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
Date Deposited	17 Oct 2011 12:55