Introduction/Aim
The aim of the study was to examine regions implicated in autoimmune diseases for association with AS. A previous association with AS has been described in the aminopetidase ERAP1.
Methods
9074 European and 1550 east Asian AS cases (defined by the modified New York Criteria), and 13607 European and 1567 Asian controls were studied. Samples were genotyped on the Illumina Infinium Immunochip (196,524 SNVs), clustering performed using Opticall, and analysis performed using linear mixed modelling (FaST-LMM) to control for population stratification.
Results
After QC and removal of non-polymorphic variants, 129,030 SNPs remained. The two previously described independent associations in ERAP1 were replicated in the European cohort (rs30187, OR=0.77, p=1.3x10-41; rs10050860, OR=0.77, p=3.2x10-32), and suggestive association was noted with rs30187 in the Asian cohort (OR=0.81, p=2.1x10-5). rs10050860 was found to have low MAF (0.037) in the Asian cohort and therefore for this SNP in this ethnic group, the study had low power. In the combined cohort, controlling for the association with ERAP1, SNPs in ERAP2 and LNPEP were also associated with AS (lead SNP: rs2549782, OR=1.2, p=7x10-5). Two functionally important SNPs were AS-associated: rs2549782, which leads to a change in the catalytic activity of ERAP2, and rs2248374, where the AS-protective G allele causes a complete loss of ERAP2 mRNA and no expression of ERAP2 protein. In HLA-B27 negative AS cases association was observed with the ERAP2 SNP also associated with Crohn’s disease (rs2549794, OR=1.2, p=8x10-6). Genomewide significant association was noted at chromosome 17q21 at a locus encoding the aminopeptidase NPEPPS (rs9901869, p=3.2 x10-14; OR = 0.88).
Conclusions
This study identifies robust association with three loci housing four aminopeptidases, ERAP1, ERAP2, LNPEP and NPEPPS. This implicates peptide handling as a major mechanism in the aetiology of both HLA-B27 positive and negative AS.