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Genetics of spondyloarthritis—beyond the MHC

Nature Reviews Rheumatology volume 8, pages 296–304 (2012)Cite this article

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Abstract

Ankylosing spondylitis (AS), psoriasis and inflammatory bowel disease (IBD) often coexist in the same patient and in their families. In AS, genes within the MHC region, in particular HLA-B27, account for nearly 25% of disease hereditability, with additional small contributions from genes outside of the MHC locus, including those involved in intracellular antigen processing (that is, ERAP1, which interacts with HLA-B27) and cytokine genes such as those involved in the IL-17–IL-23 pathway. Similar to AS, the strongest genetic signal of susceptibility to psoriasis and psoriatic arthritis also emanates from the MHC region (attributable mostly to HLA-C*06:02 although other genes have been implicated), and gene–gene interaction of HLA-C with ERAP1. The remaining hereditary load is from genes involved in cytokine production, specifically genes in the IL-17–IL-23 pathway, the NFκB pathway and the type 2 T-helper pathway. In IBD, similar genetic influences are operative. Indeed, genes important in the regulation of the IL-17–IL-23 pathway and, in Crohn's disease, genes important for autophagy (that is, NOD2 and ATG16L1 and IRGM) have a role in conferring susceptibility of individuals to these diseases. Thus, AS, psoriasis and IBD seem to share similar pathogenic mechanisms of aberrant intracellular antigen processing or elimination of intracellular bacteria and cytokine production, especially in the IL-17–IL-23 pathway.

Key Points

  • Ankylosing spondylitis (AS), psoriasis and inflammatory bowel disease (IBD) exhibit both shared as well as disease-specific genes that are operative in susceptibility

  • Genes within the MHC region (especially HLA-B27) account for the majority of the currently known susceptibility of individuals to AS

  • Genes outside of the MHC region involved in intracellular antigen processing and cytokine production (especially genes in the IL-17–IL-23 pathway), also predispose individuals to AS, although their overall contribution to hereditability is small

  • Psoriasis and psoriatic arthritis have similar characteristics to AS: the majority of disease susceptibility is from the MHC region, and most of the remaining susceptibility is from genes involved in cytokine production

  • In IBD, genes important in autophagy (in Crohn's disease) and regulation of the IL-17–IL-23 pathway have a large role in disease susceptibility

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Figure 1: Innate immunity, antigen presentation and the TH17 pathway are all implicated in conferring susceptibility to AS, psoriasis/PsA and IBD.

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Acknowledgements

The author's research is supported by NIH grants P01-052,915-01 and 1U01AI090909-01.

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  1. The University of Texas Health Science Center at Houston, MSB 5.270, 6431 Fannin, Houston, 77030, TX, USA

    John D. Reveille

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Supplementary information

Supplementary Table 1

Non-MHC genes associated with susceptibility to ankylosing spondylitis* (DOC 51 kb)

Supplementary Table 2

Genes associated with psoriasis and psoriatic arthritis susceptibility not shared with ankylosing spondylitis* (DOC 54 kb)

Supplementary Table 3

Genes associated with Crohn's disease susceptibility not shared with ankylosing spondylitis or psoriasis* (DOC 53 kb)

Supplementary Table 4

Genes associated with ulcerative colitis susceptibility not shared with ankylosing spondylitis, psoriatic arthritis, or Crohn's Disease* (DOC 46 kb)

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Reveille, J. Genetics of spondyloarthritis—beyond the MHC. Nat Rev Rheumatol 8, 296–304 (2012). https://doi.org/10.1038/nrrheum.2012.41

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