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Review
. 2021 Mar 5:12:603726.
doi: 10.3389/fimmu.2021.603726. eCollection 2021.

Perspectives on the Genetic Associations of Ankylosing Spondylitis

B Paul Wordsworth  1   2 , Carla J Cohen  2 , Connor Davidson  3 , Matteo Vecellio  1   2   3
Affiliations
Review

Perspectives on the Genetic Associations of Ankylosing Spondylitis

B Paul Wordsworth et al. Front Immunol. .

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.

Keywords: aetiology; epigenetics; interleukin-23; pathogenesis; spondyloarthropathy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
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 T2-weighted images consistent with inflammation at the vertebral corners consistent with the attachment of vertebral ligaments and discs. (B) Computed tomographic reconstruction of the thoracic spine of a 25-year-old man with AS since the age of 12. There is clear bony fusion between the adjacent vertebrae and also at the costovertebral joints. (C) Bilateral sacroiliitis shown by MRI (STIR sequence) worse on the sacral side of the right SI joint.
Figure 2
Figure 2
Studies of concordance for AS in UK twins recruited through the National Ankylosing Spondylitis Society. The clear difference on concordance rates between MZ twins and DZ twins is highly indicative of a major genetic component, which can only partly be explained by the influence of HLA-B27.
Figure 3
Figure 3
Timelines of progress in translating the genetics of ankylosing spondylitis towards therapeutics.
See this image and copyright information in PMC

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