Abstract
Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.
Highlights
Ankylosing spondylitis (AS) is the archetype of a group of inflammatory disorders known as spondyloarthropathies (SpA) because they often affect the spine
We focus on AS and axSpA as might be diagnosed using the algorithm presented by Taurog et al [4]
The main single nucleotide polymorphisms (SNP) primarily associated with AS, psoriasis and inflammatory bowel disease (IBD) causes a loss-of function mutation in the cytoplasmic tail of IL23R that reduces IL-17 and IL22 production by Th17 effector cells [32, 33] and modulates responses to pattern recognition receptors [34]
Summary
Ankylosing spondylitis (AS) is the archetype of a group of inflammatory disorders known as spondyloarthropathies (SpA) because they often affect the spine (axial skeleton). The classic way of investigating the genetic component of a disease by twin studies reveals a highly significant genetic contribution to AS, and one in which HLA-B27 is the major but by no means the only factor (Figure 2) [13] Armed with this limited but convincing information and the enthusiastic support of Sir John Bell and Mark Lathrop at the newly instituted Wellcome Trust Centre for Human Genetics a number of us from around the world set out in the 1990’s to try to identify at least some of FIGURE 1 | (A) Sagittal magnetic resonance image of the thoracic spine of a 44-year-old man with active ankylosing spondylitis, showing high signal on these T2weighted images consistent with inflammation at the vertebral corners consistent with the attachment of vertebral ligaments and discs. There would appear to be scope for developing small molecule inhibitors of ERAP1 (and possibly other aminopeptidases) in the quest for new therapies for the prevention or treatment of AS
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