Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

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

ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients

The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study. Variants in ERAP2 have also been associated with inflammatory bowel disease, psoriasis, acute anterior uveitis and birdshot chorioretinopathy. Subsequent investigation demonstrated an association of ERAP2 with AS which was present when one conditioned on one of the two independent haplotypes of ERAP1 associated with AS or when HLA-B27-negative patients were analysed separately. These two analyses provide analogous evidence for the association of ERAP2 with AS in HLA-B27-negative cases because of the genetic interaction between HLA-B27 and the AS-associated ERAP1 variants in AS cases. ERAP1 and ERAP2 are located on chromosome 5q15 in the opposite orientation. The locus is challenging to analyse because of the strong linkage disequilibrium (LD) across the locus and the epistasis between ERAP1 and HLA-B alleles associated with AS. We therefore sought to investigate the association of ERAP2 with AS in HLA-B27-positive patients. This is of clinical importance because functional studies have demonstrated that the strongly AS-protective variant rs2248374 causes a functional ERAP2 protein knockout, because its G allele causes a loss of ERAP2 protein expression. There is also a variant of ERAP2 which changes its enzyme catalytic activity and specificity (rs2549782, K392A). Because this is in almost complete LD with rs2248374 (1000 Genomes D′=1.00, r²=0.90), it is almost never translated in vivo. Further, the very strong LD between these markers means that analysis of rs2549782 for association would yield results almost identical to the results for rs2248374 presented below. Therefore, it is of relevance to determine whether the association of ERAP2 with HLA-B27-negative disease is also found in HLA-B27-positive cases, since ERAP inhibition may offer a novel therapeutic for AS..

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

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