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

Abstract

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: David M Evans, Chris C A Spencer, Jennifer J Pointon, Zhan Su, David Harvey, Grazyna Kochan, Udo Oppermann, Udo Opperman, Alexander Dilthey, Matti Pirinen, Millicent A Stone, Louise Appleton, Loukas Moutsianas, Loukas Moutsianis, Stephen Leslie, Tom Wordsworth, Tony J Kenna, Tugce Karaderi, Gethin P Thomas, Michael M Ward, Michael H Weisman, Claire Farrar, Linda A Bradbury, Patrick Danoy, Robert D Inman, Walter Maksymowych, Dafna Gladman, Proton Rahman, Spondyloarthritis Research Consortium of Canada (SPARCC), Ann Morgan, Helena Marzo-Ortega, Paul Bowness, Karl Gaffney, J S Hill Gaston, Malcolm Smith, Jacome Bruges-Armas, Ana-Rita Couto, Rosa Sorrentino, Fabiana Paladini, Manuel A Ferreira, Huji Xu, Yu Liu, Lei Jiang, Carlos Lopez-Larrea, Roberto Díaz-Peña, Antonio López-Vázquez, Tetyana Zayats, Gavin Band, Céline Bellenguez, Hannah Blackburn, Jenefer M Blackwell, Elvira Bramon, Suzannah J Bumpstead, Juan P Casas, Aiden Corvin, Nicholas Craddock, Panos Deloukas, Serge Dronov, Audrey Duncanson, Sarah Edkins, Colin Freeman, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E Hunt, Janusz Jankowski, Alagurevathi Jayakumar, Cordelia Langford, Jennifer Liddle, Hugh S Markus, Christopher G Mathew, Owen T McCann, Mark I McCarthy, Colin N A Palmer, Leena Peltonen, Robert Plomin, Simon C Potter, Anna Rautanen, Radhi Ravindrarajah, Michelle Ricketts, Nilesh Samani, Stephen J Sawcer, Amy Strange, Richard C Trembath, Ananth C Viswanathan, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Nicholas W Wood, Gilean McVean, John D Reveille, B Paul Wordsworth, Matthew A Brown, Peter Donnelly, Australo-Anglo-American Spondyloarthritis Consortium (TASC), Wellcome Trust Case Control Consortium 2 (WTCCC2)
• Journal: Nature genetics (Nat Genet) Vol. 43 Issue 8 Pg. 761-7 (Jul 10 2011) ISSN: 1546-1718 [Electronic] United States
• PMID: 21743469 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Aminopeptidases (genetics, 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, metabolism)
• White People