and immune cells, including regulatory T cells. Spatial transcriptomics confirmed that WNT10A is expressed in both surface and tunnel epithelium, along with the immune cell-rich dermis of HS lesions. The latter findings suggest potential WNT10A involvement in immune responses and augment its known roles in follicular biology, wrote Perez and colleagues.
With few treatments approved by the US Food and Drug Administration for HS, trials to date largely have attempted to repurpose existing drugs that target the inflammatory cascade. Conversely, Perez and colleagues wrote that the GWAS findings highlighted the potential of targeting hair follicle biology and that a shorter follicular growth phase may explain the success of laser hair removal in HS management.
A Developing Story
Lasers appeared to address HS through ablation rather than targeting any specific cytokine or gene, Christopher Sayed, MD, professor of dermatology at the University of North Carolina School of Medicine, Chapel Hill, North Carolina, said in an interview. 'If the initial event in disease development is centered on the hair follicle, then reducing the number of follicles present should help slow down the development of new lesions and progression.' He was not involved with JAAD studies but was asked to comment.
Christopher Sayed, MD
More broadly, Sayed said, Perez and colleagues' paper resonates with prior research, including a study published in JAMA Dermatology in 2023 that he co-authored, all suggesting that HS involves follicular dysregulation that probably also affects processes such as wound healing and inflammatory responses. 'That's potentially another thread that we should be pulling on, beyond the inflammatory process, when it comes to treatment, to see if there's a way to improve how the follicles differentiate and how the chronic wounds in HS could perhaps be coaxed into healing better,' he said.
Perez and colleagues' findings also could counter the long-standing misconception that HS stems largely from modifiable factors such as hygiene issues, infection, or obesity, Sayed noted. 'There's a very strong genetic correlation, and multiple genes now implicated have to do with follicular regulation and epidermal differentiation,' he explained. 'While environmental factors may play a role, it's probably a much smaller role than people used to think.'
As with other inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease, said Sayed, probably the biggest HS risk factor is heredity. 'So, when we talk to patients and the public about hidradenitis suppurativa, we can describe it as a chronic inflammatory condition with a strong genetic component — rather than something where there should be blame and stigma placed on patients.'
Regarding new therapeutics, Sayed said he is unaware of any HS drugs in development that specifically target hair follicle biology. 'It's an area that has just started to come into focus over the last couple of years as genome-wide association studies have highlighted a role for these pathways that are intertwined with inflammatory processes and wound healing.'
Regardless of what triggers HS, he added, the process results in inflammation, which is the target of many drugs in HS trials. 'As we understand hidradenitis suppurativa and how pathways around epidermal and follicular differentiation are dysregulated,' Sayed said, 'it will hopefully present opportunities for more deliberate drug development.'
The letter authors reported funding from the National Institutes of Health, Sanofi-Aventis US, and the Irma T. Hirschl Charitable Trust. These authors reported no relevant conflicts of interest. GWAS authors reported financial relationships with more than a dozen pharmaceutical companies, including Eli Lilly, LEO Pharma, Novartis, and others. Additionally, several of these authors are employees of deCODE genetics/Amgen. Sayed reported no relevant conflicts of interest.