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 Moutsianas; 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; Colin N. A. Palmer; Wellcome Trust Case Control Consor, Australo-Anglo-Amer Spondyloarthri, Spondyloarthrit Res Consortium Can

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

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 Moutsianas
, 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, Colin N. A. Palmer, Wellcome Trust Case Control Consor, Australo-Anglo-Amer Spondyloarthri, Spondyloarthrit Res Consortium Can

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

762 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 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.

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

Keywords

GENOME-WIDE ASSOCIATION
INFLAMMATORY-BOWEL-DISEASE
GENETIC ASSOCIATION
TRIMS PRECURSORS
AMINOPEPTIDASE
RISK
HLA
POPULATION
PROMOTES
CELLS

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Evans, D. M., Spencer, C. C. A., Pointon, J. J., Su, Z., Harvey, D., Kochan, G., Opperman, U., Dilthey, A., Pirinen, M., Stone, M. A., Appleton, L., Moutsianas, L., Leslie, S., Wordsworth, T., Kenna, T. J., Karaderi, T., Thomas, G. P., Ward, M. M., Weisman, M. H., ... Wellcome Trust Case Control Consor, Australo-Anglo-Amer Spondyloarthri, Spondyloarthrit Res Consortium Can (2011). Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature Genetics, 43(8), 761-767. https://doi.org/10.1038/ng.873

@article{0492c56cf5084c7aab9803151d6f15d8,

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 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.",

keywords = "GENOME-WIDE ASSOCIATION, INFLAMMATORY-BOWEL-DISEASE, GENETIC ASSOCIATION, TRIMS PRECURSORS, AMINOPEPTIDASE, RISK, HLA, POPULATION, PROMOTES, CELLS",

author = "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 Moutsianas 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 Ana-Rita Couto 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 Diaz-Pena and Antonio Lopez-Vazquez and Tetyana Zayats and Gavin Band and Celine Bellenguez and Hannah Blackburn and Blackwell, \{Jenefer M.\} and Elvira Bramon and Palmer, \{Colin N. A.\} and \{Wellcome Trust Case Control Consor, Australo-Anglo-Amer Spondyloarthri, Spondyloarthrit Res Consortium Can\}",

year = "2011",

month = aug,

doi = "10.1038/ng.873",

language = "English",

volume = "43",

pages = "761--767",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "8",

}

Evans, DM, Spencer, CCA, Pointon, JJ, Su, Z, Harvey, D, Kochan, G, Opperman, U, Dilthey, A, Pirinen, M, Stone, MA, Appleton, L, Moutsianas, L, Leslie, S, Wordsworth, T, Kenna, TJ, Karaderi, T, Thomas, GP, Ward, MM, Weisman, MH, Farrar, C, Bradbury, LA, Danoy, P, Inman, RD, Maksymowych, W, Gladman, D, Rahman, P, Morgan, A, Marzo-Ortega, H, Bowness, P, Gaffney, K, Gaston, JSH, Smith, M, Bruges-Armas, J, Couto, A-R, Sorrentino, R, Paladini, F, Ferreira, MA, Xu, H, Liu, Y, Jiang, L, Lopez-Larrea, C, Diaz-Pena, R, Lopez-Vazquez, A, Zayats, T, Band, G, Bellenguez, C, Blackburn, H, Blackwell, JM, Bramon, E, Palmer, CNA & Wellcome Trust Case Control Consor, Australo-Anglo-Amer Spondyloarthri, Spondyloarthrit Res Consortium Can 2011, 'Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility', Nature Genetics, vol. 43, no. 8, pp. 761-767. https://doi.org/10.1038/ng.873

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 - Opperman, Udo

AU - Dilthey, Alexander

AU - Pirinen, Matti

AU - Stone, Millicent A.

AU - Appleton, Louise

AU - Moutsianas, 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 - Diaz-Pena, Roberto

AU - Lopez-Vazquez, Antonio

AU - Zayats, Tetyana

AU - Band, Gavin

AU - Bellenguez, Celine

AU - Blackburn, Hannah

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Palmer, Colin N. A.

AU - Wellcome Trust Case Control Consor, Australo-Anglo-Amer Spondyloarthri, Spondyloarthrit Res Consortium Can

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 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.

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 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.

KW - GENOME-WIDE ASSOCIATION

KW - INFLAMMATORY-BOWEL-DISEASE

KW - GENETIC ASSOCIATION

KW - TRIMS PRECURSORS

KW - AMINOPEPTIDASE

KW - RISK

KW - HLA

KW - POPULATION

KW - PROMOTES

KW - CELLS

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 -

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

Abstract

Keywords

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