THU0364 Rare Erap1 Allotype Combinations Do Not Explain The ERAP1 Association with Ankylosing Spondylitis
Authors: L.H. Appleton, A.R. Roberts, M. Vecellio, B.P. Wordsworth
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Single nucleotide polymorphisms (SNPs) in <i>ERAP1</i> are strongly associated with ankylosing spondylitis (AS) (1,2). ERAP1 is an aminopeptidase involved in the generation of optimal peptide epitopes for presentation by T-cells in the context of major histocompatibility complex (MHC) class I molecules such as HLA-B27. One small study (17 AS cases and 19 controls) suggested that the frequencies of functionally different <i>ERAP1</i> allotypes differ between patients and controls in AS (3,4). In this study 13 ERAP1 alleles were identified, many of which were rare and previously unreported; allotype *001 was reported in 44% of cases and 8% controls; allotype *002 in 3% of cases and 45% of controls; allotype *005 in 11% of cases and 29% of controls. The authors also reported that the frequencies of particular allotype combinations differed greatly between AS and controls. For example, the allotype combination *001+*005 was found in 53% of cases, but no controls. This allotype combination (and several other less common combinations) were reported exclusively in AS cases, and were shown in parallel <i>in vitro</i> experiments to be associated with poor processing of peptides and altered HLA class I expression. The results of these unexpected <i>ERAP1</i> associations clearly required verification in a larger population sample in view of their potentially dramatic implications for understanding one of the most enduring mysteries of the pathogenesis of AS, namely its association with HLA-B27. <h3>Objectives</h3> Our study was performed in a much larger sample to assess the veracity of previous suggestions that rare <i>ERAP1</i> alleles and allotype combinations are associated with AS. <h3>Methods</h3> We genotyped 213 AS families and 46 control families using KASP™ technology for 5 SNPs (M349V, K528R, D575N, R725Q, Q730E) to infer <i>ERAP1</i> allotypes. Allotype and genotype frequencies were compared. <h3>Results</h3> Several of the reported rare variants were not observed in our sample. We did not confirm the previously reported <i>ERAP1</i> associations with rare allotype combinations; the *001 allotype was seen in 17.1% of cases and 23.9% controls. Allotype *002 was seen in 34.7% of cases and 25% controls. The *005 allotype, which was common in the previous report among cases, was not seen in either of our AS cases or controls. The *001+*005 allotype combination, which was observed in 53% of cases in the previous small study was completely absent from both our larger sample of 213 cases and 46 controls. <h3>Conclusions</h3> We were unable to confirm the suggested association of AS with rare <i>ERAP1</i> allotype combinations in this much larger population study. We were also unable to confirm the diversity of <i>ERAP1</i> haplotypes previously suggested. Further investigation will be required to clarify the correlation of <i>ERAP1</i> allotype combinations with both functional effects and their potential association with AS. <h3>References</h3> Evans DM, et al. Nat Genet 2011;43:761–7. Cortes A, et al. Nat Genet 2013;45:730–40. Reeves E, et al. PNAS 2014;111:17594–9. Reeves E, et al. J Immunol 2013;191:35–43. <h3>Disclosure of Interest</h3> None declared