Background/Purpose: Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis. Thus far, 27 susceptibility loci have been identified in and outside the MHC in populations of European and Asian ancestry. The HLA-B*27 allele is the major genetic risk factor to AS and its role in disease aetiology remains elusive to this date. Potential mechanisms include disorders of the antigenic presentation function of HLA Class I proteins, or on abnormal intracellular effects unique to the HLA-B*27 protein variant. Prior studies have suggested that other HLA-B alleles and MHC genes are involved in AS-susceptibility. In this study we aim to better define the MHC associations of AS and to identify functional and potentially causal variants to shed light on the mechanisms by which the HLA-B*27 molecule confers risk to disease.

Methods: We successfully genotyped 7,264 MHC polymorphic SNPs in 9,069 AS affected individuals and 13,578 healthy controls of European descent using the Illumina Immunochip microarray, designed for immunogenetic studies. High-density genotype data was then followed by imputation of HLA Class I and II classical alleles and residues at polymorphic amino acid positions of HLA Class I and II proteins. Association to disease susceptibility was assessed by logistic regression correcting for population structure.

Results: As expected, strong association was observed with SNPs in the HLA-B locus (P-value < 1 × 10^-320). Analysis of HLA-B alleles revealed other non-HLA-B*27 alleles affecting susceptibility to AS of moderate effect size (HLA-B*40:01, OR=1.13; *40:02, OR=1.59; *51:01, OR=1.36; *07:02, OR=0.77; *57:01, OR=0.73; all P-value<5x10^-8). After controlling for the associated haplotypes in HLA-B we observed independent association signals with SNPs in the HLA-A locus (rs2975033, P-value = 4.94 × 10^-10, OR = 1.22), which tagged the classical allele HLA-A*02:01 (P-value = 7.95 × 10^-10, OR = 1.22), and in HLA-DRB1 (rs1126513, P-value = 5.12 × 10^-8, OR = 1.22). Analysis of polymorphic amino acid positions demonstrated that the most significant polymorphisms in the HLA-B and HLA-DPB1 loci were amino acid residues located in the binding pocket of these molecules. We have previously shown that AS is associated with ERAP1 polymorphisms only in HLA-B*27 carriers, which we confirm here. Additionally, we show that amongst HLA-B*27 negative cases, ERAP1 variants are AS-associated in HLA-B*40:01-positive but not –negative subjects, indicating that ERAP1 variants also interact with HLA-B*40:01.

Conclusion: This study has identified susceptibility alleles in MHC Class I and II loci. The identification of multiple HLA-B alleles affecting AS susceptibility and the interaction between ERAP1 variants and the HLA-B alleles *27:02, *27:05 and *40:01 suggests that these alleles all operate by similar mechanisms to induce AS, and further supports antigen presentation as the molecular mechanism by which HLA-B*27 confers risk to disease. The presence of associated polymorphism in both HLA Class I and II loci suggests that antigen presentation to both CD4⁺ and CD8⁺ T lymphocytes are important in AS pathogenesis and/or tissue specificity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fine-mapping-major-histocompatibility-complex-variation-associated-with-ankylosing-spondylitis-susceptibility/