P18 Genome-wide meta-analysis identifies <i>ERAP1</i> in epistasis with MHC class I alleles in frontal fibrosing alopecia

Abstract Introduction and aims Frontal fibrosing alopecia (FFA) is a scarring, inflammatory form of hair loss that predominantly affects postmenopausal women and has become more prevalent in recent years. This study aims to identify novel genetic loci associated with FFA to enhance understanding of its pathogenesis Methods We conducted a genome-wide association meta-analysis in four independent European FFA cohorts from the UK and Spain, comprising 1585 female FFA cases and 5083 controls. Results We identified genome-wide significant associations at four loci: 2p22.2, 6p21.1, 15q26.1 and, for the first time, 5q15. The major histocompatibility complex (MHC) region on chromosome 6 had the largest effect on FFA risk, with statistically independent associations of major histocompatibility complex (MHC) class I four-digit alleles of both HLA-A and HLA-B. At 5q15, we identified a novel FFA susceptibility locus and fine-mapped the signal to a single-nucleotide substitution in the 5′ untranslated region of ERAP1 [rs10045403, odds ratio (ORMETA) 1.30, 95% confidence interval (CI) 1.19–1.43; P = 3.6 × 10−3]. Epistatic interactions in human disease risk are rare, with notable examples including between MHC class I alleles and ERAP1 in immune-mediated inflammatory diseases. Our two-locus interaction analysis provided evidence of epistasis between HLA-A and HLA-B risk alleles and rs10045403 at the ERAP1 locus (additive per-allele ORinteraction 1.40, 95% CI 1.06–1.85, PMETA = 0.01). This interaction indicates that variation at the ERAP1 locus increases FFA risk only in individuals carrying one or more identified HLA-A and HLA-B risk alleles. Conclusions Our findings demonstrate a supra-additive effect of genetic variation that influences peptide trimming and antigen presentation, potentially underpinning follicular immune privilege collapse in FFA. ERAP-mediated processes could therefore be of translational interest as a therapeutic target in FFA.