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

Nat Genet. 2011 Jul 10;43(8):761-7. doi: 10.1038/ng.873.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / genetics*
  • Aminopeptidases / metabolism*
  • CARD Signaling Adaptor Proteins / genetics
  • CD8-Positive T-Lymphocytes / metabolism
  • Case-Control Studies
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Disease Susceptibility
  • 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*
  • Spondylitis, Ankylosing / metabolism
  • White People


  • ANTXR2 protein, human
  • CARD Signaling Adaptor Proteins
  • CARD9 protein, human
  • Core Binding Factor Alpha 3 Subunit
  • HLA-B27 Antigen
  • IL12B protein, human
  • Interleukin-12 Subunit p40
  • LTBP4 protein, human
  • Latent TGF-beta Binding Proteins
  • Membrane Proteins
  • Minor Histocompatibility Antigens
  • PTGER4 protein, human
  • Peptide Fragments
  • Receptors, Peptide
  • Receptors, Prostaglandin E, EP4 Subtype
  • Receptors, Tumor Necrosis Factor, Type I
  • Runx3 protein, human
  • TNFRSF1A protein, human
  • Aminopeptidases
  • ERAP1 protein, human