FFA componente genetico

Brief Report 

February 12, 2025

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

Tuntas Rayinda, MD, MSc, PhD^1,2; Nick Dand, PhD³; Sheila M. McSweeney, MB, MSc¹; et alEvangelos Christou, MD¹; Chuin Ying Ung, MBBS, PhD¹; Catherine M. Stefanato, MD¹; David A. Fenton, MBChB¹; Matthew Harries, MBChB, PhD^4,5; Ioulios Palamaras, MD, PhD⁶; Alice Tidman, BSc, MBChB⁷; Susan Holmes, BSc(Hons), MBChB, MD⁷; Anastasia Koutalopoulou, MD⁸; Michael Ardern-Jones, BSc, MBBS, DPhil⁸; Manjit Kaur, BMedSci(Hons), BMBS⁹; Sofia Papanikou, MD, MSc¹⁰; Vasiliki Chasapi, MD, PhD¹⁰; Sergio Vañó-Galvan, MD, PhD¹¹; David Saceda-Corralo, MD, PhD¹¹; Ana Melián-Olivera, MD¹¹; Carlos Azcarraga-Llobet, MD¹¹; Alejandro Lobato-Berezo, MD¹²; Mariona Bustamante, PhD¹³; Jordi Sunyer, MD, PhD¹³; Michela Valeria Rita Starace, MD, PhD^14,15; Bianca Maria Piraccini, MD, PhD^14,15; Isabel Pupo Wiss, BA¹⁶; Maryanne Makredes Senna, MD¹⁶; Rashmi Singh, MD¹⁷; Kathrin Hillmann, MD¹⁷; Varvara Kanti-Schmidt, MD^17,18; Ulrike Blume-Peytavi, MD, PhD¹⁷; John A. McGrath, MBBS, MD¹; Michael A. Simpson, PhD³; Christos Tziotzios, MA, MB, BChir(Cantab), PhD¹¹

Author Affiliations

JAMA Dermatol. Published online February 12, 2025. doi:10.1001/jamadermatol.2024.6434

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Key Points

Question  Is there any novel genetic variation contributing to the risk of frontal fibrosing alopecia (FFA)?

Findings  In this meta-analysis of 4 FFA cohorts including 1585 female individuals with FFA and 5083 controls, there was genome-wide significant evidence of an association at a new locus at 5q15. Within the major histocompatibility complex (MHC) class I region, stepwise conditional association analyses revealed independent associations for 4 classical MHC class I alleles (HLA-A*11:01, HLA-A*33:01, HLA-B*07:02, and HLA-B*35:01), and there was a statistical interaction between the MHC class I allele and the lead variant at 5q15.

Meaning  These findings highlight synergistic genetic associations with FFA susceptibility via peptide processing and antigen presentation pathways and highlight potential relevance of endoplasmic reticulum aminopeptidase–mediated therapeutic targets.

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.

• Editorial
  Clinical Implications of Genetic Discoveries on Frontal Fibrosing Alopecia
  JAMA Dermatology

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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