A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility

F. David Carmona, Sarah L. Mackie, Jose Ezequiel Martin, J C Taylor, Augusto Vaglio, Steve Eyre, L. Bossini-Castillo, s Castenada, Maria C. Cid, José Hernández-Rodríguez, Sergio Prieto-González, Roser Solans, Marc Ramentol-Sintas, María F. González-Escribano, Lourdes Ortiz-Fernández, Inmaculada C. Morado, Javier Narváez, José A. Miranda-Filloy, Luciano Beretta, Claudio LunardiMarco A. Cimmino, Davide Gianfreda, Daniele Santilli, Giuseppe A. Ramirez, Alessandra Soriano, F. Muratore, Giulia Pazzola, Olga Addimanda, Cisca Wijmenga, t witte, Jan H. Schirmer, Frank Moosig, Verena Schönau, a franke, Øyvind Palm, Øyvind Molberg, A.P. Diamantopulos, Simon Carette, David Cuthbertson, Lindsy J. Forbess, Gary S. Hoffman, NA Khalidi, Curry L. Koening, Carol A. Langford, Carol A. McAlear, Larry Moreland, Paul A. Monach, C. Pagnoux, Philip Seo, Robert Spiera, Antoine G. Sreih, Kenneth J. Warrington, Steven R. Ytterberg, Peter K. Gregersen, Colin T. Pease, Andrew Gough, Michael Green, Lesley Hordon, Stephen Jarrett, Richard Watts, Sarah Levy, Yusuf Patel, Sanjeet Kamath, B Dasqupta, Jane Worthington, Bobby P C Koeleman, PI De Bakker, Jennifer H. Barrett, Carlo Salvarani, Peter A. Merkel, Miguelángel González-Gay, Ann W. Morgan, J Martin

Research output: Contribution to journalArticle


We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.
Original languageEnglish
Pages (from-to)565-580
Number of pages15
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 2015

Fingerprint Dive into the research topics of 'A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility'. Together they form a unique fingerprint.

  • Cite this

    David Carmona, F., Mackie, S. L., Martin, J. E., Taylor, J. C., Vaglio, A., Eyre, S., Bossini-Castillo, L., Castenada, S., Cid, M. C., Hernández-Rodríguez, J., Prieto-González, S., Solans, R., Ramentol-Sintas, M., González-Escribano, M. F., Ortiz-Fernández, L., Morado, I. C., Narváez, J., Miranda-Filloy, J. A., Beretta, L., ... Martin, J. (2015). A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. American Journal of Human Genetics, 96(4), 565-580. https://doi.org/10.1016/j.ajhg.2015.02.009