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 Díaz-Peña; Antonio Lóepez-Vázquez; Tetyana Zayats; Gavin Band; Céline Bellenguez; Hannah Blackburn; Jenefer M. Blackwell; Elvira Bramon; Suzannah J. Bumpstead

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 Moutsianis, 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 Díaz-Peña, Antonio Lóepez-Vázquez, Tetyana Zayats, Gavin Band, Céline Bellenguez, Hannah Blackburn, Jenefer M. Blackwell, Elvira Bramon, Suzannah J. Bumpstead

570 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
Journal	Nature Genetics
Volume	43
Issue number	8
Pages (from-to)	761-767
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.873
Publication status	Published - 1 Aug 2011
Externally published	Yes

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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., Moutsianis, L., Leslie, S., Wordsworth, T., Kenna, T. J., Karaderi, T., Thomas, G. P., Ward, M. M., Weisman, M. H., ... Bumpstead, S. J. (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

Evans, DM, Spencer, CCA, Pointon, JJ, Su, Z, Harvey, D, Kochan, G, Opperman, U, Dilthey, A, Pirinen, M, Stone, MA, Appleton, L, Moutsianis, 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, AR, Sorrentino, R, Paladini, F, Ferreira, MA, Xu, H, Liu, Y, Jiang, L, Lopez-Larrea, C, Díaz-Peña, R, Lóepez-Vázquez, A, Zayats, T, Band, G, Bellenguez, C, Blackburn, H, Blackwell, JM, Bramon, E & Bumpstead, SJ 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

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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",

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 = "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.}",

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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 - 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.

PY - 2011/8/1

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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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SN - 1061-4036

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JO - Nature Genetics

JF - Nature Genetics

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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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