The Genetics of Ankylosing Spondylitis and Axial Spondyloarthritis

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Key Points

  • •

    Ankylosing spondylitis is a polygenic disease with a strong association with HLA-B27.

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    Thirteen non-MHC loci are now also associated with ankylosing spondylitis.

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    The MHC class I presentation, IL-23, and tumor necrosis factor pathways are implicated in the cause of AS.

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    The carriage rate of HLA-B27 is lower in cohorts of axial spondyloarthritis compared with cohorts of ankylosing spondylitis.

Genetic epidemiology

AS is a highly heritable polygenic disease, in which environmental factors in developed countries play only a minor role in determining risk of developing the disease. The prevalence of AS varies according to some genetic and as yet undescribed environmental factors. Differences in HLA-B27 prevalence drives most of the variation in prevalence seen worldwide.1 For example, the carriage rate of HLA-B27 is approximately 8% to 10% in white European populations and the prevalence of AS is estimated

HLA-B Alleles

The association of HLA-B27 with AS was described in 1973, and remains one of the strongest genetic associations with any common human disease. Nonetheless, only a minority (likely <5%) of B27-positive individuals develop AS. The discovery that allelic variation of HLA-DRB1*01 and *04 influenced the risk of rheumatoid arthritis stimulated research into variation in HLA-B27 itself. There are now known to be more than 90 subtypes of HLA-B*27, which have arisen from the common ancestral subtype,

Non-MHC genes

Rapid progress has been made in identifying new non-MHC gene associations in recent years through GWAS. Several these are in genomic regions and involve pathways not thought to be associated with AS, and this further validates the hypothesis-free approach this type of study design affords. The contribution of the described associations to the heritability of AS, as calculated by the variance in liability method, is shown in Table 1.

Overlap with other diseases

There is overlap of important risk variants between AS and a whole host of other immune-mediated diseases including but not limited to psoriasis, IBD, multiple sclerosis, rheumatoid arthritis, and anterior uveitis (see Table 1).

Psoriasis is a chronic inflammatory autoimmune skin condition present in 3% to 4% of the general population; about 15% of patients with AS have psoriasis. Psoriasis has a major class I MHC association in HLA-Cw6, and in a directly analogous situation to AS, there is also

The genetics of axial spondyloarthritis versus AS

Consistent with the differences in the clinical phenotypes seen in patients with SpA there are differences in the genetics between AS and axial SpA. To date the only published data on the genetics of axial SpA is on HLA-B27 carriage rate. A summary of the published cohorts of patients with SpA is presented in Table 3. One of the limitations of examining the HLA-B27 carriage rate in cohorts of patients with axial SpA is the ascertainment bias that may result from recruiting patients based on

Genetic predictors of radiographic progression

Studies on the heritability of radiographic change in AS have found that there is a good correlation (r = 0.86) between siblings, and the additive heritability of radiographic disease severity based on the Bath Ankylosing Spondylitis Radiographic Index (BASRI) is 0.62.64, 65

Haroon and colleagues66 genotyped 13 coding SNPs from antigen-presentation genes (ERAP1, LMP2, LMP7, TAP1, and TAP2) in the Spondyloarthritis Research Consortium of Canada cohort with the aim of investigating the genetic

Future developments

The continuing development of genomics offers further potential for genetic discoveries in AS. Study design features likely to lead to further progress include the following:

  • 1.

    Increase in sample sizes: Thus far the largest genetic study in AS involved a GWAS of 3023 cases, far fewer than have been studied for other autoimmune diseases of similar population frequency, such as multiple sclerosis,73 or even rheumatic diseases of much lower population frequency than AS, such as systemic lupus

Summary

Genetic discoveries in AS have identified associated pathways previously not considered important. These discoveries have enabled direct translation to clinical practice as agents to target the pathways have been developed with other uses in mind but are now being turned to treat AS. This is the exciting future for the genetics of AS, from the laboratory to the clinic, and in doing so improving the lives of patients.

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    Conflict of interest: The University of Queensland has applied for patents related to the genetic findings in AS.

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