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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    688 Citations (Scopus)


    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 languageEnglish
    Pages (from-to)761-767
    Number of pages7
    JournalNature Genetics
    Issue number8
    Publication statusPublished - Aug 2011


    • RISK
    • HLA
    • CELLS


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