Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Abstract

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

ERAP1/ERAP2 and RUNX3 polymorphisms are not associated with ankylosing spondylitis susceptibility in Chinese Han

“…SNPs in ERAP1/ERAP2 may affect the peptide repertoire, possibly resulting in an aberrant CD8 + T cell response 20, 23. ERAP1 gene polymorphisms have been confirmed to be associated with AS in Caucasians 8, 9, 10. However, our meta‐analysis of all data reported on the association of polymorphisms in these genes with AS indicated that population and geographical differences might be one of the causes of heterogeneity.…”

“…The SNPs rs27037, rs27980 and rs27582 were reported to be in strong linkage disequilibrium (LD), as well as the SNPs rs30187 and rs27434 and the SNPs rs2549782 and rs2248374. Based on conflicting results in several studies 9, 10, 24, 25, 26, all sites were selected for the current study (Fig. 1).…”

“…Contradictory results have, however, been reported in several studies on the genetic association of gene polymorphisms in ERAP1/ERAP2 and RUNX3 with AS susceptibility worldwide 9, 10, 24, 25, 26. The aim of our study was therefore to re‐evaluate the association of polymorphisms in ERAP1/ERAP2 and RUNX3 with AS susceptibility in a large cohort of Chinese Han patients.…”

“…Twin and family studies showed that genetic factors play a very important role in the occurrence of AS 3, 7. Recently, genomewide association studies (GWAS) in European Caucasians show that gene polymorphisms in endoplasmic reticulum‐associated aminopeptidase (ERAP1/ERAP2) and runt‐related transcription factor 3 (RUNX3) are associated significantly with AS susceptibility 8, 9, 10.…”

Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

“…First, in vitro studies have suggested that ERAP1 may function as a 'sheddase', cleaving cytokine receptors off the cell surface, including interleukin-6 receptor subunit alpha (IL-6R), interleukin-1 receptor type 2 (IL-1R2) and tumour necrosis factor receptor (TNF-R), each of which are encoded by genes associated with AS. [3][4][5][6] However, we have demonstrated that spleen cells from ERAP − / − mice did not show altered cleavage of IL-6R and TNF-R in vitro. 2 Moreover, in the context of AS, Haroon et al 7 demonstrated that ERAP1 polymorphisms do not alter serum levels of inflammatory cytokines.…”