Epistasis of ERAP1 With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia: A Genome-Wide Association Study Meta-Analysis.

• Tác giả: Michael Ardern-Jones, Carlos Azcarraga-Llobet, Ulrike Blume-Peytavi, Mariona Bustamante, Vasiliki Chasapi, Evangelos Christou, Nick Dand, David A Fenton, Matthew Harries, Kathrin Hillmann, Susan Holmes, Varvara Kanti-Schmidt, Manjit Kaur, Anastasia Koutalopoulou, Alejandro Lobato-Berezo, John A McGrath, Sheila M McSweeney, Ana Melián-Olivera, Ioulios Palamaras, Sofia Papanikou, Bianca Maria Piraccini, Tuntas Rayinda, David Saceda-Corralo, Maryanne Makredes Senna, Michael A Simpson, Rashmi Singh, Michela Valeria Rita Starace, Catherine M Stefanato, Jordi Sunyer, Alice Tidman, Christos Tziotzios, Chuin Ying Ung, Sergio Vañó-Galvan, Isabel Pupo Wiss
• Ngôn ngữ: eng
• Ký hiệu phân loại: 271.6 *Passionists and Redemptorists
• Thông tin xuất bản: United States : JAMA dermatology , 2025
• Bộ sưu tập: NCBI
• ID: 66773

Tóm tắt

 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.