Research Closes in on the Genetic Factors Underlying HS Risk
This is the first report of its kind to successfully identify risk loci for HS.
Researchers have identified genetic locations for increased risk of hidradenitis suppurativa (HS).
“This discovery is highly relevant because these changes may effect nearby genes in a way that leads to improper development of hair follicles and predispose them to the rupture,” says study author Christopher Sayed, MD, of the University of North Carolina (UNC) School of Medicine in Chapel Hill, in a news release. “This results in inflammation and chronic wound formation, which are the classic findings of hidradenitis suppurativa.”
The study appears in JAMA Dermatology.
To better understand the genetic factors behind HS, the research team performed a genome-wide association study (GWAS).
A total of 720 patients in the Hidradenitis Suppurativa Program for Research and Care Excellence (ProCARE) at UNC’s Department of Dermatology participated in the study. After collecting saliva and blood samples from patients, the DNA was isolated and taken to the UNC Genotyping Core, so that researchers could examine the DNA sequences up close to identify differences between people.
As part of the final GWAS, researchers integrated the genetic information from the ProCARE patients with controls from the National Longitudinal Study of Adolescent to Adult Health (AddHealth) study – a large longitudinal study of 20,000 adolescents in the United States. Then, researchers combined the results with biological and genetic samples from Finland (FinnGen), the United Kingdom (UK BioBank) and the Vanderbilt University Medical Center (BioVU).
Through the course of the study, researchers found genetic variants pointing to two genes, SOX9 and KLF5, which are thought to play a role in hair follicle and epidermal development. Certain mutations at these loci were more likely to be found in patients with HS than in patients without HS.
The gene SOX9 has two functions in the body: maintaining the structure of the hair follicle and assigning stem cells to become, or differentiate into, the cells that line the hair follicle. SOX9 also triggers the activation of three other genes: MMP1, MMP2, and IL-8, which are linked to the formation of basal cell carcinomas, melanomas, and inflammation.
The other suspected gene, KLF5, promotes the generation of keratinocytes and the secretion of enzymes to eat up dead skin cells. If unchecked, the body produces so much keratin that the epidermis becomes thick and hair follicles can become blocked.
“While more studies are needed to understand how DNA variants near SOX9 and KLF5 contribute to the pathophysiology of HS, both genes are potentially highly relevant and have not previously been linked to the condition,” says study author Karen Mohlke, PhD, a member of the UNC Lineberger Comprehensive Care Center.
Variations in this gene may explain the development of the characteristic cysts, skin-colored bumps, and tunnels that are seen in patients with HS. Where KLF5 functions to keep epidermal stem cells levels in check, SOX9 is does the same for hair follicle stem cells.
If this careful balance between the expression patterns is disrupted by genetic factors, it may explain why the body forms chronic wounds such as inflammatory tunnels and ulcers, as well as cysts and epithelialized tunnels.
Potential Overlap with Other Inflammatory Conditions
Researchers also wanted to see if there was a potential overlap with other inflammatory conditions. Through a genetic correlation analysis, they found that inflammatory bowel disease (IBD), psoriasis, and type 2 diabetes may share certain genetic factors with HS. However, further study is needed to evaluate other comorbidities and uncover the biological links between HS and other conditions.
“As is often the case in research, new discoveries lead to many new questions,” says Yun Li, PhD, a professor of genetics and biostatistics and an associate professor of applied physical sciences at UNC. “We plan to expand our work to larger and more diverse cohorts to identify additional HS risk loci.”
Moving forward, Sayed and his research team are going to use the genetic basis of HS to inform new potential treatments for the disease. By learning more about how these recently discovered variants and the risk loci affect gene expression and influence the pathogenesis of HS, it may be possible for researchers to suggest novel treatment strategies to mitigate the disease’s effects.
Their additional research objectives include locating additional risk loci in larger patient populations and comprehending how some of those variants may predict the severity and course of the disease.
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