Epistasis of ERAP1 With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia: A Genome-Wide Association Study Meta-Analysis.
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Rayinda Tuntas, Dand Nick, McSweeney Sheila M, Christou Evangelos, Ung Chuin Ying, Stefanato Catherine M, Fenton David A, Harries Matthew, Palamaras Ioulios, Tidman Alice, Holmes Susan, Koutalopoulou Anastasia, Ardern-Jones Michael, Kaur Manjit, Papanikou Sofia, Chasapi Vasiliki, Vañó-Galvan Sergio, Saceda-Corralo David, Melián-Olivera Ana, Azcarraga-Llobet Carlos, Lobato-Berezo Alejandro, Bustamante Mariona, Sunyer Jordi, Starace Michela Valeria Rita, Piraccini Bianca Maria, Wiss Isabel Pupo, Senna Maryanne Makredes, Singh Rashmi, Hillmann Kathrin, Kanti-Schmidt Varvara, Blume-Peytavi Ulrike, McGrath John A, Simpson Michael A, Tziotzios Christos
Аннотация
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.