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

Journal of Human Genetics volume 65, pages 325–335 (2020)Cite this article

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Abstract

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.

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Data availability

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher. The distribution of the human genetic data is personally identifiable and can only be shared upon approval from Danish authorities.

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Acknowledgements

We thank Angels Mateu Regue for technical assistance with the luciferase reporter assays.

Funding

This work was supported by the Danish National Research Foundation (grant number 126).

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Authors and Affiliations

  1. Centre of Excellence for Health, Immunity and Infection (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Chrysoula Dimopoulou & Jens D. Lundgren

  2. Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Chrysoula Dimopoulou, Finn C. Nielsen & Rasmus L. Marvig

  3. Department of Infectious Diseases, Stavanger University Hospital, Stavanger, Norway

    Jon Sundal

  4. Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Henrik Ullum

  5. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Pål Aukrust

  6. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Pål Aukrust

  7. Insitute of Clinical Medicine, University of Oslo, Oslo, Norway

    Pål Aukrust

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  1. Chrysoula Dimopoulou
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Contributions

JDL, FCN, and RLM conceived the study. CD, JDL, FCN, and RLM designed the experiments. CD and RLM performed the experiments. JDL, JS, HU, and PA contributed materials and provided clinical information. CD and RLM analyzed the data. CD and RLM drafted the manuscript. All authors revised the manuscript.

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Correspondence to Rasmus L. Marvig.

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Dimopoulou, C., Lundgren, J.D., Sundal, J. et al. Variant in ERAP1 promoter region is associated with low expression in a patient with a Behçet-like MHC-I-opathy. J Hum Genet 65, 325–335 (2020). https://doi.org/10.1038/s10038-019-0709-y

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