Genetics of spondyloarthritis--beyond the MHC

Nat Rev Rheumatol. 2012 Apr 10;8(5):296-304. doi: 10.1038/nrrheum.2012.41.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Arthritis, Psoriatic / epidemiology
  • Arthritis, Psoriatic / genetics
  • Arthritis, Psoriatic / physiopathology
  • Cytokines / genetics
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation
  • Genes, MHC Class I / genetics*
  • Genetic Predisposition to Disease / epidemiology*
  • HLA-B27 Antigen / genetics*
  • HLA-C Antigens / genetics*
  • Humans
  • Inflammatory Bowel Diseases / epidemiology
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / physiopathology
  • Interleukin-17 / genetics
  • Male
  • Psoriasis / epidemiology
  • Psoriasis / genetics
  • Psoriasis / physiopathology
  • Risk Assessment
  • Sensitivity and Specificity
  • Spondylarthritis / epidemiology
  • Spondylarthritis / genetics*
  • Spondylarthritis / physiopathology
  • Spondylitis, Ankylosing / epidemiology
  • Spondylitis, Ankylosing / genetics
  • Spondylitis, Ankylosing / physiopathology


  • Cytokines
  • HLA-B27 Antigen
  • HLA-C Antigens
  • Interleukin-17