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Genetic contribution of endoplasmic reticulum aminopeptidase 1 polymorphisms to liver fibrosis progression in patients with HCV infection

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Abstract

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses, trimming peptides and loading onto HLA class I molecules. Coding single nucleotide polymorphisms within ERAP1 are associated with autoimmune diseases, viral infections, and cancer development. Our purpose was to analyze the influence of ERAP1 variants on fibrogenesis in hepatitis C virus (HCV)–infected patients. A range of ERAP1 polymorphisms were genotyped in 722 unrelated Caucasian patients diagnosed with chronic HCV from two Spanish cohorts. Patients were classified according to their fibrosis stage. Paraffin-embedded tissue microarrays were constructed to assess ERAP1 expression (HCV = 38; alcoholic = 20) by immunohistochemistry. A statistical algorithm was applied to derive a fibrogenesis prediction model. The ERAP1 variants rs30187/T (K528, pc < 0.001) and rs27044/G (Q730, pc < 0.001) were related with severe fibrosis. These results were validated in the two independent cohorts. Furthermore, patients with the rs30187/T allele had stronger ERAP1 protein expression than those with the rs30187/C (p < 0.05). The statistical model showed that patients with rs30187 C/T and T/T genotypes took 15.58 years (median) to develop advanced fibrosis, but this value was 32.08 years in patients carrying C/C genotype (p < 0.005). ERAP1 variants may influence the clinical course of fibrogenesis in HCV-infected patients. These polymorphisms could be exploited as constitutive new markers of fibrosis evolution. The results highlight the possibility of using modulators of ERAP1 to generate a protective immune response against chronic HCV infection.

Key messages

What is known

  • Several ERAP1 polymorphisms are associated with autoimmune diseases and cancer.

  • ERAP1 trims peptides to HLA class I presentation.

What is new here

  • ERAP1 polymorphisms are associated with fibrogenesis.

  • The ERAP1 polymorphisms genotype could help us in clinical management of patients.

Potential translational impact

  • The use of modulators of ERAP1 could generate a protective response depending on SNPs.

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Acknowledgments

We particularly wish to acknowledge the collaboration of the Principado de Asturias BioBank (PT17/0015/0023), which is financed jointly by the Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III, and Fundación Bancaria Cajastur, and is a member of the Spanish National Biobank Network.

Funding

This work was supported by the Plan Nacional de I + D + I 2013–2016 ISCIII (Spanish Institute of Health Carlos III; grant numbers PI16/01318, PI17/01244, and PI19/00184); Gobierno del Principado de Asturias, PCTI-Plan de Ciencia, Tecnología e Innovación 2013–2017 (grant number IDI/2018/144); FEDER “Funding Program of the European Union”; and the Red Española de Investigación Renal (REDinREN, grant number RD16/0009/0020).

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Authors and Affiliations

  1. Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain

    Jose Ramón Vidal-Castiñeira, Antonio López-Vázquez, Paula Diaz-Bulnes, Leonardo Márquez-Kisinousky, Jesús Martínez-Borra & Carlos López-Larrea

  2. Immunology Service, Hospital Universitario Central de Asturias, Av. de Roma s/n, 33011, Oviedo, Spain

    Antonio López-Vázquez, Jesús Martínez-Borra & Carlos López-Larrea

  3. Statistical Department, Universidad de Oviedo, Oviedo, Spain

    Susana Díaz-Coto

  4. Gastroenterology Service, Hospital Universitario Central de Asturias, Oviedo, Spain

    Carmen A. Navascues & Manuel Rodríguez

  5. Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid and CIBERehd, Instituto de Salud Carlos III, Madrid, Spain

    Paloma Sanz-Cameno

  6. Gastroenterology Service, Hospital San Agustín, Avilés, Spain

    Juan de la Vega

  7. Pathology Service, Hospital Universitario Central de Asturias, Oviedo, Spain

    Aurora Astudillo

Authors
  1. Jose Ramón Vidal-Castiñeira
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  9. Juan de la Vega
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Contributions

Concept and design: JRV, ALV, MR, CLL

Experiments and procedures: JRV, PDB, LMK, JMB, AA

Writing of article: JRV, ALV, AA, MR, CLL

Statistical analysis: SDC, JMB

Patient selection: MR, CAN, PSC, JDV

Corresponding author

Correspondence to Carlos López-Larrea.

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Vidal-Castiñeira, J.R., López-Vázquez, A., Diaz-Bulnes, P. et al. Genetic contribution of endoplasmic reticulum aminopeptidase 1 polymorphisms to liver fibrosis progression in patients with HCV infection. J Mol Med 98, 1245–1254 (2020). https://doi.org/10.1007/s00109-020-01948-1

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  • DOI: https://doi.org/10.1007/s00109-020-01948-1

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