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

Evans, D. M., Spencer, C. C. A., Pointon, J. J., Su, Z., Harvey, D., Kochan, G., Opperman, U., Dilthey, A., Pirinen, M., Stone, M. A., Appleton, L., Moutsianis, L., Leslie, S., Wordsworth, T., Kenna, T. J., Karaderi, T., Thomas, G. P., Ward, M. M., Weisman, M. H., Farrar, C., Bradbury, L. A., Danoy, P., Inman, R. D., Maksymowych, W., Gladman, D., Rahman, P., Morgan, A., Marzo-Ortega, H., Bowness, P., Gaffney, K., Gaston, J. S. H., Smith, M., Bruges-Armas, J., Couto, A. R., Sorrentino, R., Paladini, F., Ferreira, M. A., Xu, H., Liu, Y., Jiang, L., Lopez-Larrea, C., Díaz-Peña, R., Lóepez-Vázquez, A., Zayats, T., Band, G., Bellenguez, C., Blackburn, H., Blackwell, J. M., Bramon, E., Bumpstead, S. J., Casas, J. P., Corvin, A., Craddock, N., Deloukas, P., Dronov, S., Duncanson, A., Edkins, S., Freeman, C., Gillman, M., Gray, E., Gwilliam, R., Hammond, N., Hunt, S. E., Jankowski, J., Jayakumar, A., Langford, C., Liddle, J., Markus, H. S., Mathew, C. G., McCann, O. T., McCarthy, M. I., Palmer, C. N. A., Peltonen, L., Plomin, R., Potter, S. C., Rautanen, A., Ravindrarajah, R., Ricketts, M., Samani, N., Sawcer, S. J., Strange, A., Trembath, R. C., Viswanathan, A. C., Waller, M., Weston, P., Whittaker, P., Widaa, S., Wood, N. W., McVean, G., Reveille, J. D., Wordsworth, B. P., Brown, M. A., & Donnelly, P. (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.

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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.

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ID Code: 89376
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By :226 Export Date: 21 September 2015 CODEN: NGENE Correspondence Address: Donnelly, P.; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; email:
Keywords: HLA antigen class 1, HLA B27 antigen, interleukin 12, transcription factor RUNX3, ankylosing spondylitis, antigenicity, arthritis, article, case control study, controlled study, disease association, disease predisposition, gene locus, human, major clinical study, major histocompatibility complex, pelvis, priority journal, single nucleotide polymorphism, spine, Aminopeptidases, CARD Signaling Adaptor Proteins, Case-Control Studies, CD8-Positive T-Lymphocytes, Core Binding Factor Alpha 3 Subunit, Disease Susceptibility, European Continental Ancestry Group, Genome-Wide Association Study, HLA-B27 Antigen, Humans, Interleukin-12 Subunit p40, Latent TGF-beta Binding Proteins, Membrane Proteins, Meta-Analysis as Topic, Peptide Fragments, Polymorphism, Genetic, Receptors, Prostaglandin E, EP4 Subtype, Receptors, Tumor Necrosis Factor, Type I, Spondylitis, Ankylosing
DOI: 10.1038/ng.873
ISSN: 1061-4036
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright Nature America Inc
Deposited On: 22 Oct 2015 02:45
Last Modified: 21 Mar 2016 04:17

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