Molecular Genetics of Ankylosing Spondylitis


Ankylosing spondylitis (AS) is a chronic immune‐mediated arthritic condition affecting the spine that can result in disabling fusion of the vertebrae and sacroiliac joints. Genetics plays a more dominant role in conferring risk for AS than in most autoimmune diseases, as evidenced by a heritability greater than 90%. The HLA‐B*27 gene allele represents the greatest single risk factor identified to date, and multiple theories have been proposed to explain its contribution to pathogenesis. Genomewide association studies in AS have revealed other key genetic players, such as the polymorphic ERAP1, and implicated specific immune pathways, notably the IL‐23/IL17 cytokine pathway. However, much of the genetic basis for AS remains to be explained, providing future challenges to researchers and hope for clinicians.

Key Concepts

  • Ankylosing spondylitis belongs to a group of related inflammatory conditions typified by spinal arthritis, extraarticular inflammation and high prevalence of the MHC class I allele HLA‐B*27.
  • Ankylosing spondylitis has unusually high heritability, suggesting a strong genetic basis.
  • HLA‐B*27 remains the greatest genetic risk factor identified to date.
  • Multiple theories have been proposed to explain the link between HLA‐B*27 and disease ranging from immune recognition at the cell surface to unusual characteristics of its biosynthesis.
  • Genomewide association studies (GWAS) have identified other MHC genes, non‐MHC key molecules and immune pathways that contribute to ankylosing spondylitis.
  • The relevance of one of the GWAS pathways, the IL‐23/IL‐17 pathway, has borne out in treatment efficacy of related monoclonal antibody therapy in patients.
  • The genetic overlap between ankylosing spondylitis, inflammatory bowel disease and psoriasis may explain the frequently observed gut and skin inflammation comorbidities in ankylosing spondylitis.
  • Most of the ankylosing spondylitis heritability (about 70%) remains unexplained.

Keywords: ankylosing spondylitis; spondyloarthritis; genomewide association studies; genetics; HLA‐B*27; ERAP1; IL‐17; pathogenesis; unfolded protein response

Figure 1. Hypotheses of how HLA‐B*27 contributes to ankylosing spondylitis pathogenesis. Current theories of how HLA‐B*27 causes disease include (1) presentation of a cross‐reactive peptide to CD8 T cells, the ‘arthritogenic’ peptide theory; (2) recognition of peptide‐free cell surface dimers by KIR receptors; (3) generation of a proinflammatory ER stress response by HLA‐B*27 misfolding during biosynthesis and (4) mishandling of microbiota in HLA‐B*27‐positive cells.
Figure 2. Genetic overlap between ankylosing spondylitis (AS), inflammatory bowel disease (IBD) and psoriasis/psoriatic arthritis (Ps/PsA). The Venn diagram lists candidate genes from disease‐associated genetic loci described in GWAS studies of AS, Crohn disease (CD) and both cutaneous psoriasis and psoriatic arthritis (Ps/PsA). Regarding the last two entities, some associations are stronger for psoriatic arthritis (e.g. IL13) and some for psoriasis (HLA‐C*06:02), but most genes in this diagram circle have been linked to both conditions.


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Further Reading

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Smith, Judith A(Jun 2016) Molecular Genetics of Ankylosing Spondylitis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023591]