title: 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: Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: David M
authors: DM
authors: Evans
authors: Chris C A
authors: CC
authors: Spencer
authors: Jennifer J
authors: JJ
authors: Pointon
authors: Zhan
authors: Z
authors: Su
authors: David
authors: D
authors: Harvey
authors: Grazyna
authors: G
authors: Kochan
authors: Udo
authors: U
authors: Oppermann
authors: Udo
authors: U
authors: Opperman
authors: Alexander
authors: A
authors: Dilthey
authors: Matti
authors: M
authors: Pirinen
authors: Millicent A
authors: MA
authors: Stone
authors: Louise
authors: L
authors: Appleton
authors: Loukas
authors: L
authors: Moutsianas
authors: Loukas
authors: L
authors: Moutsianis
authors: Stephen
authors: S
authors: Leslie
authors: Tom
authors: T
authors: Wordsworth
authors: Tony J
authors: TJ
authors: Kenna
authors: Tugce
authors: T
authors: Karaderi
authors: Gethin P
authors: GP
authors: Thomas
authors: Michael M
authors: MM
authors: Ward
authors: Michael H
authors: MH
authors: Weisman
authors: Claire
authors: C
authors: Farrar
authors: Linda A
authors: LA
authors: Bradbury
authors: Patrick
authors: P
authors: Danoy
authors: Robert D
authors: RD
authors: Inman
authors: Walter
authors: W
authors: Maksymowych
authors: Dafna
authors: D
authors: Gladman
authors: Proton
authors: P
authors: Rahman
authors: Ann
authors: A
authors: Morgan
authors: Helena
authors: H
authors: Marzo-Ortega
authors: Paul
authors: P
authors: Bowness
authors: Karl
authors: K
authors: Gaffney
authors: J S Hill
authors: JS
authors: Gaston
authors: Malcolm
authors: M
authors: Smith
authors: Jacome
authors: J
authors: Bruges-Armas
authors: Ana-Rita
authors: AR
authors: Couto
authors: Rosa
authors: R
authors: Sorrentino
authors: Fabiana
authors: F
authors: Paladini
authors: Manuel A
authors: MA
authors: Ferreira
authors: Huji
authors: H
authors: Xu
authors: Yu
authors: Y
authors: Liu
authors: Lei
authors: L
authors: Jiang
authors: Carlos
authors: C
authors: Lopez-Larrea
authors: Roberto
authors: R
authors: Díaz-Peña
authors: Antonio
authors: A
authors: López-Vázquez
authors: Tetyana
authors: T
authors: Zayats
authors: Gavin
authors: G
authors: Band
authors: Céline
authors: C
authors: Bellenguez
authors: Hannah
authors: H
authors: Blackburn
authors: Jenefer M
authors: JM
authors: Blackwell
authors: Elvira
authors: E
authors: Bramon
authors: Suzannah J
authors: SJ
authors: Bumpstead
authors: Juan P
authors: JP
authors: Casas
authors: Aiden
authors: A
authors: Corvin
authors: Nicholas
authors: N
authors: Craddock
authors: Panos
authors: P
authors: Deloukas
authors: Serge
authors: S
authors: Dronov
authors: Audrey
authors: A
authors: Duncanson
authors: Sarah
authors: S
authors: Edkins
authors: Colin
authors: C
authors: Freeman
authors: Matthew
authors: M
authors: Gillman
authors: Emma
authors: E
authors: Gray
authors: Rhian
authors: R
authors: Gwilliam
authors: Naomi
authors: N
authors: Hammond
authors: Sarah E
authors: SE
authors: Hunt
authors: Janusz
authors: J
authors: Jankowski
authors: Alagurevathi
authors: A
authors: Jayakumar
authors: Cordelia
authors: C
authors: Langford
authors: Jennifer
authors: J
authors: Liddle
authors: Hugh S
authors: HS
authors: Markus
authors: Christopher G
authors: CG
authors: Mathew
authors: Owen T
authors: OT
authors: McCann
authors: Mark I
authors: MI
authors: McCarthy
authors: Colin N A
authors: CN
authors: Palmer
authors: Leena
authors: L
authors: Peltonen
authors: Robert
authors: R
authors: Plomin
authors: Simon C
authors: SC
authors: Potter
authors: Anna
authors: A
authors: Rautanen
authors: Radhi
authors: R
authors: Ravindrarajah
authors: Michelle
authors: M
authors: Ricketts
authors: Nilesh
authors: N
authors: Samani
authors: Stephen J
authors: SJ
authors: Sawcer
authors: Amy
authors: A
authors: Strange
authors: Richard C
authors: RC
authors: Trembath
authors: Ananth C
authors: AC
authors: Viswanathan
authors: Matthew
authors: M
authors: Waller
authors: Paul
authors: P
authors: Weston
authors: Pamela
authors: P
authors: Whittaker
authors: Sara
authors: S
authors: Widaa
authors: Nicholas W
authors: NW
authors: Wood
authors: Gilean
authors: G
authors: McVean
authors: John D
authors: JD
authors: Reveille
authors: B Paul
authors: BP
authors: Wordsworth
authors: Matthew A
authors: MA
authors: Brown
authors: Peter
authors: P
authors: Donnelly
mesh_terms: D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D004198:Disease Susceptibility; D055106:Genome-Wide Association Study; D015796:HLA-B27 Antigen / Q000235:genetics*; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D015201:Meta-Analysis as Topic; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D018000:Receptors, Peptide; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000378:metabolism; D044465:White People
chemical_list: C447150:ANTXR2 protein, human; D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D050677:Core Binding Factor Alpha 3 Subunit; D015796:HLA-B27 Antigen; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; C545650:PTGER4 protein, human; D010446:Peptide Fragments; D018000:Receptors, Peptide; D058309:Receptors, Prostaglandin E, EP4 Subtype; D047888:Receptors, Tumor Necrosis Factor, Type I; C493729:Runx3 protein, human; C506235:TNFRSF1A protein, human; D000626:Aminopeptidases; C464841:ERAP1 protein, human