Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

The Australo-Anglo-American Spondyloarthritis Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2)

doi:10.1038/ng.873

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

The Australo-Anglo-American Spondyloarthritis Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2)

Research output: Contribution to journal › Article › peer-review

732 Citations (Scopus)

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.

Original language	English
Pages (from-to)	761-767
Number of pages	7
Journal	Nature Genetics
Volume	43
Issue number	8
DOIs	https://doi.org/10.1038/ng.873
Publication status	Published - Aug 2011
Externally published	Yes

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@article{dd445435b518447ab8666cb8fccc5ade,

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.",

author = "{The Australo-Anglo-American Spondyloarthritis Consortium} and {Wellcome Trust Case Control Consortium 2 (WTCCC2)} and Evans, {David M.} and Spencer, {Chris C.A.} and Pointon, {Jennifer J.} and Zhan Su and David Harvey and Grazyna Kochan and Udo Opperman and Alexander Dilthey and Matti Pirinen and Stone, {Millicent A.} and Louise Appleton and Loukas Moutsianis and Stephen Leslie and Tom Wordsworth and Kenna, {Tony J.} and Tugce Karaderi and Thomas, {Gethin P.} and Ward, {Michael M.} and Weisman, {Michael H.} and Claire Farrar and Bradbury, {Linda A.} and Patrick Danoy and Inman, {Robert D.} and Walter Maksymowych and Dafna Gladman and Proton Rahman and Ann Morgan and Helena Marzo-Ortega and Paul Bowness and Karl Gaffney and Gaston, {J. S.Hill} and Malcolm Smith and Jacome Bruges-Armas and Couto, {Ana Rita} and Rosa Sorrentino and Fabiana Paladini and Ferreira, {Manuel A.} and Huji Xu and Yu Liu and Lei Jiang and Carlos Lopez-Larrea and Roberto D{\'i}az-Pe{\~n}a and Antonio L{\'o}epez-V{\'a}zquez and Tetyana Zayats and Gavin Band and C{\'e}line Bellenguez and Hannah Blackburn and Blackwell, {Jenefer M.} and Elvira Bramon and Bumpstead, {Suzannah J.} and Casas, {Juan P.} and Aiden Corvin and Nicholas Craddock and Panos Deloukas and Serge Dronov and Audrey Duncanson and Sarah Edkins and Colin Freeman and Matthew Gillman and Emma Gray and Rhian Gwilliam and Naomi Hammond and Hunt, {Sarah E.} and Janusz Jankowski and Alagurevathi Jayakumar and Cordelia Langford and Jennifer Liddle and Markus, {Hugh S.} and Mathew, {Christopher G.} and McCann, {Owen T.} and McCarthy, {Mark I.} and Palmer, {Colin N.A.} and Leena Peltonen and Robert Plomin and Potter, {Simon C.} and Anna Rautanen and Radhi Ravindrarajah and Michelle Ricketts and Nilesh Samani and Sawcer, {Stephen J.} and Amy Strange and Trembath, {Richard C.} and Viswanathan, {Ananth C.} and Matthew Waller and Paul Weston and Pamela Whittaker and Sara Widaa and Wood, {Nicholas W.} and Gilean McVean and Reveille, {John D.} and Wordsworth, {B. Paul} and Brown, {Matthew A.} and Peter Donnelly",

year = "2011",

month = aug,

doi = "10.1038/ng.873",

language = "English",

volume = "43",

pages = "761--767",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. / The Australo-Anglo-American Spondyloarthritis Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2).
In: Nature Genetics, Vol. 43, No. 8, 08.2011, p. 761-767.

Research output: Contribution to journal › Article › peer-review

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 - The Australo-Anglo-American Spondyloarthritis Consortium

AU - Wellcome Trust Case Control Consortium 2 (WTCCC2)

AU - Evans, David M.

AU - Spencer, Chris C.A.

AU - Pointon, Jennifer J.

AU - Su, Zhan

AU - Harvey, David

AU - Kochan, Grazyna

AU - Opperman, Udo

AU - Dilthey, Alexander

AU - Pirinen, Matti

AU - Stone, Millicent A.

AU - Appleton, Louise

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 - Lóepez-Vázquez, Antonio

AU - Zayats, Tetyana

AU - Band, Gavin

AU - Bellenguez, Céline

AU - Blackburn, Hannah

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Bumpstead, Suzannah J.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Craddock, Nicholas

AU - Deloukas, Panos

AU - Dronov, Serge

AU - Duncanson, Audrey

AU - Edkins, Sarah

AU - Freeman, Colin

AU - Gillman, Matthew

AU - Gray, Emma

AU - Gwilliam, Rhian

AU - Hammond, Naomi

AU - Hunt, Sarah E.

AU - Jankowski, Janusz

AU - Jayakumar, Alagurevathi

AU - Langford, Cordelia

AU - Liddle, Jennifer

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - McCann, Owen T.

AU - McCarthy, Mark I.

AU - Palmer, Colin N.A.

AU - Peltonen, Leena

AU - Plomin, Robert

AU - Potter, Simon C.

AU - Rautanen, Anna

AU - Ravindrarajah, Radhi

AU - Ricketts, Michelle

AU - Samani, Nilesh

AU - Sawcer, Stephen J.

AU - Strange, Amy

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Waller, Matthew

AU - Weston, Paul

AU - Whittaker, Pamela

AU - Widaa, Sara

AU - Wood, Nicholas W.

AU - McVean, Gilean

AU - Reveille, John D.

AU - Wordsworth, B. Paul

AU - Brown, Matthew A.

AU - Donnelly, Peter

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.

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U2 - 10.1038/ng.873

DO - 10.1038/ng.873

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AN - SCOPUS:79960899377

SN - 1061-4036

VL - 43

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EP - 767

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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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