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

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.

Figure 1. Association results with ankylosing spondylitis susceptibility in the MHC.

Omnibus SNP and amino-acid association tests are shown in a, c, e, g and i, and classical allele association tests with two- and four-digit resolution in b, d, f, h and j. The strongest association was found with positions in the polymorphic nucleotide rs41558317 and in the polymorphic amino acid 97 of HLA-B (a), and with the HLA-B*27 allele (b). Controlling for the effect of HLA-B susceptibility alleles, an independent association was observed with SNPs and amino-acid position in the HLA-A locus (c) corresponding to the HLA-A*02:01 allele (d). Further conditioning on HLA-A and HLA-B loci an independent association with SNPs and amino-acid positions in the HLA-DPB1 locus was evident (e); no HLA-DPB1 classical allele was significant at the same magnitude as the SNPs and amino-acid positions (f). Further controlling for the effect of variation in the HLA-DPB1 locus association was observed with SNPs in the HLA-DRB1 locus (g, h). SNP association tests are shown in blue circles, colour coded by linkage disequilibrium from the SNP with the strongest association. Amino-acid position tests are shown as red triangles. Classical allele tests are shown as bars for two- and four-digit imputation resolution.

Figure 2. Amino-acid residue frequencies in 13,578 controls and 9,069 cases within associated amino-acid positions within HLA proteins.

Figure 3. Three-dimensional models for the HLA-B, HLA-A and HLA-DPβ1 proteins.

Three-dimensional models for the (a) HLA-B, (b) HLA-A and (c) HLA-DPB1 proteins. These structures are based on Protein Data Bank entries 3LV3, 3UTQ and 3LQZ, respectively, with a direct view to the peptide-binding groove.

Figure 4. Interaction between ERAP1 and HLA-B susceptibility alleles.

For each stratified group, effect size for the ERAP1 variant rs30187 is given. Error bars represent 95% confidence intervals. Number of samples in each group (controls/cases) is given below the HLA-B*40 genotype.