Searching for the genetic origins of a debilitating skin disease

UNC dermatologist Chris Sayed used an NC TraCS pilot grant to kickstart his research career.

Chris Sayed, a dermatologist at the UNC School of Medicine, has spent much of his career focused on what he calls "the worst and most common disease you've never heard of."

Hidradenitis suppurativa or HS is a skin condition that manifests as painful lumps, abscesses, and scarring that can be unbearably uncomfortable. Symptoms generally occur out of the public eye, with lumps growing in places where the skin rubs together like the armpits or inner thighs, so many people walk around without advertising their disease. And for a while, many doctors and scientists assumed that HS only affected a small proportion of the population and dedicated little research toward understanding the disease's causes or possible treatments.

In recent years, that outlook has changed. Sayed says that many experts now believe millions of Americans likely have HS, potentially affecting up to 1% of the population. Yet the lack of existing research on the disease means scientists still don't fully understand what causes it in the first place, and dermatologists have few good options to help patients, who suffer in private.

Sayed has long been the go-to dermatologist for HS at UNC, and a few years ago, he started feeling a need to use his growing expertise to uncover some of the secrets surrounding the disease. "All the patients would leave, and it was like 'Man, I could have done something'," he says. "It was a missed opportunity every time they walked out the door."

Dermatologists will tell you all the time that HS is the worst thing we treat. The patients are often miserable, and the dermatologists don't know how to help.

But as a full-time clinician, he didn't have the time, funding, or resources to undertake a study on the fundamental science of a mysterious illness. So, he turned to the North Carolina Translational and Clinical Sciences (NC TraCS) Institute.

In 2018, Sayed received a pilot grant from NC TraCS that allowed him to pursue research on the possible genetic origins of HS. That eventually set the stage for a larger grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), a division of the National Institutes of Health (NIH). This past fall, Sayed and his colleagues received another grant from NIAMS, this time totaling $2.3 million, to expand their work—giving them a shot at finally helping those quietly suffering with the condition.

"Dermatologists will tell you all the time that HS is the worst thing we treat," Sayed says. "The patients are often miserable, and the dermatologists don't know how to help."

While dermatologists don't know exactly what causes the painful lumps to show up in the first place, they know that something inflammatory happens around a hair follicle, starting as a small lump and progressing into a large abscess. As a result, clinicians often prescribe immunomodulating medications to try and calm that inflammation, or antibiotics, which can sometimes help alleviate symptoms.

In 2015, the anti-inflammatory drug adalimumab (Humira) became the first medication approved for moderate to severe HS in the US. It ended up selling well, Sayed says, prompting other drug companies to start trialing other possible therapies. To really tackle the root cause of the disease, however, researchers would first need to understand what causes HS.

Through his practice, Sayed stumbled onto a potential clue: many of his patients said that members of their family also had HS. This observation led him to wonder if there might be genetics at play. If researchers could pinpoint specific genes associated with the disease, they could potentially find out where the symptoms came from, and maybe even discover a path toward developing a cure.

To start looking into this, Sayed first recruited some of his colleagues to help. Karen Mohlke and Yun Li, two UNC geneticists, both have extensive experience with genome-wide association studies—when researchers compare the DNA of many people to find variations associated with certain traits or diseases. "I walked in completely unknown to them and said: Here's a condition you've never heard of before, I see a ton of patients, they suffer terribly," Sayed recalls. "If I can collect some samples, would you be interested in helping with the experiments and analysis?" He also had critical support from his research associate, Sharon Edmiston, a PhD student in genetics and molecular biology, who coordinates the lab effort.

Then he turned to NC TraCS, which awarded him a $50,000 pilot grant. That money went toward things like supplies for DNA sample collection—but most of all, the progress he made with the TraCS pilot award allowed him to show external funders that he was prepared to take on this ambitious investigation.

"Being able to prove that we were organized and able to do that work required having those early funds," Sayed says.

Soon enough, Sayed, Mohlke, and Li got their first grant from NIAMS to start searching for the genetic origins of HS. Their genome-wide association study, which included more than 700 HS patients at UNC, found two genes, SOX9 and KLF5, that had variations associated with the disease. Both genes are important to epidermal health, Sayed says. SOX9 plays a key role in the function of hair follicles and KLF5 tends to be expressed at high levels in people with Crohn's disease, another inflammatory condition.

This discovery was a breakthrough in HS research. But even though the team now suspected that something was happening with SOX9 and KLF5 in HS patients, they still didn't know what, exactly, was happening. Their latest grant from NIAMS, awarded last fall, is going to try and answer that question. In addition to expanding their genetic analysis of HS patients, the team is going to study how these variations affect biological processes—for example, by causing the cells to produce too much, or too little, of a certain protein. That information could shed a lot of light on what causes the follicular inflammation.

In recent years, the research community has finally started to take HS seriously. Sayed was on the leading edge of this push, and the team's initial grant in 2019 was the first time NIH had awarded any money toward HS research. Since then, millions more in funding have been devoted to the effort.

Through this process, Sayed has also expanded the scope of his own career. Now, he works as both a patient-focused clinician and a researcher investigating the origins of his patients' disease. And he knows just how much this work means to people.

"HS is this miserable thing that has been terribly underserved by society and the healthcare system over time," Sayed says. "And there's a huge opportunity to raise awareness, understand it better, and find better treatments."