Epistasis of ERAP1 With 4 major histocompatibility complex class I alleles in frontal fibrosing alopecia: a genome-wide association study meta-analysis
Rayinda, Tuntas Dand, Nick McSweeney, Sheila M Christou, Evangelos Ung, Chuin Ying Stefanato, Catherine M Fenton, David A Harries, Matthew Palamaras, Ioulios Tidman, Alice
Rayinda, Tuntas
Dand, Nick
McSweeney, Sheila M
Christou, Evangelos
Ung, Chuin Ying
Stefanato, Catherine M
Fenton, David A
Harries, Matthew
Palamaras, Ioulios
Tidman, Alice
Affiliation
King's College London; Universitas Gadjah Mada; King's College London; University of Manchester; Northern Care Alliance NHS Foundation Trust; Royal Free NHS Foundation Trust; NHS Greater Glasgow and Clyde; University Hospitals Southampton NHS Foundation Trust; University Hospitals Birmingham NHS Foundation Trust; Andreas Syngros Hospital; Ramon Y Cajal Hospital; University of Alcala; Hospital del Mar-Parc de Salut Mar; Institute for Global Health Barcelona; Universitaria di Bologna; Harvard Medical School; Lahey Hospital and Medical Center; Charité-Universitätsmedizin Berlin; University Hospital of the Ruhr; University of Bochum
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Publication date
2025-02-12
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Abstract
Importance: 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.
Objective: To identify novel genomic loci at which common genetic variation affects FFA susceptibility and assess nonadditive effects on genetic risk between susceptibility loci.
Design, setting, and participants: 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) loci.
Main outcomes and measures: Genome-wide significant locus associated with FFA and nonadditive effects on genetic risk between susceptibility loci.
Results: 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' untranslated region of ERAP1 (rs10045403; odds ratio, 1.30; 95% CI, 1.19-1.43; P = 3.6 × 10-8). 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 locus only in individuals who carried at least 1 of the MHC class I risk alleles.
Conclusions and relevance: 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.
Citation
Rayinda T, Dand N, McSweeney SM, Christou E, Ung CY, Stefanato CM, Fenton DA, Harries M, Palamaras I, Tidman A, Holmes S, Koutalopoulou A, Ardern-Jones M, Kaur M, Papanikou S, Chasapi V, Vañó-Galvan S, Saceda-Corralo D, Melián-Olivera A, Azcarraga-Llobet C, Lobato-Berezo A, Bustamante M, Sunyer J, Starace MVR, Piraccini BM, Wiss IP, Senna MM, Singh R, Hillmann K, Kanti-Schmidt V, Blume-Peytavi U, McGrath JA, Simpson MA, Tziotzios C. Epistasis of ERAP1 With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia: A Genome-Wide Association Study Meta-Analysis. JAMA Dermatol. 2025 Mar 1;161(3):310-314. doi: 10.1001/jamadermatol.2024.6434. Erratum in: JAMA Dermatol. 2025 Jun 1;161(6):670. doi: 10.1001/jamadermatol.2025.1299.
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Article