Variant in ERAP1 promoter region is associated with low expression in a patient with a Behçet-like MHC-I-opathy.

Dimopoulou, Chrysoula; Lundgren, Jens D; Sundal, Jon; Ullum, Henrik; Aukrust, Pål; Nielsen, Finn C; Marvig, Rasmus L

Dimopoulou, Chrysoula; Lundgren, Jens D; Sundal, Jon; Ullum, Henrik; Aukrust, Pål; Nielsen, Finn C; Marvig, Rasmus L.

Afiliación

Dimopoulou C; Centre of Excellence for Health, Immunity and Infection (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Lundgren JD; Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Sundal J; Centre of Excellence for Health, Immunity and Infection (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Ullum H; Department of Infectious Diseases, Stavanger University Hospital, Stavanger, Norway.
Aukrust P; Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Nielsen FC; Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Marvig RL; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

J Hum Genet ; 65(3): 325-335, 2020 Mar.

Article en En | MEDLINE | ID: mdl-31873220

RESUMEN

Behçet disease (BD) is an immune-mediated disease. The cause of BD remains unknown, but the existence of multiple pathological pathways is suspected, including different genetic factors. Polymorphisms in ERAP1 gene have been associated with an increased risk of BD. However, while current BD-associated ERAP1 variants are suggested to contribute to disease by altering the activity of the encoded protein, there is no knowledge of variants that alter the expression level of ERAP1, despite previous associations between ERAP1 expression and BD. Here, we used whole-exome sequencing of a patient with a Behçet-like MHC-I-opathy to identify that the patient, unlike its healthy parents, was homozygous for a rare 1-bp deletion, rs140416843, in the promoter region of ERAP1. rs140416843 has not previously been associated with disease, but is linked to ERAP1 haplotype Hap10 which is associated with BD. The expression of ERAP1 by both RT-qPCR and RNA sequencing showed that ERAP1 mRNA expression correlated with the zygosity for the identified deletion and was decreased in comparison to a healthy cohort. In conclusion, we diagnosed the patient as having BD, and hypothesize that rs140416843-mediated changes in ERAP1 expression play a causative role in BD and that this risk factor is contributing to the association between Hap10 and BD. This is the first report to identify a variant that may cause BD by altering the expression of ERAP1, and our findings suggest that downregulation of ERAP1 expression can serve as a diagnostic marker for BD.

Asunto(s)

Aminopeptidasas/genética; Síndrome de Behçet/genética; Predisposición Genética a la Enfermedad; Antígenos de Histocompatibilidad Menor/genética; Adulto; Síndrome de Behçet/patología; Estudios de Cohortes; Femenino; Regulación de la Expresión Génica; Estudios de Asociación Genética; Genotipo; Haplotipos/genética; Humanos; Masculino; Polimorfismo de Nucleótido Simple/genética; Regiones Promotoras Genéticas/genética; Secuenciación del Exoma

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antígenos de Histocompatibilidad Menor / Síndrome de Behçet / Predisposición Genética a la Enfermedad / Aminopeptidasas Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Female / Humans / Male Idioma: En Revista: J Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido

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