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A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

2016; Elsevier BV; Volume: 100; Issue: 1 Linguagem: Inglês

10.1016/j.ajhg.2016.11.013

1537-6605

F. David Carmona, Augusto Vaglio, Sarah Mackie, José Hernández‐Rodríguez, Paul A. Monach, Santos Castañeda, Roser Solans, Inmaculada C. Morado, Javier Narváez, Marc Ramentol-Sintas, Colin Pease, Bhaskar Dasgupta, Richard A. Watts, Nader Khalidi, Carol A. Langford, Steven R. Ytterberg, Luigi Boiardi, Lorenzo Beretta, Marcello Govoni, Giacomo Emmi, Francesco Bonatti, Marco A. Cimmino, Torsten Witte, Thomas Neumann, Julia U. Holle, Verena Schönau, L. Sailler, T. Papo, Julien Haroche, Alfred Mahr, Luc Mouthon, Øyvind Molberg, Andreas P. Diamantopoulos, Alexandre E. Voskuyl, Elisabeth Brouwer, Thomas Daikeler, Christoph T. Berger, Eamonn Molloy, Lorraine O’Neill, Daniël Blockmans, Benedicte A. Lie, Paul J. McLaren, Timothy J. Vyse, Cisca Wijmenga, Yannick Allanore, Bobby P. C. Koeleman, Jennifer H. Barrett, María C. Cid, Carlo Salvarani, Peter A. Merkel, Ann W. Morgan, Miguel Á. González‐Gay, Javier Martı́n, José Luis Callejas‐Rubio, Luis Caminal‐Montero, Marc Corbera‐Bellalta, Eugenio de Miguel, J. Bernardino Díaz López, María Jesús García-Villanueva, Carmen Gómez‐Vaquero, Mercedes Guijarro‐Rojas, Ana Hidalgo-Conde, Begoña Marí-Alfonso, Agustín Martínez Berriochoa, Aleida Martínez Zapico, Victor M. Martinez-Taboada, José A. Miranda‐Filloy, Jordi Monfort, Norberto Ortego‐Centeno, Mercedes Pérez-Conesa, Sergio Prieto‐González, Enrique Raya, Raquel Ríos-Fernández, Julio Sánchez-Martín, B. Sopeña, Laura Tío, Ainhoa Unzurrunzaga, Andrew Gough, John D. Isaacs, Michael R. Green, Neil McHugh, Lesley Hordon, Sanjeet Kamath, Mohammed Nisar, Yusuf Patel, Cee-Seng Yee, Robert C. Stevens, P. K. Nandi, Anupama Nandagudi, Stephen Jarrett, Zhongxia Li, Sarah Levy, Susan P. Mollan, Abdel Salih, Oliver Wordsworth, Emma Sanders, Esme Roads, Anne Gill, Lisa Carr, Christine Routledge, Karen Culfear, Asanka Nugaliyadde, Lynne James, Jenny Spimpolo, Andy Kempa, Felicity Mackenzie, Rosanna Fong, Genessa Peters, Bridie Rowbotham, Zahira Masqood, Jane Hollywood, Prisca Gondo, Rose Wood, Steve Martin, Lubna Rashid, James Robinson, Mike Morgan, Louise Sørensen, John Taylor, Simon Carette, Sharon A. Chung, David Cuthbertson, Lindsy Forbess, Ora Gewurz‐Singer, Gary S. Hoffman, Curry L. Koening, Kathleen Maksimowicz‐McKinnon, Carol A. McAlear, Larry W. Moreland, Christian Pagnoux, Philip Seo, Ulrich Specks, Robert Spiera, Antoine G. Sreih, Kenneth J. Warrington, Michael Weisman,

Cell Adhesion Molecules Research

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.