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 Martín, John C. Taylor, Augusto Vaglio, Stephen Eyre, Lara Bossini-Castillo, Santos Castañeda, Maria C. Cid, José Hernández-Rodríguez, Sergio Prieto-González, Roser Solans, Marc Ramentol-Sintas, M. Francisca González-Escribano, Lourdes Ortiz-Fernández, Inmaculada C. Morado, Javier Narváez, José A. Miranda-Filloy, Lorenzo Beretta, Claudio LunardiMarco A. Cimmino, Davide Gianfreda, Daniele Santilli, Giuseppe A. Ramirez, Alessandra Soriano, Francesco Muratore, Giulia Pazzola, Olga Addimanda, Cisca Wijmenga, Torsten Witte, Jan H. Schirmer, Frank Moosig, Verena Schönau, Andre Franke, Oyvind Palm, Oyvind Molberg, Andreas P. Diamantopoulos, Simon Carette, David Cuthbertson, Lindsy J. Forbess, Gary S. Hoffman, Nader A. Khalidi, Curry L. Koening, Carol A. Langford, Carol A. McAlear, Larry Moreland, Paul A. Monach, Christian 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, Bhaskar Dasgupta, Jane Worthington, Bobby P.C. Koeleman, Paul I.W. De Bakker, Jennifer H. Barrett, Carlo Salvarani, Peter A. Merkel, Miguel A. González-Gay, Ann W. Morgan, Javier Martín

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


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-DRB104. 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 (US)
Pages (from-to)565-580
Number of pages16
JournalAmerican journal of human genetics
Issue number4
StatePublished - Apr 2 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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