{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T23:50:33Z","timestamp":1784418633271,"version":"3.55.0"},"reference-count":15,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2025,3,1]]},"abstract":"Importance<\/jats:title>Frontal fibrosing alopecia (FFA) is an inflammatory and scarring form of hair loss of increasing prevalence that most commonly affects women. An improved understanding of the genetic basis of FFA will support the identification of pathogenic mechanisms and therapeutic targets.<\/jats:p><\/jats:sec>Objective<\/jats:title>To identify novel genomic loci at which common genetic variation affects FFA susceptibility and assess nonadditive effects on genetic risk between susceptibility loci.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>Four genome-wide association studies were combined using an SE-weighted meta-analysis. Within the major histocompatibility complex (MHC) locus, stepwise conditional analysis was undertaken to determine independently associated classical MHC class I alleles. Statistical tests for epistatic interaction were performed between risk alleles at the MHC and endoplasmic reticulum aminopeptidase 1 (ERAP1<\/jats:italic>) loci.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Genome-wide significant locus associated with FFA and nonadditive effects on genetic risk between susceptibility loci.<\/jats:p><\/jats:sec>Results<\/jats:title>Of 6668 included patients, there were 1585 European female individuals with FFA and 5083 controls. Genome-wide significant associations were identified at 4 genomic loci, including a novel susceptibility locus at 5q15, and the association signal could be fine-mapped to a single nucleotide substitution (rs10045403) in the 5\u2032 untranslated region of ERAP1<\/jats:italic> (rs10045403; odds ratio, 1.30; 95% CI, 1.19-1.43; P<\/jats:italic>\u2009=\u20093.6\u2009\u00d7\u200910\u22128<\/jats:sup>). Within the MHC, FFA risk was statistically independently associated with HLA-A*11:01, HLA-A*33:01, HLA-B*07:02, and HLA-B*35:01. FFA risk was affected by genetic variation at the ERAP1<\/jats:italic> locus only in individuals who carried at least 1 of the MHC class I risk alleles.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this genome-wide meta-analysis, a supra-additive effect of genetic variation was found that affected peptide trimming and antigen presentation on FFA susceptibility. Patients with FFA may benefit from emerging therapeutic approaches that modulate ERAP-mediated processes.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamadermatol.2024.6434","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T16:00:37Z","timestamp":1739376037000},"page":"310","source":"Crossref","is-referenced-by-count":7,"title":["Epistasis of ERAP1<\/i> With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia"],"prefix":"10.1001","volume":"161","author":[{"given":"Tuntas","family":"Rayinda","sequence":"first","affiliation":[{"name":"St John\u2019s Institute of Dermatology, King\u2019s College London, London, United Kingdom"},{"name":"Department of Dermatology and Venereology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Dand","sequence":"additional","affiliation":[{"name":"Department of Medical 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London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fenton","sequence":"additional","affiliation":[{"name":"St John\u2019s Institute of Dermatology, King\u2019s College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Harries","sequence":"additional","affiliation":[{"name":"Centre for Dermatology Research, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom"},{"name":"Department of Dermatology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioulios","family":"Palamaras","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Barnet and Chase Farm Hospitals, Royal Free NHS Foundation Trust, London, United 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