Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
21743469
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.
DATE PUBLISHED
2011 Aug
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2011/12/21
accepted 2011/06/03
aheadofprint 2011/07/10
entrez 2011/07/12 06:00
pubmed 2011/07/12 06:00
medline 2011/10/04 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Evans DM Evans David M DM Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Spencer CC Spencer Chris C A CC
Pointon JJ Pointon Jennifer J JJ
Su Z Su Zhan Z
Harvey D Harvey David D
Kochan G Kochan Grazyna G
Oppermann U Oppermann Udo U
Opperman U Opperman Udo U
Dilthey A Dilthey Alexander A
Pirinen M Pirinen Matti M
Stone MA Stone Millicent A MA
Appleton L Appleton Louise L
Moutsianas L Moutsianas Loukas L
Moutsianis L Moutsianis Loukas L
Leslie S Leslie Stephen S
Wordsworth T Wordsworth Tom T
Kenna TJ Kenna Tony J TJ
Karaderi T Karaderi Tugce T
Thomas GP Thomas Gethin P GP
Ward MM Ward Michael M MM
Weisman MH Weisman Michael H MH
Farrar C Farrar Claire C
Bradbury LA Bradbury Linda A LA
Danoy P Danoy Patrick P
Inman RD Inman Robert D RD
Maksymowych W Maksymowych Walter W
Gladman D Gladman Dafna D
Rahman P Rahman Proton P
Spondyloarthritis Research Consortium of Canada (SPARCC)
Morgan A Morgan Ann A
Marzo-Ortega H Marzo-Ortega Helena H
Bowness P Bowness Paul P
Gaffney K Gaffney Karl K
Gaston JS Gaston J S Hill JS
Smith M Smith Malcolm M
Bruges-Armas J Bruges-Armas Jacome J
Couto AR Couto Ana-Rita AR
Sorrentino R Sorrentino Rosa R
Paladini F Paladini Fabiana F
Ferreira MA Ferreira Manuel A MA
Xu H Xu Huji H
Liu Y Liu Yu Y
Jiang L Jiang Lei L
Lopez-Larrea C Lopez-Larrea Carlos C
Díaz-Peña R Díaz-Peña Roberto R
López-Vázquez A López-Vázquez Antonio A
Zayats T Zayats Tetyana T
Band G Band Gavin G
Bellenguez C Bellenguez Céline C
Blackburn H Blackburn Hannah H
Blackwell JM Blackwell Jenefer M JM
Bramon E Bramon Elvira E
Bumpstead SJ Bumpstead Suzannah J SJ
Casas JP Casas Juan P JP
Corvin A Corvin Aiden A
Craddock N Craddock Nicholas N
Deloukas P Deloukas Panos P
Dronov S Dronov Serge S
Duncanson A Duncanson Audrey A
Edkins S Edkins Sarah S
Freeman C Freeman Colin C
Gillman M Gillman Matthew M
Gray E Gray Emma E
Gwilliam R Gwilliam Rhian R
Hammond N Hammond Naomi N
Hunt SE Hunt Sarah E SE
Jankowski J Jankowski Janusz J
Jayakumar A Jayakumar Alagurevathi A
Langford C Langford Cordelia C
Liddle J Liddle Jennifer J
Markus HS Markus Hugh S HS
Mathew CG Mathew Christopher G CG
McCann OT McCann Owen T OT
McCarthy MI McCarthy Mark I MI
Palmer CN Palmer Colin N A CN
Peltonen L Peltonen Leena L
Plomin R Plomin Robert R
Potter SC Potter Simon C SC
Rautanen A Rautanen Anna A
Ravindrarajah R Ravindrarajah Radhi R
Ricketts M Ricketts Michelle M
Samani N Samani Nilesh N
Sawcer SJ Sawcer Stephen J SJ
Strange A Strange Amy A
Trembath RC Trembath Richard C RC
Viswanathan AC Viswanathan Ananth C AC
Waller M Waller Matthew M
Weston P Weston Paul P
Whittaker P Whittaker Pamela P
Widaa S Widaa Sara S
Wood NW Wood Nicholas W NW
McVean G McVean Gilean G
Reveille JD Reveille John D JD
Wordsworth BP Wordsworth B Paul BP
Brown MA Brown Matthew A MA
Donnelly P Donnelly Peter P
Australo-Anglo-American Spondyloarthritis Consortium (TASC)
Wellcome Trust Case Control Consortium 2 (WTCCC2)
INVESTIGATORS
JOURNAL
VOLUME: 43
ISSUE: 8
TITLE: Nature genetics
ISOABBREVIATION: Nat. Genet.
YEAR: 2011
MONTH: Aug
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1546-1718
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Genet
COUNTRY: United States
ISSNLINKING: 1061-4036
NLMUNIQUEID: 9216904
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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CommentIn Nat Rev Rheumatol. 2011 Sep;7(9):498 21808290
ErratumIn Nat Genet. 2011 Sep;43(9):919 21808290 Opperman, Udo [corrected to Oppermann, Udo]; Moutsianis, Loukas [corrected to Moutsianas, Loukas]
GRANTS
GRANTID AGENCY COUNTRY
068545/Z/02 Wellcome Trust United Kingdom
076113 Wellcome Trust United Kingdom
083948/Z/07/Z Wellcome Trust United Kingdom
090532 Wellcome Trust United Kingdom
092809 Wellcome Trust United Kingdom
18797 Arthritis Research UK United Kingdom
19536 Arthritis Research UK United Kingdom
G0000934 Medical Research Council United Kingdom
G0600705 Medical Research Council United Kingdom
G0800582 Medical Research Council United Kingdom
G19/2 Medical Research Council United Kingdom
MO1-RR00425 NCRR NIH HHS United States
P01-052915 PHS HHS United States
PDA/02/06/016 Department of Health United Kingdom
R01-AR046208 NIAMS NIH HHS United States
UL1RR024188 NCRR NIH HHS United States
ZIA AR041153-07 Intramural NIH HHS United States
Canadian Institutes of Health Research Canada
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Aminopeptidases metabolism
CARD Signaling Adaptor Proteins genetics
CD8-Positive T-Lymphocytes metabolism
Case-Control Studies metabolism
Core Binding Factor Alpha 3 Subunit genetics
Disease Susceptibility genetics
European Continental Ancestry Group genetics
Genome-Wide Association Study genetics
HLA-B27 Antigen genetics
Humans genetics
Interleukin-12 Subunit p40 genetics
Latent TGF-beta Binding Proteins genetics
Membrane Proteins genetics
Meta-Analysis as Topic genetics
Peptide Fragments metabolism
Polymorphism, Genetic genetics
Receptors, Peptide genetics
Receptors, Prostaglandin E, EP4 Subtype genetics
Receptors, Tumor Necrosis Factor, Type I genetics
Spondylitis, Ankylosing metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 ANTXR2 protein, human
0 CARD Signaling Adaptor Proteins
0 CARD9 protein, human
0 Core Binding Factor Alpha 3 Subunit
0 HLA-B27 Antigen
0 IL12B protein, human
0 Interleukin-12 Subunit p40
0 LTBP4 protein, human
0 Latent TGF-beta Binding Proteins
0 Membrane Proteins
0 PTGER4 protein, human
0 Peptide Fragments
0 Receptors, Peptide
0 Receptors, Prostaglandin E, EP4 Subtype
0 Receptors, Tumor Necrosis Factor, Type I
0 Runx3 protein, human
0 TNFRSF1A protein, human
EC 3.4.11.- Aminopeptidases
EC 3.4.11.- ERAP1 protein, human
OTHER ID's
OTHERID SOURCE
NIHMS405164 NLM
PMC3640413 NLM
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