title: Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis.
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.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kenna
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: M C
authors.initials: MC
authors.lastname: Lau
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Keith
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Palermo, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ciccia
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: M-E
authors.initials: ME
authors.lastname: Costello
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Bradbury
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: P-L
authors.initials: PL
authors.lastname: Low
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Triolo
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Palermo, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Alessandro
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: P C
authors.initials: PC
authors.lastname: Robinson
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: G P
authors.initials: GP
authors.lastname: Thomas
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D000328:Adult; D000626:Aminopeptidases / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015796:HLA-B27 Antigen / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015796:HLA-B27 Antigen; C000717247:HSPA5 protein, human; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human