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 C. A. Spencer; Jennifer J. Pointon; Zhan Su; David Harvey; Grazyna Kochan; Udo Opperman; Alexander Dilthey; Matti Pirinen; Millicent A. Stone; Louise Appleton; Loukas Moutsianis; 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; Ann Morgan; Helena Marzo-Ortega; Paul Bowness; Karl Gaffney; J. S. 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 Diaz-Pena; Antonio Lopez-Vazquez; Tetyana Zayats; Gavin Band; Celine 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 N. A. 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-Amer Spondyloarthri

doi:10.1038/ng.873

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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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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 C. A. Spencer, Jennifer J. Pointon, Zhan Su, David Harvey, Grazyna Kochan, Udo Opperman, Alexander Dilthey, Matti Pirinen, Millicent A. Stone, …

Nature genetics, Vol.43(8), pp.761-U67

01/08/2011

DOI: https://doi.org/10.1038/ng.873

PMCID: PMC3640413

PMID: 21743469

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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 x 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 x 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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Title: Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility
Creators - without role: David M. Evans - University of Bristol
Chris C. A. Spencer - University of Oxford
Jennifer J. Pointon - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Zhan Su - University of Oxford
David Harvey - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Grazyna Kochan - University of Oxford
Udo Opperman - University of Oxford
Alexander Dilthey - University of Bristol
Matti Pirinen - University of Bristol
Millicent A. Stone - University of Bath
Louise Appleton - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Loukas Moutsianis - University of Oxford
Stephen Leslie - University of Oxford
Tom Wordsworth - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Tony J. Kenna - University of Queensland
Tugce Karaderi - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Gethin P. Thomas - University of Queensland
Michael M. Ward - NIAMSD, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA
Michael H. Weisman - College Station Medical Center
Claire Farrar - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Linda A. Bradbury - University of Queensland
Patrick Danoy - University of Queensland
Robert D. Inman - University of Toronto
Walter Maksymowych - University of Alberta
Dafna Gladman - University of Toronto
Proton Rahman - Mécanique et Engrenage Moderne
Ann Morgan - University of Leeds
Helena Marzo-Ortega - University of Leeds
Paul Bowness - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Karl Gaffney - Norwich University
J. S. Hill Gaston - University of Cambridge
Malcolm Smith - Repatriat Gen Hosp, Adelaide, SA, Australia
Jacome Bruges-Armas - Hosp Santo Espirito, Serv Especializado Epidemiol & Biol Mol, Terceira, The Azores, Portugal
Ana-Rita Couto - Hosp Santo Espirito, Serv Especializado Epidemiol & Biol Mol, Terceira, The Azores, Portugal
Rosa Sorrentino - Univ Roma La Sapienza, Dept Biol & Biotechnol Charles Darwin, Rome, Italy
Fabiana Paladini - Univ Roma La Sapienza, Dept Biol & Biotechnol Charles Darwin, Rome, Italy
Manuel A. Ferreira - College Station Medical Center
Huji Xu - College Station Medical Center
Yu Liu - College Station Medical Center
Lei Jiang - College Station Medical Center
Carlos Lopez-Larrea - Hosp Univ Cent Asturias, Dept Immunol, Oviedo, Spain
Roberto Diaz-Pena - Hosp Univ Cent Asturias, Dept Immunol, Oviedo, Spain
Antonio Lopez-Vazquez - Hosp Univ Cent Asturias, Dept Immunol, Oviedo, Spain
Tetyana Zayats - University of Bristol
Gavin Band - University of Oxford
Celine Bellenguez - University of Oxford
Hannah Blackburn - Hosp Univ Cent Asturias, Dept Immunol, Oviedo, Spain
Jenefer M. Blackwell - University of Western Australia
Elvira Bramon - Wellcome Sanger Institute
Suzannah J. Bumpstead - Wellcome Sanger Institute
Juan P. Casas - Supreme Council Of Health
Aiden Corvin - College Station Medical Center
Nicholas Craddock - Cardiff University
Panos Deloukas - Wellcome Sanger Institute
Serge Dronov - Wellcome Sanger Institute
Audrey Duncanson - Wellcome Trust
Sarah Edkins - Wellcome Sanger Institute
Colin Freeman - University of Oxford
Matthew Gillman - Wellcome Sanger Institute
Emma Gray - Wellcome Sanger Institute
Rhian Gwilliam - Wellcome Sanger Institute
Naomi Hammond - Wellcome Sanger Institute
Sarah E. Hunt - Wellcome Sanger Institute
Janusz Jankowski - Supreme Council Of Health
Alagurevathi Jayakumar - Wellcome Sanger Institute
Cordelia Langford - Wellcome Sanger Institute
Jennifer Liddle - Wellcome Sanger Institute
Hugh S. Markus - University of London
Christopher G. Mathew - College Station Medical Center
Owen T. McCann - Wellcome Sanger Institute
Mark I. McCarthy - Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England
Colin N. A. Palmer - University of Dundee
Leena Peltonen - Wellcome Sanger Institute
Robert Plomin - Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England
Simon C. Potter - Wellcome Sanger Institute
Anna Rautanen - Wellcome Sanger Institute
Radhi Ravindrarajah - Wellcome Sanger Institute
Michelle Ricketts - Wellcome Sanger Institute
Nilesh Samani - University of Leicester
Stephen J. Sawcer - University of Cambridge
Amy Strange - University of Oxford
Richard C. Trembath - College Station Medical Center
Ananth C. Viswanathan - Moorfields Eye Hosp NHS Fdn Trust, Glaucoma Res Unit, London, England
Matthew Waller - Wellcome Sanger Institute
Paul Weston - Wellcome Sanger Institute
Pamela Whittaker - Wellcome Sanger Institute
Sara Widaa - Wellcome Sanger Institute
Nicholas W. Wood - Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England
Gilean McVean - University of Oxford
John D. Reveille - Univ Texas Hlth Sci Ctr Houston, Houston, TX USA
B. Paul Wordsworth - Nuffield Orthopaed Ctr, Natl Inst Hlth Res Musculoskeletal Biomed Res Uni, Oxford OX3 7LD, England
Matthew A. Brown - University of Queensland
Peter Donnelly - University of Oxford
Australo-Anglo-Amer Spondyloarthri
Publication Details: Nature genetics, Vol.43(8), pp.761-U67
Publisher: Springer Nature
Number of pages: 9
Grant note: Rebecca Cooper Medical Research Foundation P01-052915; R01-AR046208 / National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) Intramural Research Program Wolfson-Royal Society Merit Award; Royal Society G0000934 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) G19/2; G0600705; G0000934; G1000800g; G0901310; G0800582; G9817803B / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Australian Cancer Research Foundation Lions Medical Research Foundation fellowship Genome Canada through the Ontario Genomics Institute; Genome Canada Swedish Foundation for Strategic Research; Swedish Foundation for Humanities & Social Sciences National Institute for Health Research (NIHR); National Institutes of Health Research (NIHR) A91202 / Oxford Comprehensive Biomedical Research Centre Karolinska Institutet Merck Co., Inc.; Merck & Company NIHR Thames Valley Comprehensive Local Research Network Canadian Institutes for Health Research; Canadian Institutes of Health Research (CIHR) Swedish Agency for Innovation Systems; Vinnova Knut and Alice Wallenberg Foundation; Knut & Alice Wallenberg Foundation Canadian Foundation for Innovation; Canada Foundation for Innovation Arthritis Society (Canada) G0600705; G0000934; G0901310; G19/2; G0800582 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 19536; 18797 / Arthritis Research UK; Versus Arthritis National Health and Medical Research Council (Australia); National Health and Medical Research Council (NHMRC) of Australia UL1RR024188 / University of Texas at Houston Clinical and Translational Science Rebecca Cooper Foundation (Australia) Novartis Research Foundation Ontario Innovation Trust 083948/Z/07/Z; 076113; 068545/Z/02 / Wellcome Trust Oxford Musculoskeletal Biomedical Research Unit GlaxoSmithKline MO1-RR00425 / Cedars-Sinai General Clinical Research Centre NIAMS/US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) PDA/02/06/016; NF-SI-0507-10379 / National Institute for Health Research; National Institutes of Health Research (NIHR) 566938; 569829 / National Health and Medical Research Council (Australia); National Health and Medical Research Council (NHMRC) of Australia Ontario Ministry for Research and Innovation; Ministry of Research and Innovation, Ontario
Identifiers: 9936823208331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article