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

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 <i>endoplasmic reticulum aminopeptidase 1</i> (<i>ERAP1</i>) and <i>HLA-B27</i> 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 <i>ERAP1</i> variants increase ER-stress and concomitant pro-inflammatory cytokine production in <i>HLA-B27</i>^{<span class="mb"></span>} but not <i>HLA-B27</i> AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to <i>HLA-B27</i> status and AS-associated <i>ERAP1</i> rs30187 genotypes: HLA-B27^{<span class="mb"></span>}ERAP1^risk, HLA-B27^{<span class="mb"></span>}<i>ERAP1</i>^protective, HLA-B27ERAP1^risk and HLA-B27<i>ERAP1</i>^protective. Expression levels of ER-stress markers <i>GRP78</i> (<i>8<span class="mb"><span class="mb"></span></span>kDa glucose-regulated protein</i>), <i>CHOP</i> (<i>C<span class="mb"></span>EBP-homologous protein</i>) 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^{<span class="mb"></span>} 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 <i>IL17A</i> or <i>TNF</i> (tumour necrosis factor) in HLA-B27^{<span class="mb"></span>}ERAP1^risk, HLA-B27^{<span class="mb"></span>}<i>ERAP1</i>^protective and HLA-B27<i>ERAP1</i>^protective cases. These data demonstrate that aberrant ERAP1 activity and <i>HLA-B27</i> carriage does not alter ER-stress levels in AS, suggesting that ERAP1 and HLA-B27 may influence disease susceptibility through other mechanisms