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 FarrarLinda 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

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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 Publishing Group",

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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