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

David M Evans; Chris CA Spencer; Jennifer J Pointon; Zhan Su; David Harvey; Grazyna Kochan; Udo Oppermann; Alexander Dilthey; Matti Pirinen; Millicent A Stone; +86 more... Louise Appleton; Loukas Moutsianas; 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; JS 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 NA 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); (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature genetics, 43 (8). pp. 761-767. ISSN 1061-4036 DOI: 10.1038/ng.873

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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.

Item Type	Article
Keywords	genome-wide association, inflammatory-bowel-disease, genetic, association, trims precursors, aminopeptidase, risk, hla, population, promotes, cells
ISI	293178300012