Portal de Periódicos da CAPES

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

2011; Nature Portfolio; Volume: 43; Issue: 8 Linguagem: Inglês

10.1038/ng.873

1546-1718

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

Psoriasis: Treatment and Pathogenesis

Matthew Brown, Peter Donnelly and colleagues report results of a genome-wide association meta-analysis and follow-up study of ankylosing spondylitis. They identify three new risk variants and report a genetic interaction between ERAP1 and HLA-B27, implicating aberrant peptide handling in the pathophysiology of this disease. 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.