The influence of ERAP1 gene variants on clinical phenotype in ankylosing spondylitis.
OBJECTIVE
Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene variants diminish the risk of developing ankylosing spondylitis (AS) through a reduction in ERAP1 activity. We investigated whether disease expression was altered in patients who developed AS despite the presence of two protective ERAP1 variants.


METHODS
We conducted a cross-sectional and longitudinal cohort study of patients with established AS (n = 334, 90% B27+, mean age at study 45 years) for whom clinical data and biological samples were collected during a research visit. Genotyping for the single nucleotide polymorphisms (SNPs) rs27044 and rs30187 was performed on genomic DNA by reverse transcription polymerase chain reaction (RT-PCR) with interleukin (IL)-6 and tumour necrosis factor (TNF) levels determined by a sandwich enzyme-linked immunosorbent assay (ELISA). Associations between genotypes and haplotypes, clinical and serological findings were analysed using SNPstats.


RESULTS
Both SNPs were in strong linkage disequilibrium and formed three common haplotypes (C/C 0.65, G/T 0.30, and C/T 0.04). Haplotype C/T carried a lower risk for uveitis [odds ratio (OR) 0.32, p = 0.03] and elevated C-reactive protein (CRP) levels (OR 0.26, p = 0.04). There was no effect of ERAP1 haplotypes on cytokine levels or major outcomes after 8 years of follow-up.


CONCLUSIONS
The ERAP1 rs27044/rs30187 haplotype C/T is associated with lower risk of extraspinal disease and systemic inflammation in Nordic AS patients but has no impact on IL-6 or TNF levels.
a University of Western Australia, Sir Charles Gairdner Hospital , Perth , Australia.|b Department of Clinical Medicine , The Arctic University , Tromsø , Norway.
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Nossent
c Norwegian University of Life Sciences , Aars , Norway.
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S
Johnsen
b Department of Clinical Medicine , The Arctic University , Tromsø , Norway.|d University Hospital of North Norway (UNN) , Tromsø , Norway.
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Bakland
D000328:Adult; D000626:Aminopeptidases / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000097:blood / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
C508600:IL6 protein, human; D015850:Interleukin-6; D015778:Minor Histocompatibility Antigens; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000626:Aminopeptidases; C464841:ERAP1 protein, human