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


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, HJ; Liu, Y; Jiang, L; Lopez-Larrea, C; Diaz-Pena, R; Lopez-Vazquez, 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, CNA; 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; Donnelly, P; Australo-Anglo-, AmerSpondyloarthri; , WellcomeTrustCaseControlConsor; Spondyloarthrit Res Consortium, C; Lin A, VP; (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-U67. ISSN 1061-4036 DOI: https://doi.org/10.1038/ng.873

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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.

Item Type: Article
Keywords: genome-wide association, inflammatory-bowel-disease, genetic, association, trims precursors, aminopeptidase, risk, hla, population, promotes, cells
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
Research Centre: Centre for Global Non-Communicable Diseases (NCDs)
PubMed ID: 21743469
Web of Science ID: 293178300012
URI: http://researchonline.lshtm.ac.uk/id/eprint/281

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