TY - JOUR
T1 - Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility
AU - Evans, David M
AU - Spencer, Chris C A
AU - Pointon, Jennifer J
AU - Su, Zhan
AU - Harvey, David
AU - Kochan, Grazyna
AU - Oppermann, Udo
AU - Opperman, Udo
AU - Dilthey, Alexander
AU - Pirinen, Matti
AU - Stone, Millicent A
AU - Appleton, Louise
AU - Moutsianas, Loukas
AU - Moutsianis, Loukas
AU - Leslie, Stephen
AU - Wordsworth, Tom
AU - Kenna, Tony J
AU - Karaderi, Tugce
AU - Thomas, Gethin P
AU - Ward, Michael M
AU - Weisman, Michael H
AU - Farrar, Claire
AU - Bradbury, Linda A
AU - Danoy, Patrick
AU - Inman, Robert D
AU - Maksymowych, Walter
AU - Gladman, Dafna
AU - Rahman, Proton
AU - Morgan, Ann
AU - Marzo-Ortega, Helena
AU - Bowness, Paul
AU - Gaffney, Karl
AU - Gaston, J S Hill
AU - Smith, Malcolm
AU - Bruges-Armas, Jacome
AU - Couto, Ana-Rita
AU - Sorrentino, Rosa
AU - Paladini, Fabiana
AU - Ferreira, Manuel A
AU - Xu, Huji
AU - Liu, Yu
AU - Jiang, Lei
AU - Lopez-Larrea, Carlos
AU - Díaz-Peña, Roberto
AU - López-Vázquez, Antonio
AU - Zayats, Tetyana
AU - Band, Gavin
AU - Bellenguez, Céline
AU - Jayakumar, Alagurevathi
AU - Palmer, Colin N A
AU - Spondyloarthritis Research Consortium of Canada (SPARCC)
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
KW - Aminopeptidases/genetics
KW - CARD Signaling Adaptor Proteins/genetics
KW - CD8-Positive T-Lymphocytes/metabolism
KW - Case-Control Studies
KW - Core Binding Factor Alpha 3 Subunit/genetics
KW - Disease Susceptibility
KW - European Continental Ancestry Group
KW - Genome-Wide Association Study
KW - HLA-B27 Antigen/genetics
KW - Humans
KW - Interleukin-12 Subunit p40/genetics
KW - Latent TGF-beta Binding Proteins/genetics
KW - Membrane Proteins/genetics
KW - Meta-Analysis as Topic
KW - Minor Histocompatibility Antigens
KW - Peptide Fragments/metabolism
KW - Polymorphism, Genetic/genetics
KW - Receptors, Peptide
KW - Receptors, Prostaglandin E, EP4 Subtype/genetics
KW - Receptors, Tumor Necrosis Factor, Type I/genetics
KW - Spondylitis, Ankylosing/genetics
U2 - 10.1038/ng.873
DO - 10.1038/ng.873
M3 - Article
C2 - 21743469
SN - 1061-4036
VL - 43
SP - 761
EP - 767
JO - Nature Genetics
JF - Nature Genetics
IS - 8
ER -