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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 publication

DOI

10.1038/ng.873

Type

Journal article

Journal

Nature genetics

Publication Date

10/07/2011

Volume

43

Pages

761 - 767

Addresses

Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

Keywords

Spondyloarthritis Research Consortium of Canada (SPARCC), Australo-Anglo-American Spondyloarthritis Consortium (TASC), Wellcome Trust Case Control Consortium 2 (WTCCC2), CD8-Positive T-Lymphocytes, Humans, Spondylitis, Ankylosing, Disease Susceptibility, Aminopeptidases, Peptide Fragments, Membrane Proteins, Receptors, Tumor Necrosis Factor, Type I, Receptors, Peptide, HLA-B27 Antigen, Minor Histocompatibility Antigens, Case-Control Studies, Polymorphism, Genetic, European Continental Ancestry Group, Core Binding Factor Alpha 3 Subunit, Latent TGF-beta Binding Proteins, Interleukin-12 Subunit p40, CARD Signaling Adaptor Proteins, Meta-Analysis as Topic, Genome-Wide Association Study, Receptors, Prostaglandin E, EP4 Subtype