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 (TASC), Wellcome Trust Case Control Consortium 2 (WTCCC2), Evans, David M., Spencer, Chris C. A., Pointon, Jennifer J., Su, Zhan, Harvey, David, Kochan, Grazyna, Opperman, Udo, Dilthey, Alexander, Pirinen, Matti, Stone, Millicent A., Appleton, Louise, Moutsianis, Loukas, Leslie, Stephen, Wordsworth, Tom, Kenna, Tony J., Karaderi, Tugce, Thomas, Gethin P., Ward, Michael M., Weisman, Michael H., Farrar, Claire, Bradbury, Linda A., Danoy, Patrick, Inman, Robert D., Maksymowych, Walter, Gladman, Dafna, Rahman, Proton, Spondyloarthritis Research Consortium of Canada (SPARCC), Morgan, Ann, Marzo-Ortega, Helena, Bowness, Paul, Gaffney, Karl, Gaston, J. S. Hill, Smith, Malcolm, Bruges-Armas, Jacome, Couto, Ana-Rita, Sorrentino, Rosa, Paladini, Fabiana, Ferreira, Manuel A., Xu, Huji, Liu, Yu, Jiang, Lei, Lopez-Larrea, Carlos, Díaz-Pena, Roberto, López-Vázquez, Antonio, Zayats, Tetyana, Band, Gavin, Bellenguez, Céline, Blackburn, Hannah, Blackwell, Jenefer M., Bramon, Elvira, Bumpstead, Suzannah J., Casas, Juan P., Corvin, Aiden, Craddock, Nicholas, Deloukas, Panos, Dronov, Serge, Duncanson, Audrey, Edkins, Sarah, Freeman, Colin, Gillman, Matthew, Gray, Emma, Gwilliam, Rhian, Hammond, Naomi, Hunt, Sarah E., Jankowski, Janusz, Jayakumar, Alagurevathi, Langford, Cordelia, Liddle, Jennifer, Markus, Hugh S., Mathew, Christopher G., McCann, Owen T., McCarthy, Mark I., Palmer, Colin N. A., Peltonen, Leena, Plomin, Robert, Potter, Simon C., Rautanen, Anna, Ravindrarajah, Radhi, Ricketts, Michelle, Samani, Nilesh, Sawcer, Stephen J., Strange, Amy, Trembath, Richard C., Viswanathan, Ananth C., Waller, Matthew, Weston, Paul, Whittaker, Pamela, Widaa, Sara, Wood, Nicholas W., McVean, Gilean, Reveille, John D., Wordsworth, B. Paul, Brown, Matthew A. and Donnelly, Peter (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. doi:10.1038/ng.873


Author The Australo-Anglo-American Spondyloarthritis Consortium (TASC)
Wellcome Trust Case Control Consortium 2 (WTCCC2)
Evans, David M.
Spencer, Chris C. A.
Pointon, Jennifer J.
Su, Zhan
Harvey, David
Kochan, Grazyna
Opperman, Udo
Dilthey, Alexander
Pirinen, Matti
Stone, Millicent A.
Appleton, Louise
Moutsianis, Loukas
Leslie, Stephen
Wordsworth, Tom
Kenna, Tony J.
Karaderi, Tugce
Thomas, Gethin P.
Ward, Michael M.
Weisman, Michael H.
Farrar, Claire
Bradbury, Linda A.
Danoy, Patrick
Inman, Robert D.
Maksymowych, Walter
Gladman, Dafna
Rahman, Proton
Spondyloarthritis Research Consortium of Canada (SPARCC)
Morgan, Ann
Marzo-Ortega, Helena
Bowness, Paul
Gaffney, Karl
Gaston, J. S. Hill
Smith, Malcolm
Bruges-Armas, Jacome
Couto, Ana-Rita
Sorrentino, Rosa
Paladini, Fabiana
Ferreira, Manuel A.
Xu, Huji
Liu, Yu
Jiang, Lei
Lopez-Larrea, Carlos
Díaz-Pena, Roberto
López-Vázquez, Antonio
Zayats, Tetyana
Band, Gavin
Bellenguez, Céline
Blackburn, Hannah
Blackwell, Jenefer M.
Bramon, Elvira
Bumpstead, Suzannah J.
Casas, Juan P.
Corvin, Aiden
Craddock, Nicholas
Deloukas, Panos
Dronov, Serge
Duncanson, Audrey
Edkins, Sarah
Freeman, Colin
Gillman, Matthew
Gray, Emma
Gwilliam, Rhian
Hammond, Naomi
Hunt, Sarah E.
Jankowski, Janusz
Jayakumar, Alagurevathi
Langford, Cordelia
Liddle, Jennifer
Markus, Hugh S.
Mathew, Christopher G.
McCann, Owen T.
McCarthy, Mark I.
Palmer, Colin N. A.
Peltonen, Leena
Plomin, Robert
Potter, Simon C.
Rautanen, Anna
Ravindrarajah, Radhi
Ricketts, Michelle
Samani, Nilesh
Sawcer, Stephen J.
Strange, Amy
Trembath, Richard C.
Viswanathan, Ananth C.
Waller, Matthew
Weston, Paul
Whittaker, Pamela
Widaa, Sara
Wood, Nicholas W.
McVean, Gilean
Reveille, John D.
Wordsworth, B. Paul
Brown, Matthew A.
Donnelly, Peter
Title Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility
Formatted title
Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
1546-1718
Publication date 2011-08-01
Year available 2011
Sub-type Article (original research)
DOI 10.1038/ng.873
Open Access Status Not yet assessed
Volume 43
Issue 8
Start page 761
End page 767
Total pages 7
Place of publication New York, NY, U.S.A.
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
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.
Formatted 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.
Keyword Genome-wide association
Inflammatory-bowel-disease
Genetic association
Trims precursors
Aminopeptidase
Risk
HLA
Population
Promotes
Cells
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 083948/Z/07/Z
P01-052915
UL1RR024188
MO1-RR00425
19536
A91202
566938
G0000934
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
UQ Diamantina Institute Publications
 
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