Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

Kenna, T. J., Lau, M. C., Keith, P., Ciccia, F., Costello, M. E., Bradbury, L., Low, P. L., Agrawal, N., Triolo, G., Alessandro, R., Robinson, P. C., Thomas, G. P., & Brown, M. A. (2015) Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis. Genes and Immunity, 16(1), pp. 35-42.

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Abstract

The mechanism by which human leukocyte antigen B27 (HLA-B27) contributes to ankylosing spondylitis (AS) remains unclear. Genetic studies demonstrate that association with and interaction between polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 influence the risk of AS. It has been hypothesised that ERAP1-mediated HLA-B27 misfolding increases endoplasmic reticulum (ER) stress, driving an interleukin (IL) 23-dependent, pro-inflammatory immune response. We tested the hypothesis that AS-risk ERAP1 variants increase ER-stress and concomitant pro-inflammatory cytokine production in HLA-B27 + but not HLA-B27-AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to HLA-B27 status and AS-associated ERAP1 rs30187 genotypes: HLA-B27 + ERAP1 risk, HLA-B27 + ERAP1 protective, HLA-B27-ERAP1 risk and HLA-B27-ERAP1 protective. Expression levels of ER-stress markers GRP78 (8 kDa glucose-regulated protein), CHOP (C/EBP-homologous protein) and inflammatory cytokines were determined in peripheral blood mononuclear cell and ileal biopsies. We found no differences in ER-stress gene expression between HLA-B27 + and HLA-B27-cases or healthy controls, or between cases or controls stratified by carriage of ERAP1 risk or protective alleles in the presence or absence of HLA-B27. No differences were observed between expression of IL17A or TNF (tumour necrosis factor) in HLA-B27 + ERAP1 risk, HLA-B27 + ERAP1 protective and HLA-B27-ERAP1 protective cases. These data demonstrate that aberrant ERAP1 activity and HLA-B27 carriage does not alter ER-stress levels in AS, suggesting that ERAP1 and HLA-B27 may influence disease susceptibility through other mechanisms. © 2015 Macmillan Publishers Limited.

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ID Code: 94063
Item Type: Journal Article
Refereed: Yes
Keywords: CCAAT enhancer binding protein, cytokine, endoplasmic reticulum aminopeptidase 1, glucose regulated protein 78, HLA B27 antigen, protein, unclassified drug, aminopeptidase, ERAP1 protein, human, adult, aged, allele, ankylosing spondylitis, Article, CHOP gene, clinical article, controlled study, correlation analysis, cytokine production, disease predisposition, endoplasmic reticulum stress, enzyme activity, ERAP1 gene, female, gene, gene expression, genetic association, genetic polymorphism, genetic variability, genotype, GRP78 gene, human, human tissue, ileum, immune response, immunohistochemistry, inflammation, male, middle aged, mononuclear cell, priority journal, protein expression, TNF gene, young adult, genetics, metabolism, pathology, single nucleotide polymorphism, Aminopeptidases, HLA-B27 Antigen, Humans, Polymorphism, Single Nucleotide, Spondylitis, Ankylosing
DOI: 10.1038/gene.2014.62
ISSN: 1476-5470
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2015 Macmillan Publishers Limited
Deposited On: 23 Mar 2016 00:39
Last Modified: 23 Mar 2016 21:27

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