Abstract
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
Highlights
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, its role in the aetiology of AS remains elusive
The allele HLA-B*51:01 is the major genetic risk factor for Behcet’s disease[31], a seronegative disease complicated by sacroiliitis resembling AS in up to 10% of cases[32]
In the HLA-B*27transgenic rat model of AS, the HLA-B*27-negative control carries the HLA-B*07 allele, and does not develop disease, consistent with the protective effect of this allele in humans[33]. It has recently been shown in HLA-B7/B27 co-expressing mice that there is partial negative selection of HLA-B27 þ T cells in the course of defining the immunodominant response to influenza infection[34]
Summary
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, its role in the aetiology of AS remains elusive. One of the first non-MHC susceptibility loci to be identified in AS was endoplasmic reticulum aminopeptidase 1 (ERAP1)[5], the main function of which is to trim peptides in the endoplasmic reticulum (ER) to optimal length for binding to MHC class I molecules on antigen-presenting cells for subsequent interaction with CD8 þ T cells[12,13]. This association is so far uniquely found in HLA-B*27-positive disease[7]. ER stress is evident in the HLA-B*27-transgenic rat model of AS and correlates with production of IL-23 (ref. 21), but has not been demonstrated in HLA-B*27-positive patients[22,23,24]
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