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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




Journal article


Nat Genet

Publication Date





761 - 767


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