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A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

2015; Elsevier BV; Volume: 96; Issue: 4 Linguagem: Inglês

10.1016/j.ajhg.2015.02.009

1537-6605

F. David Carmona, Sarah Mackie, Jose‐Ezequiel Martín, John Taylor, Augusto Vaglio, Stephen Eyre, Lara Bossini‐Castillo, Santos Castañeda, María C. Cid, José Hernández‐Rodríguez, Sergio Prieto‐González, Roser Solans, Marc Ramentol-Sintas, Marı́a-Francisca González-Escribano, Lourdes Ortiz‐Fernández, Inmaculada C. Morado, Javier Narváez, José A. Miranda‐Filloy, Lorenzo Beretta, Claudio Lunardi, Marco A. Cimmino, Davide Gianfreda, Daniele Santilli, Giuseppe A. Ramirez, Alessandra Soriano, Francesco Muratore, Giulia Pazzola, Olga Addimanda, Cisca Wijmenga, Torsten Witte, Jan Henrik Schirmer, Frank Moosig, Verena Schönau, André Franke, Øyvind Palm, Øyvind Molberg, Andreas P. Diamantopoulos, Simon Carette, David Cuthbertson, Lindsy Forbess, Gary S. Hoffman, Nader Khalidi, Curry L. Koening, Carol A. Langford, Carol A. McAlear, Larry W. Moreland, Paul A. Monach, Christian Pagnoux, Philip Seo, Robert Spiera, Antoine G. Sreih, Kenneth J. Warrington, Steven R. Ytterberg, Peter K. Gregersen, Colin Pease, Andrew Gough, Michael R. Green, Lesley Hordon, Stephen Jarrett, Richard A. 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 Á. González‐Gay, Ann W. Morgan, Javier Martı́n, Agustín Martínez-Berriochoa, Ainhoa Unzurrunzaga, Ana Hidalgo-Conde, Ana Belén Madroñero-Vuelta, Antonio Fernández‐Nebro, M. Carmen Ordóñez-Cañizares, B. Escalante, Begoña Marí-Alfonso, B. Sopeña, César Magro‐Checa, Enrique Raya, Elena Grau, José A. Ruiz San Román, Eugenio de Miguel, FJ López-Longo, Lina Martínez, Carmen Gómez‐Vaquero, Benjamín Fernández‐Gutiérrez, Luis Rodríguez‐Rodríguez, J. Bernardino Díaz-López, Luis Caminal‐Montero, Aleida Martínez Zapico, Jordi Monfort, Laura Tío, Julio Sánchez-Martín, Juan José Alegre Sancho, Luis Sáez‐Comet, Mercedes Pérez-Conesa, Marc Corbera‐Bellalta, María Jesús García-Villanueva, M.E. Fernández-Contreras, Olga Sánchez‐Pernaute, Ricardo Blanco, Norberto Ortego‐Centeno, Raquel Ríos-Fernández, José Luis Callejas‐Rubio, P. Fanlo-Mateo, Víctor Martínez‐Taboada,

Cell Adhesion Molecules Research

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. 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.