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.

Figure 1

IL6R polymorphism alters IL-6R serum concentrations. IL-6R concentrations were determined in cases and controls who were homozygous for either the T or C allele at the rs4129267 SNP. In both cases and controls, individuals homozygous for the C allele showed significantly lower concentrations of circulating IL-6R. *** P < 0.0001; NS, not significant. Bars represent mean ± s.e.m.

Figure 2

Ankylosing spondylitis susceptibility associations in the MHC region conditioning on the HLA-B*27–tagging SNP rs116488202 and further conditioning on the HLA-A*02–tagging SNP rs2394250. The 85-kb gap between positions 32,465 kb and 32,550 kb corresponds to an assembly correction between NCBI Genome Builds 36 and 37 of the human genome.

Figure 3

Ankylosing spondylitis genetic susceptibility loci overlap with those of other autoimmune diseases. Diseases are represented in columns, and ankylosing spondylitis susceptibility loci are represented in rows. Shared susceptibility loci are colored green if effect size is concordant and purple if effect size is discordant. Data are shown in supplementary table 8. SLE, systemic lupus erythematosus; T1D, type 1 diabetes.