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

Reference:

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. J., Liu, Y., Jiang, L., Lopez-Larrea, C., Diaz-Pena, R., Lopez-Vazquez, 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. and 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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Official URL:

http://dx.doi.org/10.1038/ng.873

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.

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