Background Endoplasmic reticulum aminopeptidase-1 (ERAP1) is an enzyme that trims peptides for presentation on the MHC class I complex and also contributes to cytokine receptor cleaving. ERAP1 gene variants affect the susceptibility for HLA B27 positive Ankylosing Spondylitis (AS), but the impact of ERAP1 polymorphisms on AS phenotype is less well characterized.
Objectives Toinvestigate the relation between two loss of function variants (rs27044 (C-G) and rs30187 (A-T)) that lead to decreased peptide trimming activity by ERAP1 and the broad phenotype in AS including bioactivity of inflammatory cytokines
Methods 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 was done by Taqman RT-PCR with IL-6 and TNF levels determined by sandwich ELISA. Associations between genotypes, clinical and serological findings were analyzed using SNPstats
Results Allele and genotype distribution for both SNPs was similar in HLA B27+ and B27– patients. Both SNPs were in strong linkage disequilibrium and formed three common haplotypes (C/C 0.65, G/T 0.30, C/T 0.04). Haplotype C/T was more frequent in HLA B27 + patients (OR 3.2, p=0.038), and carried a lower risk for extra-spinal manifestations (OR 0.2, p=0.03), especially uveitis (OR 0.32, p=0.03), elevated CRP (OR 0.26 p=0.04) and elevated ESR (OR 0, p=0.03). There was no effect of ERAP-1 haplotypes on cytokine levels or maior outcomes (death or disability) during eight years of follow-up.
Conclusions ERAP-1 rs27044/rs30187 haplotype C/T associates strongly with HLA-B27 and reduces the risk of extra-spinal disease and systemic inflammation in patients with AS. However ERAP-1 haplotype has no direct bearing on serum IL-6 or TNF-levels.
Acknowledgements The authors wish to thank Kirsten Nilsen at the Rheumatology Research Laboratory for excellent technical support and drs J. Gran, A. Becker-Merok, E,. Bakke, B. Nordvag for help with data collection. Supported by an unrestricted investigator grant to JCN from Abbott Norway AS (grantnr. IMM 09- 0054) and a grant from Odd Fellow Norway Medical Research Fund.
Disclosure of Interest None declared
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