Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Spondyloarthritis Research Consortium of Canada (SPARCC)

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693 Citations (Scopus)


Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Original languageEnglish
Pages (from-to)761-767
Number of pages7
JournalNature Genetics
Issue number8
Early online date10 Jul 2011
Publication statusPublished - Aug 2011


  • Aminopeptidases/genetics
  • CARD Signaling Adaptor Proteins/genetics
  • CD8-Positive T-Lymphocytes/metabolism
  • Case-Control Studies
  • Core Binding Factor Alpha 3 Subunit/genetics
  • Disease Susceptibility
  • European Continental Ancestry Group
  • Genome-Wide Association Study
  • HLA-B27 Antigen/genetics
  • Humans
  • Interleukin-12 Subunit p40/genetics
  • Latent TGF-beta Binding Proteins/genetics
  • Membrane Proteins/genetics
  • Meta-Analysis as Topic
  • Minor Histocompatibility Antigens
  • Peptide Fragments/metabolism
  • Polymorphism, Genetic/genetics
  • Receptors, Peptide
  • Receptors, Prostaglandin E, EP4 Subtype/genetics
  • Receptors, Tumor Necrosis Factor, Type I/genetics
  • Spondylitis, Ankylosing/genetics

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