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

Evans, DM; Spencer, CC; Pointon, JJ; Su, Z; Harvey, D; Kochan, G; Oppermann, U; Dilthey, A; Pirinen, M; Stone, MA; +86 more...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; Spondyloarthritis Research Consortium of Canada (SPARCC); Morgan, A; Marzo-Ortega, H; Bowness, P; Gaffney, K; Gaston, JH; Smith, M; Bruges-Armas, J; Couto, A; Sorrentino, R; Paladini, F; Ferreira, MA; Xu, H; Liu, Y; Jiang, L; Lopez-Larrea, C; Díaz-Peña, R; López-Vázquez, A; Zayats, T; Band, G; Bellenguez, C; Blackburn, H; Blackwell, JM; Bramon, E; Bumpstead, SJ; Casas, JP; Corvin, A; Craddock, N; Deloukas, P; Dronov, S; Duncanson, A; Edkins, S; Freeman, C; Gillman, M; Gray, E; Gwilliam, R; Hammond, N; Hunt, SE; Jankowski, J; Jayakumar, A; Langford, C; Liddle, J; Markus, HS; Mathew, CG; McCann, OT; McCarthy, MI; Palmer, CN; Peltonen, L; Plomin, R; Potter, SC; Rautanen, A; Ravindrarajah, R; Ricketts, M; Samani, N; Sawcer, SJ; Strange, A; Trembath, RC; Viswanathan, AC; Waller, M; Weston, P; Whittaker, P; Widaa, S; Wood, NW; McVean, G; Reveille, JD; Wordsworth, BP; Brown, MA; Donnelly, P; Australo-Anglo-American Spondyloarthritis Consortium (TASC); Wellcome Trust Case Control Consortium 2 (WTCCC2) and (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). pp. 761-767. ISSN 1061-4036 DOI: 10.1038/ng.873

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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.

Item Type	Article
Keywords	genome-wide association, inflammatory-bowel-disease, genetic, association, trims precursors, aminopeptidase, risk, hla, population, promotes, cells
ISI	293178300012
Date Deposited	17 Oct 2011 12:55