King's College London researchers have identified a gene-to-gene interaction that elevates the risk of frontal fibrosing alopecia (FFA), publishing the meta-analysis in JAMA Dermatology on 16 February 2025.

The team examined four cohorts of women with FFA across the UK and Europe and pinpointed changes in the major histocompatibility complex (MHC), a cluster of immune genes that helps the body recognize foreign substances. These changes interact with ERAP1 variants to raise disease risk.

The interaction is a form of epistasis (where one gene's effect depends on another), a phenomenon that remains rare in human genetics.

What did the study isolate?

The interaction targets ERAP1, a gene encoding an enzyme that trims peptides (short protein fragments) for immune presentation. Specific MHC Class I alleles — variant forms of immune-recognition genes — modify the risk carried by ERAP1, the authors report under DOI: 10.1001/jamadermatol.2024.6434.

Different versions of the two implicated genes have surfaced in research on psoriasis and ankylosing spondylitis, both autoimmune diseases. Earlier work tied ERAP1 and ERAP2 variants to survival of the mid-1300s Black Death pandemic; those same protective variants may predispose carriers to immune dysregulation today.

Why does FFA matter behind the chair?

FFA is a scarring (cicatricial) alopecia driven by inflammation that destroys hair follicles permanently. It almost exclusively affects women, and incidence has climbed sharply since the condition's first clinical description in 1994.

Sufferers typically present with progressive hairline recession, eyebrow loss and perifollicular erythema (redness around the follicle opening). Salon professionals are often the first to notice these early signs.

A band-like frontal recession with smooth, pale scalp and lost follicular openings (the small dots where hair emerges) warrants immediate dermatologist referral. Follicles lost to scarring cannot regenerate.

What do the investigators say?

Dr Christos Tziotzios, Senior Lecturer at King's College London's St John's Institute of Dermatology and Consultant Dermatologist at Guy's and St Thomas' NHS Foundation Trust, framed the work as the largest genome-wide association study on FFA to date.

"Our study is the largest ever genome-wide association study into frontal fibrosing alopecia," he said. "It is an inflammatory and scarring condition affecting almost exclusively women."

He added: "Since the disease was described in 1994, the number of people affected has increased dramatically. Our newest finding sheds more light into the autoimmune basis of the condition and provides direction for further research into drug development."

What's next for treatment pipelines?

The team is pursuing two translational paths: a predictive genetic test to flag at-risk individuals and highly specific drugs that target ERAP1.

Phil Brady, Chief Operating Officer at the British Skin Foundation, which funded the study, said the discovery could reshape clinical management.

"This research is a big step forward in understanding frontal fibrosing alopecia and why some people are more at risk," Brady said.

"It's a condition that can be incredibly distressing, and finding out how genes interact to influence that risk could help us develop better ways to predict and treat it in the future."

What support underpins the paper?

The Medical Research Council funds Dr Tziotzios's clinical academic partnership with Professor Michael Simpson. Clinical recruitment was coordinated through Guy's and St Thomas' NHS Foundation Trust, with other UK NHS sites and hospitals across Europe contributing.

With FFA incidence still trending upward and no approved disease-modifying therapy, the researchers plan to test whether ERAP1 inhibition — blocking the enzyme to interrupt the immune cascade — can halt follicle loss before reserves are exhausted.