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

Journal article

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.

Authors: Evans, D; Spencer, C; Pointon, J; Su, Z; Harvey, D

• Publication status: Published
• Journal: Nature genetics
• Volume: 43
• Issue: 8
• Pages: 761-767
• Publication date: 2011-08-01
• DOI: 10.1038/ng.873
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Membrane Proteins; Spondylitis, Ankylosing; Receptors, Prostaglandin E, EP4 Subtype; Core Binding Factor Alpha 3 Subunit; Case-Control Studies; Peptide Fragments; Latent TGF-beta Binding Proteins; CARD Signaling Adaptor Proteins; HLA-B27 Antigen; Disease Susceptibility; Aminopeptidases; Meta-Analysis as Topic; Humans; Receptors, Peptide; CD8-Positive T-Lymphocytes; Wellcome Trust Case Control Consortium 2 (WTCCC2); European Continental Ancestry Group; Polymorphism, Genetic; Receptors, Tumor Necrosis Factor, Type I; Interleukin-12 Subunit p40; Australo-Anglo-American Spondyloarthritis Consortium (TASC); Genome-Wide Association Study; Spondyloarthritis Research Consortium of Canada (SPARCC)