A genome-wide meta-analysis has identified novel genetic interactions between the ERAP1 gene and four major histocompatibility complex class I alleles in frontal fibrosing alopecia.

In the study, published in JAMA Dermatology, investigators combined four genome-wide association studies (GWAS) involving 1,585 female patients with frontal fibrosing alopecia (FFA) and 5,083 controls, and analyzed over 8 million genetic variants to identify susceptibility loci and interactions influencing FFA risk.

The investigators found a novel susceptibility locus at 5q15 linked to ERAP1, with independent associations to four major histocompatibility complex (MHC) class I alleles (HLA-A*11:01, HLA-A*33:01, HLA-B*07:02, HLA-B*35:01). ERAP1 variants increased FFA risk only in individuals carrying at least one of these MHC alleles, suggesting a supra-additive genetic effect. ERAP1 is crucial in antigen presentation through MHC class I molecules, and these interactions may contribute to the immune privilege collapse in hair follicles, a hallmark of FFA.

The findings characterized FFA as an oligogenic, immune-mediated disorder distinct from lichen planus, and suggested that targeting ERAP1 could offer a novel therapeutic approach. However, the study’s focus on European female participants called for further research in more diverse populations. Additional functional studies are needed to clarify how ERAP1-MHC interactions drive FFA pathogenesis.

"Our findings characterize FFA as an oligogenic, genetically distinct form of lichen planus, highlighting potential for developing therapeutic approaches that target ERAP1 and motivating further functional and genetic risk prediction studies," concluded lead study author Tuntas Rayinda, MD, MSc, PhD, of the St. John’s Institute of Dermatology at King’s College London, and colleagues.

The study was supported by the British Skin Foundation and the Medical Research Council, with no major conflicts of interest reported.