Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility |
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| Authors: | Evans David M,Spencer Chris C A,Pointon Jennifer J,Su Zhan,Harvey David,Kochan Grazyna,Oppermann Udo,Opperman Udo,Dilthey Alexander,Pirinen Matti,Stone Millicent A,Appleton Louise,Moutsianas Loukas,Moutsianis Loukas,Leslie Stephen,Wordsworth Tom,Kenna Tony J,Karaderi Tugce,Thomas Gethin P,Ward Michael M,Weisman Michael H,Farrar Claire,Bradbury Linda A,Danoy Patrick,Inman Robert D,Maksymowych Walter,Gladman Dafna,Rahman Proton Spondyloarthritis Research Consortium of Canada ,Morgan Ann,Marzo-Ortega Helena,Bowness Paul,Gaffney Karl,Gaston J S Hill,Smith Malcolm,Bruges-Armas Jacome |
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| Affiliation: | Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK. |
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| 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. |
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